Pyridin derivatives as dipeptidyl peptidase iv inhibitors

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

 

The technical field to which the invention relates.

The present invention relates to a derivative of pyridine, with the inhibitory peptidase activity, which is useful as a tool for prevention or treatment of diabetes and the like.

Background of invention

It is known that peptidase associated with various diseases. Dipeptidylpeptidase-IV (hereinafter sometimes referred to as DPP-IV), which is a type of peptidase, is semipretioase specifically bind to the peptide containing Proline or alanine), in the 2nd from the N-terminal position, and splitting the connection on the C-end of Proline or alanine) with the formation of the dipeptide. DPP-IV has the same molecule, as CD26, and reportedly involved in the immune system. Although the role of DPP-IV in mammals is not entirely clarified, but it is believed that it plays an important role in the metabolism of neuropeptides activate T cells, adhesion of cancer cells to endothelial cells, the penetration of HIV (HIV) cells and the like. In particular, from the point of view of the metabolism of carbohydrates DPP-IV is involved in the inactivation of GLP-1 (glucagon-like peptide-1) and GIP (gastroenerology peptide/glucosidation insulinotropic peptide), which are regulators of internal secretion. In addition, with regard to GLP-1, it is known that physiological GLP-1 markedly reduced, because he has a short, 1-2 minutes, the half-life in plasma, and GLP-1(9-36)amide, which is a product of decomposition under the action of DPP-IV, effect on GLP-1 receptor as an antagonist, resulting in a DPP-IV breaks down GLP-1. It is also known that the inhibition of the degradation of GLP-1 by inhibiting the activity of DPP-IV leads to increased physiological activity, which demonstrates GLP-1, such as the amplification of insulin secretion depending on the glucose concentration and the like. In view of these facts it is expected that the compounds having inhibiting DPP-IV activity, will have an effect on impaired glucose tolerance, hyperglycemia that occurs after a meal, and hyperglycemia in the fasting state, observed in diabetes type I and type II, and the like, obesity or related to diabetic complications and the like.

As derivatives of pyridine already described, the following compounds.

(1) a Compound represented by the formula

where R2and R6each independently represents hydrogen, hydroxy, alkyl and the like; R3represents hydroxy, amido, and the like; R4represents hydrogen, hydroxy, halogen and the like, and R5represents hydrogen, hydroxy, halogen and the like, which is about lady inhibitory effect on protein carrying cholesterol ester (hereinafter abbreviated denoted as SETR) (see WO99/41237).

(2) the Compound represented by the formula

where A represents a C6-10aryl, optionally substituted with halogen, and the like; D represents an unbranched or branched alkyl with 8 or less carbon atoms, optionally substituted by hydroxy; E and L are identical or different and each represents an unbranched or branched alkyl with 8 or less carbon atoms, optionally substituted C3-8cycloalkyl, and the like; T is an R7-X - or R8-(R9)(R10)C- (where R7and R8are the same or different and each represents a C3-8cycloalkyl, C6-10aryl and the like; R9represents hydrogen and the like; R10represents hydrogen, halogen, azido and the like), which has an inhibitory effect on SER or antagonistic effect on glucagon;

the compound represented by the formula

where a represents a C6-10aryl, optionally substituted with halogen, and the like; D and E are the same or different and each represents an unbranched or branched alkyl with 8 Il is less carbon atoms, optionally substituted by hydroxy; V represents O, S or NR5(where R5represents hydrogen, an unbranched or branched alkyl containing 6 or less carbon atoms, or phenyl); R1represents a C3-6cycloalkyl,6-10aryl and the like; L and T are the same or different and each represents trifluoromethyl and the like; and

the compound represented by the formula

where Ar represents an optionally substituted aromatic or heteroaromatic group; R4and R5independently represent hydrogen, C1-6alkyl and the like; R1aand R1bindependently represent trifluoromethyl, C1-6alkyl and the like (see WO98/04528, U.S. patent No. 6218431).

(3) the Compound represented by the formula

where A and E are the same or different and each represents a C6-10aryl, optionally substituted with halogen, and the like; D represents an unbranched or branched alkyl with 8 or less carbon atoms, optionally substituted by hydroxy; L represents a C3-8cycloalkyl, unbranched or branched alkyl containing 8 or less carbon atoms, and the like; T is an R3X - or R 4-(R5)(R6)C- (where R3and R4are the same or different and each represents a C3-8cycloalkyl, C6-10aryl and the like; R5represents hydrogen and the like; R6represents hydrogen, halogen, azido and the like), or its salt, with traveler inhibitory effect on CETP (see U.S. patent No. 5925645).

(4) the Compound represented by the formula

where R2and R6independently represent bromacil, chloroalkyl and the like; R4represents alkyl, cycloalkyl, alkylthiomethyl, cycloalkyl, alkoxyalkyl or dialkylaminoalkyl; one of R3and R5is a CO-Y (where Y represents alkylthio, alkoxy or N-containing heterocyclic group), and the other represents -(C(R9)(R10)-)n-X (where n is an integer of 1-3; R9and R10independently represent hydrogen, alkyl and the like; X represents a halogen, HE and the like) and the like, or its salt, which the traveler has herbicide action (see WO92/20659).

(5) a Compound represented by the formula

where R1represents hydrogen or lower alkyl; R2represents a heterocyclic group or aryl group, each and which are optionally substituted lower alkyl, and the like; R3and R4may form a phenyl ring, and the like, each optionally substituted with halogen, and the like, together with their associated carbon atoms, or its salt, which(Aya) has inhibitory effect on DPP-4 (see WO03/068748).

(6) the Compound represented by the formula

where X represents N or CR5(where R5represents hydrogen or lower alkyl); R1and R2independently represent hydrogen or lower alkyl; R3represents a heterocyclic group or aryl group, each of which is optionally substituted lower alkyl, and the like; R4represents lower alkyl and the like, or its salt that traveler has an inhibitory effect on DPP-4 (see WO03/068757).

However, there are no reports about the connection of the present invention.

Description of the invention

There is a need to develop compounds with inhibitory effect on peptides useful as a means for prevention or treatment of diabetes and the like and superior in terms of efficacy, duration of action, specificity, low toxicity, and the like.

The authors of the present invention, first found that the compound represented by the formula

img src="https://img.russianpatents.com/886/8861218-s.jpg" height="23" width="49" />

where

R1and R2are the same or different and each represents an optionally substituted hydrocarbon group or optionally substituted by a hydroxy-group;

R3represents an optionally substituted aromatic group;

R4represents optionally substituted by an amino group;

L represents a divalent hydrocarbon group;

Q represents a bond or a divalent hydrocarbon group, and

X represents a hydrogen atom, a cyano, a nitro-group, acyl group, substituted by a hydroxy-group, optionally substituted Tilney group, optionally substituted by an amino group or an optionally substituted cyclic group;

provided that when X represents ethoxycarbonyl group, Q represents a divalent hydrocarbon group, and that the connection is not

2,6-aminobutiramida 3-methylaminomethyl-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida 3-aminomethyl-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-(dimethylamino)methyl-4-(4-forfinal)-5-pentylpyridine;

2,6-aminobutiramida-3-(ethylamino)methyl-4-(4-forfinal)-5-pentylpyridine and

3-(tert-butyldimethylsilyloxy)-2,6-aminobutiramida-4-(4-forfinal)-5-(indol-5-aminomethyl)pyridine,

or its salt

[hereinafter sometimes with rasenna called(th) as the compound (I)], characterized by a chemical structure in which optionally substituted amino group attached to position 3 of the pyridine ring through a divalent hydrocarbon group, and optionally substituted aromatic group attached to position 4, has an excellent inhibitory effect on peptidase and useful as a tool for prevention or treatment of diabetes and the like. Based on this findings, the authors of the present invention conducted intensive studies, completed the present invention.

Thus, in accordance with the present invention include:

1) compound (I);

2) compound (I), where R1and R2are the same or different and each represents an optionally substituted hydrocarbon group, and X represents a cyano, a nitro-group, acyl group, substituted by a hydroxy-group, optionally substituted Tilney group, optionally substituted by an amino group or an optionally substituted cyclic group;

3) compound (I), where the acyl group for X is a carboxyl group;

4) compound (I), where R1and R2are the same or different and each represents a C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl the th group, With1-6alkoxycarbonyl group and1-6alkoxygroup;

5) compound (I), where R3represents a C6-14aryl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, and halogen atom;

6) the compound (I), where R4represents an amino group;

7), the compound (I), where L represents a C1-10alkylenes group;

8), the compound (I), where Q is a bond;

9) compound (I), where X represents an acyl group substituted by a hydroxy-group, optionally substituted Tilney group or optionally substituted by an amino group;

10) the compound (I), where X represents a carboxyl group;

11) the compound (I), which is a

5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid;

5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid;

methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate;

{[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}amine;

methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate;

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isoxazol-4-carboxamid,

or it is salt;

12) a prodrug of compound (I);

13) a pharmaceutical agent containing the compound (I) or its prodrug;

14) the pharmaceutical agent according to item 13), which is an agent for the prophylaxis or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity;

15) an inhibitor of peptidases containing compound (I) or its prodrug;

16) the inhibitor according to item 15)where peptidase is dipeptidylpeptidase-IV;

17) use of compound (I) or its prodrug to obtain funds for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity;

18) use of compound (I) or its prodrug to obtain an inhibitor of peptidases;

19) a method for preventing or treating diabetes, diabetic complications, impaired glucose tolerance or obesity in a mammal, comprising the administration to a mammal the compound (I) or its prodrug;

20) the method of inhibiting the peptidases in a mammal, comprising the administration to a mammal the compound (I) or its prodrug;

21) the method of obtaining the compound represented by the formula

where

R1, R2, R3and Q are as defined for compound (I);

La is Vasili divalent hydrocarbon group, and

Ha represents a hydrogen atom, a nitro-group, acyl group, substituted by a hydroxy-group, optionally substituted Tilney group, optionally substituted by an amino group or an optionally substituted cyclic group;

or its salt, comprising the exposure of the compounds represented by the formula

wherein each symbol is as defined above, or its salt of reduction reaction; and the like.

The compound of the present invention has excellent inhibitory effect on peptidase and useful as a tool for prevention or treatment of diabetes and the like.

The best way of carrying out the invention

Then each symbol in the formula (I) are described in more detail.

As the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R1or R2can be called, for example, C1-10alkyl group, a C2-10alkenylphenol group, C2-10alkylamino group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkenyl group, C6-14aryl group, a C7-13aracelio group, C8-13arylalkyl group, C3-10cycloalkyl-C1-6alkyl group and the like.

As C1-10the alkyl group in this description can name the th for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

As C2-10alkenylphenol groups include, for example, ethynyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

As C2-10alkenylphenol groups include, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.

As C3-10cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,

bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl,

bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and

the like.

As C3-10cycloalkenyl groups include, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

As C4-10cycloalkyl jenilee group can be called, for example, 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like.

As C6-14aryl groups include, for example, phenyl, naphthyl, antril, tenantry, acenaphthylene, biphenylyl and the like. Of them, preferred are phenyl, 1-naphthyl, 2-naphthyl and the like.

As C7-13aranceles groups include, for example, benzyl, phenethyl, naphthylmethyl, biphenylyl and the like.

As C8-13arylalkylamines groups include, for example, styryl and the like.

As C3-10cycloalkyl-C1-6alkyl groups include, for example, cyclohexylmethyl and the like.

These C1-10alkyl group, a C2-10Alchemilla group and C2-10Alchemilla group optionally contains 1-3 substituent in the substituted provisions. As these substituents include, for example:

(1) C3-10cycloalkyl group (for example, cyclopropyl, cyclohexyl);

(2) C6-14aryl group (e.g. phenyl, naphthyl);

(3) an aromatic heterocyclic group (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, hinely, indolyl), optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C16 alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(4) non-aromatic heterocyclic group (for example, tetrahydrofuryl, morpholino, thiomorpholine, piperidine, pyrrolidine, piperazinil, oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl, oxohexanoyl), optionally substituted C1-6alkyl group (e.g. methyl, ethyl);

(5) an amino group, optionally mono - or disubstituted by substituents selected from C1-6alkyl groups (e.g. methyl, ethyl), C1-6alkylcarboxylic group (for example, acetyl, Isobutanol, isopentanol) and C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(6) C1-6alkylsulfonamides (for example, methylsulfonylamino);

(7) amidinopropane;

(8) C1-6alkylcarboxylic group (for example, acetyl, Isobutanol, isopentanol);

(9) C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);

(10) C1-6alkylsulfonyl group (for example, methylsulphonyl);

(11) karbamoilnuyu group, optionally mono - or disubstituted by C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g., f the PR, chlorine, bromine, iodine);

(12) thiocarbamoyl group, optionally mono - or disubstituted by C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(13) sulfamoyl group, optionally mono - or disubstituted by C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(14) a carboxyl group;

(15) a hydroxy-group;

(16) C1-6alkoxygroup (for example, methoxy, ethoxy), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(17) C2-6alkenylacyl (for example, adenylate), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(18) C3-10cycloalkylation (for example, cyclohexyloxy);

(19) C7-13aralkylated (e.g., benzyloxy);

(20) C6-14alloctype (for example, phenyloxy, naphthyloxy);

(21) C1-6alkylcarboxylic (for example, atomic charges, tert-BUTYLCARBAMATE);

(22) Tilney group;

(23) C1-6allylthiourea (for example, methylthio, ethylthio), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(24) C7-13arkitip (for example, benzylthio);

(25) C6-14killigrew (for example, phenylthio, naphthylthio);

(26) when lithograph;

(27) cyano;

(28) sidegroup;

(29) the nitro-group;

(30) nitrosourea;

(31) a halogen atom (e.g. fluorine, chlorine, bromine, iodine);

(32) C1-6alkylsulfonyl group (for example, methylsulfinyl) and the like.

C3-10Cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkenyl group, C6-14aryl group, a C7-13kalkilya group, C8-13arylalkylamine group and C3-10cycloalkyl-C1-6alkyl group, listed as examples of the above "hydrocarbon group"optionally contains 1-3 substituent in the substituted provisions.

As these substituents include, for example, the groups listed as the substituents for the above C1-10alkyl groups and the like, for example:

C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1-3 substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a carboxyl group, a C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl) and carbamoyl group;

C2-6alkenylphenol group (for example, ethynyl, 1-propinyl), optionally substituted by 1-3 substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a carboxyl group, a C1-6alkoxycarbonyl group (EmOC is emer, methoxycarbonyl, etoxycarbonyl) and carbamoyl group;

C7-13aracelio group (e.g. benzyl) and the like.

"Hydrocarbon group" of the "optionally substituted hydrocarbon group" for R1or R2represents preferably C1-10alkyl group, a C6-14aryl group or a C7-13aracelio group, more preferably a C1-10alkyl group.

"Optionally substituted hydrocarbon group" for R1or R2preferably represents:

(1) C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group, C1-6alkoxygroup and the like;

(2) C6-14aryl group, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycarbonyl group, carbamoyl group and the like; or

(3) C7-13aracelio group.

Of them, preferred is a C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group, C1-6alkoxygroup and the like.

As examples of the "substituted hydroxy-group" of the "optionally substituted hydroxy-group" d the I R 1or R2can be used in the examples listed below for X.

Each of R1and R2represents preferably an "optionally substituted hydrocarbon group", more preferably C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group, C1-6alkoxygroup and the like.

As the "aromatic group" of the "optionally substituted aromatic group" for R3can be called, for example, an aromatic hydrocarbon group, aromatic heterocyclic group and the like.

As the aromatic hydrocarbon group include, for example, C6-14aryl group, which is given as an example for the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2, and the like.

As the aromatic heterocyclic group include, for example, a 5-7-membered monocyclic aromatic heterocyclic group containing 1-4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom as part of the ring atoms in addition to carbon atoms, and condensed aromatic heterocyclic group. As the condensed aroma is practical heterocyclic group can be called, for example, a group in which the specified 5-7-membered monocyclic aromatic heterocyclic group and a 6-membered ring containing 1 or 2 nitrogen atom, benzene ring or 5-membered ring containing one sulfur atom, condensed, and the like.

As preferred examples of the aromatic heterocyclic group can be called a monocyclic aromatic heterocyclic groups such as furyl (e.g. 2-furyl, 3-furyl), thienyl (for example, 2-thienyl, 3-thienyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (for example, 2-pyrazinyl), pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolin, oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazole-2-yl), triazolyl (for example, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole-4-yl), tetrazolyl (for example, tetrazol-1-yl, tetrazol-5-yl) and the like; condensed the romantic heterocyclic group, such as chinolin (for example, 2-chinolin, 3-chinolin, 4-chinolin), chinadoll (for example, 2-chinadoll, 4-chinadoll), Minoxidil (for example, 2-Minoxidil), benzofuran (for example, 2-benzofuran, 3-benzofuran), sensational (for example, 2-benzothiazyl, 3-benzothiazol), benzoxazolyl (for example, 2-benzoxazolyl), benzothiazolyl (for example, 2-benzothiazolyl), benzimidazolyl (for example, the benzimidazole-1-yl, benzimidazole-2-yl), indolyl (e.g., indol-1-yl, indol-3-yl), indazole (for example, 1H-indazol-3-yl), pyrrolopyrazine (for example, 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridine (for example, 1H-imidazo[4,5-b]pyridine-2-yl, 1H-imidazo[4,5-c]pyridine-2-yl), imidazolidinyl (for example, 1H-imidazo[4,5-b]pyrazin-2-yl) and the like, and the like.

"Aromatic group" of the "optionally substituted aromatic group" for R3represents preferably an aromatic hydrocarbon group, more preferably a C6-14aryl group, more preferably phenyl.

"Aromatic group" of the "optionally substituted aromatic group" for R3optionally contains 1-3 substituent in the substituted provisions.

As these substituents include, for example, the groups listed as examples of the substituents for C3-10cycloalkyl group, given in the number of examples for "Ugledar the ne group" of the "optionally substituted hydrocarbon group" for the above R 1or R2.

These substituents are preferably

C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

halogen atom (e.g. fluorine, chlorine, bromine, iodine);

C1-6alkoxycarbonyl group;

carboxyl group;

the hydroxy-group;

C1-6alkoxygroup, optionally substituted by 1 to 3 halogen atoms, and the like, more preferably

C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

halogen atom (e.g. fluorine, chlorine, bromine, iodine) and the like.

"Optionally substituted aromatic group" for R3represents preferably C6-14aryl group (where C6-14aryl group is preferably phenyl), optionally substituted by 1-3 substituents selected from C1-6alkyl groups (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atom (e.g. fluorine, chlorine, bromine, iodine) and the like.

As the "optionally substituted amino group" for R4can be called, for example, amino group, optionally substituted by 1 or 2 substituents selected from C1-10alkyl group, a C2-10alkenylphenol groups who, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group and C8-13arylalkylamines groups, each of which is optionally substituted; acyl group and the like.

As C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group and C8-13arylalkylamines group in this description you can use the groups given as examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

Each of these C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group and C8-13arylalkylamines group optionally contains 1-3 substituent in the substituted provisions. As these substituents include, for example,

halogen atom (e.g. fluorine, chlorine, bromine, iodine);

C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl);

C1-6alkylcarboxylic group;

the cyano;

karbamoilnuyu group, optionally mono - Il is disubstituted by C 1-10alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

the hydroxy-group;

carboxyl group; and the like.

As the acyl group, named example Deputy "optional substituted amino group", you can use the groups mentioned above as examples for X. Of them preferred are:

(1) C1-6acylcarnitine group (for example, acetyl, Isobutanol, isopentanol);

(2) C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl), optionally substituted C1-6alkoxycarbonyl group;

(3) C3-10cycloalkylcarbonyl group (for example, cyclopentanecarbonyl, cyclohexylcarbonyl);

(4) C6-14arylcarbamoyl group (e.g. benzoyl), optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl group, a C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group, an aromatic heterocyclic group (for example, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (for example, oxohexanoate) and carbamoyl group;

(5) C7-13aracelikarsaalyna group (for example, benzyloxycarbonyl), optional sameena is 1-3 substituents, selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(6) carnemolla group;

(7) a mono - or dis1-6acylcarnitine group (for example, dimethylcarbamoyl);

(8) C1-6alkylsulfonyl group (for example, methylsulphonyl);

(9) C6-14arylsulfonyl group, optionally substituted C1-6alkylsulfonyl group (for example, phenylsulfonyl, methylsulfonylbenzoyl);

(10) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)sulfonylurea group, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino group (for example, 2-acetylamino-4-methyl-5-triazolylmethyl);

(11) C7-13analceleberty group (for example, benzylcarbamoyl, ventilkappen);

(12) C8-13arylalkylamine group (for example, strikeball);

(13) an aromatic heterocyclic (for example, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl, pyrazinyl, benzofuran, benzothiazyl, honokalani)carbonyl group (for example, fullcarbon, thienylboronic, thiazolidinones, pyrazolidinone, pyridylcarbonyl, PersonalCabinet, benzofurazanyl, benzotriazolyl, hinoklidilkarbinola), optional what about substituted by 1-3 substituents, selected from C1-6alkyl group, a C6-14aryl group, a C7-13aranceles group, C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(14) nitrogen-containing heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazinil, morpholino, oxopiperidin)carbonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(15) C6-14areasofstudy heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonyl group;

(16) 4-oxo-4,5,6,7-tetrahydro-1-benzofurazanyl group;

(17) tetrahydroprotoberberine group;

(18) C6-14aryloxyalkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(19) C7-13aralkylamines group (for example, benzylcarbamoyl);

(20) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)carnemolla group (the example thiazolecarboxamide, oxazolidinyl), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group, and the like.

As preferred examples of the substituted amino group include:

(1) a mono - or dis1-10alkylamino (for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino);

(2) a mono - or dis2-10alkanolamines (for example, diallylamine);

(3) a mono - or dis3-10cycloalkylation (for example, cyclohexylamino);

(4) C6-14killingray (for example, phenylamino);

(5) mono - or di(C1-6alkylsulphonyl)amino group (for example, acetylamino, propionamido, butanilicaine, isobutyramide, isopentylamine);

(6) C1-6alkoxycarbonylmethyl (for example, methoxycarbonylamino), optionally substituted C1-6alkoxycarbonyl group;

(7) carbamoyl1-10alkylamino (for example, carbamoylmethyl);

(8) C1-6alkoxycarbonyl1-10alkylamino (for example, methoxycarbonylmethylene, ethoxycarbonylmethylene, tert-butoxycarbonylmethylene);

(9) carboxy1-10alkylamino (for example, carboxymethylamino);

(10) C3-10cycloalkylcarbonyl (for example, cyclopentylamine is amino, cyclohexylcarbodiimide);

(11) C6-14arylcarboxylic (for example, benzoylamine), optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl group, a C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group, an aromatic heterocyclic group (for example, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (for example, oxohexanoate) and carbamoyl group;

(12) C7-13arachidonoylethanolamine (for example, benzyloxycarbonylamino), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(13) carbamoylating;

(14) a mono - or dis1-6alkylcarboxylic (for example, dimethylcarbamoyl);

(15) C1-6alkylsulfonamides (for example, methylsulfonylamino);

(16) C6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group (for example, phenylcarbonylamino, methylsulfonylamino);

(17) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)sulphonylamino, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - is whether di(C 1-6alkylsulphonyl)amino group (for example, 2-acetylamino-4-methyl-5-thiazolecarboxamide);

(18) C7-13aralkylamines (for example, benzylmorphine, fenethylline);

(19) C8-13arylalkylamines (for example, strykersville);

(20) an aromatic heterocyclic (for example, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl, pyrazinyl, benzofuran, benzothiazyl, honokalani)carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group, a C7-13aranceles group, C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(21) nitrogen-containing heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazinil, morpholino, oxopiperidin)carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(22) C6-14arylacetamides heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazin the sludge, morpholino)carbonylation;

(23) tetrahydroprotoberberine;

(24) 4-oxo-4,5,6,7-tetrahydro-1-bestfurnitureonline.com;

(25) C6-14aryloxypropanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(26) C7-13aralkylamines (for example, benzylcarbamoyl);

(27) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)carbamoylating, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; and the like.

"Optionally substituted amino group" for R4preferably represents an amino group, optionally mono - or disubstituted by C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl). It is especially preferred when R4represents an amino group.

As the "divalent hydrocarbon group" for L or Q can be called, for example, divalent hydrocarbon group containing 1-10 carbon atoms. Specific examples include:

(1) C1-10alkylenes group (for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-,-(CH 2)6-, -CHCH3-, -C(CH3)2-, -(CH(CH3))2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2-);

(2) C2-10alkenylamine group (for example, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH=CH-CH2-CH2-, -C(CH3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2-);

(3) C2-10alkynylamino group (for example, -C≡C-, -CH2-C≡C-, -CH2-C≡C-CH2-CH2-) and the like.

"Divalent hydrocarbon group" is preferably a C1-10alkylenes group or a C2-10alkynylamino group, more preferably-CH2-, -(CH2)2-, -CH=CH - and the like.

L preferably represents C1-10alkylenes group, more preferably-CH2- and the like.

Q preferably represents a bond, C1-10alkylenes group or a C2-10alkynylamino group, more preferably a bond, -CH2-, -(CH2)2-, -CH=CH - and the like. It is especially preferred when Q is a bond.

As the "acyl group" for X include, for example, a group represented by the formula: -COR5, -CO-OR5, -SO2R5, -SOR5, -PO3R5R6, -CO-NR5aR6a, -CS-NR5aR6[where R and R6are the same or different and each represents a hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group; R5and R6are the same or different and each represents a hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group, or R5and R6may form optionally substituted nitrogen-containing heterocycle together with the adjacent nitrogen atom], and the like.

As the "optionally substituted hydrocarbon group" for R5, R6, R5or R6you can use the groups listed as examples for the above R1or R2.

As the "heterocyclic group" of the "optionally substituted heterocyclic group" for R5, R6, R5or R6you can call the aromatic heterocyclic group and non-aromatic heterocyclic group.

As the aromatic heterocyclic group include groups listed as examples of the "aromatic group" of the "optionally substituted aromatic group" for the above R3.

As a non-aromatic heterocyclic group include, for example, 5-7-clenn the Yu monocyclic non-aromatic heterocyclic group, containing 1-4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom as part of the ring atoms in addition to carbon atoms, and condensed non-aromatic heterocyclic group. As the condensed non-aromatic heterocyclic group can be mentioned, for example, a group in which the specified 5-7-membered monocyclic non-aromatic heterocyclic group and a 6-membered ring containing 1 or 2 nitrogen atom, benzene ring or 5-membered ring containing one sulfur atom, condensed, and the like.

As preferred examples of non-aromatic heterocyclic group can be called pyrrolidinyl (for example, 1-pyrrolidinyl), piperidinyl (for example, piperidine), morpholinyl (for example, morpholino), thiomorpholine (for example, thiomorpholine), piperazinil (for example, 1-piperazinil), hexamethylenimine (for example, hexamethylenimine-1-yl), oxazolidinyl (for example, oxazolidin-3-yl), diazolidinyl (for example, thiazolidin-3-yl), imidazolidinyl (for example, imidazolidin-3-yl), Oxymetazoline (for example, 2-Oxymetazoline-1-yl), dioxoimidazolidin (for example, 2,4-dioxoimidazolidin-3-yl), dioxoimidazolidin (for example, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxoimidazolidin-5-yl, 2,4-dioxoimidazolidin-1-yl), dioxothiazolidine (for example, 2,4-dioxothiazolidine-3-yl, 2,4-dioxetane the one-5-yl), dikshithar (for example, 1,3-dioxobenzo-2-yl), oxooctanoate (for example, 5-oxohexanoate-3-yl), oxadiazoles (for example, 5-oxadiazol-3-yl), oxopiperidine (for example, 3-oxopiperidin-1-yl), dioxopiperazinyl (for example, 2,3-dioxopiperazinyl-1-yl, 2,5-dioxopiperazinyl-1-yl), oxadiazolyl (for example, 2-oxo-1,3-dioxol-4-yl), oxadiazolyl (for example, 2-oxo-1,3-dioxolane-4-yl), oxo-2-benzofuranyl (for example, 3-oxo-2-benzofuran-1-yl), oxodegradable (for example, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl), 4-oxo-2-thioxo-1,3-thiazolidin-5-yl, 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, tetrahydropyranyl (for example, 4-tetrahydropyranyl), 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl (for example, 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-yl), 1,3(2H,5H)-dioxotetrahydrofuran[1,5-a]pyridinyl, 1,3(2H,5H)-dioxo-10,10a-dihydroimidazo[1,5-b]ethenolysis and the like.

"Heterocyclic group" of the "optionally substituted heterocyclic group" for R5, R6, R5or R6optionally contains 1-3 substituent in the substituted provisions.

As these substituents include, for example, mentioned as examples of substituents for C3-10cycloalkyl group that is specified as an example of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

C is mstiteli preferably represent

C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

halogen atom (e.g. fluorine, chlorine, bromine, iodine);

C6-14aryl group;

C7-13aracelio group;

the hydroxy-group;

C1-6alkoxygroup;

carboxyl group;

C1-6alkoxycarbonyl group;

karbamoilnuyu group;

C1-6alkyl group substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

mono - or di(C1-6alkylsulphonyl)the amino group and the like.

As the "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocycle"formed by R5and R6together with the adjacent nitrogen atom, can be mentioned, for example, a 5-7 membered nitrogen-containing heterocycle containing at least one nitrogen atom and optionally additionally containing 1-2 heteroatom selected from oxygen atom, sulfur atom and nitrogen atom as part of the ring atoms in addition to carbon atoms. As preferable examples of the "nitrogen-containing heterocycle" can be called pyrrolidin, imidazolidin, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperidin and the like.

Nitrogen-containing heterocycle, the optional is positive contains 1-3 (preferably 1 or 2) substituent in the substituted provisions. As these substituents can be called

the hydroxy-group;

C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

C7-13aracelio group (for example, benzyl, diphenylmethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

C6-14aryl group (e.g. phenyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl);

C1-6alkyl group substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

carboxyl group;

karbamoilnuyu group and the like.

As preferable examples of the "acyl group" include:

(1) a formyl group;

(2) a carboxyl group;

(3) karbamoilnuyu group;

(4) C1-6alkylcarboxylic group (for example, acetyl, Isobutanol, isopentanol);

(5) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylcarboxylic (for example, methoxycarbonyl, etoxycarbonyl, propox is carbonyl,

tert-butoxycarbonyl, carboxylesterases,

carboxylesterases, carboxylesterases,

carbamoylmethyl, thiocarbamoylation,

ethoxycarbonylmethoxy, ethoxycarbonylmethyl,

methoxycarbonylpropionyl, ethoxycarbonylmethyl,

tert-butylcarbamoyl);

(6) an aromatic heterocyclic (for example, furyl, thienyl, pyridyl, thiazolyl, oxazolyl, pyrazinyl, indolyl)1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group (for example, pyridylcarbonyl,

carboxytetramethyl,

carbamoylaspartate,

ethoxycarbonylmethylene);

(7) non-aromatic heterocyclic (for example, oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl)1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group (for example,

metronidazolemetronidazole,

oxo-2-benzophenonetetracarboxylic);

(8) C3-10cycloalkylcarbonyl group (for example, cyclopentanecarbonyl, cyclohexylcarbonyl);

(9) C6-14arylcarbamoyl group (for example, benzoyl, 1-naphtol, 2-naphtol), obazatelno substituted by 1-3 substituents, selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl groups (i.e. C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine)), C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group, an aromatic heterocyclic group (for example, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (for example, oxohexanoate) and carbamoyl group;

(10) C6-14aryloxyalkyl group (for example, vinyloxycarbonyl, naphthalocyanines), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(11) C7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group, halogen atom, ceanography, nitro, C1-6alkoxygroup, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group) (for example, benzyloxycarbonyl,

ventilatsioonil, carboxyl silexcolor,

methoxycarbonylaminophenyl, biphenylmethanol);

(12) karbamoilnuyu group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and (C1-6alkoxygroup (for example, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino, propellerblades, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric, triptoreline, N-methoxyethyl-N-methylcarbamoyl);

(13) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) (for example, carbamoylmethyl, carbamoylation, dimethylcarbamodithioato, dimethylcarbamodithioato);

(14) C1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group (for example, methoxycarbonylmethylene, ethoxycarbonylmethylene, N-ethoxycarbonylmethyl-N-methylcarbamoyl);

(15) C6-14arylcarbamoyl group (for example, phenylcarbamoyl), optionally substituted by 1-3 substituents selected from amino, optionally mono - or disubstituted by C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group, aromatic heterocyclic group (for example, tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (for example, oxohexanoate) and carbamoyl group;

(16) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group (for example, cyclopropanecarbonyl, cyclopentanecarbonyl,

dicyclohexylcarbodiimide, N-cyclohexyl-N-methylcarbamoyl);

(17) C7-13aralkylamines group, optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), hydroxy-group, carboxyl group, C1-6alkoxycarbonyl group and C1-6alkyl groups (for example, benzylcarbamoyl, phenetically,

phenylpropionyl, hydroxyphenylarsonic,

chlorobenzylamino, methoxycarbonylmethylene,

N-benzyl-N-methylcarbamoyl);

(18) an aromatic heterocyclic (for example, pyridyl, thienyl, furyl, thiazolyl, oxazolyl, indolyl)1-6alkylcarboxylic group (for example, intolerably,

pyridylmethylene, taylmeinerova,

thiazolinediones), optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(19) C1-6alkylsulfonyl group, neobyazatel is substituted by 1-3 substituents, selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group (for example, methylsulphonyl, carboxymethylation);

(20) C6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylsulfonyl group (for example, phenylsulfonyl, methylphenylsulfonyl,

carboxypenicillins, methoxycarbonylaminophenyl,

methylsulfonylbenzoyl);

(21) nitrogen-containing heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazinil, morpholino, oxopiperidin)carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group (for example, pyrrolidinylcarbonyl,

piperidinylcarbonyl, piperazinylcarbonyl,

oxopiperidine, morpholinoethyl,

methoxycarbonylpropionyl);

(22) C6-14arylacetamides heterocyclic (for example, p is rollitini, piperidinyl, piperazinil, morpholino)carbonyl group (for example, phenylpiperazines, phenylpiperidines), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(23) C7-13erolkilutera heterocyclic (for example, pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonyl group (for example, benzylpiperazine), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

(24) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)sulfonyloxy group, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino group (for example, 2-acetylamino-4-methyl-5-triazolylmethyl);

(25) non-aromatic heterocyclic (for example, oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl)oxycarbonyl group (for example, exodeoxyribonuclease, oxo-2-benzofurazanyl);

(26) C1-6alkylsulfonyl group (for example, methylsulfinyl);

(27) thiocarbamoyl group;

(28) phosphonopropyl, optionally mono - or disubstituted by C1-6alkyl group (for example, dimethylphosphino, diethylphosphino);

(29) C7-13aralkylamines group (for example, benzylcarbamoyl, ventilkappen);

(30) C8-13aryl is kenolkobil group (for example, strikeball);

(31) an aromatic heterocyclic (for example, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl, pyrazinyl, benzofuran, benzothiazyl, honokalani)carbonyl group (for example, fullcarbon, thienylboronic, thiazolidinones, pyrazolidinone, pyridylcarbonyl, PersonalCabinet, benzofurazanyl, benzotriazolyl, hinoklidilkarbinola), optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group, a C7-13aranceles group, C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(32) tetrahydropyranyloxy group;

(33) 4-oxo-4,5,6,7-tetrahydro-1-benzofuranyl group;

(34) C3-10cycloalkyl-C1-6alkoxycarbonyl group (for example, cyclohexyloxycarbonyl), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(35) an aromatic heterocyclic (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, hinely, indolyl)7-13aracelikarsaalyna group (for example, tetracarbonylnickel);

(36) an aromatic heterocyclic (for example, thienyl, furyl, pyridyl, thiazolyl, ACS who were Salil, indolyl)karbamoilnuyu group (for example, taylornol, fullcarbon, thiazolecarboxamide, oxazolidinyl), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group, and the like.

"Acyl group" for X preferably represents:

(1) carboxyl group;

(2) karbamoilnuyu group;

(3) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylcarboxylic (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl,

tert-butoxycarbonyl, carboxylesterases,

carboxylesterases, carboxylesterases,

carbamoylmethyl, thiocarbamoylation,

ethoxycarbonylmethoxy, ethoxycarbonylmethyl,

methoxycarbonylpropionyl, ethoxycarbonylmethyl,

tert-butylcarbamoyl);

(4) karbamoilnuyu group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup (for example, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl,

IER is ylcarbonyl, ethylmethylamino, propellerblades,

isopropylcarbamate, butylcarbamoyl, isobutylbarbituric,

triptoreline, N-methoxyethyl-N-methylcarbamoyl);

(5) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms (e.g., carbamoylmethyl, carbamoylation,

dimethylcarbamodithioato, dimethylcarbamodithioato), and the like. Of them, preferred is a carboxyl group.

As "substituted hydroxy-group for X include, for example, the hydroxy-group, substituted Deputy selected from C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C8-13arylalkylamines group, C1-6alkylcarboxylic group (for example, acetyl, Isobutanol, isopentanol), 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl), condensed aromatic heterocyclic group (for example, indolyl and the like, each of which is optionally substituted.

As C1-10alkyl group, a C2-10alkenylphenol g is uppy, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group and C8-13arylalkylamines group in this description can be used by groups listed as examples for the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

Each of the above C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C8-13arylalkylamines group, C1-6alkylcarboxylic group, 5 - or 6-membered aromatic heterocyclic group and condensed aromatic heterocyclic group optionally contains 1-3 substituent in the substituted provisions. As these substituents include, for example,

halogen atom (e.g. fluorine, chlorine, bromine, iodine);

the hydroxy-group;

the cyano;

C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), a carboxyl group, a C1-6alkoxycarbonyl group (for example, methoxycarbonyl, tert-butoxycarbonyl) and carbamoyl group;

C1-6alkoxygroup, optionally substituted 1 or zamestitelyami, selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), a carboxyl group, and C1-6alkoxycarbonyl group (e.g. tert-butoxycarbonyl);

C1-6allylthiourea (for example, methylthio, ethylthio);

C1-6alkylcarboxylic group;

carboxyl group;

C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl);

karbamoilnuyu group, optionally mono - or disubstituted by C1-10alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

the amino group, optionally mono - or disubstituted by C1-10alkyl group (e.g. methyl, ethyl, propyl, isopropyl, neopentyl);

C1-6alkylcarboxylic;

aromatic heterocyclic group (e.g., furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl), optionally substituted by 1-3 substituents selected from C1-6alkyl groups (e.g. methyl, ethyl), a carboxyl group, a C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl) and carbamoyl group;

C1-6alkylsulfonyl group (for example, methylsulfinyl);

C1-6alkylsulfonyl group (for example, methylsulphonyl) and the like.

As preferred examples of the substituted hydroxy-group" can the criminal code is now:

(1) C1-6alkylcarboxylic;

(2) C1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(3) C6-14alloctype, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycarbonyl group, C1-6allylthiourea, carbamoyl group, C1-6alkoxygroup, C1-6alkylsulfonyl group, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);

(4) a 5 - or 6-membered aromatic geterotsiklicheskikh (preferably titilate, thiazolidone, oxazolidone, imidazolinone, triazolinone, pyrazolinone, pyridyloxy, pyrimidinone), optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted with 1-2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(5) condensed aromati the definition of geterotsiklicheskikh (preferably intolerance), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(6) an aromatic heterocyclic (preferably pyridyl)1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(7) an aromatic heterocyclic (preferably tetrazolyl)6-14alloctype and the like.

As the "optionally substituted Tilney group" for X you can specify, for example, Tilney group optionally substituted by the Deputy, is selected from C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C8-13arylalkylamines group, C1-6alkylcarboxylic group (for example, acetyl, Isobutanol, isopentanol), 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl), condensed aromatic heterocyclic group (for example, indolyl and the like, each of which is optionally substituted.

As C1-10alkyl group, a C2-10alkenylphenol group, C3-1 cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group and C8-13arylalkylamines group in this case you can use groups listed as examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

Each of the above C1-10alkyl group, a C2-10alkenylphenol group, C3-10cycloalkyl group, C3-10cycloalkenyl group, C6-14aryl group, a C7-13aranceles group, C8-13arylalkylamines group, C1-6alkylcarboxylic group, 5 - or 6-membered aromatic heterocyclic group and condensed aromatic heterocyclic group optionally contains 1-3 substituent in the substituted provisions. As these substituents can be used substitutes for C1-10alkyl groups and the like for "substituted hydroxy-group" for the above X.

As preferable examples of the "optionally substituted Tilney group, you can specify:

(1) C1-6allylthiourea, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(2) C6-14killigrew, long is Ino substituted by 1-3 substituents, selected from a carboxyl group, a C1-6alkoxycarbonyl group, C1-6ancilliary and carbamoyl group;

(3) a 5-or 6-membered aromatic heterocyclisation (preferably tianity, thiazolino, oxazolyl, imidazolidine, triazoline, personilty, pyridylthio, pyrimidinyl), optionally substituted by 1-3 substituents selected from C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group, and the like.

As the "optionally substituted amino group" for X, you can use groups listed as examples for the above R4.

As the "cyclic group" of the "optionally substituted cyclic group" for X you can specify, for example, an aromatic hydrocarbon group, non-aromatic cyclic hydrocarbon group, aromatic heterocyclic group, non-aromatic heterocyclic group and the like.

As the aromatic hydrocarbon groups and aromatic heterocyclic groups you can use groups listed as examples for the "aromatic group" of the "optionally substituted aromatic group" for the above R3.

In addition, as a non-aromatic heterocyclic groups you can use groups, is shown as examples for the "heterocyclic group" of the "optionally substituted heterocyclic group" for the above R 5.

As a non-aromatic cyclic hydrocarbon group, you can specify, for example, C3-10cycloalkyl group, C3-10cycloalkenyl group, C4-10cycloalkenyl group and the like, each of which is optionally condensed with a benzene ring.

As C3-10cycloalkyl group, C3-10cycloalkenyl group and C4-10cycloalkenyl groups you can use groups listed as examples for the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

"Cyclic group" of the "optionally substituted cyclic group" for X optionally contains 1-3 substituent in the substituted provisions.

As substituents in this case you can specify, for example, the substituents listed as examples for C3-10cycloalkyl group that is specified as an example for the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for the above R1or R2.

The substituents preferably represents

C1-6alkyl group (e.g. methyl, ethyl), optionally substituted by 1-3 substituents selected from a halogen atom (e.g. fluorine, chlorine, bromine, iodine), carbamoyl group, carboxyl group and C1-6 alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl);

halogen atom (e.g. fluorine, chlorine, bromine, iodine);

carboxyl group;

C1-6alkoxycarbonyl group;

karbamoilnuyu group and the like.

X preferably represents an acyl group substituted by a hydroxy-group, optionally substituted Tilney group or optionally substituted by an amino group, and more preferably acyl group. Of them, preferred are:

(1) carboxyl group;

(2) carnemolla group;

(3) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylcarboxylic;

(4) carnemolla group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;

(5) carbamoyl1-6acylcarnitine group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, and the like, and particularly preferred is a carboxyl group.

When in the compound (I) X is ethoxycarbonyl group, Q represents a DV is valentno hydrocarbon group.

In addition, compound (I) does not include:

2,6-aminobutiramida 3-methylaminomethyl-4-(4-forfinal)-5-pentylpyridine [this compound is also called {[4-(4-forfinal)-2,6-aminobutiramida 5-pentylpyridine-3-yl]methyl}methylamine];

2,6-aminobutiramida 3-aminomethyl-4-(4-forfinal)-5-pentylpyridine [this compound is also called {[4-(4-forfinal)-2,6-aminobutiramida 5-pentylpyridine-3-yl]methyl}amine];

2,6-aminobutiramida-3-(dimethylamino)methyl-4-(4-forfinal)-5-pentylpyridine [this compound is also called 1-[4-(4-forfinal)-2,6-aminobutiramida 5-pentylpyridine-3-yl]-N,N-dimethylethanamine];

2,6-aminobutiramida-3-(ethylamino)methyl-4-(4-forfinal)-5-pentylpyridine [this compound is also called N-{[4-(4-forfinal)-2,6-aminobutiramida 5-pentylpyridine-3-yl]methyl}ethanamine]

3-(tert-butyldimethylsilyloxy)-2,6-aminobutiramida-4-(4-forfinal)-5-(indol-5-aminomethyl)pyridine [this compound is also called N-{[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(4-forfinal)-2,6-diisopropylaniline-3-yl]methyl}-1H-indol-5-amine].

As preferable examples of compound (I) you can specify the following connection.

[Compound A]

Connection, where:

R1and R2are the same or different and each represents a C1-10alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl), optionally substituted by 1-3 substituent and, selected from C3-10cycloalkyl group (preferably cyclopropyl), C1-6alkoxycarbonyl group (preferably ethoxycarbonyl) and the like;

R3represents a C6-14aryl group (C6-14aryl group is preferably phenyl), optionally substituted by 1-3 substituents selected from C1-6alkyl groups (e.g. methyl, ethyl), optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atom (e.g. fluorine, chlorine, bromine, iodine) and the like;

R4represents an amino group, optionally mono - or disubstituted by C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl);

L represents a C1-10alkylenes group (preferably-CH2-);

Q is a bond, C1-10alkylenes group or a C2-10alkenylamine group (preferably a bond, -CH2-, -(CH2)2-, -CH=CH -), and

X represents a carboxyl group, karbamoilnuyu group, C1-6alkoxycarbonyl group, karbamoilnuyu group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 halogen atoms, or carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 atoms is halogen.

[Compound B]

Connection, where:

R1and R2are the same or different and each represents:

(1) C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group (preferably cyclopropyl), C1-6alkoxycarbonyl group, C1-6alkoxygroup and the like;

(2) C6-14aryl group (preferably phenyl), optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycarbonyl group, carbamoyl group and the like; or

(3) C7-13aracelio group (preferably benzyl);

R3represents a C6-14aryl group (C6-14aryl group is preferably phenyl), optionally substituted by 1-3 substituents selected from C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, halogen atom, a C1-6alkoxycarbonyl group, carboxyl group, hydroxy-group, C1-6alkoxygroup, optionally substituted by 1 to 3 halogen atoms, and the like;

R4represents an amino group, optionally mono - or disubstituted by C1-6alkyl group (preferably an amino group);

L represents a C1-10alkylenes group (preferably-CH2 -);

Q is a bond, C1-10alkylenes group or a C2-10alkenylamine group (preferably a bond, -CH2-, -(CH2)2-, -CH=CH -), and

X represents:

(1) a hydrogen atom;

(2) cyano;

(3) (3a) a carboxyl group;

(3b) karbamoilnuyu group;

(3c) C1-6alkoxycarbonyl group, optionally substituted with substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylcarboxylic;

(3d) an aromatic heterocyclic (preferably pyridyl, thiazolyl, oxazolyl, indolyl)1-6alkoxycarbonyl group, optionally substituted with substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group;

(3e) non-aromatic heterocyclic (preferably oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl)1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;

(3f) C7-13aracelikarsaalyna group, optionally substituted with substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group;

(3g) karbamoilnuyu group, mono - or disubstituted by C 1-6alkyl group, optionally substituted with substituents selected from 1-3 halogen atoms and C1-6alkoxygroup;

(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms;

(3i) C1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;

(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group;

(3k) C7-13aralkylamines group, optionally substituted with substituents selected from halogen atom, hydroxy-group, C1-6alkoxycarbonyl group and C1-6alkyl groups;

(3l) an aromatic heterocyclic (preferably pyridyl, thiazolyl, oxazolyl, indolyl)1-6alkylcarboxylic group;

(3m) C1-6alkylsulfonyl group, optionally substituted with substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(3n) C6-14arylsulfonyl group, optionally substituted with substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylsulfate the ilen group;

(3o) nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidino, piperazinil, morpholino)carbonyl group, optionally substituted with substituents selected from hydroxy-group and C1-6alkoxycarbonyl group;

(3p) C6-14arylacetamides heterocyclic (preferably pyrrolidinyl, piperidino, piperazinil, morpholino)carbonyl group optionally substituted by a halogen atom;

(3q) C7-13erolkilutera heterocyclic (preferably pyrrolidinyl, piperidino, piperazinil, morpholino)carbonyl group optionally substituted by a halogen atom;

(3r) non-aromatic heterocyclic (preferably oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl)oxycarbonyl group; or

(3s) phosphonopropyl, optionally mono - or disubstituted by C1-6alkyl group;

(4) C1-6alkylcarboxylic;

(5) (5a) C1-6allylthiourea, optionally substituted with substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(5b) C6-14killigrew (preferably phenylthio), optionally substituted with substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and C1-6allylthiourea, or

(5c) a 5-membered aromatic gets is rollertype (preferably Tesorillo, oxazolyl, triazolyl), optionally substituted C1-6alkyl group;

(6) (6a) amino group;

(6b) C1-6alkoxycarbonyl1-10alkylamino

(preferably methoxycarbonylmethylene,

ethoxycarbonylmethylene, tert-butoxycarbonylmethylene);

(6c) carboxin1-10alkylamino;

(6d) C7-13arachidonoylethanolamine;

(6e) carbamoylating;

(6f) a mono - or dis1-6alkylcarboxylic;

(6g) C1-6alkylsulfonamides;

(6h) C6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group; or

(6i) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)sulphonylamino, optionally substituted with substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino; or

(7) tetrazolyl, Oxymetazoline (preferably 2-Oxymetazoline-1-yl), dioxoimidazolidin (preferably 2,4-dioxoimidazolidin-3-yl), oxopiperidine (preferably 3-oxopiperidin-1-yl), dioxopiperazinyl (preferably 2,3-dioxopiperazinyl-1-yl, 2,5-dioxopiperazinyl-1-yl) or oxodegradable (preferably 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl).

[Compound C]

Connection, where R4represents the AMI is Gruppo and X represents any of the groups listed above (3a)-(3s) in the above connection B.

[Connection D]

Connection, where:

R1, R2, R3, R4L and Q are as defined for the above compound B, X represents:

(1) a hydrogen atom;

(2) cyano;

(3) (3a) a carboxyl group;

(3b) karbamoilnuyu group;

(3c) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylcarboxylic;

(3d) an aromatic heterocyclic (preferably furyl, thienyl, pyridyl, thiazolyl, oxazolyl, pyrazinyl, indolyl)1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group;

(3e) non-aromatic heterocyclic (preferably oxadiazolyl, oxadiazolyl, oxo-2-benzofuranyl)1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;

(3f) C7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group, halogen atom, ceanography, nitro group is, C1-6alkoxygroup, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);

(3g) karbamoilnuyu group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;

(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms;

(3i) C1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;

(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group;

(3k) C7-13aralkylamines group, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy-group, carboxyl group, C1-6alkoxycarbonyl group and C1-6alkyl groups;

(3l) an aromatic heterocyclic (preferably pyridyl, thienyl, furyl, thiazolyl, oxazolyl, indolyl)1-6alkylcarboxylic group, optionally substituted by 1-3 substituents selected from carboxyl gr is PPI, carbamoyl group and C1-6alkoxycarbonyl group;

(3m) C1-6alkylsulfonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(3n) C6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylsulfonyl group;

(3o) nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, carboxyl group and C1-6alkoxycarbonyl group;

(3p) C6-14arylacetamides heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonyl group optionally substituted by 1 to 3 halogen atoms;

(3q) C7-13erolkilutera heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonyl group optionally substituted by 1 to 3 halogen atoms;

(3r) non-aromatic heterocyclic (preferably oxadiazolyl, oxadiazolyl,

oxo-2-benzofuranyl)oxycarbonyl the second group;

(3s) phosphonopropyl, optionally mono - or disubstituted by C1-6alkyl group;

(3t) an aromatic heterocyclic (preferably tetrazolyl)7-13aracelikarsaalyna group;

(3u) C3-10cycloalkyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(3v) C6-14arylcarbamoyl group, optionally substituted by 1-3 substituents selected from amino, optionally mono - or disubstituted by C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group, an aromatic heterocyclic group (preferably tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (preferably oxohexanoate) and carbamoyl group; or

(3w) an aromatic heterocyclic (preferably thienyl, furyl)karbamoilnuyu group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(4) (4a) C1-6alkylcarboxylic;

(4b) C1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl g is uppy;

(4c) C6-14alloctype, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycarbonyl group, C1-6allylthiourea, carbamoyl group, C1-6alkoxygroup, C1-6alkylsulfonyl group, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);

(4d) a 5 - or 6-membered aromatic geterotsiklicheskikh (preferably titilate, thiazolidone, oxazolidone, imidazolinone, triazolinone, pyrazolinone, pyridyloxy, pyrimidinone), optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(4e) condensed aromatic geterotsiklicheskikh (preferably intolerance), optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(4f) aromaticas the heterocyclic (preferably pyridyl) 1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or

(4g) aromatic heterocyclic (preferably tetrazolyl)6-14alloctype;

(5) (5a) C1-6allylthiourea, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;

(5b) C6-14killigrew, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group, C1-6ancilliary and carbamoyl group, or

(5c) a 5 - or 6-membered aromatic heterocyclisation (preferably tianity, thiazolino, oxazolyl, imidazolidine, triazoline, personilty, pyridylthio, pyrimidinyl), optionally substituted by 1-3 substituents selected from C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(6) (6a) amino group;

(6b) C1-6alkoxycarbonyl1-10alkylamino;

(6c) carboxin1-10alkylamino;

(6d) C7-13arachidonoylethanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl gr is PPI and carbamoyl group;

(6e) carbamoylating;

(6f) a mono - or dis1-6alkylcarboxylic;

(6g) C1-6alkylsulfonamides;

(6h) C6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group;

(6i) an aromatic heterocyclic (for example, pyridyl, thiazolyl, oxazolyl, indolyl)sulphonylamino, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino;

(6j) mono - or di(C1-6alkylsulphonyl)amino group;

(6k) C3-10cycloalkylcarbonyl;

(6l) C6-14arylcarboxamide, optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl group, a C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group, an aromatic heterocyclic group (preferably tetrazolyl, oxadiazolyl), non-aromatic heterocyclic group (preferably oxohexanoate) and carbamoyl group;

(6m) C7-13aralkylamines;

(6n) C8-13arylalkylamine;

(6o) an aromatic heterocyclic (preferably furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyrazolyl, pyridyl, pyrazinyl, benzop the reel, sensational, honokalani)carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group, a C7-13aranceles group, C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(6p) nitrogen-containing heterocyclic (preferably pyrrolidinyl, piperidinyl, piperazinil, morpholino)carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;

(6q) C6-14arylacetamides heterocyclic (for example,

pyrrolidinyl, piperidinyl, piperazinil,

morpholino)carbonylation;

(6r) tetrahydroprotoberberine;

(6s) 4-oxo-4,5,6,7-tetrahydro-1-bestfurnitureonline.com;

(6t) C1-6alkoxycarbonylmethyl, optionally substituted C1-6alkoxycarbonyl group;

(6u) C6-14aryloxypropanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and CT is emailnow group;

(6v) C7-13aralkylamines or

(6w) an aromatic heterocyclic (preferably thiazolyl, oxazolyl)carbamoylating, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or

(7) (7a) tetrazolyl;

(7b) Oxymetazoline (preferably 2-Oxymetazoline-1-yl);

(7c) dioxoimidazolidin (preferably 2,4-dioxoimidazolidin-3-yl, 2,4-dioxoimidazolidin-1-yl), optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;

(7d) oxopiperidine (preferably 3-oxopiperidin-1-yl);

(7e) dioxopiperazinyl (preferably 2,3-dioxopiperazinyl-1-yl, 2,5-dioxopiperazinyl-1-yl);

(7f) oxodegradable (preferably 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl);

(7g) dikshithar;

(7h) oxazolyl, optionally substituted C1-6alkoxycarbonyl group;

(7i) dioxoimidazolidin (preferably 2,4-dioxoimidazolidin-5-yl) or dioxothiazolidine (preferably 2,4-dioxothiazolidine-5-yl), each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;

(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;

(7k) 1,3(2H,5H)-dioxotetrahydrofuran[1,5-a]pyridinyl;

(7l) 1,3(2H,5H)-dioxo-10,10a-dihydroimidazo[1,5-b]ethenolysis or

(7m) C6-14aryl group, optionally substituted C1-6alkoxycarbonyl group.

[Connection E]

The above compound D where:

R1and R2are the same or different and each represents a C1-10alkyl group (preferably R1represents isobutyl or neopentyl; R2represents methyl);

R3represents a C6-14aryl group, optionally substituted C1-6alkyl group (R3preferably represents 4-were);

R4represents the amino group and

X represents the above group (3a), (3c)and (3f), (3o), (3v), (4d), (5b), (6l) or (6o) [preferably (3a), (3o), (3v), (4d) or (6o)].

[Connection F]

5-(Aminomethyl)-2-methyl-4-(4-were)-6-neopentadactyla acid (example 22);

5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (example 40);

methyl-3-{[5-(aminomethyl)-6-isobutyl-2-ethyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (example 305);

{[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}amine (example 312);

methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (example 336);

N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isoxazol-4-carboxamide (example 350); or its salt, preferably the hydrochloride, triptorelin, fumarate).

As the salt of compound (I) is preferred pharmacologically acceptable salt. Examples of such salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like.

Preferred examples of the salt with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals such as calcium salt, magnesium salt and the like; aluminum salt; ammonium salt and the like.

Preferred examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [Tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

Preferred examples of the salt with inorganic acid include a salt with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferred examples of the salt with organic acid include salts with formic acid, acetic acid, triperoxonane acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like.

Preferred examples of salts with basic amino acid include a salt with arginine, lysine, ornithine and the like.

Preferred examples of salts with acidic amino acid include a salt with aspartic acid, glutamic acid and the like.

Of the above salts are preferred salt with inorganic acid, salt with organic acid, and most preferred are the hydrochloride, triptorelin, fumarate and the like.

The prodrug of compound (I) is a compound that is converted into compound (I) as a result of interaction with the enzyme, acid indigestion, and the like under physiological conditions in the body, i.e. the compound, which is converted into compound (I) by enzymatic oxidation, recovery, hydrolysis and the like, and a compound which is converted into compound (I) by hydrolysis and the like under the action of gastric acid and the like. Examples of prodrugs of compound (I) include a compound in which the amino group of compound (I) allyawan, alkylated, phosphorylated (for example, the connection, where the amino group of compound (I) eikozanoidov, alanalanalana, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinedione, pivaloyloxymethyl, tert-Butlerova and the like); a compound in which the hydroxy-group of the compound (I) allyawan, alkylated, phosphorylated, Borisovna (for example, the connection, where the hydroxy-group of the compound (I) azetilirovanna, palmitoylation, propanolamine, pihlajasaari, succinylcholine, omarileaman, alanalanalana, dimethylaminoethylacrylate and the like); a compound in which a carboxyl group of compound (I) etherification or liderovna (for example, the connection, where the carboxyl group of compound (I) utilitarian, phenylacetylamino, karboksimetilcelljuloza, dimethylaminoethylacrylate,

pivaloyloxymethyl,

ethoxycarbonylmethylene, Telegraaf is verified,

(5-methyl-2-oxo-1,3-dioxolan-4-yl)methylethylamine,

cyclohexyloxycarbonyloxy, methylenediamine and

like. These compounds can be obtained from compound (I) is known as such ways.

The prodrug of compound (I) may be a compound which is converted into compound (I) under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990).

The compound (I) can be observed isotope (for example,3H,14C,35S125I and the like) and the like.

The compound (I) may be anhydrous or hydrate.

The compound (I) and its prodrug (hereinafter sometimes referred to simply as the compound of the present invention) show low toxicity and can be used as a means for the prevention or treatment of various diseases in the following mammals (e.g. human, mouse, rat, rabbit, dog, cat, cattle, horse, pig, monkey and the like) as such or in a mixture with a pharmaceutically acceptable carrier and the like, forming a pharmaceutical composition.

In this case, as the pharmacologically acceptable carrier use organic or inorganic carriers conventionally used as materials for producing pharmaceutically what drugs which is added in the form of excipient, lubricant, binder, disintegrant for hard drugs and solvents, substances that promote the dissolving, suspending means, means providing isotonicity solution, a buffer, a sedative, and the like for liquid preparations. If necessary, you can use this Supplement to pharmaceutical preparations as a preservative, antioxidant, coloring agent, sweetening agent and the like.

Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pre-gelatinizing starch, dextrin, crystalline cellulose, nitrosamino hydroxypropylcellulose, ntrihalomethylthio, powdery Arabian gum, pullulan, light silicic anhydride, synthetic aluminum silicate, metasilicate of magnesium aluminate, and the like.

Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

Preferred examples of the binder include pre gelatinizing starch, sucrose, gelatin, powder Arabian gum, methylcellulose, carboxymethylcellulose, natrocarbonatite, crystalline cellulose, sucrose, D-Mann is t, trehalose, dextrin, pullulan, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone and the like.

Preferred examples of disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcixerollic, nitrocresols, natrocarbonatite, light silicic anhydride, nitrosamino hydroxypropylcellulose and the like.

Preferred examples of the solvent include water for injection, physiological saline, ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferred examples of substances that promote dissolution, include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

Preferred examples of the suspending means comprise surface-active substances, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl, lecithin, benzylaniline, benzathine, glycerylmonostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, m is etilzelluloza, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.

Preferred examples of the means providing isotonicity solution include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffer include phosphate buffer, acetate buffer, carbonate buffer, citrate buffer, and the like.

Preferred examples of sedative include benzyl alcohol and the like.

Preferred examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid and the like.

Preferred examples of the antioxidant include sulfite, ascorbate and the like.

Preferred examples of the coloring matter include edible water-soluble resin pigments (e.g., food colors such as food color red No. 2 and No. 3, food color yellow No. 4 and 5, food color blue No. 1 and 2 and the like), water insoluble colorful lacquers (e.g., aluminum salt of the above edible water-soluble resin pigment, and the like), natural pigments (e.g., betakaroten, chlorophyll, red Gelato the easen pigment, etc. and the like.

Preferred examples of sweeteners include Nachrichten, glycerinate of dicale, aspartame, stevia and the like.

Dosage form of the above pharmaceutical composition is, for example, an oral agent such as tablets (including sublingual tablets and razzhevyvanie tablets), capsules (including soft capsules and microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions and the like; or a parenteral agent such as a form for injection (for example, forms for subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions, etc.), external means (for example, preparations for percutaneous injection, ointments, etc.), suppositories (e.g. rectal suppositories, vaginal suppositories, etc), pills, nasal preparations, pulmonary preparations (forms for inhalation), ocular drugs, and the like. These dosage forms can be safely administered orally or parenterally.

These tools can represent drugs with controlled release, such as drugs with quick release and preparations with protracted release (e.g., microcapsules with prolonged release).

The pharmaceutical composition can be obtained by the method usually used is used in the pharmaceutical field, such as the method described in the Pharmacopoeia of Japan, and the like. Specific ways to obtain pharmaceutical preparations are described in detail below.

Although the content of the compounds of the present invention in the pharmaceutical composition varies depending on the dosage forms, doses of the compounds of the present invention and the like, it is, for example, about 0.1-100 wt.%.

Oral means receive, for example, by adding to the active ingredient excipients (e.g. lactose, sucrose, starch, D-mannitol and the like), disintegrant (for example, calcixerollic and the like), binders (for example, pre-gelatinizing starch, powder Arabian gum, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like), lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000 and the like) and the like, shaping by molding the resulting mixture and, when necessary, covering it with a base coating for taste masking, giving ability dissolution in the intestine or the ability of the extended release manner known in itself.

Examples of bases for coating include the basis for the sugar coating, the basis for obtaining water-soluble film based who have to get intersolubility film, the basis for the film, providing a prolonged release of the active component.

As the basis for sugar coating, you can use sucrose, if necessary together with one or more additives selected from talc, precipitated calcium carbonate, gelatin, powder Arabian gum, pullulan, Carnauba wax and the like.

As the basis for obtaining water-soluble film is used, for example, cellulose polymers such as hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers, such as diethylaminoacetate polyvinylacetal, copolymer E aminoalkylsilane [Eudragit E, trademark, Roehm Pharma], polyvinylpyrrolidone and the like; polysaccharides, such as pullulan and the like; and the like.

As the basis for intersolubility film, using, for example, cellulose polymers, such as phthalate of hydroxypropylmethylcellulose, acetosella hydroxypropylmethylcellulose, karboksimetiltselljuloza, acatitla cellulose and the like; polymers of acrylic acid such as a copolymer L, methacrylic acid [Eudragit L, trademark, Roehm Pharma], the copolymer LD, methacrylic acid [Eudragit L-30D55, trademark, Roehm Pharma], the copolymer's meta is iloveu acid [Eudragit S, trademark, Roehm Pharma] and the like; natural products such as shellac and the like; and the like.

As the basis for applying the coating to obtain a film for a long release, using, for example, cellulose polymers such as ethylcellulose and the like; polymers of acrylic acid such as a copolymer RS aminoalkylsilane [Eudragit RS, trademark, Roehm Pharma], the suspension of a copolymer of acrylate and methacrylate [Eudragit NE, trademark, Roehm Pharma] and the like.

During the application can be mixed two or more kinds of the above bases for coating in a suitable ratio. In addition, during the coating can be used light shielding substance such as titanium oxide, iron oxide(3) and the like.

Injectable dosage form obtained by dissolution, suspendirovanie or emulsifying the active ingredient in an aqueous solvent (e.g. distilled water, physiological saline, ringer's solution and the like) or an oil solvent (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil and the like, together with a dispersing agent (e.g., Polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol carboxymethylcellulose, the sodium alginate and the like), a preservative (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol and the like), a substance that provides isotonicity solution (for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like). At this stage, if necessary, may be used additives such as substances that promote dissolution (e.g., sodium salicylate, sodium acetate and the like), stabilizers (for example, human serum albumin and the like), a soothing agent (for example, benzyl alcohol and the like) and the like.

The compound of the present invention shows low toxicity (such as acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiovascular toxicity, Carcinogenicity), causes minor side effects and can be used as a tool for prevention, treatment or diagnosis of various diseases in mammals (e.g., human, cattle, horse, dog, cat, monkey, mouse, rat, especially people).

The compound of the present invention has a high inhibitory peptidase activity and can suppress caused by peptidase degradation of physiologically active substances, such as peptide the hormones, cytokines, neurotransmitters and the like.

Examples of peptide hormones include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GIP, hormone release growth hormone (GHRH) and the like.

Examples of cytokines include chemokine, such as RANTES, and the like.

Examples of neurotransmitters include neuropeptide Y, and the like.

Examples of peptidases include

EC 3.4.11.1 (lallapalooza),

EC 3.4.11.2 (membrane alanineaminotransferase),

EC 3.4.11.3 (continentalunited),

EC 3.4.11.4 (tripitena aminopeptidase),

EC 3.4.11.5 (polyaminoacids),

EC 3.4.11.6 (aminopeptidase B)

EC 3.4.11.7 (glutamyltranspeptidase),

EC 3.4.11.9 (Xaa-Pro aminopeptidase),

EC 3.4.11.10 (bacterial laelapidae),

EC 3.4.11.13 (clostridiumdifficile),

EC 3.4.11.14 (the cytosolic alanylaminopeptidase),

EC 3.4.11.15 (litholaminated),

EC 3.4.11.16 (Xaa-Trp aminopeptidase),

EC 3.4.11.17 (Tripropylamine),

EC 3.4.11.18 (methioninamide),

EC 3.4.11.19 (D-stereospecific aminopeptidase),

EC 3.4.11.20 (aminopeptidase Ey),

EC 3.4.11.21 (hasparticipated),

EC 3.4.11.22 (aminopeptidase I)

EC 3.4.13.3 (Xaa-His dipeptidase),

EC 3.4.13.4 (Xaa-Arg dipeptidase),

EC 3.4.13.5 (Xaa-methyl-His, dipeptidase),

EC 3.4.13.7 (Glu-Glu dipeptidase),

EC 3.4.13.9 (Xaa-Pro dipeptidase),

EC 3.4.13.12 (Met-Xaa dipeptidase),

EC 3.4.13.17 (n is the stereospecific dipeptidase),

EC 3.4.13.18 (cytosolic nonspecific dipeptidase),

EC 3.4.13.19 (membrane dipeptidase),

EC 3.4.13.20 (beta-Ala-His dipeptidase),

EC 3.4.14.1 (dipeptidyl peptidase I),

EC 3.4.14.2 (dipeptidyl peptidase II)

EC 3.4.14.4 (dipeptidyl peptidase III)

EC 3.4.14.5 (dipeptidyl peptidase IV)

EC 3.4.14.6 (dipeptidylpeptidase),

EC 3.4.14.9 (tripeptidylpeptidase I)

EC 3.4.14.10 (tripeptidylpeptidase II)

EC 3.4.14.11 (Xaa-Pro dipeptidylpeptidase) and the like in accordance with the classification of the International Union of biochemistry and molecular biology. As peptidases you can also specify FAPα, DPP8, DPP9 and the like.

From the above examples of peptidases are preferred EC 3.4.14.1, EC 3.4.14.2, EC 3.4.14.4, EC 3.4.14.5, EC 3.4.14.6, EC 3.4.14.9, EC 3.4.14.10 and EC 3.4.14.11. Especially preferred is the EC 3.4.14.5 (dipeptidyl peptidase IV).

The compound of the present invention may also in addition to the inhibitory effect on peptidase at the same time to have an antagonistic effect on glucagon and inhibitory effect on SER. When the compound of the present invention simultaneously has the appropriate actions, it is more effective as an agent for the prophylaxis or treatment of diabetes (such as diabetes type 1, diabetes type 2, diabetes pregnant etc) and hyperlipidemia (e.g., hypertriglyceridemia, hypercholesteremia, hipolite, hyperlipidemia pet is eating and so on).

The compound of the present invention is useful as a means for prevention or treatment of diabetes (such as diabetes type 1, diabetes type 2 diabetes gestational diabetes and the like); a means for the prevention or treatment of hyperlipidemia (e.g., hypertriglyceridemia, hypercholesteremia, hipolite, hyperlipidemia after a meal, and the like); a means for the prevention or treatment of arteriosclerosis; means for prevention or treatment of impaired glucose tolerance [IGT]; a means of enhancing insulin secretion, and means to prevent the development of impaired glucose tolerance into diabetes.

With regard to diagnostic indicators, in 1999, the Japanese diabetes society (Japan Diabetes Society) reported new diagnostic parameters.

According to the message that diabetes is a condition in which the glucose level in the blood (glucose concentration of intravenous plasma) on an empty stomach is not less than 126 mg/DL, when determining glucose tolerance after oral administration of 75 g glucose (75 g OGTT) level (glucose concentration of intravenous plasma) in 2 hours is not lower than 200 mg/DL and a glucose level in the blood (glucose concentration of intravenous plasma) of not fasting is not lower than 200 ml/DL. The state that do not fall under the above criteria of diabetes and the tives such off "state, when the level of glucose in the blood (glucose concentration of intravenous plasma) on an empty stomach is not lower than 110 mg/DL or when determining glucose tolerance after oral administration of 75 g glucose (75 g OGTT) level (glucose concentration of intravenous plasma) in 2 hours is not lower than 140 mg/DL" (normal type)is called a state of "edge type".

In addition, in 1997, reported new diagnostic indicators ADA (American diabetes Association), and in 1998 the world health organization (WHO).

According to the reports, the diabetes is a condition in which the glucose level in the blood (glucose concentration of intravenous plasma) on an empty stomach is not less than 126 mg/DL and the determination of glucose tolerance after oral administration of 75 g glucose level (glucose concentration of intravenous plasma) in 2 hours is not lower than 200 mg/DL.

According to the above messages impaired glucose tolerance is a condition in which the glucose level in the blood (glucose concentration of intravenous plasma) on an empty stomach is lower than 126 mg/DL and the determination of glucose tolerance after oral administration of 75 g glucose level (glucose concentration of intravenous plasma) in 2 hours is not lower than 140 mg/DL and less than 200 mg/DL. According to the ADA, a condition in which the level glitch the gases in the blood (glucose concentration of intravenous plasma) on an empty stomach is not lower than 110 mg/DL and lower than 120 mg/DL, is called IFG (impaired fasting glucose). According to who among States IFG (impaired fasting glucose) a condition in which when the determination of glucose tolerance after oral administration of 75 g glucose level (glucose concentration of intravenous plasma) after 2 hours is lower than 140 mg/DL is called IFG (impaired fasting glucose).

The compound of the present invention can also be used as a means for prevention or treatment of diabetes, state of borderline type, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glucose) when determining on the above-mentioned new diagnostic criteria. In addition, the compound of the present invention can prevent the development of borderline type, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG (impaired fasting glucose) diabetes.

The compound of the present invention can also be used as a means to prevent or treat, for example, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract, gastro-intestinal infection, the infection is agcih tissues of the skin, infection of the lower limb and the like), diabetic gangrene, xerostomia, hypacusia, cerebrovascular disorder, impaired peripheral circulation, and the like], obesity, osteoporosis, cachexia (e.g., tumor cachexia, tuberculous cachexia, diabetic cachexia, cachexia when blood disease cachexia in endocrine disease cachexia in infectious disease or cachexia due to acquired immunodeficiency syndrome), fatty infiltration of the liver, hypertension, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal failure and the fact similar), muscular dystrophy, myocardial infarction, angina, stroke (for example, cerebral infarction, cerebral apoplexy), Alzheimer's disease, Parkinson's disease, anxiety, dementia, insulin resistance syndrome, syndrome X, metabolic syndrome, hyperinsulinemia-induced hyperinsulinemia sensory disorder, tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer, and the like), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g. chronic rawmat idny arthritis, deforming spondylitis, osteoarthritis, lumbago, gout, postoperative or traumatic inflammation, tomance, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory disease of the colon), ulcerative colitis, damage of the gastric mucosa (including the mucosa of the stomach caused by aspirin), and the like), a small injury of the mucous membrane of the intestine, malabsorption, renal function testis syndrome obesity internal organs and the like.

The compound of the present invention can also be used to reduce the amount of internal fat, curbing the accumulation of visceral fat, improve glycometabolism, improve lipid metabolism, inhibition of production of oxidized LDL metabolism of lipoproteins, metabolism in coronary arteries, prevention and treatment of cardiovascular complications, prevention and treatment of complications of heart failure, reduce blood residue, prevention and treatment of anovulation, prophylaxis and treatment of hypertrichosis, prevention and treatment of hyperandrogenemia, improve the function of the pancreas (β-cells), regeneration of β-cells of the pancreas, with whom sobstveny regeneration of β-cells of pancreas gland, regulation of appetite and the like.

The compound of the present invention can also be used for secondary prevention of the development of the above various diseases (for example, in the case of cardiovascular diseases such as myocardial infarction and the like).

The compound of the present invention is glucosidation means of enhancing insulin secretion, which selectively promotes insulin secretion in patients suffering from hyperglycemia (e.g., patients with a level of blood glucose on an empty stomach no less than 126 mg/DL or when determining glucose tolerance after oral administration of 75 g glucose level after 2 h not less than 140 mg/DL, and the like). Thus, the connection of the present invention is useful as a safe means for the prevention or treatment of diabetes with a low risk caused by insulin vascular complications, induction of hypoglycemia and the like.

The compound of the present invention is also useful as a therapeutic agent against diabetes side failure response to sulfonylurea and has an excellent effect on the secretion of insulin and hypoglycemic effect on diabetic patients who have connections sulfonylureas and fast means of enhancing insulin secretion is dostatochno capable of providing the effect of insulin secretion and, therefore, unable to provide sufficient hypoglycemic effect.

As sulfonylureas in this case can be called a compound having a skeleton of a sulfonylurea, or its derivative, such as tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole and the like.

As a rapid means of enhancing insulin secretion can be called a connection, which promotiom insulin secretion from β-cells of the pancreas as well as sulfonylurea, although not having the structure of the sulfonylureas, such as glinide (for example, Repaglinide, sinapinic, Notepad, mitiglinide, hydrate their calcium salts, etc. and the like.

The dose of a compound of the present invention varies depending on subject of administration, route of administration, disease-target condition and the like, but the connection of the present invention as the active ingredient is administered in a single dose is usually about 0.01 to 100 mg/kg body weight, preferably 0.05 to 30 mg/kg body weight, more preferably 0.1 to 10 mg/kg of body weight in the case of, for example, oral administration to adult patients with diabetes. The specified dose is preferably administered 1-3 times per day.

The compound of the present invention can be used in combination with such drugs is advised funds as a therapeutic agent for diabetes, a therapeutic agent of diabetic complications, antihyperlipidemic agent, antihypertensive agent, anti-obesity, diuretic, a chemotherapeutic agent, immunotherapy agent, antithrombotic agent, a therapeutic agent of osteoporosis, a remedy for dementia, the means to improve erectile dysfunction, therapeutic tool for the treatment of incontinence or pollakiuria, therapeutic treatment for dysuria and the like (hereinafter, such a drug referred to as combined drug). In this case, the timing of the introduction of the compounds of the present invention and the combined drug is not limited. You can enter the subject of the introduction of simultaneously or alternately. In addition, the compound of the present invention and the combined drug can be entered as two types of drugs, each of which contains an active ingredient, or as a single preparation containing both the active component.

A suitable dose of combined drug can be determined based on the clinically used dose. A suitable ratio of the compounds of the present invention and the combined drug can be defined is Elena depending on subject of administration, route of administration, disease-target condition, combination and the like. When, for example, the subject of this introduction is man, combine the medicinal product is used in an amount of 0.01-100 parts by weight per 1 part by weight of compounds of the present invention.

As a therapeutic agent against diabetes, you can specify the insulin preparations (e.g., animal insulin preparations extracted from the pancreas of a cow or bull and pig; insulin human genetically synthesized usingEscherichia colior yeast; zinc insulin; Protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1 etc), oral insulin product, and the like), insulinsensitizing (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate), regexen (JTT-501), GI-262570, netoglitazone (MCC-555), YM-440, DRF-2593, BM-13.1258, KRP-297, R-119702, rivoglitazone (CS-011), FK-614, compounds described in WO99/58510 (e.g., (E)-4-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzylamino]-4-fenilalanina acid), compounds described in WO01/38325, tesaglitazar (AZ-242), ragaglitazar (NN-622), muraglitazar (BMS-298585), ONO-5816, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929, balaglitazone (NN-2344), T-131 or its salt, THR-0921 etc), a PPARγ agonist, a PPARγ antagonist, a dual agonist of PPARγ/α inhibitors of α-glucosidase for example, voglibose, acarbose, miglitol, emiglitate etc), biguanides (e.g., phenformin, Metformin, buformin or their salts (e.g. hydrochloride, fumarate, succinate, and so on), tools that enhance insulin secretion [sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc), Repaglinide, sinapinic, Notepad, mitiglinide or hydrate their calcium salt], a GPR40 agonist, the agonist receptor GLP-1 [e.g., GLP-1, GLP-1MR, NN-2211, AC-2993 (basis 4), BIM-51077, Aib(8,35)hGLP-1(7,37)NH2, CJC-1131], Amylin agonists (for example, pramlintide etc), inhibitors phosphoribosyltransferase (for example, sodium Vanadate, etc.)inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, PT-100, P32/98, LAF-237, P93/01, TS-021, MK-431, BMS-477118, etc.), β3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc), inhibitors of gluconeogenesis (e.g., glycogen phosphorylase inhibitor, an inhibitor of glucose-6-phosphatase, an antagonist of glucagon and so on), SGLT inhibitors (joint vector of sodium and glucose) (e.g., T-1095 etc), inhibitors of 11β-hydroxysteroid dehydrogenase (e.g., BVT-3498 etc), adiponectin or agonist, IKK inhibitors (e.g., AS-2868 etc), medicines that increase the resistance to leptin agonists somatostatinomas receptor (compounds described in WO01/25228, WO03/42204, WO98/44921, WO98/45285, WO99/22735 is so), the glucokinase activators (e.g., Ro-28-1675) and the like.

Examples of a therapeutic agent of diabetic complications include inhibitors alsoreported (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), CT-112 etc), neurotrophic factors and increasing their drugs (e.g., NGF, NT-3, BDNF, promoters production and secretion neurotrophin described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazol etc), and the like), stimulants nerve regeneration (e.g., Y-128, and so on), PKC inhibitors (e.g., mesilate ruboxistaurin; LY-333531 etc), AGE inhibitors (e.g., ALT946, pimagedine, piratensender, N-phenacylthiazolium (ALT766), ALT-711, EXO-226, pyridorin, pyridoxamine, and so on), the acceptors of reactive oxygen species (e.g., thioctic acid etc), cerebral vasodilators (e.g., tiaprid, mexiletin etc), agonists somatostatinomas receptor (BIM23190) and inhibitors of kinase-1, control signal apoptosis (ASK-1).

Examples antihyperlipidemia tools include statins, which are inhibitors of cholesterol synthesis (e.g., tseriwastatina, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin and their salts (e.g. sodium salt, potassium salt) and so on), ing bitory stvalentines (for example, compounds described in WO97/10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid, etc.), fibrates (e.g., bezafibrat, clofibrate, simfibrate, clinofibrate etc), ACAT inhibitors (e.g., avasimibe, eflucimibe etc), anion exchange resin (eg, cholestyramine, etc.), probucol, medicines on the basis of nicotinic acid (for example, nicomol, niceritrol and the like), emilyosment, plant sterols (e.g., sisterol, γ-oryzanol, etc. and the like.

Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (e.g. captopril, enalapril, delapril etc), antagonists of angiotensin II (e.g., candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2'-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipin, efonidipine, nicardipine etc), activators of potassium channels (for example, levcromakalim, L-27152, AL 0671, NIP-121, etc.), clonidine and the like.

Examples of anti-obesity include anti-obesity acting on the Central nervous system (for example, dexfenfluramin finfloor is in, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (e.g., SB-568849; SNAP-7941; compounds described in WO01/82925 and WO01/87834. etc); antagonists of neuropeptide Y (e.g., CP-422935 etc.); antagonists of cannabinoid receptor (e.g., SR-141716, SR-147778, etc.); Greenaway antagonist; inhibitors of 11β-hydroxysteroid of dehydrogenase (e.g., BVT-3498 etc), and the like), inhibitors of pancreatic lipase (e.g., orlistat, ATL-962 and so on), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc), peptide means of reducing appetite (e.g., leptin, CNTF (ciliary neurotropic factor), and so on), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc), the moderator of the ingestion of food (e.g., P-57, and so on), and the like.

Examples of the diuretic include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine etc), drugs thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydroxylamine, panflutes, polythiazide, methyclothiazide etc), drugs antialdosterone (e.g., spironolactone, triamterene etc), inhibitors carbonatehydroxide (e.g., acetazolamide and the like), drugs chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside, indapamide etc),azosemide, isosorbide, etakrinova acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating tools (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil or its derivative, and so on), antitumor antibiotics (e.g., mitomycin, adriamycin etc), antitumor agents of vegetable origin (e.g., vincristine, vindesine, Taxol etc), cisplatin, carboplatin, etoposide and the like. Of them, preferred are furtulon and neopentylene representing derivatives of 5-fluorouracil and the like.

Examples of immunotherapy include microorganism or bacterially components (e.g., derived muramyldipeptide, picibanil etc), polysaccharides having potentiate the immune system activity (e.g., lentinan, sizofiran, christenings etc), cytokines obtained by genetic engineering methods (e.g., interferon, interleukin (IL) etc), colony-stimulating factors (such as granulocyte colony-stimulating factor, erythropoietin etc) and the like, of which preferred are the interleukins, such as IL-1, IL-2, IL-12, and the like.

Examples of antithrombotic agents include heparin (e.g., heparin sodium, gaari is-calcium, dalteparin-sodium etc), warfarin (e.g., warfarin-potassium etc), antithrombine medicines (for example, argatroban etc), thrombolytic tools (e.g., urokinase, isocynate, alteplaza, nameplate, monteplase, pamiteplase etc), platelet aggregation inhibitors (e.g., hydrochloride, ticlopidine, Cilostazol, emilyosment, beraprost-sodium, hydrochloride of sarpogrelate etc) and the like.

Examples of therapeutic agents for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate-disodium, alendronate hydrate of sodium, encadrant-disodium and the like.

Examples of anti-dementia include taken, donepezil, rivastigmine, galantamine and the like.

Examples of tools to improve erectile dysfunction include apomorphine, sildenafilcitrate and the like.

Examples of therapeutic agent from incontinence or pollakiuria include hydrochloride flavoxate, hydrochloride of oxibutinina, hydrochloride of propiverine and the like.

Examples of therapeutic agent from dysuria include acetylcholinesterase inhibitors (for example, distigmine) and the like.

In addition, in combination with the compound of the present invention can be used established in animal models and clinically the conditions of the medicinal product, with improving the condition of cachexia action, such as cyclo-oxygenase inhibitors (e.g., indomethacin etc), derivatives of progesterone (for example, registeralarm), glucosteroid (e.g., dexamethasone etc), metoclopramide funds tetrahydrocannabinol means, means improving fat metabolism (e.g., eicosapentaenoic acid and so on), growth hormones, IGF-1, or antibodies to a cachexia-induced factor such as TNF-α, LIF, IL-6, oncostatin M and the like.

Preferably combine a drug is a drug is insulin, insulinsensitizing, an inhibitor of α-glucosidase, biguanid tool that enhance insulin secretion (preferably a sulfonylurea), and the like.

Can be used in combination in a suitable ratio of two or more of the above combine drugs. The preferred combinations in the case of two or more combined medicines are, for example, such as shown below:

1) a means of enhancing insulin secretion (preferably a sulfonylurea), and inhibitor of α-glucosidase;

2) a means of enhancing insulin secretion (preferably a sulfonylurea), and biguanide;

3) a means of enhancing insulin secretion (preferably, sulfonylmethane is a), biguanid and inhibitor of α-glucosidase;

4) insulinsensitizing and inhibitor of α-glucosidase;

5) insulinsensitizing and biguanide;

6) insulinsensitizing, biguanide and inhibitor of α-glucosidase.

When the compound of the present invention is used in combination with the combined drugs, their number can be reduced to safe limits with regard to counter these funds. In particular, the dose of insulinsensitizing, tools that enhance insulin secretion (preferably a sulfonylurea), and biguanide can be reduced compared with the normal dose. Thus, a side effect that may be caused by specified means, can be reduced to a safe level. In addition, you can reduce the dose of a therapeutic agent of diabetic complications, antihyperlipidemia tools and antihypertensive agents, making it possible to effectively prevent a side effect that may be caused by specified means.

Further explains the methods for obtaining compounds of the present invention.

The compound of the present invention can be obtained in a known per se method, such as method, described in detail below, or an equivalent method.

The compound (I-a), which is a compound of formula (I), where L PR is dstanley a La-CH 2- (where La is a bond or a divalent hydrocarbon group, X represents a Xa where Xa represents a hydrogen atom, a nitro-group, acyl group, substituted by a hydroxy-group, optionally substituted Tilney group, optionally substituted by an amino group or an optionally substituted cyclic group) and R4represents an amino group, can be obtained by the following method or an equivalent method.

As the "divalent hydrocarbon group" for La, you can specify a group similar to the "divalent hydrocarbon group"listed as examples for the above group L. Preferably La is a bond or C1-9alkylenes group.

In addition, as the "acyl group", "substituted hydroxy-group", "optionally substituted Tilney group", "optionally substituted amino" and "optionally substituted cyclic group" for each Ha, you can use the groups listed as examples for the above group X.

When Ha is ethoxycarbonyl group, Q preferably represents a divalent hydrocarbon group.

[Method]

where the symbols are as defined above.

In this way connected to the e is subjected to reduction reaction of obtaining the compound (I-a).

The reduction is carried out in the presence of a reducing agent in a solvent which has no adverse effect on the reaction, in accordance with the traditional method.

As reducing agent, you can specify, for example, metal hydrides such as bis(2-methoxyethoxy)aluminiumhydride sodium, diisobutylaluminium and the like; complexes with metal hydrides, such as borohydride sodium, cyanoborohydride sodium, sociallyengaged, natroalunite and the like; and the like.

The amount of reducing agent is generally 0.1 to 20 equivalents relative to the compound (II).

As a solvent which has no adverse influence on the reaction, it is possible to use, for example, alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, Isobutanol, tert-butanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like; esters such as methyl acetate, the ethyl acetate, n-butyl acetate, tert-butyl acetate and the like; amides, such as dimethylformamide, dimethylacetamide, N-organic and that of podobn the E. These solvents can be used in mixture of two or more kinds of them, mixed in a suitable ratio.

The reaction temperature is usually from -70°C to 150°C, preferably from -20°C. to 100°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 40 hours.

The reduction can also be carried out in the presence of a metal catalyst such as palladium on carbon, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney-Nickel, Raney cobalt and the like, and a hydrogen source in a solvent which has no adverse effect on the reaction.

The amount of metal catalyst is usually 0.001 to 1000 equivalents, preferably 0.01 to 100 equivalents relative to the compound (II).

As a hydrogen source, you can specify, for example, hydrogen gas, formic acid, amine salt of formic acid, salt of phosphinic acid, hydrazine and the like.

As a solvent which has no adverse influence on the reaction, you can specify the solvents used in the reaction described above recovery using a reducing agent.

The reaction temperature and reaction time are the same as described above for the reaction of recovery using the restore is I.

This reaction may optionally be carried out in the presence of ammonia (for example, aqueous ammonia, the mixture of ammonia-ethanol and the like). When carrying out the reaction in the presence of ammonia can be suppressed by reaction of the compound (I-a) can be obtained with high yield.

Obtained in the manner described compound (I-a) can be isolated and purified by the known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (II)used as starting compound in the above-described method And can be obtained by a method known per se.

For example, the compound (II-a), which is compound (II), where Q and La are the connection and XA represents an acyl group, can be obtained in the following way Century.

[Method]

where the symbols are as defined above.

The compound (II-a) can be obtained by a method known per se, for example by the implementation of interaction (III) and an oxidizing agent, such as dilute nitric acid, demolitionist and the like, in a solvent which has no adverse effect on the reaction, such as 14-dioxane, the acetone and the like.

The compound (III) may be obtained in known per se manner, for example, from compound (IV) and compound (VII) in accordance with the method of synthesis of pyridine on Hantzch, as described in “Shin Jikken Depending Kouza (The Chemical Society of Japan ed.), Vol. 14, Synthesis and Reaction of Organic Compound IV, Maruzen (1978), page 2057, or an equivalent method.

The compound (IV) can be obtained in known per se manner, for example by the interaction of the compounds (VI) and compound (V) by a known method of Knoevenagel (Knoevenagel).

The compound (VII) can be obtained in known per se manner, for example, from compound (VIII) by the method described in Synthesis (1999), vol. 11, pages 1951-1960; Journal of Chemical Society Perkin Transactions 1, (2002), pages 1663-1671, and the like, or an equivalent method.

The above compound (V), the compound (VI) and compound (VIII) can be obtained in a known per se method.

The compound (I-b), which is a compound of formula (I), where R4represents an amino group, mono - or disubstituted With1-10alkyl group, can be obtained by an alkylation reaction of compound (I-C), which is a compound of formula (I), where R4represents an amino group.

The above reaction is carried out (1) in the presence of a base, when necessary, using an alkylating agent in a solvent which does not give a time is its influence on the reaction, or (2) in the presence of a reducing agent, when necessary, with the use of carbonyl compounds in the solvent which has no adverse effect on the reaction, in accordance with the known method.

As the alkylating agent in this case can be called, for example, With1-10alkylhalogenide,1-10alkylsulfonate and the like.

As carbonyl compounds include, for example, aldehydes, ketones and the like.

The amount of alkylating agent and carbonyl compounds is preferably from about 1 to about 5 equivalents relative to the compound (I-C).

As grounds include, for example, alkali metal salts, such as sodium hydroxide, potassium carbonate and the like; amines such as pyridine, triethylamine and the like; metal hydrides such as sodium hydride and the like; alkoxides of alkali metals such as sodium methoxide, tert-piperonyl potassium and the like, and the like.

The amount of base is preferably from about 1 to about 5 equivalents relative to the compound (I-C).

As the reducing agent include, for example, metal hydrides such as hydride diisobutylaluminum and the like; complexes with metal hydrides, such is how cyanoborohydride sodium and the like, and the like.

The amount of the reducing agent is generally 0.1 to 20 equivalents relative to the compound (I-C).

The reaction using the specified carbonyl compounds can also be carried out in the presence of a metal catalyst such as palladium on carbon and the like, and a hydrogen source, without a reducing agent, in a solvent which has no adverse effect on the reaction.

The amount of metal catalyst is preferably 0.01 to 100 equivalents relative to the compound (I-C).

As a hydrogen source, you can specify, for example, hydrogen gas, formic acid, amine salt of formic acid, and the like.

As a solvent which has no adverse effect on the reaction used for the alkylation reaction, it is possible to specify, for example, aromatic hydrocarbons such as toluene and the like; ethers such as tetrahydrofuran and the like; halogenated hydrocarbons such as chloroform and the like; amides such as N,N-dimethylformamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like, and the like. These solvents can be used in the form of a mixture of solvents, mixed in a suitable ratio.

The temperature of the alkylation reaction is preferably from about -10°to about 100°C.

Time alkylation reaction is usually from about 0.5 hour to about 20 hours.

Obtained in the manner described compound (I-b) can be isolated and purified by the known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, phase transfer, chromatography and the like.

When the connection of the present invention, when the original connection may contain as a substituent an amino group, a carboxyl group, a hydroxy-group or carbonyl group, these groups may be introduced protective group commonly used in the chemistry of peptides, and the like. Remove, when necessary, the protective group after the reaction can be obtained from the target connection.

Aminosidine group includes, for example, formyl group1-6alkylcarboxylic group (for example, acetyl, propionyl and the like), With1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), benzoyloxy group7-13aracelikarsaalyna group (for example, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and that of podobn the e), trityloxy group, palolo group, N,N-dimethylaminomethylene group, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), With2-6alkenylphenol group (e.g., 1-allyl and the like) and the like. These groups are optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), With1-6alkoxygroup (for example, methoxy, ethoxy, propoxy and the like), a nitro-group, and the like.

Carboxyamide group represents, for example, With1-alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), With7-13aracelio group (for example, benzyl and the like), phenyl group, trityloxy group, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), With2-6alkenylphenol group (e.g., 1-allyl and the like) and the like. These groups optionally substituted by 1-3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), With1-6alkoxygroup (for example, methoxy, ethoxy, propoxy and the like), or a nitro-group, and the like.

Hidroxizina group represents, for example, With1-alkyl is the Rupp (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl group, trityloxy group7-13aracelio group (for example, benzyl and the like), formyl group1-6alkylcarboxylic group (for example, acetyl, propionyl and the like), benzoyloxy group7-13aralkylamines group (for example, benzylcarbamoyl and the like), 2-tetrahydropyranyloxy group, 2-tetrahydrofuranyl group, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl and the like), With2-6alkenylphenol group (e.g., 1-allyl and the like) and the like. These groups are optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine and the like), With1-6alkyl group (e.g. methyl, ethyl, propyl and the like), With1-6alkoxygroup (for example, methoxy, ethoxy, propoxy and the like), or a nitro-group, and the like.

Carbonintensity group represents, for example, cyclic acetal (e.g., 1,3-dioxane, and the like), non-cyclic acetal (e.g., dis1-6alkylaryl and the like) and the like.

The introduction and removal of these protective groups can be carried out in known per se manner, for example as described in Protective Grops in Organic Synthesis, John Wiley and Sons (1980), and the like. For example, apply the method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium, palladium acetate, trialkylsilyl (for example, trimethylsilyloxy, trimethylsilylpropyne and the like) and the like, recovery and the like.

When the original compound can form a salt when the connection of the present invention may be used in connection in the form of a salt. As such salts can be used above as examples of salts of compound (I).

When the compound (I) contains an optical isomer, stereoisomer, isomer position or rotary isomer, they are also covered by compound (I) can be obtained as a separate product known methods of synthesis and separation. For example, when compound (I) contains an optical isomer, compound (I) also covers and separated from it by the optical isomer.

The optical isomer can be obtained in known per se manner. In particular, the use of optically active synthetic intermediate connection or end racemic product is subjected to conventional methods of optical separation of obtaining optical isomer.

A method of optical separation can be what is known in itself, this method as fractional recrystallization, chiral method column, diastereomer method and the like.

1) a Method fractional recrystallization

Form a salt of the racemate with an optically active compound (for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, and the like), which is shared by the method of fractional recrystallization, and, if necessary, receive a free optical isomer stage neutralization.

2) Method of chiral columns

The racemate or its salt is applied to the column for separation of optical isomer (chiral column)to allow division. In the case of liquid chromatography, for example, a mixture of optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or a series of CHIRAL (manufactured by Daicel Chemical Industries, Ltd.) and the like, and elute with water, various buffers (e.g. phosphate buffer solution) and organic solvents (e.g. ethanol, methanol, isopropanol, acetonitrile, triperoxonane acid, diethylamine and the like) separately or in a mixture for separating optical isomers. In the case of gas chromatography, for example, is used to separate chiral column, such caxr-Chirasil-DeX CB (manufactured by GL Sciences Inc.) and the like.

3) Diastereomeric method

Racemic mixture transform chemical interaction with the optically active reagent in diastereomer mixture which is converted into single substance by a typical separation method (e.g., fractional recrystallization, chromatography method and the like) and subjected to chemical treatment such as hydrolysis and the like to separate an optically active reagent, resulting in the optical isomer. For example, when compound (I) contains in the molecule of the hydroxy-group or primary or secondary amino group, the compound and an optically active organic acid (e.g., MTR [α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-metacercaria acid and the like) and the like are subjected to condensation reaction with getting diastereoisomer ester form or diastereoisomer amide form, respectively. When the compound (I) contains a carboxyl group, this compound and the reagent in the form of optically active amine or an optically active alcohol is subjected to the condensation reaction with getting diastereoisomer amide form or ester diastereoisomer forms, respectively. The separated diastereoisomer turn into an optical isomer of the original compound acidic or basic hydrolysis.

The compound (I) may be in the form of a crystal is A.

The crystal of compound (I) (hereinafter sometimes referred to as the crystal of the present invention) can be obtained by crystallization of compound (I) is known in itself by the method of crystallization.

Examples of the crystallization method include crystallization from solution, crystallization from the vapor crystallization from the melt, and the like.

Crystallization from solution" is a typical method comprising offset unsaturated state in the saturated state change factors characterizing the solubility of compounds (solvent composition, pH, temperature, ionic strength, the state of oxidation-reduction, and so on), or the amount of the solvent. In particular, we can mention, for example, a method of concentration, annealing method, the reaction method (diffusion method, electrolysis method), a hydrothermal method of cultivation, the method using a flux, and the like. Examples of the solvent include aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g. hexane, heptane, cyclohexane, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), NITRILES (e.g. acetonitrile etc), ketones (e.g. acetone, etc.), sulfoxidov (for example, dimethyls lipoxin etc), amides of acids (for example, N,N-dimethylformamide and the like), esters (e.g. ethyl acetate, etc), alcohols (e.g. methanol, ethanol, isopropyl alcohol etc), water and the like. These solvents are used individually or in combination of two or more solvents in an appropriate ratio (e.g. 1:1-1:100 (volume ratio)).

Crystallization of the pair represents, for example, evaporation method (method a sealed tube, a method of gas flow), gas-phase reaction method, the method of chemical transport, and the like.

Crystallization from the melt" represents, for example, the method of normal curing (Czochralski method (Czockralski), the method of temperature gradient, the method Bridgman (Bridgman)), zone melting method (method of leveling zones, method, floating zone), a special method of cultivation (VLS method (P-W-T), liquid-phase epitaxy method) and the like.

Preferable examples of the crystallization method include a method that contains dissolving compound (I) in a suitable solvent (e.g. alcohols such as methanol, ethanol, etc. and the like) at a temperature of 20-120°C. and cooling the resulting solution to a temperature not higher than the temperature of dissolution (e.g., 0-50°C, preferably 0-20°C), and the like.

Obtained in this way the crystals of the present invention MoE the ut to be allocated, for example, by filtration, and the like.

In this specification, the melting point is the melting temperature measured using, for example, apparatus for measuring the temperature of microplate (Yanako MP-500D or Buchi, B-545) or instrument DSC (differential scanning calorimeter) (SEIKO, EXSTAR6000) and the like.

Typically, the melting temperature varies depending on the measuring instruments, the measurement conditions and the like. The crystal in this description may show different melting points given in this description, only that it was in the General range of error.

The crystal of the present invention is excellent in physical and chemical properties (such as melting point, solubility, stability, etc) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), the expression efficiency etc) and is very useful as pharmaceuticals.

Examples

The present invention is described in more detail in the following examples, experimental examples and examples of the compositions. These examples do not limit the present invention can be modified within the scope of the invention.

Abbreviations in the examples have the following meanings:

(c): singlet, d: doublet, t: triplet, q: Quartet, m: a mule is tiplet, (OSS): broad singlet, J: the interaction constant, 4-Me-phenyl: 4-were, 4-F-phenyl: 4-forfinal, 2,6-di-F-phenyl: 2,6-differenl.

In the examples, room temperature means a temperature of 1-30°C and % means% by weight unless otherwise indicated.

Example 1

Methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) Suspension of sodium hydride (60% in oil, 8.0 g, 0.2 mol) in tetrahydrofuran (80 ml) was heated at boiling under reflux with vigorous stirring. A mixture of methylisocyanate (11.6 g, 0.1 mol), acetonitrile (10.5 ml, 0.2 mol) and tetrahydrofuran (25 ml) was added dropwise to the resulting suspension for 30 min and the mixture was heated at the boil under reflux for 5 hours the Reaction mixture was allowed to cool to room temperature and added to it 2-propanol (5 ml). The mixture was stirred at room temperature for 30 minutes the Reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (100 ml) and washed successively with hexane and mixed with a solution of hexane-diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 5-methyl-3-oxopentanenitrile (12,6 g, output is 100%) as a yellow oil. The obtained yellow oil was used in the next stage without additional purification.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), 2.05 is-is 2.30 (1H, m), 2,50 (2H, d, J=7,0 Hz), of 3.43 (2H, s).

2) a Mixture of 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol), piperidine (0.34 g, 4.0 mmol), acetic acid (0,48 g, 8.0 mmol) and toluene (200 ml) was heated at the boil under reflux for 12 h using a trap Dean-stark. The reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in methanol (50 ml). To the solution was added methyl-3-aminocrotonate (4.6 g, 40 mmol) and the mixture was heated at the boil under reflux for 6 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (7,45 g, yield 57%) as colorless crystals.

1H-NMR (CDCl3) δ: of 0.93 (3H, d, J=6.6 Hz), and 0.98 (3H, d, J=6.6 Hz), 1,80-2,00 (1H, m), of 2.10 to 2.35 (2H, m), is 2.30 (3H, s), a 2.36 (3H, s)to 3.58 (3H, s), of 4.57 (1H, s), of 5.68 (1H, USS), 7,00-7,20 (4H, m).

3) Methyl-5-cyano-6-isobutyl-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (7,3 g of 22.5 mmol) was dissolved in 1,4-dioxane (20 ml), the solution is added 2n. nitric acid (100 ml) and the mixture was stirred at 70°C for 1 h while stirring in a bath with ice to the mixture was added ethyl acetate (100 ml) and 2n. an aqueous solution of sodium hydroxide (100 ml). The aqueous layer was separated and was extracted with ethyl acetate. The organic layer and the extract were combined, and the mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinate (5,94 g, yield 82%) as a white powder.

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), of 2.20 to 2.35 (1H, m), is 2.41 (3H, s), 2.63 in (3H, s), 2,95 (2H, d, J=7,4 Hz), of 3.60 (3H, s), 7,20-7,30 (4H, m).

4) a Mixture of methyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,00 g, 3.10 mmol), Raney Nickel (4 ml), 25% aqueous ammonia (6 ml), tetrahydrofuran (15 ml), methanol (45 ml) was stirred in a hermetically sealed tube in an atmosphere of hydrogen at 0.5 MPa at room temperature for 6 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was distributed between ethyl acetate and 10% aqueous potassium carbonate solution. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column is cromatografia on silica gel with obtaining methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.97 g, yield 95%) as yellow crystals.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (2H, USS), 2,15-of 2.30 (1H, m), 2,39 (3H, s), of 2.53 (3H, s), 2,80 (2H, d, J=7,2 Hz), 3,50 (3H, s), 3,66 (2H, s), 7,11 (2H, d, J=8.0 Hz), 7,21 (2H, d, J=8.0 Hz).

TPL: 56-57°C

Example2

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid

1) To a solution of methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,90 g, was 2.76 mmol) in tetrahydrofuran (25 ml) was added di-tert-BUTYLCARBAMATE (0,76 ml of 3.31 mmol) and the mixture was stirred at room temperature for 12 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel with obtaining methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,16 g, yield 98%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,10-of 2.30 (1H, m), 2,39 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,2 Hz), 3,50 (3H, s)to 4.15 (2H, d, J=4.9 Hz), 4,24 (1H, t, J=4.9 Hz), 7,06 (2H, d, J=7.9 Hz), then 7.20 (2H, d, J=7.9 Hz).

2) To a solution of methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.0 g, 2.34 mmol) in methanol (30 ml) was added 1N. an aqueous solution of sodium hydroxide (10 ml) and the mixture was heated at the boil under reflux for 3 days. The reaction mixture was allowed to cool to room temperature, acidified 0,5h. hydrochloric acid is th and were extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was led from a mixture of water-methanol to obtain 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0,58 g, yield 60%) as a white powder.

1H-NMR (CDCl3) δ: of 0.87 (6H, d, J=6,4 Hz)of 1.39 (9H, s), 1,95-2,10 (1H, m), of 2.38 (3H, s)to 2.67 (3H, s)of 2.75 (2H, d, J=7,2 Hz), 4,13 (2H, d, J=4,7 Hz), 4,30 (1H, t, J=4,7 Hz), to 7.15 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz).

3) To a solution of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.20 g, 0.48 mmol) in 1,4-dioxane (4 ml) was added 4n. 1,4-dioxane solution of hydrogen chloride (4 ml, 16 mmol) and the mixture was stirred at room temperature for 2 hours the Reaction mixture was concentrated under reduced pressure and the resulting white solid washed with diisopropyl ether to obtain the hydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.18 g, yield 95%) as a white powder.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2.05 is-is 2.30 (1H, m), of 2.38 (3H, s)to 2.65 (3H, s), to 3.02 (2H, s), 3,83 (2H, d, J=5.5 Hz), 7,26 (2H, d, J=8,2 Hz), 7,32 (2H, d, J=8,2 Hz), 8,45 (3H, USS).

Example3

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinamide

1) a Mixture of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-m is Tyl-4-(4-were)nicotinic acid (0.11 g, 0.27 mmol), ammonium salt 1-hydroxy-1H-benzotriazole (0.10 g, of 0.65 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0,13 g of 0.65 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was distributed between ethyl acetate (100 ml) and 0.1 m aqueous solution of citric acid (50 ml). The organic layer and the extract obtained by extraction of the aqueous layer with ethyl acetate were combined and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl{[5-(aminocarbonyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,090 g, yield 82%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,10-of 2.30 (1H, m), 2,39 (3H, s), 2,61 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,14 (2H, d, J=4,7 Hz), 4,15-4,30 (1H, m), with 5.22 (1H, USS), 5,41 (1H, USS), 7,11 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7.9 Hz).

2) Dihydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinamide (0,050 g, yield 82%) was obtained as a white powder from tert-butyl{[5-(aminocarbonyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,065 g, 0.16 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (H, d, J=6.6 Hz), 2.05 is-is 2.30 (1H, m), is 2.37 (3H, s)to 2.66 (3H, s), to 3.02 (2H, s), 3,82 (2H, d, J=4.9 Hz), 7,20-to 7.35 (4H, m), 7,54 (1H, OSS), to 7.84 (1H, USS), 8,32 (3H, USS).

Example4

The dihydrochloride of 5-(aminomethyl)-N-(3-amino-3-oxopropyl)-6-isobutyl-2-methyl-4-(4-were)nicotinamide

1) a Mixture of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.12 g, 0.29 mmol), hydrochloride of β-alaninemia (by 0.055 g, 0.44 mmol), 1-hydroxy-1H-benzotriazole (0,059 g, 0.44 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0,084 g, 0.44 mmol), triethylamine (0,061 ml, 0.44 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 14 hours, the Reaction mixture was distributed between a mixture of ethyl acetate-tetrahydrofuran (1:1, 100 ml) and 0.1 m aqueous solution of citric acid (100 ml). The organic layer and the extract obtained by extraction of the aqueous layer with ethyl acetate were combined and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[(3-amino-3-oxopropyl)amino]carbonyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.075 g, yield 54%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s) to 1.98 (2H, t, J=6.0 Hz), 2,10-of 2.25 (1H, m), of 2.38 (3H, s)to 2.55 (3H, s), was 2.76 (2H, d, J=7,2 Hz), to 3.36 (2H, q, J=6.0 Hz), 4,11 (2H, d, J=5.5 Hz), 4,23 (1H, USS), 5,23 (1H, USS), 5,38 (1H, OSS), to 6.22 (1H, t, J=5.5 Hz), to 7.09 (2H, d, J=8.1 Hz), 7,19 (2H, d, J=8,1 Hz).

2) Dihydrochloride 5-(aminomethyl)-N-(3-amino-3-oxopropyl)-6-isobutyl-2-methyl-4-(4-were)nicotinamide (0,048 g, 99%) was obtained as a white powder from tert-butyl{[5-[(3-amino-3-oxopropyl)amino]carbonyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,050 g, 0,10 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), to 1.98 (2H, t, J=6,7 Hz), 2,10-of 2.25 (1H, m), is 2.37 (3H, s), to 2.57 (3H, s), 2,96 (2H, OSS), to 3.09 (2H, q, J=6,7 Hz), 3,82 (2H, d, J=5.3 Hz), PC 6.82 (1H, USS), 7,21 (2H, d, J=8.0 Hz), 7,27 (2H, d, J=8.0 Hz), 7,28 (1H, USS), 8,24 (3H, OSS), at 8.36 (1H, USS).

Example5

[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetonitrile

1) a Suspension of methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (3.4 g, 7.9 mmol) in toluene (80 ml) was cooled to -78°C and added to it dropwise 0,M toluene solution of the hydride of diisobutylamine (33 ml, 32 mmol) over 15 minutes After stirring at -78°C for 1.5 h the mixture was allowed to warm to 0°C and was further stirred for 30 minutes To the reaction mixture were added successively methanol (1 ml) and 10-hydrate of sodium sulfate (10.2 g, 32 mmol) and the mixture was stirred at room temperature for 1 h Insoluble the substance was filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.9 g, yield 60%) as oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,32 (9H, s), 2,13 was 2.25 (1H, m), 2,42 (3H, s), 2,68 (3H, s)of 2.75 (2H, d, J=7,4 Hz), of 4.05 (2H, d, J=4,7 Hz), 4,19 (1H, USS), 4,36 (2H, d, J=5.7 Hz), 7,05 (2H, d, J=7.9 Hz), 7,24-7,26 (2H, m).

2) a Mixture of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.50 g, 1.3 mmol), triethylamine (0.35 ml, 2.5 mmol) and tetrahydrofuran (10 ml) was cooled to 0°C and added to it dropwise methanesulfonanilide (0,22 g, 1.9 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 ml) and to the solution was added potassium cyanide (0,41 g, 6.3 mmol). The mixture was stirred at 60°C for 30 minutes To the reaction mixture was added ethyl acetate, and the mixture was washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl{[5-(cyanomethyl)-2-image is Teal-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.36 g, yield 72%) as oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,16 was 2.25 (1H, m), 2,43 (3H, s)to 2.66 (3H, s), 2,77 (2H, d, J=7,2 Hz), and 3.31 (2H, s)4,07 (2H, d, J=4,7 Hz),? 7.04 baby mortality (2H, d, J=8.0 Hz), 7,31 (2H, d, J=8.0 Hz).

3) Triperoxonane acid (5 ml) was added to tert-butyl{[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.11 g, 0.27 mmol) and the mixture was stirred at room temperature for 15 minutes the Reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetonitrile (0,084 g, yield 99%) as oil.

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-2,22 (1H, m), of 2.45 (3H, s)to 2.66 (3H, s), 2,80 (2H, d, J=7,2 Hz), 3,47 (2H, s), 3,74 (2H, USS), 7,17 (2H, d, J=7.8 Hz), 7,42 (2H, d, J=7,8 Hz).

Example6

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ndimethylacetamide

1) To a solution of tert-butyl{[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (from 0.90 g, 2.2 mmol) in ethanol (20 ml) was added 2n. an aqueous solution of sodium hydroxide (5.5 ml, 11 mmol) and the mixture was heated at the boil under reflux for 2 hours was Added 6N. chlorostoma orodno acid for acidification of the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain tert-butyl{[5-(2-amino-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.25 g, yield 27%) as a colourless solid.

2) Triperoxonane acid (5 ml) was added to tert-butyl{[5-(2-amino-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.25 g, 0.59 mmol) and the mixture was stirred at room temperature for 20 minutes, the Reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. To the residue was added 4n. 1,4-dioxane solution of hydrogen chloride (4 ml, 16 mmol) was added to the residue, and the solvent evaporated under reduced pressure. The residue is washed with diisopropyl ether to obtain the dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ndimethylacetamide (0,19 g, yield 81%) as a white powder.

1H-NMR (CD3OD) δ: 1,09-of 1.13 (6H, m), 2,09-2,22 (1H, m), the 2.46 (3H, s), 2.77-to 2,80 (3H, m), 3.00 and-to 3.09 (2H, m), 3,51-3,55 (2H, m), 4,08 (2H, USS), 7,15-7,22 (2H, m), 7,47 (2H, d, J=8,1 Hz).

Example7

The dihydrochloride methyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate

<> 1) To a solution of tert-butyl{[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (from 0.90 g, 2.2 mmol) in ethanol (20 ml) was added 2n. an aqueous solution of sodium hydroxide (5.5 ml, 11 mmol) and the mixture was heated at the boil under reflux for 1.5 hours. Added 6N. hydrochloric acid for acidification of the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was dissolved in N,N-dimethylformamide (5 ml). To the solution was added methyliodide (0.65 g, 4.4 mmol) and potassium carbonate (and 0.61 g, 4.4 mmol) and the mixture was stirred at room temperature for 1 h was Added to the reaction mixture ethyl acetate, and the mixture was washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate(0,097 g, yield 10%) as oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.28 (1H, m), is 2.40 (3H, s), 2.49 USD (3H, s)of 2.75 (2H, d, J=7,4 Hz)to 3.36 (2H, s), 3,61 (3H, s), 4.04 the-of 4.05 (2H, m), 4,27 (1H, USS), 6,98 (2H, d, J=7.8 Hz), 7.23 percent (2H, d, J=7,8 Hz).

2) Dihydrochloride methyl[5-(aminomethyl)-6-image is Teal-2-methyl-4-(4-were)pyridine-3-yl]acetate (0,069 g, yield 76%) was obtained as a white powder from methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (0,097 g, 0.22 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,09-of 1.13 (6H, m), 2,12-of 2.26 (1H, m), 2,47 (3H, s)2,84 (3H, s), of 3.12 (2H, d, J=7,4 Hz), 3,29-and 3.31 (2H, m), 3,63 (3H, s)4,08 (2H, s), 7,19 (2H, d, J=7,7 Hz), of 7.48 (2H, d, J=7,7 Hz).

Example8

Ethyl-(2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate

1) To a solution of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,95 g, 4.9 mmol) in tetrahydrofuran (50 ml) was added manganese dioxide (4.9 g, 56 mmol) and the mixture was stirred at room temperature for 19 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.25 g, yield 65%) as a yellow solid.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2.21 are to 2.35 (1H, m), 2,43 (3H, s), and 2.79 (3H, s), 2,82 (2H, d, J=7,2 Hz), 4,15 (2H, d, J=4.9 Hz), to 4.38 (1H, USS), 7,10 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=8.1 Hz), 9,71 (1H, s).

2) To a solution of triethylphosphate(0,033 g, 1.5 mmol) in tetrahydrofuran (10 ml) was added sodium hydride (60% in oil, to 0.060 g, 1.5 mmol) at 0°C and the mixture was stirred for 20 minutes To the reaction mixture on balali a solution of tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,38 g, 0.98 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred at room temperature for 45 minutes To the reaction mixture was added ethyl acetate, and the mixture was washed successively with a saturated solution of salt, saturated aqueous ammonium chloride and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain ethyl(2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate (0,44 g, yield 96%) as oil.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.23 (3H, t, J=7.2 Hz), of 1.39 (9H, s), 2,16-of 2.27 (1H, m), is 2.40 (3H, s)of 2.64 (3H, s), 2,77 (2H, d, J=7,4 Hz), 4,08-4,17 (4H, m), is 4.21 (1H, USS), USD 5.76 (1H, d, J=16.4 Hz), to 6.95 (2H,, d, J=8.1 Hz), 7.23 percent (2H, d, J=8.1 Hz), 7,37 (1H, d, J=16.4 Hz).

3) a Mixture of ethyl-(2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate (0.12 g, 0.25 mmol) and 4n. 1,4-dioxane solution of hydrogen chloride (5 ml, 20 mmol) was stirred at room temperature for 10 minutes the Solvent is evaporated under reduced pressure and the residue was distributed between a mixture of ethyl acetate-tetrahydrofuran and saturated aqueous sodium bicarbonate. The organic layer and the extract obtained by extraction of the aqueous layer with a mixture of ethyl acetate-tetrahydrofuran were combined and the mixture is dried over besttranslator magnesium. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain ethyl(2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate (0,059 g, yield 64%).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.23 (3H, t, J=7.2 Hz), of 1.30 (2H, USS), 2,18 is 2.33 (1H, m), is 2.40 (3H, s), 2.63 in (3H, s), and 2.79 (2H, d, J=7,1 Hz), of 3.60 (2H, s), of 4.13 (2H, q, J=7.2 Hz), USD 5.76 (1H, d, J=16.4 Hz), 7,01 (2H, d, J=8.0 Hz), 7,24 (2H, d, J=8.0 Hz), 7,39 (1H, d, J=16.4 Hz).

Example9

The dihydrochloride (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylic acid

1) To a solution of ethyl-(2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate (0.32 g, 0.69 mmol) in tetrahydrofuran (10 ml) was added 1N. an aqueous solution of sodium hydroxide (3.4 ml, 3.4 mmol) and the mixture was stirred at 60°C for 12 hours the Reaction mixture was acidified using 1N. hydrochloric acid and was extracted with ethyl acetate. The extracts were combined and the mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain (2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylic acid (0.28 g, yield 93%) as a white solid.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.4 Hz), 1.39 in (H, C), 2,10-of 2.20 (1H, m), 2,39 (3H, s)of 2.64 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 4,00-4,20 (2H, m), 4,34 (1H, USS), USD 5.76 (1H, d, J=16.4 Hz), 6,97 (2H, d, J=7.5 Hz), 7,22 (2H, d, J=7.5 Hz), 7,41 (1H, d, J=16.4 Hz).

2) Dihydrochloride (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylic acid (0,077 g, yield 90%) was obtained as a white powder from (2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylic acid (0,093 g, 0.21 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,10 (6H, d, J=6.6 Hz), 2,12-of 2.27 (1H, m), 2,46 (3H, USS), 2,84 (3H, s), 3,05 (2H, d, J=7.5 Hz), 4,13 (2H, s), 5,98 (1H, d, J=16,3 Hz), 7,20 (2H, d, J=8.0 Hz), 7,25 (1H, d, J=16,3 Hz), 7,46 (2H, d, J=8.0 Hz).

Example10

The dihydrochloride (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylamide

1) tert-Butyl{[5-[(1E)-3-amino-3-oxoprop-1-EN-1-yl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,19 g, yield 99%) was obtained from (2E)-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylic acid (0,19 g, 0.43 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CD3OD) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,09-of 2.20 (1H, m), is 2.37 (3H, s)at 2.59 (3H, s), is 2.74 (2H, d, J=7,2 Hz), 3,99 (2H, s), 4,34 (1H, USS), 6,00 (1H, d, J=16.2 Hz), 7,06 (2H, d, J=8.1 Hz), 7,22-7,28 (3H, m).

2) Dihydrochloride (2E)-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylamide (0,078 g, yield 99%) was obtained from tert-butyl{[5-[(1E)-3-amino-3-oxoprop-1-EN-1-yl]-2-from util-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.083 g, 0,19 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,11 (6H, d, J=6.6 Hz), 2,13-2,22 (1H, m), of 2.45 (3H, s), 2,87 (3H, s), 3,10 (2H, d, J=7.5 Hz), is 4.15 (2H, s), 6,12 (1H, d, J=16.2 Hz), 7,11 (1H, d, J=16.2 Hz), 7.23 percent (2H, d, J=7.9 Hz), was 7.45 (2H, d, J=7.9 Hz).

Example11

Methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-phenyldiamine

1) Methyl-5-cyano-6-isobutyl-2-methyl-4-phenyl-1,4-dihydropyridines-3-carboxylate (10.7 g, yield 86%) was obtained as a white powder from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), benzaldehyde (4,2 g, 40 mmol) and methyl-3-aminocrotonate (4.6 g, 40 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: of 0.93 (3H, d, J=6.6 Hz), 0,99 (3H, d, J=6.6 Hz), 1,82-of 1.97 (1H, m), 2,18-of 2.34 (2H, m), of 2.38 (3H, s), of 3.57 (3H, s), br4.61 (1H, s)5,69 (1H, USS), 7,18-to 7.32 (5H, m).

2) Methyl-5-cyano-6-isobutyl-2-methyl-4-phenyldiamine (8,4 g, yield 80%) was obtained as a white powder from methyl 5-cyano-6-isobutyl-2-methyl-4-phenyl-1,4-dihydropyridines-3-carboxylate (10.7 g, 34 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.8 Hz), 2.21 are to 2.35 (1H, m)of 2.64 (3H, s), 2,96 (2H, d, J=7,2 Hz), of 3.57 (3H, s), 7,33-7,39 (2H, m), 7,44 is 7.50 (3H, m).

3) Methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-phenyldiamine (0.21 g, yield of 2.5%) was obtained as a white powder from methyl 5-cyano-6-isobutyl-2-methyl-4-phenyldiamine (8,4 g, 27 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6.6 Hz), 2,17 is 2.33 (1H, m), of 2.54 (3H, s), of 2.81 (2H, d, J=7,4 Hz), of 3.46 (3H, s), the 3.65 (2H, s), 7,207,25 (2H, m), 7,38-7,46 (3H, m).

Example12

Methyl-5-(aminomethyl)-6-isobutyl-4-(4-were)-2-propylenimine

1) a Mixture of methyl-3-oxohexanoate (7.2 g, 50 mmol), ammonium acetate (19.3 g, 250 mmol), acetic acid (3.0 g, 50 mmol) and toluene (500 ml) was heated at boiling under reflux, using a trap Dean-stark for 11 hours, the Reaction mixture was concentrated under reduced pressure and the residue was distributed between ethyl acetate and a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain methyl 3-Aminorex-2-enoate in the form of a colorless oil.

Methyl-5-cyano-6-isobutyl-4-(4-were)-2-propyl-1,4-dihydropyridines-3-carboxylate (11.8 g, yield 84%) was obtained as an oil from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the above colorless oil methyl-3-Aminorex-2-enoate a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,93-of 1.05 (6H, m)of 1.26 (3H, q, J=7.2 Hz), 1,59 was 1.69 (2H, m), 1,83 is 1.96 (1H, m), 2.23 to-2,47 (2H, m), is 2.30 (3H, s), 2,69-to 2.74 (2H, m), of 3.57 (3H, s), 4,58 (1H, s), the 5.65 (1H, OSS), to 7.09 (2H, d, J=8.1 Hz), 7,13 (2H, d, J=8,1 Hz).

2) Methyl-5-cyano-6-isobutyl-4-(4-were)-2-propylenimine (9.4 g, yield 80%) was obtained as oil from methyl 5-cyano-6-isobutyl-4-(4-were)-2-propyl-1,4-dihydropyridines-3-carboxylate (11.8 g, 33 mmol) in a manner similar to the method of example -3).

1H-NMR (CDCl3) δ: 0,98 (3H, t, J=7.4 Hz), a 1.01 (6H, d, J=6.6 Hz), 1,73-of 1.85 (2H, m), 2,22 to 2.35 (1H, m), is 2.41 (3H, s), 2,78 (2H, m), 2,96 (2H, d, J=7,4 Hz)to 3.58 (3H, s), 7.23 percent-to 7.32 (4H, m).

3) Methyl-5-(aminomethyl)-6-isobutyl-4-(4-were)-2-propylenimine (0,78 g, yield 88%) was obtained as oil from methyl 5-cyano-6-isobutyl-4-(4-were)-2-propylenimine (0.88 g, 2.6 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,94 is 0.99 (9H, m), 1.70 to to 1.83 (2H, m), 2,18-2,31 (1H, m), 2,39 (3H, s), 2,69-to 2.74 (2H, m), of 2.81 (2H, d, J=7,2 Hz), 3,48 (3H, s), the 3.65 (2H, s), 7,12 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

Example13

The dihydrochloride [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid

1) To a solution of methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (0.25 g, 0,56 mmol) in tetrahydrofuran (15 ml) was added ethanol (10 ml) and 8h. an aqueous solution of sodium hydroxide (3.0 ml, 24 mmol) and the mixture was heated at the boil under reflux for 3 hours, the Reaction mixture was acidified using 6N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (0.16 g, you are the od 65%) as a white powder.

2) Dihydrochloride [5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (0.15 g, yield 99%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (0.16 g, 0.36 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,10 (6H, d, J=6.4 Hz), 2,09 was 2.25 (1H, m), 2,48 (3H, s)2,84 (3H, s), 3,10 (2H, d, J=7,4 Hz), of 3.60 (2H, s), 4.09 to (2H, s), 7,20 (2H, d, J=7.9 Hz), 7,49 (2H, d, J=7.9 Hz).

Example14

Methyl-5-(aminomethyl)-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)nicotinate

1) Dimethyl-3-aminophen-2-entiat was obtained from dimethyl-1,3-aceondeckmusic (7.0 g, 40 mmol) in a manner similar to the method of example 12-1).

Methyl-5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)-1,4-dihydropyridines-3-carboxylate (11.5 g, yield 75%) was obtained as a yellow oil from the obtained dimethyl-3-aminophen-2-indioate, 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol) and p-tolualdehyde (4.8 g, 40 mmol).

1H-NMR (CDCl3) δ: of 0.94 (3H, d, J=6.6 Hz), and 0.98 (3H, d, J=6.6 Hz), 1.85 to a 2.00 (1H, m), 2,20-2,40 (2H, m), 2,31 (3H, s)to 3.58 (3H, s), of 3.77 (3H, s), 3,85-4,10 (2H, m), 4,59 (1H, s), 7,01 (1H, USS), 7,10 (2H, d, J=8,1 Hz), 7,16 (2H, d, J=8,1 Hz).

2) Methyl-5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)nicotinate (3.2 g, yield 28%) was obtained as a yellow-orange oil from methyl 5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)-1,4-dihydropyridines-3-carboxylate (11.5 g, 3 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), of 2.20 to 2.35 (1H, m), is 2.41 (3H, s), 2,97 (2H, d, J=7,2 Hz), of 3.54 (3H, s), 3,71 (3H, s), Android 4.04 (2H, s), 7,20-7,30 (4H, m).

3) Methyl-5-(aminomethyl)-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)nicotinate (2.5 g, yield 77%) was obtained as a pale-yellow oil from methyl 5-cyano-6-isobutyl-2-(2-methoxy-2-oxoethyl)-4-(4-were)nicotinate (3.2 g, 8.4 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (2H, USS), of 2.15 to 2.35 (1H, m), 2,39 (3H, s), 2,82 (2H, d, J=7,4 Hz), of 3.45 (3H, s)to 3.67 (2H, s), 3,70 (3H, s), of 3.94 (2H, s), 7,05-of 7.25 (4H, m).

Example15

Methyl-5-(aminomethyl)-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate

1) Methyl-5-cyano-4-(2,6-differenl)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (14.8 g, yield 36%) was obtained as yellow crystals from 5-methyl-3-oxopentanenitrile (15.0 g, 120 mmol), 2,6-diferentialglea (17.0 g, 120 mmol) and methyl-3-aminocrotonate (13.8 g, 120 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,95-1,05 (6H, m), 1,80-2,05 (1H, m), 2,10-of 2.45 (2H, m), 2,31 (3H, s), of 3.56 (3H, s), a total of 5.21 (1H, s), by 5.87 (1H, USS), 6,75-of 6.90 (2H, m), 7,05-of 7.25 (1H, m).

2) Methyl-5-cyano-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (11.7 g, yield 80%) was obtained as yellow crystals from methyl 5-cyano-4-(2,6-differenl)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (14.8 g, 43 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: to 1.15 (6H, d, J=6.6 Hz), 2,15-to 2.40 (1H, m), of 2.72 (3H,s), of 2.97 (2H, d, J=7,0 Hz), the 3.65 (3H, s), 6,95-7,10 (2H, m), 7,35-of 7.55 (1H, m).

3) Methyl-5-(aminomethyl)-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (9.8 g, yield 83%) was obtained as a pale-yellow solid from methyl 5-cyano-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (11,7 g, 34 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz)and 1.51 (2H, USS), of 2.15 to 2.35 (1H, m)2,60 (3H, s), and 2.83 (2H, d, J=7.5 Hz), of 3.56 (3H, s), 3,62 (2H, s), 6,95-7,05 (2H, m), 7,35 is 7.50 (1H, m).

TPL: 48-49°C

Example16

Methyl-5-(aminomethyl)-4-(4-forfinal)-6-isobutyl-2-methylnicotinate

1) Methyl-5-cyano-4-(4-forfinal)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (27,4 g, yield 70%) was obtained as a yellow oil from 5-methyl-3-oxopentanenitrile (15.0 g, 120 mmol), 4-forventelige (14.9 g, 120 mmol) and methyl-3-aminocrotonate (13.8 g, 120 mmol) in a manner similar to the method of example 1-2).

2) Methyl-5-cyano-4-(4-forfinal)-6-isobutyl-2-methylnicotinate (24,0 g, yield 61%) was obtained as a yellow oil from methyl 5-cyano-4-(4-forfinal)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (27 g, 82 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 2,15-to 2.40 (1H, m)of 2.64 (3H, s), 2,96 (2H, d, J=7,2 Hz), 3,61 (3H, s), 7,10-7,40 (4H, m).

3) Methyl-5-(aminomethyl)-4-(4-forfinal)-6-isobutyl-2-methylnicotinate (11.2 g, yield 85%) was obtained as a pale-yellow solid from methyl 5-cyano-4-(4-forfinal)-6-isobutyl-2-Metallica is inata (13,0 g, 40 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 1.26 in (2H, USS), of 2.15 to 2.35 (1H, m), of 2.54 (3H, s), of 2.81 (2H, d, J=7,2 Hz), 3,51 (3H, s), the 3.65 (2H, s), 7,00-7,30 (4H, m).

TPL: 55-57°C

Example17

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-4-(4-were)-2-propylresorcinol acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-propylenimine (0.71 g, 71%yield) was obtained as a white solid from methyl-5-(aminomethyl)-6-isobutyl-4-(4-were)-2-propylenimine (0,78 g, 2.2 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,94 is 0.99 (9H, m)of 1.39 (9H, s), 1.70 to to 1.83 (2H, m), 2,16-of 2.27 (1H, m), of 2.38 (3H, s), 2.70 height is 2.75 (2H, m), and 2.79 (2H, d, J=7,2 Hz), 3,48 (3H, s), 4,14 (2H, d, J=4.9 Hz), 4,24 (1H, USS), 7,06 (2H, d, J=7,9 Hz), 7,20 (2H, d, J=7.9 Hz).2)

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-propylresorcinol acid (0,59 g, yield 86%) was obtained from methyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-propylenimine (0.71 g, 1.6 mmol) in a manner similar to the method of example 2-2).

1H-NMR (CDCl3) δ: 0,94-of 1.05 (9H, m)of 1.39 (9H, s), 1,72-of 1.84 (2H, m), 2,12-2,22 (1H, m), of 2.38 (3H, s), 2,81 of 2.92 (4H, m), 4,40-4.09 to (2H, m), 7,20 (2H, d, J=8,3 Hz), 7,26 (2H, d, J=8,3 Hz).

3) Dihydrochloride 5-(aminomethyl)-6-isobutyl-4-(4-were)-2-propylresorcinol acid (0.50 g, yield 90%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-p is opiniative acid (0,59 g, 1.3 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,04-of 1.13 (9H, m), 1,76 is 1.91 (2H, m), 2.13 and was 2.25 (1H, m), is 2.44 (3H, s), 3,01-3,18 (4H, m), 4,20 (2H, USS), 7,28 and 7.36 (2H, m), the 7.43 (2H, d, J=7.9 Hz).

Example18

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-methyl-4-phenyldiamine acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-phenyldiamine (9.4 g, yield 83%) was obtained as a white solid from methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-phenyldiamine (8.5 g, 27 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.20 (1H, m)to 2.55 (3H, s), and 2.79 (2H, d, J=7,2 Hz), of 3.46 (3H, s), 4,14 (2H, d, J=4.9 Hz), 4,24 (1H, USS), 7,14-7,21 (2H, m), 7,37-7,44 (3H, m).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-phenyldiamine acid (0.39 g, yield 40%) was obtained as a white solid from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-phenyldiamine (1.0 g, 2.4 mmol) in a manner similar to the method of example 2-2).

3) Dihydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-phenyldiamine acid (0.25 g, yield 86%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-phenyldiamine acid (0.39 g, 0.98 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,04-of 1.15 (6H, m), 2,12-of 2.28 (1H, m), 2,78-2,89 (3H, m), 3,01-3,14 (2H, m), 4,13-4,20 (2H, m), 7,38-7,47 (2H, m), 7,56-7,63 (3H, m).

Example9

Methyl-5-[(dimethylamino)methyl]-6-isobutyl-2-methyl-4-(4-were)nicotinate

A mixture of methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.50 g, 1.6 mmol), formic acid (5 ml) and formalin (5 ml) was stirred at 100°C for 12 h, the Reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining methyl-5-[(dimethylamino)methyl]-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.10 g, yield 19%).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.97 (6H, s), 2,14-of 2.28 (1H, m), 2,39 (3H, s), of 2.53 (3H, s), 2,89 (2H, d, J=7,4 Hz), 3,23 (2H, s), of 3.48 (3H, s),? 7.04 baby mortality (2H, d, J=8.0 Hz), 7,17 (2H, d, J=8.0 Hz).

Example20

Methyl-5-(aminomethyl)-2-methyl-6-isobutyl[4,4'-piperidin]-3-carboxylate

1) Methyl-5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4,4'-piperidin-3-carboxylate (26,4 g, 71%yield) was obtained as a yellow oil from 5-methyl-3-oxopentanenitrile (15.0 g, 120 mmol), isonicotinamide (12.8 g, 120 mmol) and methyl-3-aminocrotonate (13.8 g, 120 mmol) in a manner similar to the method of example 1-2).

2) To a solution of methyl 5-cyano-6-isobutyl-2-methyl-1,4-dihydro-4,4'-piperidin-3-carboxylate (20 g, 64 mmol) in acetone (150 ml) was added diaminetetraacetate (45 g, 82 mmol) and the mixture was stirred at room temperature for 1 h The reaction mixture was cooled to 0°C and distributed between ethyl acetate and 2n. the sodium hydroxide. The organic layer and the extract obtained by extraction of the aqueous layer with ethyl acetate were combined and the mixture was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 5-cyano-6-isobutyl-2-methyl-4,4'-piperidin-3-carboxylate (10.2 g, yield 51%) as a yellow oil.

3) Methyl-5-(aminomethyl)-2-methyl-6-isobutyl[4,4'-piperidin]-3-carboxylate (10,9 g, yield 72%) was obtained as a pale-yellow solid from methyl 5-cyano-6-isobutyl-2-methyl-4,4'-piperidin-3-carboxylate (15.0 g, 48 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), 1,33 (2H, USS), 2,15-to 2.40 (1H, m), to 2.57 (3H, s), 2,82 (2H, d, J=7,2 Hz), 3,49 (3H, s), 3,61 (2H, s), 7,15-of 7.25 (2H, m), 8,65-to 8.70 (2H, m).

TPL: 63-65°C

Example21

Methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene

1) 5,5-Dimethyl-3-oxopentanenitrile (92.0 g, yield 99%) was obtained as oil from methyl-3,3-dimethylbutanoate (86,0 g, 0.66 mol) in a manner similar to the method of example 1-1).

1H-NMR (CDCl3) δ: of 1.05 (9H, s), 2.49 USD (2H, s), of 3.43 (2H, s).

2) a Mixture of 5,5-dimethyl-3-oxopentanenitrile (22,0 g, 158 mmol), p-tolualdehyde (19 g, 158 mmol), piperidine (1.3 g, 15.8 mmol), acetic acid (1.9 grams, of 31.6 mmol) and toluene (300 ml) was heated Ave is boiled under reflux for 12 h, using the trap Dean-stark. Allow to cool to room temperature, the reaction mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in methanol (50 ml). To the solution was added methyl-3-aminocrotonate (18.2 g, 158 mmol) and the mixture was heated at the boil under reflux for 6 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 5-cyano-2-methyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (23 g, yield 43%) as oil.

1H-NMR (CDCl3) δ: 1,01 (9H, s), and 0.98 (3H, d, J=6.6 Hz), 1,80-2,00 (1H, m), 2,14-to 2.41 (2H, m), 2,31 (3H, s), is 2.37 (3H, s)to 3.58 (3H, s), of 4.57 (1H, s)to 5.56 (1H, USS), 7,06-7,16 (4H, m).

3) Methyl-5-cyano-2-methyl-4-(4-were)-6-neopentylene (12 g, yield 60%) was obtained as colorless crystals from methyl 5-cyano-2-methyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (20 g, to 59.4 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: of 1.06 (9H, s)to 2.41 (3H, s), 2.63 in (3H, s), 3,01 (2H, s), 3,61 (3H, s), 7,26 (4H, m).

TPL: 139-140°C

4) Methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene (2.3 g, yield 56%) was obtained as colorless crystals from methyl 5-cyano-2-methyl-4-(4-were)-6-neopentanoate (4 g, to 11.9 mmol) method under the GHP method of example 1-4).

1H-NMR (CDCl3) δ: 1,02 (9H, s)of 1.44 (2H, USS), 2,39 (3H, s), of 2.53 (3H, s), is 2.88 (2H, s), 3,50 (3H, s), and 3.72 (2H, s), 7,12 (2H, m), 7,21 (2H, m).

TPL: 119-120°C

Example22

The dihydrochloride of 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid

1) To a solution of methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate (1.0 g, 2.9 mmol) in tetrahydrofuran (25 ml) was added di-tert-BUTYLCARBAMATE (0.65 g, 3.0 mmol) and the mixture was stirred at room temperature for 1 h To the reaction mixture were added 8h. an aqueous solution of sodium hydroxide (2 ml) and methanol (10 ml) and the mixture was heated at the boil under reflux for 3 days. The reaction mixture was allowed to cool to room temperature, acidified 1H. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was led from diisopropyl ether to obtain 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylglycol acid (0.5 g, yield 42%) as crystals.

1H-NMR (CDCl3) δ: 0,88 (9H, s)of 1.36 (9H, s), of 2.38 (3H, s), of 2.72 (3H, s), is 2.88 (2H, s), is 4.21 (2H, USS), the 4.29 (1H, USS), 7,18 (2H, d, J=8,3 Hz), 7.23 percent (2H, d, J=8,3 Hz).

TPL: 216-217°C

2) 4h. 1,4-Dioxane solution of hydrogen chloride (5 ml) was added to 5-{[(tert-butoxycarbonyl is)amino]methyl}-2-methyl-4-(4-were)-6-neopentylglycol acid (0,30 g, 0.7 mmol) and the mixture was stirred at room temperature for 17 hours, the Reaction mixture was concentrated under reduced pressure and the resulting white solid was washed with diethyl ether to obtain the hydrochloride 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (0.2 g, 71%yield) as a white powder.

1H-NMR (DMSO-d6) δ: 1,02 (9H, s), is 2.37 (3H, s)at 2.59 (3H, s), 3.04 from (2H, s), 3,86 (2H, d, J=5.5 Hz), 7.23 percent (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 8,24 (3H, USS).

Example23

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate

1) a Mixture of tert-butylacetoacetate (580 ml, 3.5 mol), 25% aqueous ammonia (1200 ml) and methanol (1000 ml) was stirred at room temperature for 14 hours After concentration under reduced pressure the reaction mixture was distributed between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain tert-butyl-3-aminocrotonate (550 g, yield 99%) as a pale yellow powder.

1H-NMR (CDCl3) δ: of 1.47 (9H, s)to 1.87 (3H, s), 4,46 (1H, s).

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (7.6 g, yield 62%) was obtained as a white powder from 5-methyl-3-oxopentanenitrile (4.0 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol) and tert-butyl-3-aminocrotonate (5.0 g, 32 mmol) way to pogonopoma of example 1-2).

1H-NMR (CDCl3) δ: of 0.93 (3H, d, J=6.6 Hz), 0,99 (3H, d, J=6,6 Hz)of 1.29 (9H, s), 1,80-of 1.95 (1H, m), 2,10-of 2.30 (2H, m), of 2.34 (3H, s), of 4.54 (1H, s)to 5.56 (1H, USS), 7,10-7,20 (2H, m), 7,25-7,30 (2H, m).

TPL: 185-186°C

3) To a solution of tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (7.6 g, 20 mmol) in acetone (200 ml) was added an aqueous solution (40 ml) diaminetetraacetate (27 g, 49 mmol) at room temperature for 5 minutes the Reaction mixture was distributed between ethyl acetate and water. The organic layer and the extract obtained by extraction of the aqueous layer with ethyl acetate were combined and the mixture was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methylnicotinate (7.2 g, yield 95%) as a white powder.

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6,8 Hz)of 1.27 (9H, s), of 2.15 to 2.35 (1H, m), 2,65 (3H, s)to 2.94 (2H, d, J=7,2 Hz), 7,30-to 7.35 (2H, m), 7,40-to 7.50 (2H, m).

TPL: 70-72°C

4) a Mixture of tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-methylnicotinate (1.0 g, 2.6 mmol), Raney cobalt (4 ml), 25% aqueous ammonia (2 ml), tetrahydrofuran (20 ml) and methanol (40 ml) was stirred in a hermetically sealed tube in an atmosphere of hydrogen at 0.5 MPa at room temperature for 5 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure the AI. The residue was distributed between ethyl acetate and 10% aqueous potassium carbonate solution. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl-5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate (0,98 g, yield 97%) as a white powder.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.8 Hz), 1,22 (9H, s)of 1.42 (2H, USS), 2,15-of 2.30 (1H, m)to 2.55 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 3,61 (2H, s), 7,21 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8,3 Hz).

TPL: 81-83°C

Example24

Hydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate acid

1) a Mixture of tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate (of 0.60 g, 1.5 mmol) and triperoxonane acid (4 ml) was stirred at 50°C for 4 h the Reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1,4-dioxane (4 ml). 4h. 1,4-Dioxane solution of hydrogen chloride (4 ml, 16 mmol) was added to the obtained solution and the mixture was concentrated under reduced pressure. The residue is washed with diisopropyl ether to obtain the hydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinic acid (0,63 g, yield 99%) as a colourless oil.

2) Dihydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinate key is lots (0,63 g, 1.5 mmol) was dissolved in isopropanol (10 ml) and to the solution was added propylene oxide (0.27 g, 4.6 mmol). The mixture was stirred at room temperature for 3 hours the Reaction mixture was concentrated under reduced pressure and the resulting oil was led from a mixture of isopropanol-diisopropyl ether to obtain the hydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-methylnicotinic acid (0,43 g, 76%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m), 2.49 USD (3H, s), 2,78 (2H, d, J=7,2 Hz in), 3.75 (2H, s), 7,34 (2H, d, J=7.5 Hz), 7,54 (2H, d, J=7.5 Hz), 8,43 (1H, USS).

Example25

tert-Butyl-5-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-were)nicotinate

1) To a solution of acid Meldrum (14,41 g, 0.1 mol) and pyridine (16.2 ml, 0.2 mol) in dichloromethane (100 ml) was added dropwise isobutyramide (13.4 ml, 0.11 mol) at 0°C for 30 min and the mixture was stirred at 0°C for 2 h, the Reaction mixture was poured into 0,5h. hydrochloric acid and the mixture was extracted with dichloromethane. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. A mixture of the obtained residue, tert-butanol (11.2 g, 150 mmol) and toluene (100 ml) was heated at boiling under reflux for 6 hours Allowing to cool to room temperature, the reaction mixture was washed with a saturated solution with the Lee and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain tert-butyl-4-methyl-3-oxopentanoate in the form of the crude product (9,31 g). A mixture of the crude product (9,31 g), 25% aqueous ammonia (100 ml) and methanol (100 ml) was stirred at room temperature for 12 hours the Reaction mixture was concentrated under reduced pressure and was distributed between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain tert-butyl 3-amino-4-methylpent-2-enoate in the form of the crude product (9,26 g).

2) tert-Butyl-5-cyano-6-isobutyl-2-isopropyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (12,11 g, yield 76%) was obtained as colorless crystals from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9,26 g) tert-butyl 3-amino-4-methylpent-2-enoate obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-6-isobutyl-2-isopropyl-4-(4-were)nicotinate (2,88 g, yield 73%) was obtained as oil from tert-butyl 5-cyano-6-isobutyl-2-isopropyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (3.94 g, 10 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 1,25 (9H, s)of 1.32 (6H, d, J=6.6 Hz), 2.26 and to 2.35 (1H, m), is 2.40 (3H, s)to 2.94 (2H, d, J=7,2 Hz), 3,14 is 3.23 (1H, m), 7,26-to 7.35 (4H, m).

4) tert-B is Tyl-5-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-were)nicotinate (2.15 g, yield 77%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-2-isopropyl-4-(4-were)nicotinate (2,74 g, 7 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.18 (9H, s)of 1.30 (6H, d, J=6.6 Hz), of 1.39 (2H, USS), and 2.26 to 2.35 (1H, m), 2,39 (3H, s), 2,78 (2H, d, J=6.9 Hz), 3.04 from-3,14 (1H, m), of 3.60 (2H, s), 7,13 (2H, d, J=8,2 Hz), 7,20 (2H,, d, J=8,2 Hz).

Example26

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-were)nicotinic acid

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-were)nicotinic acid (0,37 g, yield 90%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-6-isobutyl-2-isopropyl-4-(4-were)nicotinate (0.40 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), of 1.03 (6H, d, J=6.6 Hz), 2,23-is 2.37 (4H, m), 2,85 (2H, d, J=6.9 Hz), 3.04 from-3,13 (1H, m), of 3.77 (2H, d, J=5.4 Hz), 7,22 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 8,21 (3H, USS).

Example27

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylene

1) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridines-3-carboxylate (2.5 g, yield 38%) was obtained as a white powder from 5,5-dimethyl-3-oxopentanenitrile (2.6 g, 18.0 mmol), 4-chlorobenzaldehyde (2.3 g, 16.0 mmol) and tert-butyl-3-aminocrotonate (2.5 g, 16.0 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 1,01 (9H, s)of 1.29 (9H, s), 2,17 (1H, d, J=a 13.9 Hz), was 2.34 (3H, s), 2,35 (1H, d, J=13,9 is C), 4,55 (1H, s), 5,46 (1H, USS), 7,10-to 7.35 (4H, m).

TPL: 208-210°C

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentylene (2.1 g, yield 90%) was obtained as pale yellow powder from tert-butyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentyl-1,4-dihydropyridines-3-carboxylate (2.4 g, 5.9 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 1.06 (9H, s)of 1.28 (9H, s)to 2.65 (3H, s)of 3.00 (2H, s), 7,30-to 7.35 (2H, m), 7,45 is 7.50 (2H, m).

TPL: 94-95°C

3) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylene (0,93 g, yield 92%) was obtained as a white powder from tert-butyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-neopentanoate (1.0 g, 2.5 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.22 (9H, s), 1,43(2H, OSS), to 2.55 (3H, s), of 2.86 (2H, s), 3,66 (2H, s), 7,15-of 7.25 (2H, m), 7,35-7,45 (2H, m).

TPL: 116-118°C

Example28

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentylglycol acid (1.0 g, yield 98%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-methyl-6-neopentanoate (0.95 g, 2.4 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s), of 2.56 (3H, s)to 2.94 (2H, s), a-3.84 (2H, d, J=5.5 Hz), 7,35-7,40 (2H, m), 7,55-of 7.60 (2H, m), to 8.20 (3H, USS).

TPL: 246-248°C

Example29

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentyl is tinat

1) To a solution (30 ml) piperidine (0,94 g, 11 mmol) and acetic acid (0.66 g, 11 mmol) in isopropanol was added dropwise a solution (300 ml) of 5,5-dimethyl-3-oxopentanenitrile (17.0 g, 110 mmol) and p-chlorobenzaldehyde (15.5 g, 110 mmol) in isopropanol at room temperature for 30 min and the mixture was stirred for 3 days. The solvent is evaporated under reduced pressure and the residue was distributed between ethyl acetate and a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain 3-(4-chlorophenyl)-2-(3,3-dimethylbutanol)Acrylonitrile, in the form of the crude product (35.2 g).

2) tert-Butyl 3-amino-5,5-dimethylhex-2-ENOAT received in the form of the crude product (13 g) of the acid Meldrum (8.65 g, 60 mmol) and tert-butylacetamide (of 9.2 ml, 66 mmol) in a manner similar to the method of example 25-1).

3) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl-1,4-dihydropyridines-3-carboxylate (2,03 g, yield 15%) was obtained as a yellow oil from the crude product (11.7 g)obtained in the above stage 1), and the crude product (13,0 g)obtained in the above stage 2), a method similar to the method of example 1-2). Namely, these two types of crude product was dissolved in methanol (40 ml) and the mixture was heated at the boil under reflux for 3.5 hours the Reaction to shift the ü concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl-1,4-dihydropyridines-3-carboxylate.

1H-NMR (CDCl3) δ: 1.00 and (9H, s)of 1.03 (9H, s)of 1.29 (9H, s), 2,24 (4H, s), 4,58 (1H, USS), lower than the 5.37 (1H, USS), 7,20-to 7.32 (4H, m).

4) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl (0.75 g, yield 38%) was obtained from tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl-1,4-dihydropyridines-3-carboxylate (2,03 g of 4.44 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,04 (9H, s)of 1.07 (9H, s)of 1.24 (9H, s)2,84 (2H, s)of 3.00 (2H, s), 7,31 (2H, d, J=8,67 Hz), was 7.45 (2H, d, J=8,67 Hz).

5) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentyl (0.35 g, yield 46%) was obtained as a pale-yellow solid from tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-dineopentyl (0.75 g, of 1.65 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: 1,02 (9H, s), was 1.04 (9H, s)of 1.18 (9H, s), is 2.74 (2H, s), of 2.86 (2H, s)to 3.64 (2H, s), 7,21 (2H, d, J=8,48 Hz), 7,40 (2H, d, J=8,48 Hz).

Example30

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentyl acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentyl acid (0.21 g, yield 69%) was obtained as a white solid from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-dineopentyl (0,30 g, 0,653 mmol) in a manner similar to the method of example 24-1).

1H-NMR (CDCl3) δ: 0,99 (9H, s)of 1.03 (9H, s), 2,77 (2H, s), 2.91 in (2H, s), 3,83 (2H, d, J=5,65 Hz), 7,35 (2H, d, J=8,48 Hz), 7,54 (2H, d, J=8,29 Hz)to 8.12 (2H, USS).

Example31

Hemifumarate 5-(aminomethyl)-2-methyl-4-(4-meth is fenil)-6-neopentylglycol acid (sometimes referred to in this description as fumarate, bis[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid])

1) To a mixture of the dihydrochloride of 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (of 5.99 g, 15.0 mmol), tetrahydrofuran (50 ml) and 1M aqueous sodium hydroxide solution (50 ml) was added dropwise benzylchloride (95%, 2,48 ml, 16.5 mmol) at room temperature. The resulting mixture was stirred for 2 h and was added 0,1M hydrochloric acid (100 ml). The mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran (1:1). The organic layer was washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran to obtain 5-({[(benzyloxy)carbonyl]amino}methyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (5,57 g, 81%) as colorless powdery crystals.

1H-NMR (DMSO-d6) δ: 0,98 (9H, s), of 2.33 (3H, s), is 2.44 (3H, s), 2,70 (2H, s), of 3.97 (2H, d, J=4,1 Hz), to 4.98 (2H, s), 7,15-7,20 (4H, m), 7,27-7,42 (6H, m), 12,96 (1H, USS).

2) a Mixture of 5-({[(benzyloxy)carbonyl]amino}methyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (5.5 g, 12 mmol), 5% palladium on carbon (11,0 g), tetrahydrofuran (100 ml) and ethanol (100 ml) was stirred overnight in a hydrogen atmosphere at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to obtain 5-(Amin is Teal)-2-methyl-4-(4-were)-6-neopentylglycol acid (2,46 g, 63%) as colorless powdery crystals.

1H-NMR (DMSO-d6) δ: of 0.96 (9H, s), of 2.33 (3H, s), a 2.36 (3H, s), was 2.76 (2H, s), of 3.56 (2H, s), 7,12-to 7.18 (4H, m).

3) 5-(Aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (1,14 g, 3.50 mmol) and fumaric acid (0,203 g of 1.75 mmol) was dissolved in water (150 ml) under heating. The resulting aqueous solution was concentrated under reduced pressure. The residue was washed with ethanol and recrystallized from water to obtain hemifumarate 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (0,902 g, 67%) as colorless powdery crystals.

1H-NMR (DMSO-d6) δ: 0,97 (9H, s), of 2.34 (3H, s), is 2.40 (3H, s), 2,77 (2H, s), the 3.65 (2H, s), of 6.45 (1H, s), 7,14-7,21 (4H, m).

Example32

tert-Butyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (159 g, yield 27%) was obtained as a white solid from tert-butyl 3-aminocrotonate (253 g, 1,60 mol) in a manner similar to the method of example 1-2). Then got tert-butyl-5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinate (40,8 g, yield 99%) as a yellow solid from tert-butyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (41,0 g, 112 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.9 Hz), 1.26 in (9H, s), 2,21 of-2.32 (1H, m), 2,1 (3H, C)of 2.64 (3H, s), with 2.93 (2H, d, J=7.5 Hz), 7.18 in-to 7.32 (4H, m).

2) tert-Butyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (502 g, yield 96%) was obtained as a white solid from tert-butyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinate (515 g of 1.42 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 1,19 (9H, s), 2,13-2,31 (1H, m), 2,39 (3H, s), of 2.56 (3H, s), and 2.79 (2H. d, J=7,4 Hz)to 3.64 (2H, USS), 7,13 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz).

Example33

The dihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)acetic acid

1) To a solution (10 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (510 mg, of 1.24 mmol) in N,N-dimethylformamide was added benzylbromide (568 mg, 2.48 mmol) and potassium carbonate (343 mg, 2.48 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 2-(benzyloxy)-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (690 mg, yield 99%) as oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14-of 2.26 (1H, m), 2,6 (3H, C)at 2.59 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,11-4,17 (2H, m), 4,22 (1H, USS), and 4.40 (2H, s), 5,16 (2H, s), 7,05 (2H, d, J=8.1 Hz), 7,17 (2H, d, J=7.9 Hz), 7,29-7,39 (5H, m).

2) a Mixture of 2-(benzyloxy)-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (690 mg, of 1.23 mmol), palladium on carbon (10%, dry) (132 mg, 0,124 mmol) and ethanol (10 ml) was stirred in hydrogen atmosphere at room temperature for 30 minutes After filtration the solvent is evaporated under reduced pressure to obtain ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)acetic acid in the form of the crude product (580 mg).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.39 (9H, s), is 2.37 (3H, s), 2,62 (3H, s), of 2.81 (2H, d, J=7,0 Hz), 4,11-4,17 (2H, m), 4,30 (1H, USS), 4,36 (2H, s), 7,06 (2H, d, J=7,7 Hz), 7,19 (2H, d, J=7,7 Hz).

3) Dihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)acetic acid (517 mg, yield 94%) was obtained as a white powder from the crude product (580 mg)obtained in the above stage 2), a method similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,11 (6H, d, J=6.6 Hz), 2,15-of 2.27 (1H, m), of 2.45 (3H, s)to 2.94 (3H, s), 3,11 (2H, d, J=7.5 Hz), 4,20 (2H, s), 4,50 (2H, s), 7,30 (2H, d, J=8.1 Hz), 7,42 (2H, d, J=7.9 Hz).

Example34

2-Amino-2-oxoethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (10 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-and butil-2-methyl-4-(4-were)nicotinic acid (500 mg, 1,22 mmol) in N,N-dimethylformamide were added 2-iodoacetamide (673 mg, of 3.64 mmol) and potassium carbonate (337 mg, of 2.44 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 2-amino-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (570 mg, yield 99%) as oil.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,17-2,31 (1H, m), 2,39 (3H, s), to 2.57 (3H, s), 2,80 (2H, d, J=7,2 Hz), 4,13-4,18 (2H, m)to 4.23 (1H, USS), and 4.40 (2H, s), 5,12 (2H, USS), 7,12 (2H, d, J=7,7 Hz), 7,25 (2H, d, J=7.9 Hz).

2) 2-Amino-2-oxoethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (370 mg, yield 82%) was obtained as an oil from 2-amino-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (570 mg, to 1.21 mmol) in a manner similar to the method of example 8-3).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), 2,17 of-2.32 (1H, m), is 2.40 (3H, s), to 2.57 (3H, s), 2,82 (2H, d, J=7,2 Hz), 3,70 (2H, s), 4,39 (2H, s), 5,20 (2H, USS), 7,19 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=7.9 Hz).

Example35

The dihydrochloride of 4-ethoxy-4-oxobutyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) a Mixture of 5-{[(tert-butoxycarbonyl)amino]IU the Il}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0,41 g, 1.0 mmol), ethyl-4-bromobutyrate (0.21 g, 1.1 mmol), potassium carbonate (0.15 g, 1.1 mmol) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 1 h and the reaction mixture was distributed between ethyl acetate and water. The organic layer was washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain 4-ethoxy-4-oxobutyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.45 g, yield 85%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,25 (3H, t, J=7.2 Hz), of 1.39 (9H, s), 1,55-1,70 (2H, m), of 2.08 (2H, t, J=7.5 Hz), 2,15-of 2.30 (1H, m), of 2.38 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,3 Hz), of 3.95 (2H, t, J=6.2 Hz), 4,11 (2H, q, J=7.2 Hz), a 4.53 (2H, d, J=5.3 Hz), 4,23 (1H, USS), 7,07 (2H, d, J=8.0 Hz), 7,21 (2H, d, J=8.0 Hz).

2) Dihydrochloride 4-ethoxy-4-oxobutyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.12 g, yield 95%) was obtained as a white powder from 4-ethoxy-4-oxobutyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (of 0.13 g, 0.25 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.17 (3H, t, J=7.2 Hz), 1,45-to 1.60 (2H, m), is 2.05 (2H, t, J=7.4 Hz), 2,15-of 2.30 (1H, m), a 2.36 (3H, s), of 2.51 (3H, USS), 2,85 (2H, t, J=6.3 Hz), 3,82 (2H, d, J=5.7 Hz), to 3.92 (2H, t, J=6.3 Hz), a 4.03 (2H, q, J=7.2 Hz), 7,19 (2H, d, J=7.9 Hz), 7,2 (2H, d, J=7.9 Hz), 8,21 (3H, USS).

TPL: 193-195°C

Example36

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)butane acid

1) 4-Ethoxy-4-oxobutyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,30 g, or 0.57 mmol) was dissolved in ethanol (20 ml) was added 1N. an aqueous solution of sodium hydroxide (4.0 ml). The mixture was stirred at room temperature for 1 h, the Reaction mixture was poured into 0,5h. hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained crude crystals are recrystallized from a mixture of diisopropyl ether-ethyl acetate to obtain 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)butane acid (0,23 g, yield 82%) as a white powder.

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6,4 Hz)of 1.39 (9H, s), 1,55-1,70 (2H, m), 2,12 (2H, t, J=7,1 Hz), 2,15-of 2.30 (1H, m), 2,39 (3H, s)of 2.75 (3H, USS), 2,85-3,20 (2H, m)4,00 (2H, t, J=6.2 Hz), 4,20 (2H, d, J=3.6 Hz), 4,37 (1H, USS), 7,10 (2H, d, J=7,7 Hz), 7,26 (2H, d, J=7,7 Hz).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)butane acid (0.20 g, yield 99%) was obtained as a white powder from 4-({[5-{[(tert-bout xianbei)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)butane acid (0.20 g, 0.40 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 1,40-of 1.55 (2H, m)2,00 (2H, t, J=7.4 Hz), 2,15-of 2.30 (1H, m), a 2.36 (3H, s), 2,52 (3H, USS), 2,80-2,95 (2H, m), 3,83 (2H, d, J=4.3 Hz), to 3.92 (2H, t, J=6.2 Hz), 7,20 (2H, d, J=7,7 Hz), 7,29 (2H, d, J=7,7 Hz), 8,29 (3H, USS).

TPL: 221-223°C

Example37

Trihydrochloride pyridine-2-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (15 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,00 g, 2,42 mmol) in N,N-dimethylformamide was added to the hydrobromide of 2-(methyl bromide)pyridine (0,92 g of 3.64 mmol) and potassium carbonate (66,9 mg, 4,84 mmol) and the mixture was stirred for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain pyridine-2-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.20 g, yield 98%) as a pale pink solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14 was 2.25 (1H, m)to 2.35 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,2 Hz), 4,14 (2H, USS), 4,25 (1H, USS), is 5.06 (2H, s), 6.89 in (1H, d, J=7,7 Hz), 7,06 (2H, d, J=7.9 Hz), 7,13 (2H, d, J=7.9 Hz), 7,17-7,22 (1H, m), EUR 7.57 (1H, t, J=7,7 Hz), charged 8.52 (1H, d, J=4,7 Hz).

2) Trihydrochloride pyridi the-2-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.22 g, yield 99%) was obtained as a pale pink solid of pyridine-2-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.20 g, of 2.38 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.4 Hz), 2,17-of 2.28 (1H, m), of 2.34 (3H, s), 2,61 (3H, s)to 2.94 (2H, d, J=6.8 Hz), 3,81 (2H, d, J=4.9 Hz), 5,20 (2H, s), 7,19 (4H, s), 7.23 percent (1H, USS), a 7.62-7,66 (1H, m), of 8.06 (1H, t, J=7.9 Hz), 8,39 (3H, USS), 8,68 (1H, d, J=4,9 Hz).

Example38

The dihydrochloride of 2-ethoxy-1-methyl-2-oxoethyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate

1) 2 Ethoxy-1-methyl-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene (0.35 g, yield 56%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylglycol acid (0.5 g, 1.2 mmol) and ethyl-2-bromopropionate (of 0.43 g, 2.4 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s), is 1.11 (3H, d, J=7,0 Hz), 1,25 (3H, t, J=7,1 Hz)to 1.37 (9H, s), of 2.38 (3H, s), 2,62 (3H, d, J=4.9 Hz), 2,83-of 2.93 (2H, m)to 4.17 (2H, q, J=7.0 Hz), is 4.21 (3H, s), 4,82 (1H, q, J=7,1 Hz), ? 7.04 baby mortality for 7.12 (2H, m), 7,19-7,21 (2H, m).

2) of the Dihydrochloride of 2-ethoxy-1-methyl-2-oxoethyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate (0.16 g, yield 85%) was obtained as a white powder from 2-ethoxy-1-methyl-2-oxoethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentanoate (0.2 g, 0.38 mmol) spoorendonk method example 22-2).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s)of 1.06 (3H, d, J=7,0 Hz)of 1.16 (3H, t, J=7,1 Hz), is 2.37 (3H, s), 2,58 (3H, s), 2,95 (2H, s), 3,88 (2H, s), 4,11 (2H, q, J=7.0 Hz), of 4.77 (1H, q, J=7,1 Hz), 7,13-7,16 (1H, m), 7.23 percent-to 7.32 (3H, m), 8,24 (3H, s).

Example39

The dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene (0.9 g, yield 73%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylglycol acid (1.0 g, 2.3 mmol) and 4-chloromethyl-5-methyl-1,3-dioxol-2-it (0,42 g, 2.8 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)of 1.36 (9H, s)of 1.97 (3H, s), 2,39 (3H, s), of 2.53 (3H, s), is 2.88 (2H, s)to 4.16 (3H, s), 4,74 (2H, s), 7,02 (2H, d, J=7.8 Hz), 7,17 (2H, d, J=7,8 Hz).

2) To a solution (2 ml)of(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentanoate (0.8 g, 1.5 mmol) in ethyl acetate was added 4n. an ethyl acetate solution of hydrogen chloride (8 ml) and the mixture was stirred at room temperature for 4 h the Reaction mixture was concentrated under reduced pressure and the resulting white solid was recrystallized from methanol-ethyl acetate to obtain dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-2-methyl-4-(4-methylphen is)-6-neopentanoate (0.6 g, yield 77%) as a white powder.

1H-NMR (DMSO-d6) δ: 1.00 and (9H, s)to 1.99 (3H, s), of 2.34 (3H, s), 2,52 (3H, s), with 2.93 (2H, s), 3,83 (2H, d, J=5.5 Hz), is 4.93 (2H, s), 7,13 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=7.9 Hz), 8,18 (3H, s).

Example40

Hemifumarate 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (sometimes referred to in this description as fumarate, bis[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid])

1) a Mixed solution of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (53,7 g, 130 mmol) and 4n. 1,4-dioxane solution of hydrogen chloride (400 ml) was stirred at room temperature for 3 hours the Precipitated precipitated solid substance was collected by filtration and washed with diisopropyl ether (200 ml). The obtained white solid was dissolved in isopropanol (500 ml) and the mixture was stirred at 50°C for 30 minutes the mixture was allowed to cool to room temperature and the mixture was stirred at room temperature for 1 h Precipitated precipitated solid substance was collected by filtration and washed with propanol (50 ml) to obtain propane-2-Aulnay of MES (1:1) of the dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (46,5 g, yield 80%) as white solids.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), was 1.04 (6H, d, J=6.0 Hz), 2,16-of 2.27 (1H, m), is 2.37 (3H, s), 2,58 (3H, s), 2,90 (2H, d, J=7,0 Hz), to 3.73-3,86 (3H, m), 7.23 percent (2H, d, J=8.1 Hz), 7,30 (2H, d, J=7.9 Hz), compared to 8.26 (3H, USS).

2) Propane-2-Aulnay MES (1:1) hydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (35,6 g, 80 mmol) suspended in water (80 ml) was added 1N. aqueous sodium hydroxide solution (160 ml, 160 mmol) at room temperature. The mixture was stirred for 1 h Precipitated precipitated solid substance was collected by filtration and washed with ethanol (10 ml) to obtain 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (13.3 g, yield 53%) as a white solid.

1H-NMR (DMSO-d6) δ: of 0.93 (6H, d, J=6.8 Hz), 2,14 was 2.25 (1H, m), of 2.34 (3H, s), of 2.38 (3H, s), 2,70 (2H, d, J=7,2 Hz), 3,49 (2H, s), 7,14-7,20 (4H, m).

3) 5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (15,4 g, to 49.3 mmol) suspended in water (400 ml) and the mixture was heated at the boil under reflux with stirring for 30 minutes the resulting suspension was added fumaric acid (3,43 g, 29.6 mmol) and the mixture was stirred at room temperature for 1 h Precipitated precipitated solid substance was collected by filtration and the filtrate was washed with water (50 ml) to produce hemifumarate 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (13,9 g, yield 76%) as white crystals.

1H-NMR (DMSO-d6) δ: of 0.93 (6H, d, J=6.6 Hz), 2.26 and-of 2.28 (1H, m)to 2.35 (3H, s), 2,42 (3H, s), of 2.72 (2H, d, J=7,2 Hz), 3,55(2H, C)of 6.49 (1H, s), 7,17 (2H, d, J=8,3 Hz), 7,21 (2H, d, J=8,3 Hz).

Example41

The dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionamide

A mixture of tert-butyl{[5-[(1E)-3-amino-3-oxoprop-1-EN-1-yl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (97,6 mg, 0,223 mmol), 10% palladium on carbon (24 mg, 0,0223 mmol) and ethanol (5 ml) was stirred in hydrogen atmosphere at room temperature for 16 hours After filtration the solvent is evaporated under reduced pressure to obtain tert-butyl{[5-(3-amino-3-oxopropyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate in the form of a crude product. The crude product was dissolved in 4n. 1,4-dioxane solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the resulting white solid washed with diisopropyl ether to obtain the dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionamide (72,7 mg, yield 79%) as a white powder.

1H-NMR (CD3OD) δ: 1,09 (6H, d, J=6.2 Hz), 2,07-2,19 (1H, m), 2,24-to 2.29 (2H, m), 2,48 (3H, s)2,84 (2H, t, J=7.8 Hz), 2,90 (3H, s), 3,06 (2H, d, J=7,7 Hz), Android 4.04 (2H, s), 7,29 (2H, d, J=7.9 Hz), to 7.50 (2H, d, J=7,7 Hz).

Example42

The dihydrochloride ethyl-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionate

1) a Mixture of ethyl-(2E)-3-[5-[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acrylate (700 mg, 1.50 mmol), 10% palladium on carbon (160 mg, 0.15 mmol) and ethanol (15 ml) was stirred in hydrogen atmosphere at room temperature for 1 h After filtration the solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain ethyl-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionate (480 mg, yield 68%) the form of a white powder.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.18 (3H, t, J=7.2 Hz), to 1.38 (9H, s), 2,11-of 2.30 (3H, m), is 2.40 (3H, s), to 2.57 (3H, s), 2,62 of 2.68 (2H, m), 2,72 (2H, d, J=7,4 Hz), 3.96 points-4,07 (4H, m), 4,18 (1H, USS), 6,98 (2H, d, J=to $ 7.91), from 7.24 (2H, d, J=7.9 Hz).

2) Dihydrochloride ethyl-3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionate (58,3 mg, yield 85%) was obtained as white powder from ethyl-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionate (73,0 mg, 0,156 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,08 (6H, d, J=6.6 Hz), of 1.17 (3H, t, J=7.2 Hz), 2,08-of 2.21 (1H, m), 2,34-2,39 (2H, m), 2,48 (3H, s), 2,82-to 2.85 (2H, m), is 2.88 (3H, s), 3,05 (2H, d, J=7.5 Hz), 4,00-4,07 (4H, m), 7,27 (2H, d, J=7.9 Hz), to 7.50 (2H, d, J=7.9 Hz).

Example43

The dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionic acid

1) To a mixed solution (10 ml), ethyl-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionate (07 mg, 0,868 mmol) in tetrahydrofuran was added 1N. an aqueous solution of sodium hydroxide (4,30 ml, 4.30 mmol) and the mixture was stirred at 50°C for 5 h, the Reaction mixture was neutralized 6N. hydrochloric acid (0.8 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionic acid (255 mg, yield 60%) as a yellow powder.

1H-NMR (CD3OD) δ: was 1.04 (6H, d, J=6.6 Hz), 2,05-2,17 (1H, m), 2.26 and-a 2.36 (2H, m), is 2.44 (3H, s), 2,75-2,87 (5H, m), 2,97 (2H, d, J=7.5 Hz), of 4.05 (2H, s), 7,17 (2H, d, J=8.1 Hz), 7,40 (2H, d, J=7,7 Hz).

2) of the Dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionic acid (a 94.2 mg, yield 97%) was obtained as a white powder from 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propionic acid (100 mg, 0,234 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,09 (6H, d, J=6.6 Hz), 2,09-2,22 (1H, m), 2,30-of 2.38 (2H, m), 2,48 (3H, s), 2,80-is 2.88 (2H, m), 2,90 (3H, s), 3,05 (2H, d, J=7.5 Hz), of 4.05 (2H, s), 7,26 (2H, d, J=7.9 Hz), 7,51 (2H, d, J=8.1 Hz).

Example44

2-[5-(Aminomethyl)-6-isobutyl-4-(4-were)-2-propylpyridine-3-yl]ndimethylacetamide

1) tert-Butyl{[-(hydroxymethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (1.40 g, yield 60%) was obtained as a pale pink powder from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-propylenimine (2.50 g, of 5.50 mmol) in a manner similar to the method of example 5-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.02 (3H, d, J=7,4 Hz)to 1.38 (9H, s), 1,73 is 1.86 (2H, m), 2,14-of 2.28 (1H, m), is 2.41 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 2,88-of 2.93 (2H, m), Android 4.04 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 4,36 (2H, d, J=5.8 Hz), 7,06 (2H, d, J=7.9 Hz), 7,26 (2H, d, J=7,35 Hz).

2) tert-Butyl{[5-(cyanomethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (0,82 g, yield 67%) was obtained as oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (1.20 g, of 2.81 mmol) in a manner similar to the method of example 5-2).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.05 (3H, t, J=7.4 Hz), to 1.38 (9H, s)of 1.78-1.90 (2H, m), 2,18-of 2.27 (1H, m), 2,43 (3H, s), 2,77 (2H, d, J=7,4 Hz), 2,81-of 2.86 (2H, m)to 3.33 (2H, s), 4,05-4,06 (2H, m), 4,20 (1H, OSS), 7,05 (2H, d, 7.9 Hz), 7,30 (2H, d, J=7,7 Hz),

3) tert-Butyl{[5-(2-amino-2-oxoethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (814 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-(cyanomethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (0,82 g, 1.88 mmol) in a manner similar to the way example 6-1).

1H-NMR (CD3OD) δ: 0,98-1,05 (9H, m)to 1.38 (9H, s), of 1.66-1.77 in (2H, m), 2,08-2,19 (1H, m), 2,39 (3H, s), was 2.76 is 2.80 (4H, m), 3,37 (2H, s), 3,92-of 3.97 (2H, m), 4,59 (1H, USS), of 7.70 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=7,7 Hz).

4) 2-[5-(Aminomethyl)-6-isobutyl-4-(4-IU is ylphenyl)-2-propylpyridine-3-yl]ndimethylacetamide (31 mg, output 10%) was obtained as oil from tert-butyl{[5-(2-amino-2-oxoethyl)-2-isobutyl-4-(4-were)-6-propylpyridine-3-yl]methyl}carbamate (300 mg, 0.84 mmol) in a manner similar to the method of example 8-3).

1H-NMR (CD3OD) δ: 0,99 (6H, d, J=6.6 Hz), a 1.01 (3H, t, J=7.4 Hz), 1,63-1,71 (2H, m), 2,04-to 2.18 (1H, m), is 2.40 (3H, s), 2,71 was 2.76 (2H, m), and 2.79 (2H, d, J=7,4 Hz)to 3.33 (2H, s), 3,53 (2H, s), 7,11 (2H, d, J=7.9 Hz), 7,30 (2H, d, J=7.9 Hz).

Example45

tert-Butyl-5-(aminomethyl)-2,6-Diisobutyl-4-(4-were)nicotinate

1) tert-Butyl 3-amino-5-metrex-2-ENOAT received in the form of the crude product (10 g) of the acid Meldrum (14,41 g, 100 mmol) and isovaleraldehyde (11.5 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2,6-Diisobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (12,11 g, yield 74%) was obtained as an oil from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9,96 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2,6-Diisobutyl-4-(4-were)nicotinate (3,39 g, yield 83%) was obtained from tert-butyl 5-cyano-2,6-Diisobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (4.09 g, 10 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), and 1.00 (6H, d, J=6.6 Hz), of 1.23 (9H, s), 2,19 is 2.33 (1H, m), is 2.41 (3H, s), was 2.76 (2H, d, J=7.5 Hz), to 2.94 (2H, d, J=7,2 Hz), 7,20-to 7.35 (4H, m).

4) tert-Butyl-5-(aminomethyl)-2,6-Diisobutyl the-4-(4-were)nicotinate (2.85 g, yield 86%) was obtained as oil from tert-butyl 5-cyano-2,6-Diisobutyl-4-(4-were)nicotinate (3.25 g, 8 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.93 (6H, d, J=6.6 Hz), of 0.97 (6H, d, J=6.6 Hz), 1,17 (9H, s)to 1.38 (2H, USS), 2,16-of 2.30 (2H, m), 2,39 (3H, s)to 2.67 (2H, d, J=7.5 Hz), and 2.79 (2H, d, J=7,2 Hz), 3,62 (2H, s), 7,13 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

Example46

The dihydrochloride of 5-(aminomethyl)-2,6-Diisobutyl-4-(4-were)nicotinic acid

The dihydrochloride of 5-(aminomethyl)-2,6-Diisobutyl-4-(4-were)nicotinic acid (0.39 g, yield 92%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-2,6-Diisobutyl-4-(4-were)nicotinate (0,41 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: from 0.90 (6H, d, J=6.6 Hz), is 0.96 (6H, d, J=6.6 Hz), 2,16-to 2.29 (2H, m), is 2.37 (3H, s), 2,68 (2H, d, J=7,2 Hz), is 2.88 (2H, d, J=7,2 Hz), with 3.79 (2H, d, J=5,1 Hz), 7,22 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=8,1 Hz), 8,12 (3H, USS).

Example47

p-Toluensulfonate ({2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine

1) To a suspension of p-toluensulfonate sodium (9.0 g, and 50.5 mmol) in ethanol (50 ml) was added dropwise bromoacetone (6,92 g, and 50.5 mmol). The resulting mixture was heated at the boil under reflux for 30 min, allowed to cool to room temperature and distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution and dried over anhydrous Sul is blockhead magnesium. The solvent is evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 1-[(4-were)sulfonyl]acetone (8.0 g, 75%yield) as a colorless oil.

1H-NMR (CDCl3) δ: 2,41 (3H, s)to 2.46 (3H, s), 4,14 (2H, s), 7,37 (2H, d, J=8,2 Hz), to 7.77 (2H, d, J=8,2 Hz).

2) a Mixture of 1-[(4-were)sulfonyl]acetone (2.0 g, 9.4 mmol), p-tolualdehyde (1,14 g, 9.4 mmol), piperidine (0,093 ml of 0.94 mmol), acetic acid (0,11 ml, 1.9 mmol) and toluene (100 ml) was heated at boiling under reflux, using a trap Dean-stark for 3 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 4-(4-were)-3-[(4-were)sulfonyl]but-3-EN-2-it is in the form of the crude product (3.5 g).

3) a Mixture of 5-methyl-3-oxopentanenitrile (14.3 g, 100 mmol), acetic acid (6.0 g, 10 mmol), ammonium acetate (38,5 g, 500 mmol) and toluene (200 ml) was heated at boiling under reflux, using a trap Dean-stark for 17 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silicagel the e with 3-amino-5-metrex-3-onitrile in the form of a mixture of 8.2 g). Compound (0.65 g) and the crude product (1.7 g)obtained in the above stage 2), was dissolved in ethanol (50 ml) and the mixture was heated at the boil under reflux for 12 hours the Reaction mixture was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]-1,4-dihydropyridines-3-carbonitrile (1.3 g, yield 64%) as a white powder.

EIMC (M+1): 421

4) 2-Isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]nicotinamide (0,77 g, yield 68%) was obtained as a white powder from 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]-1,4-dihydropyridines-3-carbonitrile (1.13 g, 2.7 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 2.20 to 2.35 (1H, m), of 2.38 (3H, s), 2,39 (3H, s), 2.91 in (2H, d, J=7,2 Hz), of 3.07 (3H, s)6,86 (2H, d, J=8.1 Hz), was 7.08 (4H, d, J=8.1 Hz), 7.23 percent (2H, d, J=8,1 Hz).

TPL: 129-131°C

5) ({2-Isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0.64 g, yield 93%) was obtained as colorless oil from 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]nicotinanilide (0,69 g, 1.6 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), 1,41 (2H, USS), of 2.20 to 2.35 (1H, m), of 2.38 (6H, s), and 2.79 (2H, d, J=7,2 Hz), 2,96 (3H, s), 3,40 (2H, s)6,76 (2H, d, J=8.1 Hz), 7,03 (2H, d, J=8,3 Hz), to 7.09 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8 Hz).

6) To a solution of ({2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0.64 g, 1.5 mmol) in ethanol (5 ml) was added dropwise a solution of the monohydrate p-toluensulfonate acid (to 0.29 g, 1.5 mmol) in ethanol (5 ml) at room temperature. Precipitated precipitated crystals were collected by filtration, washed with cold ethanol and dried to obtain n-toluensulfonate ({2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0,57 g, yield 63%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.94 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m)to 2.29 (3H, s), is 2.37 (6H, s), 2,78 (2H, d, J=7,0 Hz), 2,84 (3H, s), of 3.57 (2H, s), 6.87 in (2H, d, J=7.9 Hz), 7,11 (4H, d, J=8.5 Hz), 7,25-7,30 (4H, m), 7,47 (2H,, d, J=7.9 Hz), 7,76 (3H, USS).

TPL: 234-235°C

Example48

tert-Butyl-5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-were)nicotinate

1) tert-Butyl 3-amino-4-phenylbut-2-ENOAT received in the form of the crude product (16 g) of the acid Meldrum (14,41 g, 100 mmol) and phenylacetylene (14,5 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl 2-benzyl-5-cyano-6-isobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (14.1 g, yield 79%) was obtained as an oil from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (16 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl 2-benzyl-5-cyano-6-from util-4-(4-were)nicotinate (2,92 g, yield 66%) was obtained from tert-butyl 2-benzyl-5-cyano-6-isobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (4,43 g, 10 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 1,10 (9H, s), 2,19 to 2.35 (1H, m), is 2.40 (3H, s)to 2.94 (2H, d, J=7,2 Hz), 4,28 (2H, s), 7,16-to 7.32 (9H, m).

4) tert-Butyl-5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-were)nicotinate (of 2.45 g, yield 55%) was obtained as oil from tert-butyl 2-benzyl-5-cyano-6-isobutyl-4-(4-were)nicotinate (4,40 g, 10 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), of 1.05 (9H, s)of 1.26 (2H, USS), 2.21 are of 2.30 (1H, m), of 2.38 (3H, s), and 2.79 (2H, d, J=7.5 Hz), 3,62 (2H, s), 4,20 (2H, s), 7,11-7,31 (9H, m).

Example49

The dihydrochloride of 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-were)nicotinic acid

The dihydrochloride of 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-were)nicotinic acid (0,38 g, yield 82%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-2-benzyl-6-isobutyl-4-(4-were)nicotinate (of 0.44 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: of 0.93 (6H, d, J=6.3 Hz), 2,16-to 2.29 (1H, m), is 2.37 (3H, s), 2,82 (2H, d, J=6.6 Hz), of 3.77 (2H, d, J=4,8 Hz), 4,13 (2H, s), 7,15-7,31 (9H, m), 8,16 (3H, USS).

Example50

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-4-(4-were)-2-phenyldiamine acid

1) Ethyl-3-amino-3-phenylacrylate received in the form of the crude product (9.5 g) of ethyl-3-oxo-3-phenylpropanoate being 9.61 g, 50 mmol) and ammonium acetate (19,27 g, 250 mmol) in a manner similar to the method of example 12-1).

2) Ethyl-5-cyano-6-isobutyl-4-(4-were)-2-phenyl-1,4-dihydropyridines-3-carboxylate (9,52 g, yield 59%) was obtained as an oil from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (9.5 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) Ethyl-5-cyano-6-isobutyl-4-(4-were)-2-phenyldiamine (4.11 g, yield 85%) was obtained as oil from ethyl 5-cyano-6-isobutyl-4-(4-were)-2-phenyl-1,4-dihydropyridines-3-carboxylate (to 4.81 g, 12 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.85 (3H, t, J=7.2 Hz), of 1.05 (6H, d, J=6.6 Hz), 2,29 is 2.44 (4H, m), 3,05 (2H, d, J=7,2 Hz), 3,91 (2H, q, J=7.2 Hz), 7,26-7,33 (4H, m), 7,43-of 7.48 (3H, m), 7,624-of 7.69 (2H, m).

4) Ethyl-5-(aminomethyl)-6-isobutyl-4-(4-were)-2-phenyldiamine (3,63 g, yield 90%) was obtained as oil from ethyl 5-cyano-6-isobutyl-4-(4-were)-2-phenyldiamine (4,40 g, 10 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,80 (3H, t, J=7.2 Hz), of 1.03 (6H, d, J=6.6 Hz), 1,36 (2H, USS), 2,29-to 2.42 (4H, m), 2,90 (2H, d, J=7,2 Hz), 3,70 (2H, s), 3,81 (2H, q, J=7.2 Hz), 7,17 (2H, d, J=8.1 Hz), 7.23 percent (2H, d, J=8.1 Hz), 7,35-the 7.43 (3H, m), 7,62-the 7.65 (2H, m).

5) a Mixture of ethyl-5-(aminomethyl)-6-isobutyl-4-(4-were)-2-phenyldiamine (0,80 g, 2 mmol), 6N. hydrochloric acid (20 ml) and acetic acid (10 ml) was heated at the boiling reverse holo is rinicom within 3 days. The reaction mixture was concentrated under reduced pressure. To the residue was added tetrahydrofuran (20 ml) and 1N. an aqueous solution of sodium hydroxide (30 ml). To the mixture was added di-tert-BUTYLCARBAMATE (0,55 ml, 2.4 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Reaction mixture was acidified using 1N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)-2-phenyldiamine acid (0,38 g, 0.8 mmol) in the form of oil. Then from the oil received dihydrochloride 5-(aminomethyl)-6-isobutyl-4-(4-were)-2-phenyldiamine acid (0.31 g, yield 88%) as a white powder by the method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,24 to 2.35 (1H, m), of 2.38 (3H, s), with 2.93 (2H, d, J=6.9 Hz), 3,82 (2H, d, J=5,1 Hz), 7,26-to 7.32 (4H, m), 7,44-7,52 (3H, m), 7,66-of 7.69 (2H, m), scored 8.38 (3H, USS).

Example51

Methyl-5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-were)nicotinate

1) Methyl-3-aminophen-2-ENOAT received in the form of the crude product (6.4 g) of methyl-3-oxopentanoate (6.50 g, 50 mmol) and ammonium acetate (19,27 g, 250 mmol) in a manner similar to the method of example 12-1).

2) Methyl-5-C the ANO-2-ethyl-6-isobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (4.12 g, yield 48%) was obtained as an oil from 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), p-tolualdehyde (4.8 g, 40 mmol) and the crude product (3.2 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) Methyl-5-cyano-2-ethyl-6-isobutyl-4-(4-were)nicotinate (3,41 g, yield 84%) was obtained from methyl 5-cyano-2-ethyl-6-isobutyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (4,06 g, 12 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 1,32 (3H, t, J=7.5 Hz), 2,24-of 2.36 (1H, m), is 2.41 (3H, s), 2,85 (2H, q, J=7.5 Hz), 2,96 (2H, d, J=6,9 Hz)and 3.59 (3H, s), 7.24 to 7,30 (4H, m).

4) Methyl-5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-were)nicotinate (2,49 g, yield 73%) was obtained as a white powder from methyl 5-cyano-2-ethyl-6-isobutyl-4-(4-were)nicotinate (4,40 g, 10 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,6 Hz)of 1.29 (3H, t, J=7.5 Hz), 2,18-2,31 (1H, m), of 2.34 (3H, s), 2,77 (2H, q, J=7.5 Hz), of 2.81 (2H, d, J=7,2 Hz), 3,49 (3H, s), the 3.65 (2H, s), 7,11 (2H, d, J=8.0 Hz), 7,21 (2H, d, J=8,0 Hz).

Example52

The dihydrochloride of 5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-were)nicotinic acid

The dihydrochloride of 5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-were)nicotinic acid (0,30 g, yield 82%) was obtained as a white powder from methyl-5-(aminomethyl)-2-ethyl-6-isobutyl-4-(4-were)nicotinate (0.34 g, 1 mmol) in a manner similar to the method of example 50-5).

1H-NMR (DMSO-d6) δ:0,97 (6H, d, J=6.6 Hz), of 1.26 (3H, t, J=7.5 Hz), 2,17-of 2.26 (1H, m), is 2.37 (3H, s), 2,89 (2H, q, J=7,3 Hz)of 3.00 (2H, d, J=6.9 Hz), 3,81 (2H, d, J=6.0 Hz), 7,25 (2H, d, J=8,2 Hz), 7,30 (2H, d, J=8,2 Hz), scored 8.38 (3H, OSS).

Example53

Maleate 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid

To a mixed solution of 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (114 mg, 0,350 mmol), acetonitrile (2 ml) and water (2 ml) was added maleic acid (40,6 mg, 0,350 mmol) and the mixture was stirred at room temperature. After the dissolution of maleic acid was added acetonitrile (8 ml) and the mixture was stirred at room temperature for 1 h the resulting solution was concentrated under reduced pressure and to the residue was added acetonitrile (10 ml). The mixture was stirred at room temperature for 1 h Precipitated precipitated crystals were collected by filtration to obtain the maleate 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (92,6 mg, 60%) as colorless powdery crystals.

1H-NMR (DMSO-d6) δ: 1.00 and (9H, s), a 2.36 (3H, s), 2.49 USD (3H, s), of 2.81 (2H, s), a-3.84 (2H, s), 6,01 (2H, s), 7,17-7,21 (2H, m), 7,27-7,31 (2H, m).

Example54

Tartrate 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid

To a mixed solution of 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (114 mg, 0,350 mmol), acetonitrile (2 ml) and water (2 ml) was added wine keys, the GTC (40,6 mg, 0,350 mmol) and the mixture was stirred at room temperature. After dissolving tartaric acid was added acetonitrile (8 ml) and the mixture was stirred at room temperature for 1 h the resulting solution was concentrated under reduced pressure and to the residue was added acetonitrile (10 ml). The mixture was stirred at room temperature for 1 h Precipitated precipitated crystals were collected by filtration to obtain tartrate 5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid (129 mg, 77%) as colorless powdery crystals.

1H-NMR (DMSO-d6) δ: 0,98 (9H, s)to 2.35 (3H, s), is 2.44 (3H, s), and 2.79 (2H, in), 3.75 (2H, s), of 3.96 (2H, s), 7,15-7,19 (2H, m), 7,21-of 7.25 (2H, m).

Example55

tert-Butyl-5-(aminomethyl)-2-isobutyl-4-(4-were)-6-neopentylene

1) tert-Butyl 3-amino-5-metrex-2-ENOAT received in the form of the crude product (10 g) of the acid Meldrum (14,41 g, 100 mmol) and isovaleraldehyde (11.5 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2-isobutyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (3.75 g, yield 22%) was obtained as oil from 5,5-dimethyl-3-oxopentanenitrile (5,57 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol) and the crude product (10 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2-isobutyl-4-(4-were)-6-neopentylglycol the NAT (1.66 g, yield 49%) was obtained from tert-butyl 5-cyano-2-isobutyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (to 3.38 g, 10 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), of 1.06 (9H, s)of 1.24 (9H, s), 2,22 to 2.35 (1H, m), is 2.40 (3H, s), was 2.76 (2H, d, J=7,2 Hz)of 3.00 (2H, s), 7,19-to 7.35 (4H, m).

4) tert-Butyl-5-(aminomethyl)-2-isobutyl-4-(4-were)-6-neopentylene (1,34 g, yield 89%) was obtained as white crystals from tert-butyl 5-cyano-2-isobutyl-4-(4-were)-6-neopentanoate (3.25 g, 8 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.93 (6H, d, J=6.6 Hz), of 1.02 (9H, s)of 1.17 (9H, s), 1,24 (2H, USS), 2,22-2,31 (1H, m), 2,39 (3H, s)to 2.66 (2H, d, J=7.5 Hz), 2,87 (2H, s), 3,68 (2H, s), 7,13 (2H, d, J=8.0 Hz), 7,21 (2H, d, J=8.0 Hz,).

Example56

tert-Butyl-5-(aminomethyl)-2-benzyl-4-(4-were)-6-neopentylene

1) tert-Butyl 3-amino-4-phenylbut-2-ENOAT received in the form of the crude product (16 g) of the acid Meldrum (14,41 g, 100 mmol) and phenylacetylene (14,5 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl 2-benzyl-5-cyano-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (12.5 g, yield 68%) was obtained as oil from 5,5-dimethyl-3-oxopentanenitrile (5,57 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol) and the crude product (11.6 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl 2-benzyl-5-cyano-4-(4-methylphen the l)-6-neopentylene (6.8 g, yield 100%) was obtained from tert-butyl 2-benzyl-5-cyano-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (6.8 g, 10 mmol) in a manner similar to the method of example 23-3).

4) tert-Butyl-5-(aminomethyl)-2-benzyl-4-(4-were)-6-neopentylene (0,48 g, yield 15%) was obtained as white crystals from tert-butyl 2-benzyl-5-cyano-4-(4-were)-6-neopentanoate (3,18 g, 7 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.96 (9H, s)of 1.07 (9H, s), 2,39 (3H, s), 2,85 (2H, s)to 3.67 (2H, s), 4,18 (2H, s), 7,11-to 7.32 (9H, m).

Example57

tert-Butyl-5-(aminomethyl)-2-ethyl-4-(4-were)-6-neopentylene

1) tert-Butyl-3-aminophen-2-ENOAT received in the form of the crude product (8.5 g) of the acid Meldrum (14,41 g, 100 mmol) and propionitrile (9.6 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2-ethyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (6.0 g, yield 38%) was obtained as oil from 5,5-dimethyl-3-oxopentanenitrile (5,57 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol) and the crude product (8.5 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2-ethyl-4-(4-were)-6-neopentylene (2.58 g, yield 43%) was obtained as a pale-yellow solid from tert-butyl 5-cyano-2-ethyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (of 5.92 g, 15 mmol) method on the window to the method of example 23-3).

1H-NMR (CDCl3) δ with 1.07 (9H, s)of 1.26 (9H, s)of 1.34 (3H, t, J=7.5 Hz), is 2.41 (3H, s), 2,89 (2H, q, J=7.5 Hz), 3,01 (2H, s), 7,20-7,29 (4H, m).

4) tert-Butyl-5-(aminomethyl)-2-ethyl-4-(4-were)-6-neopentylene (1.56 g, yield 65%) was obtained as oil from tert-butyl 5-cyano-2-ethyl-4-(4-were)-6-neopentanoate (2,36 g, 6 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 1.03 (9H, s)to 1.19 (9H, s)of 1.28 (2H, USS), of 1.32 (3H, t, J=7.5 Hz), 2,39 (3H, s), 2,80 (2H, q, J=7.5 Hz), 2,87 (2H, s), 3,68 (2H, s), 7,13 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

Example58

The dihydrochloride of 5-(aminomethyl)-2-ethyl-4-(4-were)-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-2-ethyl-4-(4-were)-6-neopentylglycol acid and 0.37 g, yield 90%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-2-ethyl-4-(4-were)-6-neopentanoate (0.39 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s)of 1.26 (3H, t, J=7.5 Hz), is 2.37 (3H, s), 2,78 (2H, q, J=7.5 Hz), 2,92 (2H, s), 3,83 (2H, d, J=5.4 Hz), 7,21 (2H, d, J=8.0 Hz), 7,29 (2H, d, J=8.0 Hz), 8,13 (3H, USS).

Example59

tert-Butyl-5-(aminomethyl)-4-(4-were)-6-neopentyl-2-propylenimine

1) tert-Butyl-3-Aminorex-2-ENOAT received in the form of the crude product (9.2 grams) of acid Meldrum (14,41 g, 100 mmol) and butyrylcholine (11,4 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-4-(4-were)-6-neopentyl-2-propyl-1,4-dihydr the pyridine-3-carboxylate (10.1 g, yield 61%) was obtained as oil from 5,5-dimethyl-3-oxopentanenitrile (5,57 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol) and the crude product (16 g)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-4-(4-were)-6-neopentyl-2-propylenimine (5,74 g, yield 58%) was obtained as oil from tert-butyl 5-cyano-4-(4-were)-6-neopentyl-2-propyl-1,4-dihydropyridines-3-carboxylate (9.8 g, 24 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,00 (3H, t, J=7.5 Hz), of 1.06 (9H, s)of 1.26 (9H, s), 1,75-of 1.88 (2H, m), is 2.41 (3H, s), 2,81-of 2.86 (2H, m)of 3.00 (2H, s), 7.18 in-7,30 (4H, m).

4) tert-Butyl-5-(aminomethyl)-4-(4-were)-6-neopentyl-2-propylenimine (3,36 g, yield 74%) was obtained as white crystals from tert-butyl 5-cyano-4-(4-were)-6-neopentyl-2-propylenimine (4,47 g, 11 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (3H, t, J=7,3 Hz)of 1.02 (9H, s), 1.14 in (2H, OSS), to 1.14 (9H, s), 1,73 is 1.86 (2H, m), 2,39 (3H, s), 2,72-2,77 (2H, m), 2,87 (2H, s), 3,68 (2H, s), 7,13 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

Example60

The dihydrochloride of 5-(aminomethyl)-4-(4-were)-6-neopentyl-2-propylresorcinol acid

The dihydrochloride of 5-(aminomethyl)-4-(4-were)-6-neopentyl-2-propylresorcinol acid (0,38 g, yield 90%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-4-(4-were)-6-neopentyl-2-propylenimine (0,41 g, 1 mmol) in a manner similar to the way note the RA 24-1).

1H-NMR (DMSO-d6) δ: of 0.93 (3H, t, J=7,3 Hz)of 1.02 (9H, s), 1,69-of 1.81 (2H, m), is 2.37 (3H, s), 2,74-and 2.79 (2H, m)to 2.94 (2H, USS), a-3.84 (2H, d, J=5,1 Hz), 7,22 (2H, d, J=8.0 Hz), 7,29 (2H, d, J=8.0 Hz), 8,14 (3H, USS).

Example61

tert-Butyl-5-(aminomethyl)-2-isopropyl-4-(4-were)-6-neopentylene

1) tert-Butyl 3-amino-4-methylpent-2-ENOAT received in the form of the crude product (9.2 grams) of acid Meldrum (14,41 g, 100 mmol) and Isobutyraldehyde (11,4 ml, 110 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl-5-cyano-2-isopropyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (4,91 g, 30%yield) was obtained as oil from 5,5-dimethyl-3-oxopentanenitrile (5,57 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol) and the crude product (9.2 grams)obtained in the above stage 1), a method similar to the method of example 1-2).

3) tert-Butyl-5-cyano-2-isopropyl-4-(4-were)-6-neopentylene (2,48 g, yield 50%) was obtained from tert-butyl 5-cyano-2-isopropyl-4-(4-were)-6-neopentyl-1,4-dihydropyridines-3-carboxylate (4,90 g, 12 mmol) in a manner similar to the method of example 23-3).

4) tert-Butyl-5-(aminomethyl)-2-isopropyl-4-(4-were)-6-neopentylene (1.26 g, yield 51%) was obtained as white crystals from tert-butyl 5-cyano-2-isopropyl-4-(4-were)-6-neopentanoate (3.25 g, 8 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 1,04 (9H, s)of 1.18 (9H, s)of 1.30 (6H, d, J=6.9 Hz), 1,32 (2H, USS), 239 (3H, C)to 2.85 (2H, s), 3.04 from-3,13 (1H, m), 3,66 (2H, s), 7,13 (2H, d, J=8.0 Hz), 7,20 (2H, d, J=8.0 Hz).

Example62

The dihydrochloride of 5-(aminomethyl)-2-isopropyl-4-(4-were)-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-2-isopropyl-4-(4-were)-6-neopentylglycol acid and 0.37 g, yield 88%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-2-isopropyl-4-(4-were)-6-neopentanoate (0,42 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 1,04 (9H, s), 1,25 (6H, d, J=6.6 Hz), a 2.36 (3H, s), 2,90 (2H, s), 3,03-3,13 (1H, m), 3,81 (2H, d, J=5.4 Hz), 7,22 (2H, d, J=8,2 Hz), 7,28 (2H, d, J=8,2 Hz), 8,18 (3H, USS).

Example63

The dihydrochloride of 5-(aminomethyl)-2-isobutyl-4-(4-were)-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-2-isobutyl-4-(4-were)-6-neopentylglycol acid (0,41 g, yield 93%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-2-isobutyl-4-(4-were)-6-neopentanoate (0,42 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 0,89 (6H, d, J=6.6 Hz), of 1.02 (9H, s), 2,18-2,31 (1H, m), is 2.37 (3H, s)to 2.66 (2H, d, J=7.2 Hz), 2.91 in (2H, s), a-3.84 (2H, d,J=5,1 Hz), 7,21 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=8.1 Hz), 8,08 (3H, USS).

Example64

The dihydrochloride of 5-(aminomethyl)-2-benzyl-4-(4-were)-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-2-benzyl-4-(4-were)-6-neopentylglycol acid (0,43 g, yield 91%) was obtained in the de white powder from tert-butyl 5-(aminomethyl)-2-benzyl-4-(4-were)-6-neopentanoate (0.45 g, 1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: of 0.95 (9H, s), is 2.37 (3H, s), 2,89 (2H, s), 3,82 (2H, d, J=5.4 Hz), 4,14 (2H, s), 7.18 in-7,31 (9H, m), 8,17 (3H, USS).

Example65

The dihydrochloride methyl-5-(aminomethyl)-6-butyl-2-methyl-4-(4-were)nicotinate

1) Methyl-6-butyl-5-cyano-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (39 g, yield 24%) was obtained as crystals from 3-oxopiperidine (64 g, 500 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: to 0.92 (3H, t, J=7,3 Hz), 1.30 and of 1.42 (2H, m), 1,49 is 1.60 (2H, m), is 2.30 (3H, s), 2,34-2,39 (2H, m)to 2.35 (3H, s)to 3.58 (3H, s), 4,56 (1H, s), 5,77 (1H, s), 7,07-7,14 (4H, m)

2) Methyl-6-butyl-5-cyano-2-methyl-4-(4-were)nicotinate (25 g, yield 65%) was obtained as crystals from methyl-6-butyl-5-cyano-2-methyl-4-(4-were)-1,4-dihydropyridines-3-carboxylate (25 g, 77 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: 0,97 (3H, t, J=7,3 Hz), 1,40-of 1.52 (2H, m), 1,74-of 1.84(2H, m), is 2.41 (3H, s), 2,62 (3H, s), 3.04 from-to 3.09 (2H, m), of 3.60 (3H, s), 7.23 percent-7,29 (4H, m).

3) Methyl-5-(aminomethyl)-6-butyl-2-methyl-4-(4-were)nicotinate (17 g, yield 68%) was obtained as oil from methyl-6-butyl-5-cyano-2-methyl-4-(4-were)nicotinate (4 g, to 11.9 mmol) in a manner similar to the method of example 1-4). Oil (3 g) was dissolved in ethyl acetate (10 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (10 ml). The mixture was concentrated under reduced pressure to obtain dihydrochloride methyl-5-(linomat the l)-6-butyl-2-methyl-4-(4-were)nicotinate in powder form.

1H-NMR (DMSO-d6) δ: of 0.95 (3H, t, J=7,3 Hz), 1,38-is 1.51 (2H, m)of 1.65 and 1.75 (2H, m), is 2.37 (3H, s), of 2.53 (3H, s), 2,98-3,03 (2H, m), 3,47 (3H, s), 3,82 (2H, d, J=5.5 Hz), 7,19 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), scored 8.38 (3H, s).

Example66

The dihydrochloride of 5-(aminomethyl)-6-butyl-2-methyl-4-(4-were)nicotinic acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-butyl-2-methyl-4-(4-were)nicotinate (16.3 g, yield 89%) was obtained as crystals from methyl-5-(aminomethyl)-6-butyl-2-methyl-4-(4-were)nicotinate (14 g, 42,9 mmol) in a manner similar to the method of example 2-1).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-6-butyl-2-methyl-4-(4-were)nicotinic acid (1.5 g, yield 77%) was obtained as crystals from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-butyl-2-methyl-4-(4-were)nicotinate (2.0 g, 4.7 mmol) in a manner similar to the method of example 2-2).

3) Dihydrochloride 5-(aminomethyl)-6-butyl-2-methyl-4-(4-were)nicotinic acid (0.56 g, yield 86%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-butyl-2-methyl-4-(4-were)nicotinic acid (0.7 g, 1.7 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (3H, t, J=7.4 Hz), 1,39-1,49 (2H, m)of 1.65 and 1.75 (2H, m), is 2.37 (3H, s), 2,61 (3H, s), 3,03-is 3.08 (2H, m), 3,81 (2H, d, J=5.3 Hz), 7,24 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz), 8,40 (3H, s).

Example67

The dihydrochloride methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-propylenecarbonate

1) Methyl-5-cyano-2-METI the-4-(4-were)-6-propyl-1,4-dihydropyridines-3-carboxylate (60 g, yield 39%) was obtained as an oil from 3-oxopentanenitrile (60 g, 500 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: of 0.96 (3H, t, J=7.4 Hz), 1,54-of 1.66 (2H, m), is 2.30 (3H, s), 2,32-to 2.41 (2H, m)to 2.35 (3H, s)to 3.58 (3H, s), 4,56 (1H, s)5,80 (1H, s), to 7.09 (2H, d, J=8.1 Hz), 7,13 (2H, d, J=8,1 Hz).

2) Methyl-5-cyano-2-methyl-4-(4-were)-6-propylenimine (34.8 g, yield 58%) was obtained as crystals from methyl 5-cyano-2-methyl-4-(4-were)-6-propyl-1,4-dihydropyridines-3-carboxylate (60 g, 193 mmol) in a manner similar to the method of example 1-3).

1H-NMR (CDCl3) δ: of 1.05 (3H, t, J=7.4 Hz), 1,79 is 1.91 (2H, m), is 2.41 (3H, s), 2,62 (3H, s), 3,02-of 3.07 (2H, m), of 3.60 (3H, s), 7.23 percent-7,29 (4H, m).

3) Methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-propylenimine (15 g, yield 67%) was obtained as oil from methyl 5-cyano-2-methyl-4-(4-were)-6-propylenimine (22 g, from 71.3 mmol) in a manner similar to the method of example 1-4). Oil (2 g) was dissolved in ethyl acetate (10 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (10 ml). The mixture was concentrated under reduced pressure to obtain dihydrochloride methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-propylenimine in powder form.

1H-NMR (DMSO-d6) δ: of 1.02 (3H, t, J=7.4 Hz), 1,69-to 1.82 (2H, m), is 2.37 (3H, s), of 2.53 (3H, s), 2,96-to 3.02 (2H, m), 3,47 (3H, s), 3,82 (2H, d, J=5.5 Hz), 7,19 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz), scored 8.38 (3H, s).

Example68

The dihydrochloride of 5-(aminomethyl)-2-methyl-4-(4-were)-6-propylresorcinol acid

1) Methyl-5-{[(tert-bout xianbei)amino]methyl}-2-methyl-4-(4-were)-6-propylenimine (12 g, yield 70%) was obtained as crystals from methyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-propylenimine (13 g, to 41.6 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: of 1.03 (3H, t, J=7.4 Hz), of 1.39 (9H, s), 1,72-to 1.79 (2H, m), of 2.38 (3H, s), of 2.53 (3H, s), 2,84-2,90 (2H, m), 3,49 (3H, s)to 4.15 (2H, d, J=5,1 Hz), 4,25 (1H, s), 7,05 (2H, d, J=8.1 Hz), 7,20 (2H, d, J=8,1 Hz).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-propylenimine acid (1.6 g, yield 83%) was obtained as crystals from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-propylenimine (2 g, 4.8 mmol) in a manner similar to the method of example 2-2).

1H-NMR (DMSO-d6) δ: of 0.96 (3H, t, J=7.4 Hz), of 1.35 (9H, s), 1,64 to 1.76 (2H, m), of 2.33 (3H, s), is 2.44 (3H, s), 2,67-of 2.72 (2H, m), a 3.87 (2H, d, J=4.5 Hz), of 6.99 (1H, s), 7,16-7,22 (4H, m), 12,92 (1H, s).

3) Dihydrochloride 5-(aminomethyl)-2-methyl-4-(4-were)-6-propylresorcinol acid (0.75 g, yield 96%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-propylresorcinol acid (0.7 g, 2.1 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.02 (3H, t, J=7.4 Hz), 1,69-to 1.82 (2H, m), is 2.37 (3H, s), 2,62 (3H, s), 3,01-of 3.07 (2H, m), 3,82 (2H, d, J=5.3 Hz), 7,24 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz), to 8.41 (3H, s).

Example69

The dihydrochloride of 5-(aminomethyl)-4-(4-forfinal)-6-isobutyl-2-methylnicotinate acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-forfinal)-6-isobutyl-2-methylnicotinic the t (2,60 g, yield 99%) was obtained as a white solid from methyl-5-(aminomethyl)-4-(4-forfinal)-6-isobutyl-2-methylnicotinate (2.00 g, 6.05 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,16-of 2.26 (1H, m), of 2.54 (3H, s), 2,78 (2H, d, J=7,2 Hz), 3,51 (3H, s), 4,08-4,17 (2H, m), 4,22 (1H, USS), 7,07-7,20 (4H, m).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-4-(4-forfinal)-6-isobutyl-2-methylnicotinate acid (2,01 g, yield 79%) was obtained as yellow solid from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-forfinal)-6-isobutyl-2-methylnicotinate (2,60 g, 6,24 mmol) in a manner similar to the method of example 2-2).

1H-NMR (CD3OD) δ: was 1.04 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,12-2,22 (1H, m), 2,71 (3H, s)to 2.94 (2H, d, J=7,4 Hz), 4,13 (2H, s), 7,17-of 7.25 (2H, m), 7,32-7,39 (2H, m).

3) Dihydrochloride 5-(aminomethyl)-4-(4-forfinal)-6-isobutyl-2-methylnicotinic acid (0.20 g, yield 76%) was obtained as a white solid from 5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-forfinal)-6-isobutyl-2-methylnicotinic acid (0.28 g, 0,673 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,04-of 1.13 (6H, m), 2,13-of 2.28 (1H, m), 2,78-of 2.86 (3H, m), 3,02-3,11 (2H, m), 4,13-4,20 (2H, m), 7,30-7,38 (2H, m), 7,42-7,51 (2H, m).

Example70

The dihydrochloride of 5-(aminomethyl)-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (2,49 g, yield 87%) is Uchali in the form of a white solid of methyl-5-(aminomethyl)-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (2.00 g, 6.38 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,16-of 2.27 (1H, m), 2,61 (3H, s), and 2.79 (2H, d, J=7,4 Hz), of 3.57 (3H, s), 4,13 (2H, d, J=5.3 Hz), 4,36 (1H, USS), 6,97-7,02 (2H, m), 7,34-7,44 (1H, m).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate acid (2,22 g, yield 92%) was obtained as yellow solid from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(2,6-differenl)-6-isobutyl-2-methylnicotinate (2,49 g, 5,55 mmol) in a manner similar to the method of example 2-2).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,11-of 2.26 (1H, m)of 2.64 (3H, s), of 2.81 (2H, d, J=7,2 Hz), 4,11-4,16 (2H, m), 4,37 (1H, USS), of 6.96-7,01 (2H, m), 7,34-the 7.43 (1H, m).

3) Dihydrochloride 5-(aminomethyl)-4-(2,6-differenl)-6-isobutyl-2-methylnicotinic acid (185 mg, yield 70%) was obtained as a white solid from 5-{[(tert-butoxycarbonyl)amino]methyl}-4-(2,6-differenl)-6-isobutyl-2-methylnicotinic acid (0.28 g, 0,635 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CD3OD) δ: 1,08 (6H, d, J=6.8 Hz), 2,19-to 2.29 (1H, m), 2,81-is 2.88 (3H, m), 2,98-is 3.08 (2H, m), 4.09 to to 4.16 (2H, m), 7,20-7,27 (2H, m), of 7.64-7,72 (1H, m).

Example71

tert-Butyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinate

1) 2-(3-Methylbutanoyl)-3-[4-(trifluoromethyl)phenyl]Acrylonitrile was obtained in the form of the crude product (9.8 g) of 5-methyl-3-oxopentanenitrile (4.0 g, 32 mmol) and 4-(trifluoromethyl)benzaldehyde (5.6 g, 32 mmol)in a manner similar to the method of example 29-1).

2) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-1,4-dihydropyridines-3-carboxylate (4.8 g, yield 36%) was obtained as a white powder from the crude product (9.8 g)obtained in the above stage 1), and tert-butyl-3-aminocrotonate (vs. 5.47 g, 35 mmol) in a manner similar to the method of example 1-2). Namely, the above crude product and tert-butyl-3-aminocrotonate was dissolved in methanol (200 ml) and the mixture was heated at the boil under reflux for 1 h the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl-5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-1,4-dihydropyridines-3-carboxylate.

1H-NMR (CDCl3) δ: of 0.93 (3H, d, J=6.6 Hz), 0,99 (3H, d, J=6.5 Hz), of 1.28 (9H, s), 1,75-2,00 (1H, m), of 2.10 to 2.35 (2H, m), a 2.36 (3H, s), with 4.64 (1H, s), ceiling of 5.60 (1H, OSS), was 7.36 (2H, d, J=8.1 Hz), 7,56 (2H, d, J=8,1 Hz).

TPL: 199-201°C

3) tert-Butyl-5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinate (3.5 g, yield 76%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-1,4-dihydropyridines-3-carboxylate (4.7 g, 11 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6.6 Hz), of 1.23 (9H, s), 2,20-2,40 (1H, m)to 2.67 (3H, s), 2,95 (2H, d, J=7,4 Hz), 7,51 (2H, d, J=8,2 Hz), 7,76 (2H, d, J=8,2 Hz).

TPL: 108-110°C

4) tert-Butyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(triptime who yl)phenyl]nicotinate (3.3 grams, yield 96%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinate (3.5 g, 8.2 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), 1,17 (9H, s)to 1.38 (2H, USS), of 2.15 to 2.35 (1H, m), to 2.57 (3H, s), 2,80 (2H, d, J=7,4 Hz), of 3.60 (2H, s), 7,42 (2H, d, J=8.0 Hz), of 7.70 (2H, d, J=8.0 Hz).

TPL: 88-90°C

Example72

Hydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinic acid

Hydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinic acid (0.51 g, yield 53%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-6-isobutyl-2-methyl-4-[4-(trifluoromethyl)phenyl]nicotinate (1.0 g, 2.3 mmol) in a manner similar to the method of example 24.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), of 2.15 to 2.35 (1H, m), of 2.51 (3H, s), 2,78 (2H, d, J=7,2 Hz in), 3.75 (2H, s), 7,56 (2H, d, J=8.0 Hz), 7,87 (2H, d, J=8.0 Hz), 8,01 (2H, USS).

Example73

tert-Butyl-5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinate

1) Methyl-4-(2-cyano-5-methyl-3-axugex-1-EN-1-yl)benzoate was obtained as crude product (10.1 g) of 5-methyl-3-oxopentanenitrile (4.0 g, 32 mmol) and methyl-4-formylbenzoate (5,3 g, 32 mmol) in a manner similar to the method of example 29-1).

2) tert-Butyl-5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methyl-1,4-dihydropyridines-3-carboxylate (5.9 g, yield 45%) was obtained as a white powder from the crude product (101 g), obtained in the above stage 1), and tert-butyl-3-aminocrotonate (5,25 g, 33 mmol) in a manner similar to the method of example 1-2). Namely, the above crude product and tert-butyl-3-aminocrotonate was dissolved in methanol (200 ml) and the mixture was heated at the boil under reflux for 2 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl-5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methyl-1,4-dihydropyridines-3-carboxylate.

1H-NMR (CDCl3) δ: of 0.91 (3H, d, J=6.6 Hz), and 0.98 (3H, d, J=6.6 Hz), 1.26 in (9H, s), 1,75-2,00 (1H, m), of 2.15 to 2.35 (2H, m), a 2.36 (3H, s), 3,90 (3H, s), 4,63 (1H, s)5,69 (1H, USS), 7,32 (2H, d, J=8,3 Hz), to 7.99 (2H, d, J=8,3 Hz).

TPL: 191-193°C

3) tert-Butyl-5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinate (5,4 g, yield 95%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methyl-1,4-dihydropyridines-3-carboxylate (5.7 g, 14 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), of 1.23 (9H, s), of 2.20 to 2.35 (1H, m)to 2.67 (3H, s)to 2.94 (2H, d, J=7,4 Hz), of 3.96 (3H, s), 7,40-to 7.50 (2H, m), 8,10-to 8.20 (2H, m).

TPL: 108-109°C

4) tert-Butyl-5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinate (5.0 g, yield 94%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinate (5.3g, 13 m is ol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), 1,17 (9H, s), for 1.49 (2H, USS), of 2.15 to 2.35 (1H, m), to 2.57 (3H, s), and 2.79 (2H, d, J=7,2 Hz)and 3.59 (2H, s), of 3.96 (3H, s), 7,30-7,40 (2H, m), 8,05-of 8.15 (2H, m).

TPL: 77-81°C

Example74

Hydrochloride 5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinic acid

Hydrochloride 5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinic acid (0.50 g, yield 66%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-6-isobutyl-4-[4-(methoxycarbonyl)phenyl]-2-methylnicotinate (0,80 g, 1.9 mmol) in a manner similar to the method of example 24.

1H-NMR (DMSO-d6) δ: of 0.93 (6H, d, J=6.6 Hz), 2,05 was 2.25 (1H, m), is 2.41 (3H, s), 2,70 (2H, d, J=7,0 Hz), of 3.54 (2H, s), 3,88 (3H, s), 7,41 (2H, d, J=8.1 Hz), 7,95 (2H, d, J=8,1 Hz).

Example75

tert-Butyl-5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate

1) 3-(4-Ethylphenyl)-2-(3-methylbutanoyl)Acrylonitrile was obtained in the form of the crude product (8.8 g) of 5-methyl-3-oxopentanenitrile (4.0 g, 32 mmol) and 4-ethylbenzaldehyde (4.3 g, 32 mmol) in a manner similar to the method of example 29-1).

2) tert-Butyl-5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (7.8 g, yield 64%) was obtained as a white powder from the crude product (8.8 g)obtained in the above stage 1), and tert-butyl-3-aminocrotonate (vs. 5.47 g, 35 mmol) in a manner similar to the method of example 1-2). Namely, the above crude product and tert-butyl-3-amino otomat was dissolved in methanol (200 ml) and the mixture was heated at the boil under reflux for 4 hours The reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl-5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate.

1H-NMR (CDCl3) δ: of 0.94 (3H, d, J=6.5 Hz), 0,99 (3H, d, J=6.5 Hz), of 1.20 (3H, t, J=7,6 Hz)of 1.28 (9H, s), 1,80-2,00 (1H, m), 2,10-of 2.30 (2H, m), 2,32 (3H, s), 2,61 (2H, q, J=7,6 Hz)to 4.52 (1H, s), of 5.55 (1H, USS), 7,10 (2H,, d, J=8,3 Hz), 7,14 (2H, d, J=8,3 Hz).

TPL: 165-166°C

3) tert-Butyl-5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate (5,2 g, yield 67%) was obtained as a white powder from tert-butyl 5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (7.8 g, 21 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), of 1.23 (9H, s)of 1.26 (3H, t, J=7,6 Hz), of 2.20 to 2.35 (1H, m)of 2.64 (3H, s), 2,71 (2H, q, J=7,6 Hz)to 2.94 (2H, d, J=7,4 Hz), 7,20-to 7.35 (4H, m).

TPL: 85-86°C

4) tert-Butyl-5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate (7.0 g, yield 97%) was obtained as a white powder from tert-butyl 5-cyano-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate (7.2 g, 19 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 1,17 (9H, s), 1,25 (3H, t, J=7.5 Hz), to 1.38 (2H, USS), 2,15-of 2.30 (1H, m)to 2.55 (3H, s), 2,69 (2H, q, J=7.5 Hz), 2,78 (2H, d, J=7,4 Hz), 3,63 (2H, s), to 7.15 (2H, d, J=7.9 Hz), from 7.24 (2H, d, J=7.9 Hz).

TPL: 50-52°C

Example76

Hydrochloride 5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate acid

<> Hydrochloride 5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinic acid (0.52 g, yield 79%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-4-(4-ethylphenyl)-6-isobutyl-2-methylnicotinate (0,70 g, 1.8 mmol) in a manner similar to the method of example 24.

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=7.5 Hz), of 1.23 (3H, t, J=7.5 Hz), 2,10-of 2.30 (1H, m), 2,47 (3H, s)to 2.67 (2H, q, J=7.5 Hz), 2,77 (2H, d, J=7,0 Hz), 3,74 (2H, s), 7,22 (2H, d, J=8.0 Hz), 7,30 (2H, d, J=8.0 Hz), 8,81 (1H, USS).

Example77

Methyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentylene

1) Methyl-3-aminophen-2-ENOAT received in the form of the crude product (20 g) of methyl-3-oxopentanoate (13 g, 100 mmol) and ammonium acetate (38,5 g, 500 mmol) in a manner similar to the method of example 12-1).

2) Methyl-4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridines-3-carboxylate (1.4 g, yield 23%) was obtained as a yellow powder from 5,5-dimethyl-3-oxopentanenitrile (of 5.1 g, 32 mmol), 4-chlorobenzaldehyde (4.5 g, 32 mmol) and the crude product (3.2 g)obtained in the above stage 1), a method similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,95-1,05 (3H, m), a 1.01 (9H, s), 2,20 (1H, d, J=13,8 Hz), is 2.37 (1H, d, J=13,8 Hz), 2,77 (2H, q, J=7.5 Hz), to 3.58 (3H, s), 4,60 (1H, s), 5,63 (1H, USS), 7,10-7,20 (2H, m), 7,25-7,30 (2H, m).

3) Methyl-4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentylene (0,58 g, yield 43%) was obtained as pale-yellow powder from methyl 4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentyl-1,4-dihydropyridines-3-to the of roxelana (1.4 g, 3.7 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ with 1.07 (9H, s)of 1.33 (3H, t, J=7.5 Hz), 2,87 (2H, q, J=7.5 Hz), 3,03 (2H, s), 3,61 (3H, s), 7,25-to 7.35 (2H, m), 7,45 is 7.50 (2H, m).

TPL: 120-121°C

4) Methyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentylene (0,49 g, yield 85%) was obtained as a pale-yellow oil from methyl-4-(4-chlorophenyl)-5-cyano-2-ethyl-6-neopentanoate (or 0.57 g, 1.5 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: of 1.03 (9H, s)of 1.30 (3H, t, J=7.5 Hz), of 1.42 (2H, USS), 2,77 (2H, q, J=7.5 Hz), 2,89 (2H, s), 3,51 (3H, s), of 3.69 (2H, s), 7,15-of 7.25 (2H, m), 7,35-7,45 (2H, m).

Example78

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentylglycol acid

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-chlorophenyl)-2-ethyl-6-neopentylene (0.52 g, yield 97%) was obtained as a white powder from methyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentanoate (0,42 g, 1.1 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)of 1.30 (3H, t, J=7.5 Hz), to 1.38 (9H, s), 2,78 (2H, q, J=7.5 Hz), 2,87 (2H, s), 3,51 (3H, s), 4,18 (3H, USS), 7,10-7,20 (2H, m), 7,30 was 7.45 (2H, m).

2) 5-{[(tert-Butoxycarbonyl)amino]methyl}-4-(4-chlorophenyl)-2-ethyl-6-neopentylglycol acid and 0.37 g, yield 81%) was obtained as a white powder from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-chlorophenyl)-2-ethyl-6-neopentanoate (0,47 g 0,99 mmol) in a manner similar to the method of example 2-2).

1H-NMR (CDCl3) δ: 1,01 (9H, C)to 1.24 (3H, t, J=7.4 Hz), of 1.33 (9H, s), 2,73 (2H, q, J=7.4 Hz), 2,73 (2H, s)to 3.92 (2H, d, J=4.5 Hz), of 6.96 (1H, t, J=4.5 Hz), 7,25-to 7.35 (2H, m), 7,47 (2H, d, J=8,3 Hz), of 13.05 (1H, USS).

TPL: 71-72°C

3) Dihydrochloride 5-(aminomethyl)-4-(4-chlorophenyl)-2-ethyl-6-neopentylglycol acid (0.24 g, yield 83%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-chlorophenyl)-2-ethyl-6-neopentylglycol acid (0,30 g of 0.65 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s)of 1.26 (3H, t, J=7.4 Hz), and 2.79 (2H, q, J=7.4 Hz), 2,90 (2H, USS), 3,83 (2H, d, J=5.7 Hz), was 7.36 (2H, d, J=8.5 Hz), 7,50-of 7.60 (2H, m), 8,12 (3H, USS).

TPL: 230-235°C

Example79

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylene

1) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6-neopentyl-1,4-dihydropyridines-3-carboxylate (2.00 g, yield 16%) was obtained as white solids from 5,5-dimethyl-3-oxopentanenitrile (5,67 grams of 36.7 mmol), 4-chlorobenzaldehyde (5,16 grams of 36.7 mmol) and tert-butyl 3-amino-4-methylpent-2-enoate (5,98 g, 30 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 1,02 (9H, s), was 1.04 (3H, d, J=6,8 Hz)to 1.21 (3H, d, J=7,0 Hz)of 1.28 (9H, s), 2,20 (1H, d, J=a 13.9 Hz), 2,33 (1H, d, J=14.1 Hz), 4,07-4,30 (1H, m), 4,55 (1H, s), the 5.65 (1H, s), 7,16 (2H, d, J=8,3 Hz), 7,22-to 7.35 (2H, m).

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6-neopentylene (1,91 g, yield 96%) was obtained as yellow solid from tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6-neope the Teal-1,4-dihydropyridines-3-carboxylate (2.00 g, of 4.66 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 1.06 (9H, s)of 1.27 (9H, s)of 1.32 (6H, d, J=6,6 Hz)of 3.00 (2H, s), 3,13-of 3.25 (1H, m), 7,32 (2H, d, J=8.5 Hz), was 7.45 (2H, d, J=8,5 Hz).

3) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylene (1.24 g, yield 67%) was obtained as a white solid from tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isopropyl-6-neopentanoate (1.80 g, 4,27 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: 1,04 (9H, s)to 1.21 (9H, s)of 1.30 (6H, d, J=6.6 Hz), 2,85 (2H, s), 3,01-and 3.16 (1H, m)to 3.64 (2H, s), 7,22 (2H, d, J=8.5 Hz), 7,40 (2H, d, J=8,5 Hz).

Example80

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentylglycol acid (393 mg, yield 93%) was obtained as yellow solid from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-isopropyl-6-neopentanoate (406 mg, 0,941 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 1,04 (9H, s), 1,25 (6H, d, J=6.8 Hz), is 2.88 (2H, s), 3,05-3,14 (1H, m), 3,81 (2H, d, J=5.3 Hz), was 7.36 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 8,11 (3H, USS).

Example81

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-isopropylaniline

1) tert-Butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-isopropyl-1,4-dihydropyridines-3-carboxylate (6,18 g, yield 50%) was obtained as yellow solid from 5-methyl-3-oxohexanoate is a (4,14 g, 33 mmol), 4-chlorobenzaldehyde (with 4.64 g, 33 mmol) and tert-butyl 3-amino-4-methylpent-2-enoate (5,98 g, 30 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,97 (6H, DD, J=8,5, 6,8 Hz)to 1.14 (3H, d, J=7,0 Hz)to 1.22 (3H, d, J=7,0 Hz)of 1.28 (9H, s), 1,81-to 1.98 (1H, m), of 2.25 (2H, d, J=7,4 Hz), 4.09 to 4.26 deaths (1H, m), 4,55 (1H, s), 5,71 (1H, s), to 7.15 (2H, d, J=8,3 Hz), 7,25-7,27 (2H, m).

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-isopropylaniline (6,10 g, yield 99%) was obtained as a yellow oil from tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-isopropyl-1,4-dihydropyridines-3-carboxylate (6,16 g of 14.8 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 1.26 in (9H, s)of 1.32 (6H, d, J=6.8 Hz), 2,22-2,39 (1H, m), 2,95 (2H, d, J=7,2 Hz), 3,19-of 3.25 (1H, m), 7,33 (2H, d, J=8.7 Hz), 7,46 (2H, d, J=8.7 Hz).

3) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-isopropylaniline (5,52 g, yield 89%) was obtained as a white solid from tert-butyl 4-(4-chlorophenyl)-5-cyano-6-isobutyl-2-isopropylacetate (6,10 g, 1.48 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6,8 Hz)to 1.21 (9H, s)of 1.30 (6H, d, J=6.8 Hz), 2,23-2,39 (1H, m), 2,78 (2H, d, J=7,2 Hz), 3,01-and 3.16 (1H, m)and 3.59 (1H, s), 7,22 (2H, d, J=8.5 Hz), 7,39 (2H, d, J=8,5 Hz).

Example82

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-isopropylamino acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-isopropylamino acid (263 mg, yield 62%) was obtained as yellow the CSO solids from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-6-isobutyl-2-isopropylacetate (404 mg, 0,969 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 1,25 (6H, d, J=6.8 Hz), 2,20-2,39 (1H, m), and 2.83 (2H, d, J=7,0 Hz), 3,01-3,19 (1H, m), of 3.77 (2H, d, J=5.3 Hz), was 7.36 (2H, d, 8.5 Hz), 7,55 (2H, d, J=8,3 Hz), 8,14 (3H, USS).

Example83

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylamine

1) tert-Butyl 3-amino-5-metrex-2-ENOAT received in the form of the crude product (20.2 g) of the acid Meldrum (17.3 g, 120 mmol) and isovaleraldehyde (15,8 ml, 132 mmol) in a manner similar to the method of example 25-1).

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2,6-Diisobutyl-1,4-dihydropyridines-3-carboxylate (10.2 g, yield 72%) was obtained as pale yellow powder of 5-methyl-3-oxopentanenitrile (4.1 g, 33 mmol), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product (10.1 g)obtained in the above stage 1), a method similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,95-1,05 (12H, m)of 1.29 (9H, s), 1,80-of 2.05 (2H, m), of 2.15 to 2.35 (2H, m), 2,55-2,70 (2H, m), 4,60 (1H, s), the 5.51 (1H, USS), 7,15-of 7.25 (2H, m), 7,25-7,30 (2H, m).

TPL: 166-168°C

3) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2,6-diisobutylamine (9.6 g, yield 99%) was obtained as a white powder from tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-Diisobutyl-1,4-dihydropyridines-3-carboxylate (9.8 g, 23 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6,8 Hz), and 1.00 (6H, d, J=6.6 Hz), 1,25 (9H, s), 2,15-to 2.40 (2H, m), was 2.76 (2H, d, J=7,2 Hz), 2,95 (2H, d, J=7,4 Hz), 7,30-to 7.35 (2H, m), 7,40-to 7.50 (2H, m).

4) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylamine (0.97 g, yield 96%) was obtained as a white powder from tert-butyl 4-(4-chlorophenyl)-5-cyano-2,6-diisobutylamine (1.0 g, 2.3 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: of 0.94 (6H, d, J=6.6 Hz), and 0.98 (6H, d, J=6.6 Hz), of 1.20 (9H, s)to 1.48 (2H, USS), of 2.15 to 2.35 (2H, m)to 2.67 (2H, d, J=7,4 Hz), 2,80 (2H, d, J=7,4 Hz), 3,61 (2H, s), 7,20-of 7.25 (2H, m), 7,35-7,45 (2H, m).

Example84

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylamine acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylamine acid (0,92 g, yield 98%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2,6-diisobutylamine (from 0.90 g, 2.1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: from 0.90 (6H, d, J=6.6 Hz), of 0.97 (6H, d, J=6.6 Hz), of 2.10 to 2.35 (2H, m), 2,66 (2H, d, J=6.4 Hz), 2,84 (2H, d, J=6.2 Hz), with 3.79 (2H, d, J=5.5 Hz), was 7.36 (2H, d, J=8.5 Hz), 7,50-of 7.60 (2H, m), 8,17 (3H, USS).

TPL: 205°C (decomposition)

Example85

tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentylene

1) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-isobutyl-6-neopentyl-1,4-dihydropyridines-3-carboxylate was obtained as crude product (7.9 g) of 5,5-dimethyl-3-oxopentanenitrile (4.6 g, 33 mmol), 4-chlorobenzaldehyde (4.6 g, 33 mmol) and the crude product (10.1 g) of tert-butyl 3-amino-5-metrex-2-enoate obtained in example 83-1), by way of example pogonopoma 1-2).

2) tert-Butyl 4-(4-chlorophenyl)-5-cyano-2-isobutyl-6-neopentylene (5.5 g, yield 37%) was obtained as a white powder from the crude product (7.9 g)obtained in the above stage 1), a method similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), of 1.06 (9H, s)of 1.26 (9H, s), of 2.20 to 2.35 (1H, m), was 2.76 (2H, d, J=7,2 Hz), 3,01 (2H, s), 7,30-to 7.35 (2H, m), 7,40-to 7.50 (2H, m).

3) tert-Butyl-5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentylene (4.5 g, yield 86%) was obtained as a yellow powder from tert-butyl 4-(4-chlorophenyl)-5-cyano-2-isobutyl-6-neopentanoate (5,2 g, 12 mmol) in a manner similar to the method of example 23-4).

1H-NMR (CDCl3) δ: of 0.93 (6H, d, J=6.8 Hz), of 1.02 (9H, s)of 1.20 (9H, s)to 1.86 (2H, USS), of 2.15 to 2.35 (1H, m)to 2.67 (2H, d, J=7,4 Hz), 2,87 (2H, s), 3,71 (2H, s), 7,20-of 7.25 (2H, m), 7,35-7,45 (2H, m).

Example86

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentylglycol acid

The dihydrochloride of 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentylglycol acid (0.29 grams, yield 56%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-4-(4-chlorophenyl)-2-isobutyl-6-neopentanoate (0.50 g, 1.1 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: from 0.90 (6H, d, J=6.6 Hz), of 1.02 (9H, s), 2,15-of 2.30 (1H, m)to 2.66 (2H, q, J=7.2 Hz), 2.91 in (2H, s), a-3.84 (2H, d, J=5.5 Hz), 7,30-7,40 (2H, m), 7,50-of 7.60 (2H, m), 8,12 (3H, USS).

TPL: 251°C (decomposition)

Example87

The dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-meth is fenil)-6-neopentylene-3-yl]acetonitrile

1) tert-Butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (4.5 g, yield 48%) was obtained as a white powder from methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentanoate (10 g, 22.7 mmol) in a manner similar to the method of example 5-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s)to 2.41 (3H, s)to 2.67 (3H, s)2,84 (2H, s), 4,10 (2H, d, J=4.9 Hz), 4,16 (1H, s), 4,36 (2H, d, J=5.7 Hz), 7,05 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8,1 Hz).

2) a Mixture of tert-butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.9 g, 2.2 mmol), triethylamine (0.4 g, 4.0 mmol) and tetrahydrofuran (30 ml) was cooled to 0°C was added dropwise methanesulfonate (0.3 g, 2.6 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate of 0.85 g, yield 79%) as a white powder.

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s)to 2.41 (3H, s)to 2.67 (3H, s)of 2.75 (3H, s), of 2.86 (2H, s), 4,11 (2H, d, J=4.9 Hz), 4,17 (1H, s), 4,91 (2H, s),? 7.04 baby mortality (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8,1 Hz).

3) [5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]ethylmethanesulfonate (0.84 g, 1.7 mmol) was dissolved in dimethyl sulfoxide (10 ml) was added potassium cyanide (0.14 g, 2.0 mmol). The mixture was stirred at 60°C for 1 h To the reaction mixture were added ethyl acetate and the mixture was washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-(cyanomethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.45 g, yield 63%) as a powder.

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s), 2,43 (3H, s)to 2.65 (3H, s), 2,85 (2H, s), 3,30 (2H, s), 4,11 (2H, d, J=4.5 Hz), 4,17 (1H, s), 7,05 (2H, d, J=8.0 Hz), 7,30 (2H, d, J=8.0 Hz).

4) Dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetonitrile (0.28 g, 76%) was obtained as a powder from tert-butyl{[5-(cyanomethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.4 g, 0.95 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (9H, s), 2,42 (3H, s), was 2.76 (3H, s), 3,06 (2H, s)and 3.59 (2H, s), 3,80 (2H, d, J=5.3 Hz), 7,24 (2H, d, J=7.9 Hz), 7,42 (2H, d, J=7.9 Hz), to 8.20 (3H, s).

Example88

The dihydrochloride of 2-[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]ndimethylacetamide

1) tert-Butyl{[5-(2-amino-2-oxoethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.3 g, 82%) was obtained as a powder from tert-butyl{[5-(cyanomethyl)-6-meth is l-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.35 g, 0.83 mmol) in a manner similar to the method of example 6-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), is 2.40 (3H, s), of 2.56 (3H, s)2,84 (2H, s), 3,30 (2H, s), 4,10 (2H, d, J=4.9 Hz), 4,19 (1H, s), 5,15 (1H, s), 5,20 (1H, s)to 7.00 (2H, d, J=7.9 Hz), 7,24 (2H, d, J=7.9 Hz).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]ndimethylacetamide (0.18 g, 85%) was obtained as a powder from tert-butyl{[5-(2-amino-2-oxoethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0,22 g, 0.5 mmol) in a manner similar to the method of example 6-2).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s)to 2.41 (3H, s), 2,77 (2H, s), 3,29 (3H, s), a 3.87 (2H, s), 4,28 (2H, s), 7,03 (1H, s), 7,20 (2H, d, J=7.8 Hz), 7,38 (2H, d, J=7.8 Hz), 7,39 (1H, s), 8,24 (3H, s).

Example89

The dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate

1) a Mixture of tert-butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.3 g, 0.73 mmol), triethylamine (0.1 g, 1.0 mmol) and tetrahydrofuran (20 ml) was cooled to 0°C was added dropwise acetylchloride (0.06 g, 0.8 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]m is tracedata (0.26 g, yield 76%) as a white powder.

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), from 2.00 (3H, s), is 2.40 (3H, s), to 2.57 (3H, s), 2,85 (2H, s), 4,11 (2H, d, J=4.9 Hz), 4,17 (1H, s), was 4.76 (2H, s)to 7.00 (2H, d, J=8.1 Hz), 7,22 (2H, d, J=8,1 Hz).

2) Dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate (99 mg, 90%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate (0.12 g, 0.26 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s)a 1.96 (3H, s), is 2.40 (3H, s), 2,78 (3H, s), 3,14 (2H, s), 3,82 (2H, s), 4.72 in (2H, s), 7,21 (2H, d, J=7.8 Hz), was 7.36 (2H, d, J=7.8 Hz), 8,23 (3H, s).

Example90

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylthio)phenyl]thio}methyl)pyridine-3-yl]methyl}amine

1) a Mixture of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (of 3.06 g of 7.68 mmol), triethylamine (1.8 ml, 12.9 mmol) and tetrahydrofuran (30 ml) was cooled to 0°C was added dropwise methanesulfonanilide (0,89 ml, 11.5 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ethylmethanesulfonate in the form of a crude product. The crude product was dissolved in N,N-dimethylformamide (30 ml). Was added potassium carbonate (1.77 g, 12.8 mmol) and 4-(methylthio)sensation (1,00 g, 6,40 mmol) and the mixture was stirred under heating at 50°C for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylthio)phenyl]thio}methyl)pyridine-3-yl]methyl}carbamate (3,43 g, yield 99%) as a yellow solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.24 (1H, m), is 2.40 (3H, s), a 2.45 (3H, s), 2.63 in (3H, s)of 2.75 (2H, d, J=7,4 Hz in), 3.75 (2H, s), was 4.02 (2H, d, J=5,1 Hz), 4,18 (1H, USS), 6,98 (2H, d, J=8,1 Hz), 7,03 (2H, d, J=8.7 Hz), was 7.08 (2H, d, J=8.7 Hz), 7,20 (2H, d, J=7.9 Hz).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylthio)phenyl]thio}methyl)pyridine-3-yl]methyl}amine (380 mg, yield 79%) was obtained as yellow solid from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylthio)phenyl]thio}methyl)pyridine-3-yl]methyl}carbamate (508 mg, 0,947 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,13-2,22 (1H, m), is 2.40 (3H, s)to 2.46 (3H, s), 2,78 (3H, s), 3,11 (2H, USS), 3,76 (2H, d, J=4.5 Hz), a 3.87 (2H, s), 7,12 (2H, d, J=8.7 Hz), 7,16 (2H, d, J=8.7 Hz), 7,22 (2H, d, J=7.9 Hz), 7,33 (H, d, J=7.9 Hz), scored 8.38 (3H, USS).

Example91

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylsulphonyl)phenyl]sulfonyl}methyl)pyridine-3-yl]methyl}amine

1) To a solution of tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylthio)phenyl]thio}methyl)pyridine-3-yl]methyl}carbamate (1.10 g, 2.05 mmol) in methanol (15 ml), water (1.5 ml) and tetrahydrofuran (1.5 ml) was added sulfuric acid (121 mg, of 1.23 mmol) and axon (trademark, of 3.78 g, x 6.15 mmol) and the mixture was stirred at room temperature for 2 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained white solid is washed with diisopropyl ether to obtain tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylsulphonyl)phenyl]sulfonyl}methyl)pyridine-3-yl]methyl}carbamate (1.06 g, yield 86%) as a white powder.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,17-of 2.27 (1H, m), 2,42 (3H, s), 2,70 (3H, s), 2,78 (2H, d, J=7,2 Hz), to 3.09 (3H, s), 4.00 points (2H, d, J=5,1 Hz), 4,19 (1H, USS), 4,36 (2H, s), 6.87 in (2H, d, J=7.9 Hz), 7,19 (2H, d, J=7.9 Hz), 7,69 (2H, d, J=8,3 Hz), 8,00 (2H, d, J=8,5 Hz).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylsulphonyl)phenyl]sulfonyl}methyl)pyridine-3-yl]methyl}amine (480 mg, in the course of 98%) was obtained as a white powder from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-({[4-(methylsulphonyl)phenyl]sulfonyl}methyl)pyridine-3-yl]methyl}carbamate (511 mg, 0,851 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,17-of 2.27 (1H, m), of 2.38 (3H, s), of 2.81 (3H, USS), of 3.00 (2H, OSS), to 3.34 (3H, s), 3,68 (2H, USS), 7,03 (2H, d, J=7,4 Hz), 7,22 (2H, d, J=7.9 Hz), to 7.77 (2H, d, J=7,0 Hz), 8,11 (2H, d, J=8.5 Hz), compared to 8.26 (3H, USS).

Example92

The dihydrochloride (6-methyl-4-(4-were)-5-{[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl}-2-neopentylene-3-yl)methylamine

1) tert-Butyl[(6-methyl-4-(4-were)-5-{[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl}-2-neopentylene-3-yl)methyl]carbamate (0.28 g, 77%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (0.35 g, 0.71 mmol) and 4-methyl-4H-1,2,4-triazole-3-thiol (99 mg, 0.86 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), 2,39 (3H, s)to 2.65 (3H, s)2,84 (2H, s)to 3.41 (3H, s)4,07 (2H, d, J=5.3 Hz), 4,17 (3H, s), 7,02 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz), 8,08 (1H, s).

2) Dihydrochloride (6-methyl-4-(4-were)-5-{[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl}-2-neopentylene-3-yl)methylamine (0.12 g, 72%) was obtained as a powder from tert-butyl[(6-methyl-4-(4-were)-5-{[(4-methyl-4H-1,2,4-triazole-3-yl)thio]methyl}-2-neopentylene-3-yl)methyl]carbamate (0.18 g, 0.35 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s), 2,39 (3H, s), 2,80 (3H, s), 3,19 (2H, s)to 3.41 (3H, s), with 3.79 (2H, s), of 4.05 (2H, s), 7,13 (2H, d, J=8.1 Hz), 7,35 (2H, d, J=8.1 Hz), of 8.25 (3H, s), a total of 8.74 (1H, s).

Example 93

The dihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(1,3-thiazol-2-ylthio)methyl]pyridine-3-yl}methylamine

1) tert-Butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(1,3-thiazol-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (0.25 g, 69%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (0.35 g, 0.71 mmol) and 2-mercaptothiazole (100 mg, 0.86 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), of 2.38 (3H, s)of 2.64 (3H, s)2,84 (2H, s)4,08 (2H, d, J=5,1 Hz), 4,17 (3H, s), 7,03 (2H, d, J=7.9 Hz), 7,18 (1H, d, J=3,4 Hz), 7,20 (2H, d, J=7.9 Hz), 7,60 (1H, d, J=3,4 Hz).

2) Dihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(1,3-thiazol-2-ylthio)methyl]pyridine-3-yl}methylamine (0.11 g, 80%) was obtained as a powder from tert-butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(1,3-thiazol-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (0.15 g, 0.29 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (9H, s), of 2.38 (3H, s), 2,78 (3H, s), 3,10 (2H, s), of 3.78 (2H, s), 4,20 (2H, s), 7,20 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8.1 Hz), 7,69 (1H, d, J=3,4 Hz), 7,71 (1H, d, J=3,4 Hz), 8,17 (3H, s).

Example94

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinanilide

1) To a solution (20 ml) of tert-Butyl{[5-(aminocarbonyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1750 mg, 4.2 mmol) in dichloromethane was added triethylamine (1.2 ml, 8.4 mmol) and relax is whether dropwise under ice cooling triftormetilfullerenov anhydride (780 ml, 8.4 mmol). The mixture was stirred for 30 min, then the reaction mixture was washed successively with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-cyano-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1130 mg, yield 68%) as white crystals.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.40 (9H, s), 2,20-to 2.29 (1H, m), 2,43 (3H, s), 2,77 (3H, s), and 2.83 (2H, d, J=9.0 Hz), 4,18 (2H, s), 4,20 (1H, USS), 7,13 (2H, d, J=6.0 Hz), 7,31 (2H, d, J=6.0 Hz).

2) Dihydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinanilide (81 mg, yield 88%) was obtained as a white powder from tert-butyl{[5-cyano-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (100 mg, 0.25 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2.21 are of 2.27(1H, m), 2,42 (3H, s), a 2.71 (3H, s), 2,89 (2H, d, J=6.9 Hz), 3,82 (2H, d, J=5.4 Hz), 7,33-7,40 (4H, m), and 8.50 (3H, USS).

Example95

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]urea

1) To a solution (3 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) in N,N-dimethylformamide was added triethylamine (170 μl, 1.5 mmol) was added dropwise under ice cooling is openinputfile (260 μl, 1.5 mmol). The mixture was stirred for 30 min and added to her water. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in toluene (3 ml). The mixture was heated at the boil under reflux with stirring for 1 h was Added to the reaction mixture of 25% aqueous ammonia (3 ml) and the mixture was stirred at 100°C for 1 h was Added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[(aminocarbonyl)amino]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (101 mg, yield 24%) as white crystals.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.26 (1H, m), 2,39 (3H, s), of 2.56 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 4,10 (2H, d, J=5,1 Hz), 4,24 (1H, OSS), to 4.38 (2H, s), of 5.50 (1H, s), 7,01 (2H, d, J=7.5 Hz,), from 7.24 (2H, d, J=7.5 Hz).

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]urea (84 mg, yield 92%) was obtained as a white powder from tert-butyl{[5-[(aminocarbonyl)amino]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}CT is Amata (100 mg, 0.23 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=5.4 Hz), 2,14-2,19 (1H, m), is 2.40 (3H, s), of 2.53 (3H, s), 3,0, (2H, USS), 3,80 (2H, USS), 3,83 (1H, USS), 5,94 (1H, USS), 7,20 (2H, d, J=7,8gts), was 7.36 (2H, d, J=7.8 Hz), 8,28 (3H, USS).

Example96

The dihydrochloride of N'-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N,N-dimethylation

1) tert-Butyl{[5-{[(dimethylamino)carbonyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (158 mg, yield 35%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and 2M tertrahydrofuran ring solution of dimethylamine (0.6 ml, 1.2 mmol) in a manner similar to the method of example 95-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15 was 2.25 (1H, m), is 2.41 (3H, s), of 2.51 (3H, s), 2,71 (6H, s)of 2.75 (2H, d, J=9.0 Hz), 4,08 (2H, d, J=5,1 Hz)to 4.23 (1H, USS), 5,32 (1H, s), 7,02 (2H, d, J=7,8 Hz), from 7.24 (2H, d, J=7,8 Hz).

2) Dihydrochloride N'-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N,N-dimethylation (108 mg, yield 73%) was obtained as a white powder from tert-butyl{[5-{[(dimethylamino)carbonyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (158 mg, 0,35 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.3 Hz), 2,17-of 2.20 (1H, m), 2,39 (3H, s), 2,64 (9H, s)to 3.09 (2H, USS), 3,83 (2H, USS), 7,20 (2H, d, J=7.8 Hz), 7,31 (2H, d, J=7.8 Hz), 7,86 (1H, USS), 8,39 (3H, USS).

b> Example97

The dihydrochloride benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate

1) Benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate (1600 mg, yield 35%) was obtained as a white powder from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (3700 mg, 8.9 mmol) and benzyl alcohol (2.3 ml, 10,7 mmol) in a manner similar to the method of example 95-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.16 (1H, m), 2,39 (3H, s), of 2.51 (3H, s)of 2.75 (2H, d, J=7,2 Hz), 4,08 (2H, s), 4,22 (1H, USS), 5,07 (2H, s)5,70 (1H, OSS), to 6.95 (2H, USS), 7,17 (2H, d, J=7,8 Hz), 7,20-7,26 (2H, m), 7,31 and 7.36 (3H, m).

2) Dihydrochloride benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate (54 mg, yield 76%) was obtained as a white powder from benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate (75 mg, 0.14 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.3 Hz), 2,15-2,22 (1H, m), 2,39 (3H, s), of 2.56 (3H, s), 2,99 (2H, s), with 3.79 (2H, s)to 5.00 (2H, s), 7,14-to 7.18 (4H, m), 7,29-to 7.35 (5H, m), 8,29 (3H, USS), the remaining 9.08 (1H, USS).

Example98

Trihydrochloride 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)-3-pyridylamine

1) To a solution (100 ml) of benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate (1500 mg, 2.9 mmol) in ethanol was added to the 5% palladium on carbon (150 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1000 mg, yield 90%) as a white powder.

1H-NMR (CDCl3) δ: of 0.94 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,09-of 2.16 (1H, m), is 2.41 (3H, s), 2,42 (3H, s), 2,65 (2H, d, J=7,2 Hz), or 3.28 (2H, s), was 4.02 (2H, USS), 4,22 (1H, USS), 7,06 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=7,7 Hz).

2) Trihydrochloride 5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)-3-pyridylamine (34 mg, yield 62%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (50 mg, 0.13 mmol) by the method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.94 (6H, d, J=6.6 Hz), 1,97-of 2.08 (1H, m), 2,42 (3H, s)to 2.65 (3H, s), 2,99 (2H, s), of 3.69 (2H, s), of 5.40 (3H, USS), 7,26 (2H, d, J=8,1 Hz), 7,44 (2H, d, J=8.1 Hz), scored 8.38 (3H, USS).

Example99

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methanesulfonamide

To a solution of tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (100 mg, 0.26 mmol) in tetrahydrofuran (2 ml) was added triethylamine (54 μl, 0,39 mmol) was added at room temperature methanesulfonamide (30 μl, 0,39 mmol). Then the mixture was stirred for 3 hours was Added to the reaction mixture water and the mixture was extracted with ethyl is the Etat. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the oil in ethyl acetate (1 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h the Solvent is evaporated under reduced pressure and the obtained residue was led from hexane to obtain the dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methanesulfonamide (25 mg, yield 22%) as a white powder.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,18-of 2.24 (1H, m), of 2.20 (3H, s), 2,39 (3H, s), a 2.71 (3H, s), 2,96 (2H, s), with 3.79 (2H, s), 7,28 (2H, d, J=6,GC), 7,34 (2H, d, J=6.9 Hz), 8,32 (3H, USS), 9,27 (1H, USS).

Example100

The dihydrochloride of N-[5-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}sulfonyl)-4-methyl-1,3-thiazol-2-yl]ndimethylacetamide

The dihydrochloride of N-[5-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}sulfonyl)-4-methyl-1,3-thiazol-2-yl]ndimethylacetamide (58 mg, yield 39%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (100 mg, 0.26 mmol) and 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulphonylchloride (76 mg, 0.3 mmol) by the method similar to the method of example 99.

1H-NMR (DMSO-d6) δ: of 0.94 (6H, d, J=6.6 Hz), 2,02 (3H, s), are 2.19 (3H, s), 2,18-of 2.23 (1H, m), and 2.27 (3H, s), of 2.53 (3H, s)2,84 (2H, USS), of 3.69 (2H, USS), 6,92-6,97 (4H, m), 8,10 (3H, USS), of 9.89 (1H, USS).

Example101

Trihydrochloride {[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine

1) a Mixture of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,16 g, only 2.91 mmol), triethylamine (0.8 ml, of 5.82 mmol) and tetrahydrofuran (15 ml) was cooled to 0°C was added dropwise methanesulfonate (500 mg, 4,37 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate in the form of a crude product. The crude product was dissolved in N,N-dimethylformamide (30 ml) was added sodium azide (379 mg, of 5.82 mmol). The mixture was stirred at 80°C for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain a residue. A mixture of the obtained residue, 10% palla the Oia on carbon (304 mg, 0,291 mmol) and ethanol (15 ml) was stirred in hydrogen atmosphere at room temperature for 2 hours After filtration the solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (690 mg, yield 60%) as a yellow oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s)of 1.41 (2H, USS), 2,14-of 2.23 (1H, m), is 2.41 (3H, s)of 2.64 (3H, s), was 4.02 (2H, d, J=5,1 Hz), 4,18 (1H, USS), 7,02 (2H, d, J=7.9 Hz), 7,25 (2H, d, J=7,0 Hz).

2) Trihydrochloride {[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine (204 mg, yield 99%) was obtained as a white powder from tert-butyl{[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (200 mg, 0,503 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,13-of 2.24 (1H, m), 2,43 (3H, s)of 2.50 (3H, s), 2,98 (2H, USS), 3,76 (4H, USS), 7,34 was 7.45 (4H, m), 8,51 (6H, USS).

Example102

The dihydrochloride of N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-4-(methylsulphonyl)benzosulfimide

1) To a solution (10 ml) of tert-butyl{[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (290 mg, advanced 0.729 mmol) and triethylamine (0.15 ml, of 1.09 mmol) in tetrahydrofuran was added 4-(methylsulphonyl)benzosulphochloride (223 mg, 0,875 mmol) and the mixture is eremetical at room temperature for 1 h The reaction mixture was diluted with ethyl acetate (100 ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting yellow solid is washed with diisopropyl ether to obtain tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[({[4-(methylsulphonyl)phenyl]sulfonyl}amino)methyl]pyridin-3-yl}methyl)carbamate (391 mg, yield 87%) as a yellow powder.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), of 1.36 (9H, s), 2,13-2,22 (1H, m), is 2.41 (3H, s), 2,61 (3H, s), 2,73 (2H, d, J=7,4 Hz), is 3.08 (3H, s), 3,83 (2H, d, J=5.8 Hz), of 3.97 (2H, d, J=4.9 Hz), 4,11-4,20 (2H, m), at 6.84 (2H,, d, J=8.1 Hz), 7,13 (2H, d, J=7,7 Hz), to 7.77 (2H, d, J=8.7 Hz), 7,98 (2H, d, J=8,5 Hz).

2) of the Dihydrochloride of N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-4-(methylsulphonyl)benzosulfimide (370 mg, yield 99%) was obtained as a yellow powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[({[4-(methylsulphonyl)phenyl]sulfonyl}amino)methyl]pyridine-3-yl}methyl)carbamate (391 mg, 0,635 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,11-2,19 (1H, m)to 2.35 (3H, s)of 2.50 (3H, s), 2,70-2,82 (2H, m), and 3.31 (3H, s), 3,66 (2H, USS), and 3.72 (2H, USS), 7,11-7,21 (4H, m), 7,83 (2H, DD, J=8,3, 1.3 Hz), 8,08 (2H, d, J=8,1 Hz), 8,31 (3H, USS).

Example103

Trihydrochloride ethyl({[5-(aminomethyl)-6-isobutyl-2-methyl-(4-were)pyridine-3-yl]methyl}amino)acetate

1) To a solution of [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (300 mg, to 0.63 mmol) in tetrahydrofuran (5 ml) was added triethylamine (223 μl, 1.6 mmol) and hydrochloride complex ethyl ester of glycine (100 mg, 0.7 mmol) and the mixture was stirred at 60°C for 3 days. Was added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain ethyl({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetate (185 mg, yield 61%) as a white powder.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.22 (3H, t, J=6,GC), to 1.38 (9H, s), 2,15-2,22 (1H, m), is 2.41 (3H, s)to 2.67 (3H, s), 2,73 (2H, d, J=7,2 Hz), 3,18 (2H, s), of 3.43 (2H, s), was 4.02 (2H, s), 4.09 to (2H, q, J=6,GC), 4,18 (1H, USS), 7,03 (2H, d, J =7,8gts), 7,25 (2H, d, J=7,8 Hz).

2) Trihydrochloride ethyl({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetate (57 mg, yield 95%) was obtained as white powder from ethyl({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetate (60 mg, 0.12 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), of 1.18 (3H, the, J=6.9 Hz), 2,11-of 2.24 (1H, m), 2,42 (3H, s), of 2.92 (3H, USS), 3,03 (2H, USS), 3,61 (2H, s), and 3.72 (2H, USS), 4,06 (2H, s)4,08 (2H, q, J=6.9 Hz), 7,35 (2H, d, J =8,1 Hz), 7,40 (2H, d, J=8.1 Hz), 8,43 (3H, USS).

Example104

Trihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetic acid

1) To a solution of ethyl({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetate (100 mg, 0.2 mmol) in ethanol (3 ml) was added 8h. an aqueous solution of sodium hydroxide (3 ml) and the mixture was stirred at 80°C for 15 h was Added 1N. hydrochloric acid to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetic acid (92 mg, yield 99%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.91 (6H, d, J=6.3 Hz), of 1.35 (9H, s), 2,11-of 2.24 (1H, m), a 2.36 (3H, s)to 2.54 (2H, s), to 2.57 (3H, s), 2,97 (2H, s), 3,39 (2H, s), 3,76 (2H, s), is 6.78 (1H, USS), 7,18 (2H, d, J =7,8gts), 7,22 (2H, d, J=7,8 Hz).

2) Trihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetic acid (75 mg, yield 80%) was obtained as a white powder ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-m is terphenyl)pyridine-3-yl]methyl}amino)acetic acid (90 mg, 0.2 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,14-of 2.21 (1H, m), 2,42 (3H, s), 2,89 (3H, s), 3,01 (2H, USS), 3,52 (2H, s), and 3.72 (2H, s), Android 4.04 (2H, s), 7,35 (2H, d, J =8.1 Hz), 7,39 (2H, d, J=8.1 Hz), of 8.37 (3H, USS), 9,29 (1H, USS).

Example105

Trihydrochloride 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2-piperazinone

1) tert-Butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(3-oxo-1-piperazinil)methyl]pyridine-3-yl}methyl)carbamate (78 mg, yield 77%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (300 mg that was 0.63 mmol) and 2-piperazinone (65 mg, of 0.65 mmol) in a manner similar to the method of example 103-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14-of 2.23 (1H, m), 2.49 USD (5H, s)of 2.64 (3H, s), 2,73 (2H, d, J=7,2 Hz), 2,89 (2H, s), up 3.22 (2H, USS), or 3.28 (2H, s)to 4.01 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 5,69 (1H, USS), of 6.96 (2H, d, J=7.8 Hz), 7,21 (2H, d, J=7,8 Hz).

2) Trihydrochloride 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2-piperazinone (64 mg, yield 87%) was obtained as a white powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(3-oxo-1-piperazinil)methyl]pyridine-3-yl}methyl)carbamate (75 mg, 0.15 mmol) by the method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), at 1.91 (2H, s), 2,09 with 2.14 (1H, m), 2,42 (3H, s)of 3.00 (3H, USS), 3,18 (4H, OSS in), 3.75 (2H, USS), 7,30 (2H, d, J=7.5 Hz), 7,41 (2H, d, J=7.5 Hz), 7,41 (1H, USS), and 8.2 (3H, OSS).

Example106

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2,4-imidazolidinedione

1) To a solution of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (100 mg, 0.25 mmol), as (38 mg, 0.38 mmol) and tributylphosphine (95 μl, 0.38 mmol) in tetrahydrofuran (3 ml) was added 1,1'-(azodicarbon)dipiperidino (96 mg, 0.38 mmol) and the mixture was stirred at room temperature for 4 h the Reaction mixture was concentrated and insoluble the substance was filtered. The filtrate was purified column chromatography on silica gel to obtain tert-butyl{[5-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (68 mg, yield 57%) as a white powder.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,11-of 2.26 (1H, m), 2,39 (3H, s)to 2.55 (3H, s), 2,73 (2H, d, J=7.5 Hz), of 3.77 (2H, s)to 3.99 (2H, d, J=5,1 Hz)to 4.23 (1H, OSS), to 4.46 (2H, s), 5,10 (1H, USS), 7,07 (2H,, d, J=7.8 Hz), 7.23 percent (2H, d, J=7,8 Hz).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2,4-imidazolidinedione (54 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate way like the way example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14-2,19 (1H, m), is 2.37 (3H, s)2,84 (3H, s), 3,11 (2H, USS, 3,71 (4H, s), 4,35 (2H, s), 7,18 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=7.8 Hz), 8,00 (1H, USS), 8,30 (1H, USS).

Example107

The dihydrochloride of 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2,5-piperazinone

1) To a solution of Z-glycine (1.2 g, 6 mmol) and N,N-dimethylformamide (10 ml) in tetrahydrofuran (5 ml) was added oxalicacid (530 ml, 6 mmol) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was added dropwise to a solution of ethyl({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}amino)acetate (1.4 g, 3 mmol), pyridine (970 ml, 12 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran (10 ml) under ice cooling and the mixture was stirred for 3 hours To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting oil was dissolved in ethanol (10 ml). Was added 5% palladium on carbon (100 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[(2,5-dioxo-1-piperazinil)methyl]-2-isobutyl-6-methyl-4-(4-methyl who enyl)pyridine-3-yl]methyl}carbamate (35 mg, the output of 2.4%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.24 (1H, m), is 2.40 (3H, s), of 2.51 (3H, s), was 2.76 (2H, d, J=7,5 Hz), 3,47 (2H, s), 3,93 (2H, s), a 4.03 (2H, d, J=5,1 Hz), 4,24 (1H, USS), 4,51 (2H, s), 5,88 (1H, USS), 6,98 (2H, d, J=7.5 Hz), 7,25 (2H, d, J=7.5 Hz).

2) of the Dihydrochloride of 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-2,5-piperazinone (14 mg, yield 60%) was obtained as a white powder from tert-butyl{[5-[(2,5-dioxo-1-piperazinil)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate way like the way example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,15-2,19 (1H, m), 2,39 (3H, s), 2,69 (3H, s)of 3.25 (2H, s)to 3.67 (2H, s), of 3.73 (2H, USS), or 4.31 (2H, s), 7,18 (2H, d, J=8.1 Hz), 7,37 (2H, d, J=7.8 Hz), of 8.06 (1H, USS), 8,24 (3H, USS).

Example108

The dihydrochloride {[2-isobutyl-4-(4-were)-6-vinylpyridin-3-yl]methyl}amine

1) To a solution (140 ml) of acetophenone (8,40 g, 70 mmol) and p-tolualdehyde (8,40 g, 70 mmol) in ethanol was added sodium hydroxide (7.0 g, 175 mmol) and the mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting yellow solid is washed with diisopropyl ether to obtain (2E)-3-(4-were)-1-phenylprop-2-EN-1-it (9,12 g, yield 59%) as a yellow powder.

1H-I Is R (CDCl 3) δ: 2,40 (3H, s), 7.23 percent (2H, d, J=8.1 Hz), 7,47 to 7.62 (6H, m), 7,80 (1H, d, J=15,8 Hz), 8,00-8,03 (2H, m).

2) a Mixture of 5-methyl-3-oxopentanenitrile (5.0 g, 40 mmol), acetic acid (2.3 ml, 40 mmol), ammonium acetate (15,4 g, 200 mmol) and toluene (250 ml) was heated at boiling under reflux, using a trap Dean-stark, within 12 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the residue (4.5 g). The residue (2.25 g) was dissolved in ethanol (100 ml) was added (2E)-3-(4-were)-1-phenylprop-2-EN-1-he (of 3.69 g of 16.6 mmol) and sodium hydroxide (0.8 g, 20 mmol). The mixture was heated at the boil under reflux for 3 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 2-isobutyl-4-(4-were)-6-fenilcetonuria (2,68 g, yield 49%) as a yellow oil.

1H-NMR (CDCl3) δ with 1.07 (6H, d, J=6.8 Hz), 2,35-2,48 (4H, m), 3,06 (2H, d, J=7,2 Hz), 7,35 (2H, d, J=7.9 Hz), 7,49-7,56 (5H, m), to 7.67 (1H, s), 8.07-a 8,13 (1H, m).

3) {[2-Isobutyl-4-(4-were)-6-vinylpyridin-3-yl]methyl}amine (1.70 g, yield 63%) was obtained as a yellow the oil from 2-isobutyl-4-(4-were)-6-fenilcetonuria (2.65 g, to 8.12 mmol) in a manner similar to the method of example 1-4). The oil was dissolved in 4n. 1,4-dioxane solution of hydrogen chloride (20 ml) and the solvent evaporated under reduced pressure. The yellow solid is washed with diisopropyl ether to obtain dihydrochloride {[2-isobutyl-4-(4-were)-6-vinylpyridin-3-yl]methyl}amine (1,99 g, yield 96%) as a yellow powder.

1H-NMR (DMSO-d6) δ: of 1.03 (6H, d, J=6.6 Hz), 2,34-to 2.41 (4H, m)to 2.94 (2H, d, J=7,0 Hz), 4,00 (2H, d, J=5.5 Hz), was 7.36 (2H, d, J=8,2 Hz), 7,41 (2H, d, J=8,3 Hz), 7,47-rate of 7.54 (3H, m), of 7.70 (1H, s), 8,15 (2H, DD, J=7,9, 1.5 Hz), 8,43 (3H, USS).

Example109

Maleate 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid

5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.50 g, 4,80 mmol) was dissolved in a mixed solvent of water (15 ml) and acetonitrile (15 ml) and the mixture was heated at the boil under reflux for 10 minutes To the resulting solution was added maleic acid (558 mg, 4,80 mmol) and the mixture was stirred at the same temperature for 10 minutes To the resulting solution was added acetonitrile (200 ml) and the mixture was allowed to cool to room temperature and stirred its at 0°C for 30 minutes, Dropped precipitated solid substance was collected by filtration and washed with acetonitrile (30 ml) to give the maleate 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (667 mg, yield 32%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m), is 2.37 (3H, s), is 2.74 (2H, d, J=7,0 Hz), with 3.79 (2H, s), 6,01 (2H, s), 7,19 (2H, d, J=7.9 Hz), 7,29 (2H, d, J=7.5 Hz).

Example110

The dihydrochloride of 5-(aminomethyl)-6-(methoxymethyl)-2-methyl-4-(4-were)nicotinic acid

1) Solution (40 ml) of methyl-4-methoxyacetanilide (5,85 g, 40 mmol), p-tolualdehyde (to 4.81 g, 40 mmol), piperidine (340 mg, 4 mmol) and acetic acid (240 mg, 4 mmol) in isopropanol was stirred at room temperature for 3 days. The solvent is evaporated under reduced pressure to obtain a residue. 3-Methyl-5-tert-butyl-2-(methoxymethyl)-6-methyl-4-(4-were)-1,4-dihydropyridines-3,5-in primary forms (5,85 g, yield 50%) was obtained as a yellow oil from the obtained residue and tert-butyl-3-aminocrotonate (4.71 g, 30.0 mol) in a manner similar to the method of example 1-2). Namely, the above residue and tert-butyl-3-aminocrotonate was dissolved in methanol (30 ml) and the mixture was heated at the boil under reflux for 1.5 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel with 3-methyl-5-tert-butyl-2-(methoxymethyl)-6-methyl-4-(4-were)-1,4-dihydropyridines-3,5-in primary forms.

1H-NMR (CDCl3) δ: of 1.40 (9H, s), of 2.28 (3H, s), 2,32 (3H, s), 3.45 points-of 3.46 (3H, m), 3,62-3,63 (3H, m), 4,55 was 4.76 (2H, m), 4,89-of 4.95 (1H, m)6,94 (1H, USS), 7,01 (2H, d, J=7,7 Hz), to 7.15 (2H, d, J=8,1 Hz).

2) 3-Methyl--tert-butyl-2-(methoxymethyl)-6-methyl-4-(4-were)pyridine-3,5-in primary forms (of 3.78 g, yield 65%) was obtained as a yellow oil from 3-methyl-5-tert-butyl-2-(methoxymethyl)-6-methyl-4-(4-were)-1,4-dihydropyridines-3,5-in primary forms (5,85 g, 15.1 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 1.23 (9H, s), is 2.37 (3H, s), 2,61 (3H, s)to 3.36 (3H, s), of 3.54 (3H, s), of 4.66 (2H, s), 7,13-to 7.15 (2H, m), 7,17-7,19 (2H, m).

3) a Suspension of 3-methyl-5-tert-butyl-2-(methoxymethyl)-6-methyl-4-(4-were)pyridine-3,5-in primary forms (of 3.78 g, 9,81 mmol) in toluene (50 ml) was cooled to -78°C and added dropwise within 15 min 1,50M toluene solution of hydride diisobutylaluminum (25 ml, 24.5 mmol). The mixture was stirred at -78°C for 30 min, allowed to warm to 0°C and was further stirred for 10 minutes was Added to the reaction mixture, methanol (0.5 ml) and 10-hydrate of sodium sulfate (8.1 g, 9.8 mmol). The mixture was stirred at room temperature for 1 h, the Insoluble substance was filtered and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl-5-(hydroxymethyl)-6-(methoxymethyl)-2-methyl-4-(4-were)nicotinate (810 mg, yield 23%) as a yellow oil.

1H-NMR (CDCl3) δ: 1,21 (9H, s), 2,39 (3H, s)at 2.59 (3H, s), 3,50 (3H, s), 4,39 (2H, d, J=6.8 Hz), was 4.76 (2H, s), 7,21 (4H, s).

4) a Mixture of tert-butyl 5-(hydroxymethyl)-6-(methoxymethyl)-2-methyl-4-(4-were)nicotinate (810 mg, of 2.27 mmol), triethylamine (0.63 ml, of 4.54 mmol) and then it is carbonated is rufuran (30 ml) was cooled to 0°C was added dropwise methanesulfonanilide (of 0.26 ml, 3,40 mmol). After stirring at room temperature for 30 min, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (20 ml) was added sodium azide (296 mg, of 4.54 mmol). The mixture was stirred at 80°C for 1 h was Added to the reaction mixture ethyl acetate, and the mixture was washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. A mixture of the residue, 10% palladium on carbon (242 mg, 0,227 mmol) and ethanol (30 ml) was stirred in hydrogen atmosphere at room temperature for 30 minutes After filtration the solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl-5-(aminomethyl)-6-(methoxymethyl)-2-methyl-4-(4-were)nicotinate (600 mg, yield 74%) as a yellow oil.

1H-NMR (CDCl3) δ: 1,19 (9H, s), is 2.40 (3H, s), to 2.57 (3H, s), of 3.48 (3H, s), 3,63 (2H, s), 4,69 (2H, s), 7,12 (2H, d, J=8.1 Hz), 7.23 percent (2H, d, J=7,7 Hz).

5) Dihydrochloride 5-(aminomethyl)-6-(methoxymethyl)-2-methyl-4-(4-were)nicotinic acid (533 mg, yield 84%) was obtained as a white powder from tert-butyl 5-(aminomethyl)-6-(is ethoxymethyl)-2-methyl-4-(4-were)nicotinate (600 mg, 1,69 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, s), of 2.53 (3H, s)to 3.41 (3H, s), 3,86 (2H, d, J=5.7 Hz), was 4.76 (2H, s), from 7.24 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 8,10 (3H, USS).

Example111

Trihydrochloride 5,6-bis(aminomethyl)-2-methyl-4-(4-were)nicotinic acid

1) Ethyl-3-amino-4-[(tert-butoxycarbonyl)amino]but-2-ENOAT (5,37g, yield 99%) was obtained as a yellow oil from ethyl-4-[(tert-butoxycarbonyl)amino]-3-oxobutanoate (5,4 g of 22.0 mmol) in a manner similar to the method of example 108-2).

1H-NMR (CDCl3) δ: 1.26 in (3H, t, J=7.2 Hz), of 1.46 (9H, s), of 3.77 (2H, d, J=6.6 Hz), of 4.12 (2H, q, J=7,1 Hz), 4,55 (1H, s).

2) a Mixture of tert-butylacetoacetate and 4.75 g, 30 mmol), p-tolualdehyde (4,51 g, 37.5 mmol), piperidine (0,30 ml, 3.00 mmol) and ethanol (0.2 ml) was stirred at room temperature for days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue and ethyl-3-amino-4-[(tert-butoxycarbonyl)amino]but-2-ENOAT (lower than the 5.37 g of 22.0 mmol) was stirred at 80°C for 30 min and was further stirred at 130°C for 3 hours the mixture was purified column chromatography on silica gel with 3-ethyl-5-tert-butyl-2-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-4-(4-were)-1,4-dihydropyridines-3,5-dicarbon elata (1,95 g, yield 18%) as a yellow oil.

1H-NMR (CDCl3) δ: 1,22 of 1.28 (3H, m)of 1.40 (9H, s)of 1.46 (9H, s), and 2.27 (6H, s), 4.04 the-4,18 (3H, m), 4,37-of 4.44 (1H, m), to 4.87 (1H, s), to 5.35 (1H, USS), 7,01 (2H, d, J=7.9 Hz), to 7.15 (2H, d, J=8,1 Hz).

3) 3-Ethyl-5-tert-butyl-2-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-4-(4-were)pyridine-3,5-in primary forms (1,94 g, yield 99%) was obtained as a yellow oil from 3-ethyl-5-tert-butyl-2-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-4-(4-were)-1,4-dihydropyridines-3,5-in primary forms (1,95 g to 4.01 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.93 (3H, t, J=7.2 Hz), of 1.23 (9H, s)of 1.47 (9H, s), is 2.37 (3H, s), 2,61 (3H, s), was 4.02 (2H, q, J=7,1 Hz), 4,50 (2H, d, J=4,7 Hz), by 5.87 (1H, USS), 7,13 (2H, d, J=8,3 Hz), 7,17 (2H, d, J=8,3 Hz).

4) tert-Butyl-6-{[(tert-butoxycarbonyl)amino]methyl}-5-(hydroxymethyl)-2-methyl-4-(4-were)nicotinate (1.45 g, yield 82%) was obtained as a yellow oil from 3-ethyl-5-tert-butyl-2-{[(tert-butoxycarbonyl)amino]methyl}-6-methyl-4-(4-were)pyridine-3,5-in primary forms (1,94 g, 4.00 mmol) method like way of example 110-3).

1H-NMR (CDCl3) δ: of 1.20 (9H, s)of 1.46 (9H, s), 2,39 (3H, s), to 2.57 (3H, s)to 3.38 (1H, OSS), to 4.46 (2H, d, J=6.0 Hz), of 4.54 (2H, d, J=5.8 Hz), by 5.87 (1H, USS), 7,18 (2H, d, J=8,3 Hz), 7,21 (2H, d, J=8,3 Hz).

5) tert-Butyl-5-(aminomethyl)-6-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)nicotinate (580 mg, yield 40%) was obtained as a white powder from tert-butyl 6-{[(tert-butoxycarbonyl)amino]methyl}-5-(hydroxymethyl)-2-methyl-4-(4-IU is ylphenyl)nicotinate (1.45 g, of 3.28 mmol) in a manner similar to the method of example 110-4).

1H-NMR (CDCl3) δ: 1,18 (9H, s), for 1.49 (9H, s), 2,39 (3H, s), of 2.56 (3H, s), 3,62 (2H, s), 4,58 (2H, d, J=4,7 Hz), to 6.22 (1H, USS), 7,10 (2H, d, J=8.1 Hz), 7,22 (2H, d, J=7.9 Hz).

6) Trihydrochloride 5,6-bis(aminomethyl)-2-methyl-4-(4-were)nicotinic acid (510 mg, yield 99%) was obtained as yellow solid from tert-butyl 5-(aminomethyl)-6-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)nicotinate (580 mg, 1,31 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, s), to 2.57 (3H, s), 3,84-to 3.89 (2H, m), 4,51-br4.61 (2H, m), 7.23 percent (2H, d, J=7.9 Hz), 7,31 (2H, d, J=7.9 Hz), 8,42 (3H, USS), 8,54 (3H, USS).

Example112

Hydrochloride 5-(aminomethyl)-6-hydroxy-2-methyl-4-(4-were)nicotinic acid

1) a Mixture of tert-butylacetoacetate and 4.75 g, 30 mmol), p-tolualdehyde (4,51 g, 37.5 mmol), piperidine (0,30 ml, 3.00 mmol) and ethanol (0.2 ml) was stirred at room temperature for days. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue, ethylcinnamate (6,79 g, 60,0 mmol) and ammonium acetate (11.6 g, 150 mmol) was stirred at 140°C for 3 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated aqueous solution of sodium bicarbonate. Organizes the second layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain tert-butyl-5-cyano-6-hydroxy-2-methyl-4-(4-were)nicotinate (0.87 g, yield 9%) as a white solid.

1H-NMR (CDCl3) δ: 1,19 (9H, s)to 2.41 (3H, s), to 2.57 (3H, s), 7.24 to 7,31 (4H, m).

2) tert-Butyl-5-(aminomethyl)-6-hydroxy-2-methyl-4-(4-were)nicotinate was obtained as a white solid from tert-butyl 5-cyano-6-hydroxy-2-methyl-4-(4-were)nicotinate (0.50 g, 1.54 mmol) in a manner similar to the method of example 1-4). Then got tert-butyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-hydroxy-2-methyl-4-(4-were)nicotinate (210 mg, yield 32%) as a colorless oil by the method similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 1,13 (9H, s)of 1.39 (9H, s), of 2.38 (3H, s), 2,43 (3H, s), was 4.02 (2H, d, J=5.8 Hz), 7,10 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz), KZT 12.39 (1H, USS).

3) Hydrochloride 5-(aminomethyl)-6-hydroxy-2-methyl-4-(4-were)nicotinic acid (167 mg, yield 99%) was obtained as a white solid from tert-butyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-hydroxy-2-methyl-4-(4-were)nicotinate (210 mg, 0,490 mmol) in a manner similar to the method of example 24-1).

1H-NMR (DMSO-d6) δ: of 2.33 (3H, s)to 2.35 (3H, s), 3,51 (2H, s), to 7.15 (2H, d, J=7.9 Hz), 7,26 (2H, d, J=7.9 Hz), 7,94 (3H, USS), 12,42 (1H, s), 12,74 (1H, s).

Example113

DATEFORMAT 5-(aminomethyl)-N,6-Diisobutyl-2-methyl-4-(4-were)nicotinamide

5-{[(tert-Buto is dicarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (23.9 mg, 0.06 mmol), isobutylamine (5.3 mg, 0,072 mmol), 1-hydroxy-1H-benzotriazole (11.0 mg, 0,072 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (13,8 mg, 0,072 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (1.25 ml)-dichloromethane (0.4 ml) and the mixture was stirred at 50°C for 2 days. The reaction mixture was diluted with dichloromethane (3 ml) and washed sequentially with saturated aqueous sodium hydrogen carbonate solution (0.5 ml) and saturated salt solution (0.5 ml). To the organic layer were added triperoxonane acid (2 ml) and the mixture was stirred for 2 hours, the Solvent is evaporated under reduced pressure and the residue was purified preparative HPLC to obtain DATEFORMAT 5-(aminomethyl)-N,6-Diisobutyl-2-methyl-4-(4-were)nicotinamide (of 22.4 mg, yield 63%) as a yellow oil.

EIMC (M+1): 368

Connection examples 114-168 synthesized from nicotinic acid and amines in accordance with the following tables 1-4 manner similar to the method of example 113. Connection examples 162-164 was obtained in a free form by neutralization of the resulting trifenatate amides of nicotinic acid with a saturated aqueous solution of sodium bicarbonate.

Table 1
Example-NR5aR6a -R3EIMC (M+1)HA
1134-Me-phenyl3682CF3COOH
1144-Me-phenyl3682CF3COOH
1154-Me-phenyl3802CF3COOH
1164-Me-phenyl4022CF3COOH
1174-Me-phenyl4162CF3COOH
1184-Me-phenyl3842CF3COOH
119 4-Me-phenyl4322CF3COOH
1204-F-phenyl4362CF3COOH
1212,6-di-F-phenyl4542CF3COOH
1224-Me-phenyl4602CF3COOH
1234-F-phenyl4642CF3COOH
1242,6-di-F-phenyl4822CF3COOH
1254-Me-phenyl4302CF3COOH
4-F-phenyl4342CF3COOH
1272,6-di-F-phenyl4522CF3COOH

Table 2
Example-NR5aR6a-R3EIMC (M+1)HA
1284-Me-phenyl4372CF3COOH
1294-F-phenyl4402CF3COOH
1302,6-di-F-phenyl4582CF3COOH
131 4-Me-phenyl4372CF3COOH
1324-F-phenyl4402CF3COOH
1332,6-di-F-phenyl4582CF3COOH
1344-Me-Phenyl4372CF3COOH
1354-F-Phenyl4402CF3COOH
1362,6-di-F-phenyl4582CF3COOH
1374-Me-phenyl4122CF3COOH
1384-Me-phenyl4122CF3COOH
1392,6-di-F-phenyl4342CF3COOH
1404-Me-phenyl3542CF3COOH
1414-Me-phenyl3662CF3COOH
1424-F-phenyl3702CF3COOH
1432,6-di-F-phenyl3882CF3COOH

Table 3
Example -NR5aR6a-R3EIMC (M+1)HA
1444-Me-phenyl3682CF3COOH
1454-Me-phenyl3822CF3COOH
1464-F-phenyl3862CF3COOH
1472,6-di-F-phenyl4042CF3COOH
1484-Me-phenyl3842CF3COOH
1492,6-di-F-phenyl4062CF3COOH
1504-Me-phenyl4082CF3COOH
1512,6-di-F-phenyl4302CF3COOH
1524-Me-phenyl4162CF3COOH
1534-Me-phenyl4242CF3COOH
1544-F-phenyl4282CF3COOH
1552,6-di-F-phenyl4462CF3COOH
1564-Me-phenyl457CF 3COOH
1574-F-phenyl4613CF3COOH
1584-Me-phenyl4713CF3COOH

Table 4
Example-NR5aR6a-R3EIMC (M+1)HA
1594-Me-phenyl4923CF3COOH
1604-F-phenyl4963CF3COOH
1614-Me-phenyl3542CF3COOH
1624-Me-phenyl455
1634-F-phenyl459
1642,6-di-F-phenyl477
1654-F-phenyl3842CF3COOH
1662,6-di-F-phenyl4022CF3COOH
1674-F-phenyl3442CF3COOH
1682,6-di-F-phenyl3622CF3COOH

P is the iMER 169

The dihydrochloride 4-(methoxycarbonyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (20 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.00 g, is 4.85 mmol) in N,N-dimethylformamide was added methyl-4-(methyl bromide)benzoate (1.22 g, 5.33 mmol) and potassium carbonate (1.01 g, 7,28 mmol) and the mixture was stirred at room temperature for 14 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of the salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.50 g, yield 92%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14 was 2.25 (1H, m)to 2.35 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,2 Hz), 3,93 (3H, s), of 4.12 (2H, d, J=7,0 Hz), is 4.21 (1H, OSS), to 4.98 (2H, s), 7,01 (2H, d, J=7.9 Hz), 7,07 for 7.12 (4H, m), to 7.93 (2H, d, J=8,3 Hz).

2) Dihydrochloride 4-(methoxycarbonyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (427 mg, yield 90%) was obtained as a white powder from 4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.50 g, 0,892 mmol) in a manner similar to the method of example 2-3.

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.8 Hz), measuring 2.20 (1H, m), of 2.34 (3H, s), 2,85 (2H, d, J=6.6 Hz), 3,80 (2H, d, J=5.3 Hz), a 3.87 (3H, s), 5,07 (2H, s), 7,13-7,16 (4H, m), 7,20 (2H, d, J=7.9 Hz), 7,87 (2H, d, J=8,3 Hz), by 8.22 (3H, USS).

Example170

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid

1) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (340 mg, yield 32%) was obtained as colorless oil from 4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.10 g, a 1.96 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,16-of 2.27 (1H, m)to 2.35 (3H, s)to 2.55 (3H, s), and 2.79 (2H, d, J=7,4 Hz), of 4.12 (2H, s), 4,22 (1H, OSS), to 5.00 (2H, s), 7,02 (2H, d, J=7,7 Hz), 7,06-7,14 (4H, m), 7,99 (2H, d, J=8,3 Hz).

2) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (326 mg, yield 93%) was obtained as a white powder from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (370 mg, 0,677 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,17-of 2.27 (1H, m), of 2.34 (3H, s), 2,80 (2H, d, J=7.5 Hz), 3,80 (2H, d, J=5.8 Hz), is 5.06 (2H, s), 7,10-7,14 (4H, m), 7,20 (2H, d, J=8.1 Hz), 8,10 (3H, USS).

Example171

D. the hydrochloride of 2-amino-2-tixati-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (50 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (3.00 g, 7,27 mmol) in N,N-dimethylformamide was added bromoacetonitrile (0,66 ml of 9.45 mmol) and potassium carbonate (1.51 g, 10.9 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain cyanomethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,78 g, yield 85%) as a yellow solid.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), 2,39 (3H, s), of 2.56 (3H, s), 2,80 (2H, d, J=7,2 Hz), 4,17 (2H, d, J=4.9 Hz), 4,24 (1H, USS), 4,50 (2H, s), 7,05 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=7.9 Hz).

2) the Sulfide was breathed into solution (25 ml) cyanomethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,78 g, 6,16 mmol) and triethylamine (0,94 ml, 6,77 mmol) in N,N-dimethylformamide for 1 h the Solvent is evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The solution was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the floor is built of yellow solid is washed with diisopropyl ether to obtain 2-amino-2-tixati-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,81 g, yield 94%) as a yellow-brown solid.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), is 2.40 (3H, s), of 2.56 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,14 (2H, d, J=4.5 Hz), 4,22 (1H, USS), 4,80 (2H, s), 6,21 (1H, USS), 6,98 (1H, USS), 7,13 (2H,, d, J=7.9 Hz), 7,27 (2H, d, J=7.5 Hz).

3) of the Dihydrochloride of 2-amino-2-tixati-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (133 mg, yield 70%) was obtained as yellow solid from 2-amino-2-tixati-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (200 mg, 0,412 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), is 2.37 (3H, s), 2,58 (3H, s), and 2.83 (2H, d, J=6.2 Hz), 3,83 (2H, d, J=5.7 Hz), of 4.45 (2H, s), 7,21 (2H, d, J=7,7 Hz), 7,29 (2H, d, J=7.9 Hz), 8,16 (3H, USS), 8,98 (1H, USS), 9,85 (1H, USS).

Example172

The dihydrochloride [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a mixed solution of dihydrochloride of 2-amino-2-tixati-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,02 g, to 4.41 mmol) in a mixture of tetrahydrofuran (30 ml), saturated aqueous sodium bicarbonate (10 ml) was added benzylchloride (903 mg, and 5.30 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous sulfate mA the deposits and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 2-amino-2-tixati-5-({[(benzyloxy)carbonyl]amino}methyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.00 g, yield 87%) as a pale yellow solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 2,16 was 2.25 (1H, m), 2,39 (3H, s), of 2.56 (3H, s), of 2.81 (2H, d, J=7,4 Hz), 4,22 (2H, d, J=5,1 Hz), 4,43 (1H, USS), 4,79 (2H, s), 5,04 (2H, s), 6,23 (1H, USS), 6,97 (1H, USS), 7,11 (2H,, d, J=8.1 Hz), 7,24 (2H, d, J=7.9 Hz), 7.29 trend and 7.36 (5H, m).

2) Solution (70 ml) of 2-amino-2-tixati-5-({[(benzyloxy)carbonyl]amino}methyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.00 g, of 3.85 mmol) and ethylbromoacetate (1.08 g, 5.00 mmol) in ethanol was heated at the boil under reflux for 1 h, the Reaction mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-({[(benzyloxy)carbonyl]amino}methyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.37 g, yield 100%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.41 (3H, t, J=7.2 Hz), 2,10-of 2.26 (1H, m), 2,32 (3H, s), of 2.56 (3H, s), 2,82 (2H, d, J=7,2 Hz), is 4.21 (2H, d, J=5.3 Hz), of 4.44 (2H, q, J=7.0 Hz), to 5.03 (3H, s), with 5.22 (2H, s), of 7.00 (2H, d, J=8.1 Hz), 7,07 (2H, d, J=7.9 Hz, 7,22-7,38 (5H, m), 8,15 (1H, s).

3) [4-(Etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-({[(benzyloxy)carbonyl]amino}methyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.37 g, of 3.85 mmol) was dissolved in 30% solution (30 ml) of hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the obtained residue was dissolved by addition of saturated aqueous sodium bicarbonate (30 ml) and tetrahydrofuran (50 ml). Was added di-tert-BUTYLCARBAMATE (1,02 g of 4.66 mmol) and the mixture was stirred at room temperature for 15 hours, the Reaction mixture was diluted with ethyl acetate (200 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,72 g, yield 78%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s)of 1.42 (3H, t, J=7.2 Hz), 2,17-of 2.27 (1H, m), of 2.33 (3H, s), of 2.56 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,11-4,16 (2H, m), 4,24 (1H, USS), of 4.44 (2H, q, J=7.2 Hz), with 5.22 (2H,with), 7,02 (2H, d, J=8.1 Hz), 7,10 (2H, d, J=7.9 Hz), 8,16 (1H, s).

4) Dihydrochloride [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nick is tinata (322 mg, yield 90%) was obtained as a white powder from [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (373 mg, 0,643 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 1,32 (3H, t, J=7.2 Hz), 2,18-of 2.27 (1H, m)to 2.29 (3H, s)to 2.55 (3H, s), 2,80 of 2.92 (2H, m), with 3.79 (2H, d, J=5.3 Hz), 4,32 (2H, q, J=7,1 Hz), and 5.30 (2H, s), 7,12 (4H, s), of 8.25 (3H, USS), 8,56 (1H, s).

Example173

The dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-1,3-thiazole-4-carboxylic acid

1) 2-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-1,3-thiazole-4-carboxylic acid (1,21 g, yield 95%) was obtained as colorless oil from [4-(etoxycarbonyl)-1,3-thiazol-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,34 g, 2,30 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,4 Hz)to 1.38 (9H, s), 2,16-of 2.28 (1H, m), of 2.33 (3H, s), 2,61 (3H, USS), 2,85 (2H, USS), 4,11-4,19 (2H, m)to 4.23 (1H, USS), with 5.22 (2H, s), 7,02 (2H, d, J=7.9 Hz), 7,10 (2H, d, J=7,4 Hz), 8,24 (1H, s).

2) of the Dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-1,3-thiazole-4-carboxylic acid (362 mg, yield 83%) was obtained as pale yellow powder from 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-methylp the Nile)pyridine-3-yl]carbonyl}oxy)methyl]-1,3-thiazole-4-carboxylic acid (460 mg, 0,831 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), is 2.30 (3H, s), of 2.53 (3H, s), 2,85 (2H, d, J=7,0 Hz), 3,80 (2H, d, J=5,1 Hz), from 5.29 (2H, s), 7,12 (4H, s), 8,21 (3H, USS), 8,48 (1H, s).

Example174

The dihydrochloride [4-(aminocarbonyl)-1,3-thiazol-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) [4-(Aminocarbonyl)-1,3-thiazol-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (420 mg, yield 70%) was obtained as colorless oil from 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-1,3-thiazole-4-carboxylic acid (602 mg, of 1.09 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,18-of 2.27 (1H, m), of 2.33 (3H, s), to 2.57 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,10-4,16 (2H, m), 4,22 (1H, OSS), to 5.17 (2H, s), 5,64 (1H, USS), 7,01 (2H, d, J=7.9 Hz), 7,09 (2H, d, J=7.9 Hz), 8,13 (1H, s).

2) Dihydrochloride [4-(aminocarbonyl)-1,3-thiazol-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (208 mg, yield 48%) was obtained as a white powder from [4-(aminocarbonyl)-1,3-thiazol-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)the nicotinate (460 mg, 0,832 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m), is 2.30 (3H, s), of 2.53 (3H, s), 2,79-2,89 (2H, m), with 3.79 (2H, d, J=5.5 Hz), 5,28 (2H, s), 7,12 (4H, s), a 7.62 (1H, whom sh), 7,66 (1H, USS), by 8.22 (3H, USS), 8,48 (1H, s).

Example175

The dihydrochloride [(2,2-dimethylpropanoyl)oxy]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (20 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.50 g, 3,37 mmol) in N,N-dimethylformamide was added chlorocyphidae (0,59 ml, 4.04 mmol) and potassium carbonate (0,93 g, 6,72 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain [(2,2-dimethylpropanoyl)oxy]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.68 g, yield 95%) as a yellow oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.16 (9H, s)of 1.39 (9H, s), 2,14-to 2.29 (1H, m), of 2.38 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,13 (2H, d, J=4.9 Hz), is 4.21 (1H, OSS), to 5.57 (2H, s), 7,06 (2H, d, J=8,1 Hz), 7,20 (2H, d, J=7.9 Hz).

2) Dihydrochloride [(2,2-dimethylpropanoyl)oxy]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,58 g, yield 99%) was obtained as a white solid from [(2,2-dimethylpropanoyl)oxy]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)Niko is inata (1.68 g, 3,19 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.09 (9H, s), 2,17-to 2.29 (1H, m), is 2.37 (3H, s), 2.49 USD (3H, s)2,84 (2H, d, J=7,0 Hz), of 3.78 (2H, d, J=5.5 Hz), 5,61 (2H, s), 7,19 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), to 8.20 (3H, USS).

Example176

The dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (20 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.50 g, 3,37 mmol) in N,N-dimethylformamide was added 4-(chloromethyl)-5-methyl-1,3-dioxol-2-he (0,60 g, 4.04 mmol) and potassium carbonate (0,93 g, 6,72 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted the ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.50 g, yield 85%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s)of 1.97 (3H, s), 2,16-of 2.26 (1H, m), is 2.40 (3H, s)to 2.54 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4.09 to (2H, s), 4,74 (2H, s), 7,10 (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7.9 Hz).

2) Dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-6-isobutyl-2-meth is l-4-(4-were)nicotinate (1,21 g, yield 85%) was obtained as a white powder from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.50 g, of 2.86 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6,6 Hz)of 1.97 (3H, s), 2,17-of 2.28 (1H, m)to 2.35 (3H, s), 2,82 (2H, d, J=7,0 Hz), with 3.79 (2H, d, J=5.5 Hz), is 4.93 (2H, s), 7,12 (2H, d, J=8.1 Hz), 7,20 (2H, d, J=7.9 Hz), 8,15 (3H, USS).

Example177

The dihydrochloride of 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (30 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.50 g, 3,37 mmol) in N,N-dimethylformamide was added 3-chloro-2-benzofuran-1(3H)-he (0,86 g, 4.04 mmol) and potassium carbonate (0,93 g, 6,72 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,83 g, yield 99%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), 2,42 (3H, s), 2.63 in (3H, s), 2,78 (2H, d, J=74 Hz), of 4.12 (2H, s), 6,98-was 7.08 (3H, m), 7,17 (2H, d, J=7.9 Hz), 7,24 (1H, s), to 7.59-to 7.64 (2H, m), 7,83-7,88 (1H, m).

2) of the Dihydrochloride of 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate was obtained as a white powder from 3-oxo-1,3-dihydro-2-benzofuran-1-yl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,83 g, to 3.36 mmol) a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,15-of 2.28 (1H, m), of 2.38 (3H, s)at 2.59 (3H, s), of 2.81 (2H, d, J=7,2 Hz), with 3.79 (2H, d, J=5.7 Hz), 7,07-to 7.15 (3H, m), 7,25-to 7.32 (2H, m), 7,40 (1H, s), 7,73 to 7.75 (1H, m), 7,79-7,84 (1H, m), 7,89 (1H, d, J=7.5 Hz), 8,12 (3H, USS).

Example178

The dihydrochloride (2E)-2-(3-oxo-2-benzofuran-1(3H)-ilidene)ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (10 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (380 mg, 0,853 mmol) in N,N-dimethylformamide was added (3E)-3-(2-chloraniline)-2-benzofuran-1(3H)-he (170 mg, 0,711 mmol) and potassium carbonate (147 mg, 1.07 mmol) and the mixture was stirred at room temperature for 1 h the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain (2E)-2-(3-oxo-2-benzofuran-1(3H)-and the Eden)ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (270 mg, yield 55%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16-of 2.26 (4H, m), 2,58 (3H, s), 2,78 (2H, d, J=7,4 Hz), of 4.12 (2H, s), is 4.21 (1H, USS), is 4.85 (2H, d, J=7,4 Hz in), 5.25 (1H, t, J=7.4 Hz), 7,07 (2H, d, J=8,3 Hz), for 7.12 (2H, d, J=8.1 Hz), 7,55-to 7.64 (2H, m), 7,72 for 7.78 (1H, m), 7,92-of 7.95 (1H, m).

2) Dihydrochloride (2E)-2-(3-oxo-2-benzofuran-1(3H)-ilidene)ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (204 mg, yield 79%) was obtained as a white powder from (2E)-2-(3-oxo-2-benzofuran-1(3H)-ilidene)ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (270 mg, 0,473 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,07 (3H, s), 2,18-to 2.29 (1H, m), and 2.79 (2H, d, J=6.6 Hz), of 3.78 (2H, d, J=7,4 Hz), to 4.81 (2H, d, J=7.5 Hz), of 5.68 (1H, t, J=7.5 Hz), 7,14 (4H, s), 7,71-to 7.77 (1H, m), of 7.90-8,00 (3H, m), of 8.06 (3H, USS).

Example179

Benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

To a solution (30 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (3.00 g, of 6.73 mmol) in N,N-dimethylformamide was added benzylbromide (0,80 ml of 6.73 mmol) and potassium carbonate (1.85 g, a 13.4 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (200 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The floor is built the residue was dissolved in triperoxonane acid (50 ml) and the mixture was stirred at room temperature for 3 hours Triperoxonane acid evaporated under reduced pressure and the residue was neutralized with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.70 g, yield 99%) as a yellow solid.

1H-NMR (CDCl3) δ: of 0.91 (6H, d, J=6.6 Hz), 2,07-to 2.18 (1H, m), of 2.34 (3H, s), of 2.51 (3H, s), of 2.72 (2H, d, J=7,4 Hz), a-3.84 (2H, s), 4,94 (2H, s), 7,02 for 7.12 (6H, m), 7.24 to 7,31 (3H, m).

Example180

The dihydrochloride of 2-oxo-1,3-dioxolane-4-yl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution (30 ml) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.50 g, 3,37 mmol) in N,N-dimethylformamide was added 4-chloro-1,3-dioxolane-2-on (0.55 g, 4.04 mmol) and potassium carbonate (0,70 g of 5.05 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography naselesele obtaining 2-oxo-1,3-dioxolane-4-yl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.39 g, yield 83%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,19-of 2.28 (1H, m), is 2.41 (3H, s), 2,60 (3H, s), of 2.81 (2H, d, J=7,4 Hz)to 3.67 (1H, DD, J=10,2, 1.5 Hz), 4,16 (2H, d, J=4.9 Hz), 4,22 (1H, USS), or 4.31 (1H, DD, J=10,0, 5.7 Hz), 4.63 to-4,82 (1H, m), 6,41-6,46 (1H, m), 7,01-7,10 (2H, m), 7,19-7,26 (2H, m).

2) Dihydrochloride 2-oxo-1,3-dioxolane-4-yl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.31 g, yield 99%) was obtained as a white powder from 2-oxo-1,3-dioxolane-4-yl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.39 g, and 2.79 mmol) a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,18-of 2.28 (1H, m), a 2.36 (3H, s)to 2.55 (3H, s), 2,85 (2H, d, J=7,0 Hz), 3,83 (2H, d, J=5.7 Hz), Android 4.04 (1H, DD, J=10,2, 1.7 Hz), 4,59 (1H, DD, J=10,1, 5.7 Hz), 6,59 (1H, DD, J=5.4 Hz), 7,14-7,20 (2H, m), 7.24 to 7,29 (2H, m), 8,23 (3H, USS).

Example181

The dihydrochloride of 5-(aminomethyl)-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate acid

1) tert-Butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (21,4 g, yield 77%) was obtained as a pale pink solid from 4-(benzyloxy)benzaldehyde (12.8 g, 60,4 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: of 0.94 (3H, d, J=6.6 Hz), 0,99 (3H, d, J=6.6 Hz), of 1.28 (9H, s), 1,80 is 1.96 (1H, m), 2,14-to 2.29 (2H, m), 2,32 (3H, s), 4,51 (1H, s)of 5.03 (2H, s)5,49 (1H, s), make 6.90 (2H, d, J=8.7 Hz), to 7.15 (2H, d, J=to 8.7 Hz), 7,29-7,46 (5H, m).

2) tert-Butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2-metelnick is tinat (2,18 g, yield 94%) was obtained as yellow solid from tert-butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2-methyl-1,4-dihydropyridines-3-carboxylate (2,33 g, 5.08 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 1,25 (9H, s), 2,17 is 2.33 (1H, m), 2.63 in (3H, s), with 2.93 (2H, d, J=7,4 Hz), 5,12 (2H, s), 7,06 (2H, d, J=8,9 Hz), 7,31 (2H, d, J=8,9 Hz), 7,39-7,49 (5H, m).

3) tert-Butyl-5-(aminomethyl)-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate received in the form of a crude product of tert-butyl 4-[4-(benzyloxy)phenyl]-5-cyano-6-isobutyl-2-methylnicotinate (2,13 g of 4.67 mmol) in a manner similar to the method of example 1-4). From the crude product was obtained as a pale yellow solid tert-butyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate (1.35 g, yield 61%) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,22 (9H, s)of 1.40 (9H, s), 2,12-of 2.27 (1H, m)to 2.55 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 4,14 (2H, d, J=4.9 Hz), 4,25 (1H, USS), of 5.50 (1H, USS), 6,85 (2H, d, J=8.5 Hz), 7,07 (2H, d, J=8,5 Hz).

4) tert-Butyl-5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate (316 mg, 0,671 mmol) and anisole (218 mg, a 2.01 mmol) was dissolved in triperoxonane acid (5 ml) and the mixture was stirred at room temperature for 5 hours Triperoxonane acid evaporated under reduced pressure and to the residue was added 4n. 1,4-dioxane solution of chloride is th hydrogen (20 ml). The mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the resulting yellow solid is washed with diisopropyl ether to obtain the hydrochloride 5-(aminomethyl)-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinic acid (259 mg, yield 99%) as a yellow powder.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,14-of 2.27 (1H, m), 2,59 (3H, s), of 2.92 (2H, d, J=5.7 Hz), 3,86 (2H, d, J=4.9 Hz), 6.87 in (2H, d, J=8.5 Hz), 7,14 (2H, d, J=8,3 Hz), compared to 8.26 (3H, USS).

Example182

The dihydrochloride of 5-(aminomethyl)-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinic acid

1) To a solution (20 ml) of tert-butyl 5-{[(tert-butoxycarbonyl)amino]methyl}-4-(4-hydroxyphenyl)-6-isobutyl-2-methylnicotinate (620 mg, 1,32 mmol) and potassium carbonate (365 mg, of 2.64 mmol) in N,N-dimethylformamide was added itmean (374 mg, of 2.64 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinate (520 mg, yield 81%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=68 Hz), to 1.21 (9H, s)of 1.39 (9H, s), 2,13-of 2.26 (1H, m)to 2.55 (3H, s), was 2.76 (2H, d, J=7,4 Hz), of 3.84 (3H, s), of 4.12 (2H, s), 4,22 (1H, USS), 6,94 (2H, d, J=8.7 Hz), 7,12 (2H, d, J=8.7 Hz).

2) Dihydrochloride 5-(aminomethyl)-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinic acid (429 mg, yield 99%) was obtained as a yellow powder from tert-butyl 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-methoxyphenyl)-2-methylnicotinate (520 mg, 1.07 mmol) in a manner similar to the method of example 181-4).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), of 2.54 (3H, s), 2,85 (2H, d, J=6.6 Hz), of 3.57(3H, s), a-3.84 (2H, s), 7,05 (2H, d, J=8.7 Hz), 7,26 (2H, d, J=8.7 Hz), 8,17 (3H, USS).

Example183

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate

1) a Mixture of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol), triethylamine (0.7 ml, 5,02 mmol) and tetrahydrofuran (20 ml) was cooled to 0°C was added dropwise methanesulfonanilide (432 mg, of 3.77 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate in the form of crude prod the KTA. The crude product was dissolved in N,N-dimethylformamide (15 ml) was added potassium carbonate (520 mg, of 3.77 mmol) and methyl-4-mercaptobenzoic (422 mg, 2.51 mmol). The mixture was stirred with heating at 50°C for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (1.01 g, yield 73%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), is 2.37 (3H, s)to 2.65 (3H, s)of 2.75 (2H, d, J=7,4 Hz), 3,86 (2H, s)to 3.89 (3H, s), Android 4.04 (2H, d, J=5,1 Hz), 4,20 (1H, USS),? 7.04 baby mortality (2H, d, J=7.9 Hz), to 7.09 (2H, d, J=8.7 Hz), 7,19 (2H, d, J=7,7 Hz), the 7.85 (2H, d, J=8.7 Hz).

2) Dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (138 mg, yield 73%) was obtained as pale-yellow powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (200 mg, 0,365 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,12-of 2.23 (1H, m)to 2.35 (3H, s), of 2.81 (3H, s)to 3.64 (2H, OSS in), 3.75 (2H, d, J=5.7 Hz), 3,83 (3H, s)to 4.01 (2H, s), 7.24 to 7,33 (6H, m), 7,82 (2H, d, J=8.7 Hz), 8,30 (3H, USS).

p> Example184

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.97 g, yield 72%) was obtained as a white solid from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (1,37 g, 2.51 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ with 1.07 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,23 to 2.35 (1H, m), 2,42 (3H, s), is 3.08 (3H, s), 3,30 is 3.40 (2H, m), 3,90 (2H, s), 4,12-4,18 (2H, m), 4,30 (1H, USS), 7,05 (2H, d, J=7.9 Hz), 7,13 (2H, d, J=8,5 Hz), of 7.23-7,31 (2H, m), to 7.93 (2H, d, J=8,5 Hz).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (198 mg, yield 77%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.27 g, worn : 0.505 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,13-of 2.23 (1H, m), a 2.36 (3H, s), of 2.81 (3H, s), 3,05 (2H, USS), 3,71-of 3.80 (2H, m)to 4.01 (2H, s), 7.23 percent-7,27 (4H, m), 7,32 (2H, d, J=8.1 Hz), 7,80 (2H, d, J=8,3 Hz), 8,32 (3H, USS).

Example185

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoate

1) Methyl-4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-IU the Il-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoate (410 mg, yield 84%) was obtained as colorless oil from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (0,46 g, 0,838 mmol) in a manner similar to the method of example 91-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,7 Hz)to 1.38 (9H, s), 2,17-of 2.26 (1H, m), is 2.41 (3H, s)of 2.64 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,98 (3H, s), 4.00 points (2H, d, J=5.3 Hz), 4,18 (1H, USS), 4,32 (2H, s), 6.87 in (2H, d, J=7,7 Hz), 7,17 (2H, d, J=7,7 Hz), 7,56 (2H, d, J=8.5 Hz), 8,08 (2H, d, J=8,5 Hz).

2) Dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoate (352 mg, yield 90%) was obtained as pale-yellow powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoate (410 mg, 0,706 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,17-of 2.27 (1H, m), of 2.38 (3H, s), 2,78 (3H, s)of 3.00 (2H, USS), 3,66-3,74 (2H, m), 3,93 (3H, s), br4.61 (2H, USS), 7,05 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7.9 Hz), 7,66 (2H, d, J=8,3 Hz), of 8.09 (2H, d, J=8.7 Hz), 8,30 (3H, USS).

Example186

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoic acid (300 mg, yield 93%) was obtained as colorless oil from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-methylp the Nile)pyridine-3-yl]methyl}sulfonyl)benzoate (330 mg, 0,568 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14-2,22 (1H, m), of 2.34 (3H, s), 2,43 (3H, s), of 2.86 (2H, d, J=7,4 Hz)4,06 (2H, d, J=4.5 Hz), 4,28 (1H, USS), 4,35 (2H, s), 6,97 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7,7 Hz), 7,60 (2H, d, J=8.1 Hz), 8,17 (2H, d, J=8,1 Hz).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoic acid (279 mg, yield 97%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfonyl)benzoic acid (300 mg, 0,530 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,17-of 2.24 (1H, m), of 2.38 (3H, s), was 2.76 (3H, USS), 2,95 (2H, USS), 3,70 (2H, USS), 7,05 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7.9 Hz), a 7.62 (2H, d, J=8,3 Hz), 8,07 (2H, d, J=8,3 Hz), 8,24 (3H, USS).

Example187

The dihydrochloride of N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}methanesulfonamide

1) To a solution (10 ml) of tert-butyl{[5-(aminomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (200 mg, 0,755 mmol) and triethylamine (of 0.14 ml, 1.00 mmol) in tetrahydrofuran was added methanesulfonamide (86 mg, 0,875 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated solution of salt. Org the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting yellow solid is washed with diisopropyl ether to obtain tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[(methylsulphonyl)amino]methyl}pyridine-3-yl)methyl]carbamate (210 mg, yield 87%) as a white solid.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), 2,42 (3H, s), 2,61 (3H, s), 2,68 (3H, s), was 2.76 (2H, d, J=7,4 Hz), a 3.87 (1H, OSS), to 4.01 (2H, d, J=5.7 Hz), a 4.03 (2H, d, J=5.3 Hz), 4,18 (1H, USS), 7,03 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=7.9 Hz).

2) of the Dihydrochloride of N-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}methanesulfonamide (126 mg, yield 64%) was obtained as a white powder from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[(methylsulphonyl)amino]methyl}pyridine-3-yl)methyl]carbamate (210 mg, 0,441 mmol) method like the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,12-of 2.23 (1H, m), is 2.41 (3H, s), a 2.71 (3H, s)2,84 (3H, USS), totaling 3.04 (2H, USS), 3,76 (2H, USS), a 3.87 (2H, USS), 7,19 (1H, USS), 7,29 (2H, d, J=7.5 Hz), 7,38 (2H, d, J=7,7 Hz), 8,28 (3H, USS).

Example188

The dihydrochloride {[4-(2,4-dichlorophenyl)-6-(4-forfinal)-2-isobutylpyrazine-3-yl]methyl}amine

1) (2E)-3-(2,4-Dichlorophenyl)-1-(4-forfinal)prop-2-EN-1-he (10.3 g, yield 64%) was obtained as a pale yellow solid from 4-fortetienne (6,91 g, 50 mmol) and 2,6-dichlorobenzamide (8,75 g, 59 mmol) in a manner similar to the method of example 108-1).

1H-NMR (CDCl3) δ: 7,16 to 7.2 (2H, m), 7,31 (1H, DD, J=8,5, and 2.1 Hz), 7,42-7,49 (2H, m), to 7.68 (2H, d, J=8.5 Hz), 8,07 (3H, m).

2) 4-(2,4-Dichlorophenyl)-6-(4-forfinal)-2-isobutyronitrile (2,94 g, yield 48%) was obtained as a yellow oil from (2E)-3-(2,4-dichlorophenyl)-1-(4-forfinal)prop-2-EN-1-it (4,54 g of 15.4 mmol) in a manner similar to the method of example 108-2).

1H-NMR (CDCl3) δ: of 1.06 (6H, d, J=6.6 Hz), 2,32 at 2.45 (1H, m), 3.04 from (2H, d, J=7,2 Hz), 7,09-7,24 (3H, m), 7,33 (1H, d, J=8,3 Hz), 7,37-7,44 (1H, m), EUR 7.57 (1H, s), to 7.59 (1H, d, J=1.9 Hz), 8,06-to 8.12 (1H, m).

3) {[4-(2,4-Dichlorophenyl)-6-(4-forfinal)-2-isobutylpyrazine-3-yl]methyl}amine (780 mg, yield 68%) was obtained as a pale-yellow oil from 4-(2,4-dichlorophenyl)-6-(4-forfinal)-2-isobutyronitrile (1,14 g, to 2.85 mmol) in a manner similar to the method of example 23-4). The oil was dissolved in 4n. 1,4-dioxane solution of hydrogen chloride (20 ml) and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the resulting pale yellow solid is washed with diisopropyl ether to obtain dihydrochloride {[4-(2,4-dichlorophenyl)-6-(4-forfinal)-2-isobutylpyrazine-3-yl]methyl}amine (895 mg, yield 97%) as a pale yellow powder.

1H-NMR (DMSO-d6) δ: 0,97 (3H, d, J=6.6 Hz), of 1.05 (3H, d, J=6.6 Hz), 2,29-of 2.38 (1H, m), 2,81-to 2.99 (2H, m), 3,57-of 3.64 (1H, m), 4.04 the-4,16 (1H, m), 7,33 (2H, t, J=8,8 Hz), to 7.59-to 7.67 (2H, m), 7,73 (1H, s), 7,86 (1H, d, J=1,9 Hz), 8,21-8,30 (5H, m).

Example189

The dihydrochloride methyl-3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]Ben is oata

1) (2E)-1-(3-Bromophenyl)-3-(4-were)prop-2-EN-1-he (to 7.09 g, yield 47%) was obtained as pale yellow powder from 3-bromoacetophenone (9.95 g, 50 mmol) in a manner similar to the method of example 108-1).

2) 6-(3-Bromophenyl)-2-isobutyl-4-(4-were)nicotinamide (2.20 g, yield 32%) was obtained as a pale-yellow solid from (2E)-1-(3-bromophenyl)-3-(4-were)prop-2-EN-1-it (of 5.03 g, and 16.7 mmol) in a manner similar to the method of example 108-2).

1H-NMR (CDCl3) δ: of 1.06 (6H, d, J=6.6 Hz), 2,35-to 2.42 (1H, m), of 2.45 (3H, s), 3,06 (2H, d, J=7,4 Hz), 7,09-7,16 (3H, m), 7,30-7,40 (4H, m), 7,53-of 7.55 (1H, m), of 7.64 (1H, s).

3) 6-(3-Bromophenyl)-2-isobutyl-4-(4-were)nicotinamide (2.20 g, 5.40 mmol), triethylamine (0.70 to ml, 10.0 mmol) and dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (410 mg, 0,500 mmol) was dissolved in a mixed solvent of methanol (10 ml) -N,N-dimethylformamide (30 ml) and the mixture was stirred in an atmosphere of carbon monoxide for 15 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain methyl 3-[5-cyano-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.39 g, yield 72%) as a colourless oil. From methyl 3-[5-cyano-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.30 grams, to 3.38 mmol) received m the Tyl-3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (780 mg, yield 58%) as a colorless oil by the method similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 1.05 (6H, d, J=6.6 Hz), 2,37-2,48 (4H, m), 2,90 (2H, d, J=7,2 Hz), a-3.84 (2H, s), of 3.94 (3H, s), 7,27-7,33 (4H, m), 7,49 (1H, s), 7,54 (1H, t, J=7.9 Hz), 8,04-8,07 (1H, m), 8,32 (1H, m), 8,61-to 8.62 (1H, m).

4) Methyl-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (730 mg, yield 76%) was obtained as a white powder from methyl 3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (0,76 g, a 1.96 mmol) in a manner similar to the method of example 2-1).

1H-NMR (CDCl3) δ: was 1.04 (6H, d, J=6.6 Hz), USD 1.43 (9H, s), 2,37 is 2.46 (4H, m), 2,87 (2H, d, J=7,2 Hz), of 3.94 (3H, s), 4,29 is 4.35 (2H, m), to 4.38 (1H, USS), of 7.23 (2H, d, J=8,3 Hz), 7,28 (2H, d, J=8.1 Hz), to 7.50 (1H, s), 7,54 (1H, t, J=7.8 Hz), 8,05-8,08 (1H, m), 8,30-to 8.34 (1H, m), 8,62-8,63 (1H, m).

5) Dihydrochloride methyl-3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (188 mg, yield 99%) was obtained as a white powder from methyl 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (200 mg, 0,409 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: was 1.04 (6H, d, J=6.4 Hz), 2,33 is 2.44 (4H, m), with 2.93 (2H, d, J=7,0 Hz), 3,90 (3H, s)to 4.01 (2H, d, J=5.5 Hz), was 7.36 (2H, d, J=8.1 Hz), 7,41 (2H, d, J=8,3 Hz), 7,66 (1H, t, J=7.8 Hz), 7,76 (1H, s), 8,01-8,08 (1H, m), 8,40 (3H, USS), 8,42-of 8.47 (1H, m), 8,71 is 8.75 (1H, m).

Example190

The dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid

1) 3-[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-from util-4-(4-were)pyridine-2-yl]benzoic acid (500 mg, yield 98%) was obtained as a white solid from methyl 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (530 mg, of 1.08 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 1.05 (6H, d, J=6.6 Hz), USD 1.43 (9H, s), 2,35-2,47 (4H, m), of 2.92 (2H, USS), or 4.31-4,37 (2H, m), 4,42 (1H, USS), 7,22-7,30 (4H, m), 7,52 (1H, s), 7,58 (1H, t, J=7.5 Hz), to 8.12 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=7.4 Hz), 8,67 (1H, s).

2) of the Dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (188 mg, yield 99%) was obtained as a white powder from 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (200 mg, 0,421 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (6H, d, J=7,4 Hz), 2,32 is 2.43 (4H, m), of 2.92 (2H, d, J=7,0 Hz), was 4.02 (2H, d, J=5.3 Hz), was 7.36 (2H, d, J=8.1 Hz), 7,41 (2H, d, J=8,3 Hz), 7,63 (1H, t, J=7.8 Hz), 7,74 (1H, s), 8,01-of 8.04 (1H, m), 8,35 (3H, USS), of 8.37-to 8.41 (1H, m), 8,71-8,72 (1H, m).

Example191

The dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzamide

1) tert-Butyl{[6-[3-(aminocarbonyl)phenyl]-2-isobutyl-4-(4-were)pyridine-3-yl]methyl}carbamate (160 mg, yield 53%) was obtained as a white solid from 3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (300 mg, 0,632 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: was 1.04 (6H, d, J=6.6 Hz), USD 1.43 (9H, s), 2,34-2,48 (4H, m), 2,87 (2H, d, J=7 Hz), 4,32 (2H, d, J=4,7 Hz), 4,39 (1H, USS), 7,22 (2H, d, J=8.1 Hz), 7,25-7,29 (2H, m)to 7.50 (1H, s), 7,55 (1H, t, J=7.8 Hz), 7,83-7,87 (1H, m), 8,21-of 8.25 (1H, m), 8,45-8,46 (1H, m).

2) of the Dihydrochloride of 3-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzamide (127 mg, yield 84%) was obtained as a white powder from tert-butyl{[6-[3-(aminocarbonyl)phenyl]-2-isobutyl-4-(4-were)pyridine-3-yl]methyl}carbamate (160 mg, 0,338 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (6H, d, J=6.6 Hz), 2,34 is 2.44 (4H, m), with 2.93 (2H, d, J=7,0 Hz)to 4.01 (2H, d, J=5.5 Hz), 7,37 (2H, d, J=8.1 Hz), 7,42 (2H, d, J=8.1 Hz), 7,47 (1H, USS), 7,60 (1H, t, J=7.8 Hz), 7,81 (1H, s), of 7.96 (1H, d, J=7,7 Hz), 8,14 (1H, USS), 8,33-8,44 (4H, m), 8,58 (1H, s).

Example192

The dihydrochloride methyl-2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate

1) (2E)-1-(2-Bromophenyl)-3-(4-were)prop-2-EN-1-he (8,86 g, yield 44%) was obtained as pale yellow powder of 2-bromoacetophenone (9.95 g, 50 mmol) in a manner similar to the method of example 108-1).

2) 6-(2-Bromophenyl)-2-isobutyl-4-(4-were)nicotinamide (3.58 g, yield 53%) was obtained as a pale-yellow solid from (2E)-1-(2-bromophenyl)-3-(4-were)prop-2-EN-1-it (of 5.03 g, and 16.7 mmol) in a manner similar to the method of example 108-2).

1H-NMR (CDCl3) δ: of 1.06 (6H, d, J=6.6 Hz), 2,34 is 2.44 (4H, m), of 3.07 (2H, d, J=7,4 Hz), 7,27-7,30 (1H, m), to 7.32 and 7.36 (2H, m), 7,41-7,47 (1H, m), 7,53-of 7.60 (3H, m), 7,71 (1H, m).

3) Methyl-2-[5-cyano-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.80 g, yield 76%) was obtained as colorless what about the oil of 6-(2-bromophenyl)-2-isobutyl-4-(4-were)nicotinanilide (2.50 g, 6,14 mmol) in a manner similar to the method of example 189-3). Namely, 6-(2-bromophenyl)-2-isobutyl-4-(4-were)nicotinamide, triethylamine (1.7 ml, 12.2 mmol) and dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (501 mg, 0,614 mmol) was dissolved in methanol (7.5 ml)-N,N-dimethylformamide (15 ml) and the mixture was stirred in an atmosphere of carbon monoxide for 13 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain methyl 2-[5-cyano-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate.

1H-NMR (CDCl3) δ: of 1.03 (6H, d, J=6.8 Hz), 2.26 and-is 2.37 (1H, m), is 2.44 (3H, s), 3,01 (2H, d, J=7,4 Hz), 3,74 (3H, s), 7,08-7,14 (1H, m), 7,34 (2H, d, J=7.9 Hz), 7,42 (1H, s)of 7.48-to 7.61 (4H, m), 7,83-7,88 (1H, m).

4) Methyl-2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate was obtained in the form of a crude product of methyl 2-[5-cyano-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.80 g, and 4.68 mmol) in a manner similar to the method of example 1-4). From the crude product was obtained methyl 2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.70 g, yield 74%) as a colorless oil by the method similar to the method of example 2-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), USD 1.43 (9H, s), 2.26 and-is 2.37(1H, m)to 2.41 (3H, s), 2,80 (2H, d, J=7,4 Hz in), 3.75 (3H, s), 4,32 (2H, d, J=4.9 Hz), 4,42 (1H, USS), 7,21-7,27 (5H, m), 7,41-7,46 (1H, m), 7,52-7,58 (2H, m), 7,76 (1H, DD, J=7,4, 1,1 Hz).

5) Dihydrochloride methyl-2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (345 mg, yield 95%) was obtained as a pale pink powder from methyl-2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (383 mg, 0.786 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,18 of-2.32 (1H, m), is 2.41 (3H, s), 2,89 (2H, d, J=6.6 Hz), of 3.69 (3H, s), 3,99-4.09 to (2H, m), of 7.36 (2H, d, J=8.1 Hz), the 7.43 (2H, d, J=8.1 Hz), 7,49 (1H, s), EUR 7.57-of 7.70 (2H, m), 7,76 (2H, d, J=7.5 Hz), 8,51 (3H, USS).

Example193

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid

1) 2-[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (0,85 g, yield 67%) was obtained as colorless oil from methyl-2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoate (1.31 g, 2,69 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6.6 Hz), of 1.42 (9H, s), 2.21 are of 2.33 (1H, m), is 2.44 (3H, s), with 2.93 (2H, d, J=7,4 Hz), 4,39 (2H, USS), 7,22 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=7.9 Hz), of 7.48 (1H, s), 7,54-7,66 (3H, m), 8,31 (1H, m).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (329 mg, yield 81%) was obtained as a white powder from 2-[5-{[(tert-butoxycarbonyl)amino]methyl-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (429 mg, 0,904 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,27-of 2.36 (1H, m), is 2.41 (3H, s), 2,90 (2H, d, J=6.6 Hz), Android 4.04 (2H, d, J=5,1 Hz), was 7.36 (2H, d, J=8,3 Hz), 7,40-7,49 (3H, m), 7,54-of 7.70 (3H, m), 7,76-to 7.84 (1H, m), 8,44 (3H, USS).

Example194

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzamide

1) tert-Butyl{[6-[2-(aminocarbonyl)phenyl]-2-isobutyl-4-(4-were)pyridine-3-yl]methyl}carbamate (290 mg, yield 69%) was obtained as colorless oil from 2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-4-(4-were)pyridine-2-yl]benzoic acid (421 mg, 0,887 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), USD 1.43 (9H, s), 2,30-is 2.37 (1H, m), is 2.41 (3H, s), and 2.83 (2H, d, J=7,4 Hz), 4,34 (2H, d, J=4,7 Hz), 4,42 (1H, USS), 5,54 (1H, USS), 6.42 per (1H, USS), 7,20 (2H, d, J=8,3 Hz), 7.24 to to 7.25 (3H, m), 7,42-7,53 (3H, m), 7,70 to 7.75 (1H, m).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-4-(4-were)pyridine-2-yl]benzamide (254 mg, yield 93%) was obtained as a yellow powder from tert-butyl{[6-[2-(aminocarbonyl)phenyl]-2-isobutyl-4-(4-were)pyridine-3-yl]methyl}carbamate (290 mg, 0,612 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,27-is 2.37 (1H, m), is 2.40 (3H, s), 2,90-to 2.99 (2H, m), Android 4.04 (2H, m), of 7.36 (2H, d, J=8.1 Hz), 7,41 (2H, d, J=8,3 Hz)to 7.50 (1H, s), 7,56-7,71 (4H, m), 7,92 shed 8.01 (1H, m), 8,61 (3H, OSS).

Example195

The dihydrochloride of 5-(aminomethyl)-N,N-DICYCLOHEXYL-6-isobutyl-2-methyl-4-(4-(were)h is codenamed

1) 5-Cyano-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.16 g, yield 85%) was obtained as a white powder from tert-butyl 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinate (3.00 g, 8,23 mmol) in a manner similar to the method of example 24-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), 2,17 of-2.32 (1H, m), 2,42 (3H, s)to 2.67 (3H, s), 2,95 (2H, d, J=7,4 Hz), 7,27-7,34 (4H, m).

2) To a solution of 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.00 g, of 6.49 mmol) in dichloromethane was added oxalicacid (0.68 ml, for 7.78 mmol) and N,N-dimethylformamide (0.05 ml) and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran. Then was added triethylamine (1.8 ml, at 13.0 mmol) and dicyclohexylamine (of 1.55 ml, for 7.78 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 5-cyano-N,N-DICYCLOHEXYL-6-isobutyl-2-methyl-4-(4-were)nicotinamide (0.35 g, yield 11%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,79-0,96 (4H, m), 1,01 (6H, DD, J=11,1, and 6.6 Hz), with 1.07 to 1.34 (4H, m), 1,40-of 1.53 (5H, m), 1,58 by 1.68 (4H, m), 1,72-of 1.84 (3H, m), 2,22-2,31 (1H, m), is 2.40 (3H, s) at 2.59 (3H, C), 2,69-and 2.79 (2H, m), 2,87 totaling 3.04 (2H, m), 7,25 (2H, d, J=8.5 Hz), 7,46 (2H, d, J=8,1 Hz).

3) Dihydrochloride 5-(aminomethyl)-N,N-DICYCLOHEXYL-6-isobutyl-2-methyl-4-(4-were)nicotinamide (0.20 g, yield 49%) was obtained as a yellow powder of 5-cyano-N,N-DICYCLOHEXYL-6-isobutyl-2-methyl-4-(4-were)nicotinamide (0.35 g, 0,742 mmol) in a manner similar to the method of example 108-3).

1H-NMR (DMSO-d6) δ: 0,73-0,88 (2H, m), 0,90-of 1.15 (12H, m), 1,24 is 1.75 (10H, m), 2,13-of 2.27 (3H, m), a 2.36 (3H, s), 2,78-of 2.86 (2H, m), 2,88-2,95 (2H, m), 3,68-3,81 (1H, m), of 3.96-4.09 to (1H, m), 7,26-7,37 (4H, m).

Example196

The dihydrochloride methyl-1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}piperidine-4-carboxylate

1) Methyl-1-{[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}piperidine-4-carboxylate (3,20 g, yield 91%) was obtained as colorless oil from 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.50 g, 8.1 mmol) and metaliconfactory (1.3 ml, 9.73 mmol) in a manner similar to the method of example 195-2).

1H-NMR (CDCl3) δ: 1,01 (6H, DD, J=12.1 is of 6.6 Hz), 1,42-of 1.85 (4H, m), 2,19-is 2.37 (3H, m), is 2.40 (3H, s), 2,55-2,60 (3H, m), 2,61-3,20 (5H, m), 3,63-3,66 (3H, m), 4,23 is 4.45 (1H, m), 7,25-7,42 (4H, m).

2) Dihydrochloride methyl-1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}piperidine-4-carboxylate (3,27 g, yield 87%) was obtained as a white powder from methyl-1-{[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}piperidine-4-carboxylate (3,20 g, 7,38 mmol method similar to the method of example 108-3).

1H-NMR (DMSO-d6) δ: 0,67-of 0.90 (1H, m), and 0.98 (6H, t, J=5,9 Hz), of 1.25 to 1.76 (3H, m), 2,16-of 2.28 (1H, m), a 2.36-is 2.37 (3H, m), 2,63 was 2.76 (1H, m), 2,90-3,03 (2H, m), 3,17-to 3.34 (1H, m), of 3.57 (3H, s), to 3.58-of 3.60 (2H, m), 3,68-of 3.97 (2H, m), 4,05-4,10 (1H, m), 7,11 and 7.36 (4H, m), 8.34 per (3H, USS).

Example197

tert-Butylamine salt 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid

5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.10 g, 0,320 mmol) was dissolved in a mixed solvent of water (1.5 ml)-acetonitrile (1.5 ml) at reflux for 10 minutes To the resulting solution was added tert-butylamine (23,4 mg, 0,320 mmol) and the mixture was stirred at the same temperature for 10 minutes was Added acetonitrile (20 ml), the mixture was allowed to cool to room temperature and then was stirred at 0°C in for 30 minutes, Dropped precipitated solid substance was collected by filtration and washed with acetonitrile (10 ml) to obtain tert-butylamine salt 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (78,4 mg, yield 63%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.91 (6H, d, J=6.6 Hz), of 1.12 (9H, s), 2.06 to to 2.25 (1H, m), 2,31 (3H, s), of 2.34 (3H, s)to 2.66 (2H, d, J=7,0 Hz)and 3.31 (2H, USS), 3,37 (2H, s), 7,10 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=8,1 Hz).

Example198

The dihydrochloride ({2-isobutyl-6-methyl-4-(4-were)-5-[(methylthio)methyl]pyridine-3-yl}methyl)amine

1) To a solution of [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-ethyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (476 mg, 1 mmol) in tetrahydrofuran (5 ml) was added 15% aqueous solution methanolate sodium (3 ml) and the mixture was stirred at 50°C for 2 hours was Added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(methylthio)methyl]pyridine-3-yl}methyl)carbamate (312 mg, yield 72%) as a white powder.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), of 1.94 (3H, s), 2,12-of 2.23 (1H, m), 2,42 (3H, s)to 2.67 (3H, s)of 2.75 (2H, d, J=6.9 Hz), 3,39 (2H, s), was 4.02 (2H, d, J=5.7 Hz), 4,19 (1H, USS),? 7.04 baby mortality (2H, d, J=8,1 Hz), from 7.24 (2H, d, J=8,1 Hz).

2) Dihydrochloride ({2-isobutyl-6-methyl-4-(4-were)-5-[(methylthio)methyl]pyridine-3-yl}methyl)amine (36 mg, yield 96%) was obtained as a white powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(methylthio)methyl]pyridine-3-yl}methyl)carbamate method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), of 1.93 (3H, s), 2,12-2,19(1H, m), 2,42 (3H, s), 2,89 (3H, s), is 3.08 (2H, USS), of 3.48 (2H, in), 3.75 (2H, s), 7,28 (2H, d, J=7.8 Hz), 7,39 (2H, d, J=7.8 Hz), at 8.36 (3H, USS).

Example199

The dihydrochloride ({2-isobutyl-6-methyl-4-(4-were)-5-[(methylsulphonyl)methyl]pyridine-3-yl}methyl)amine

1) To a solution of tert-butyl({2-isobutyl-6-methyl-(4-were)-5-[(methylthio)methyl]pyridine-3-yl}methyl)carbamate (200 mg, 0.46 mmol) in a mixture of methanol-water (10:1, 5 ml) was added Oxon (trademark, 310 mg) and then was added sulfuric acid (50 ml). The mixture was stirred at room temperature for 6 hours was Added to the reaction mixture of aqueous saturated sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(methylsulphonyl)methyl]pyridine-3-yl}methyl)carbamate (128 mg, yield 60%) as a white powder.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,19-of 2.28 (1H, m), is 2.41 (3H, s), 2,61 (3H, s), is 2.74 (3H, s)of 2.75 (2H, d, J=7,2 Hz), 4,25 (2H, d, J=5,1 Hz), 4,24 (1H, USS), 4.26 deaths (2H, s), 7,71 (2H, d, J =7,8 Hz), 7,26 (2H, d, J=8,1 Hz).

2) Dihydrochloride ({2-isobutyl-6-methyl-4-(4-were)-5-[(methylsulphonyl)methyl]pyridine-3-yl}methyl)amine (36 mg, yield 96%) was obtained as a white powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(methylsulphonyl)methyl]pyridine-3-yl}methyl)carbamate method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,17-of 2.24 (1H, m), is 2.40 (3H, s), of 2.81 (3H, s), 2,87 (3H, s), 2,89 (2H, USS), 3,68 (2H, USS), and 4.40 (2H, s), from 7.24 (2H, d, J=8.1 Hz), 7,35 (2H, d, J=7.8 Hz), to 8.20 (3H, USS).

Example200

The dihydrochloride ({[5-(aminol who yl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)acetic acid

1) To a solution of [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (952 mg, 2 mmol) in N,N-dimethylformamide (5 ml) was added potassium carbonate (415 mg, 3 mmol) and then added ethylmercaptan (240 ml, 2.2 mmol). The mixture was stirred at 50°C for 1 h was Added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in ethanol (5 ml). Added 1N. an aqueous solution of sodium hydroxide (5 ml) and the mixture was stirred at room temperature for 2 hours was Added to the reaction mixture 1H. hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)acetic acid (265 mg, yield 27%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.91 (6H, d, J=6.6 Hz), of 1.34 (9H, s), 2,13-of 2.27 (1H, m), is 2.37 (3H, s)to 2.55 (2H, d, J=6.0 Hz), 2,58 (3H, s)to 3.09 (2H, s), 3,50 (2H, s), 3,74 (2H, d, J=4, 2 Hz), for 6.81 (1H, USS), 7,18 (2H, d, J=8,1 Hz), 724 (2H, d, J=8.1 Hz), 12,49 (1H, USS).

2) Dihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)acetic acid (106 mg, yield 96%) was obtained as a white powder ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)acetic acid by a method similar to the method example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14 was 2.25 (1H, m), 2,42 (3H, s), 2,85 (3H, USS), a 3.01 (2H, s), 3,20 (2H, s)and 3.59 (2H, s), 3,70 (2H, s), 7,26 (2H, d, J=8.1 Hz), 7,37 (2H, d, J=8.1 Hz), 8,23 (3H, USS).

Example201

The dihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}sulfanyl)acetic acid

1) To a solution of ({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)acetic acid (260 mg, 0.55 mmol) in a mixture of methanol-water (10:1, 5 ml) was added Oxon (trademark, 508 mg) and then was added sulfuric acid (50 ml). The mixture was stirred at room temperature for 6 hours was Added to the reaction mixture of aqueous saturated sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. The dihydrochloride ({[5-(aminomethyl)-6-isobutyl-2-m is Tyl-4-(4-were)pyridine-3-yl]methyl}sulfanyl)acetic acid (104 mg, yield 68%) was obtained as a white powder from the oil by a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2.21 are of 2.28 (1H, m), 2,39 (3H, s)to 2.65 (3H, s), is 2.74 (2H, s), 3,61(2H, s), of 4.13 (2H, s)4,55 (2H, s), 7,18 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=7.8 Hz), 8,01 (3H, USS).

Example202

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(1H-tetrazol-5-ylmethyl)pyridine-3-yl]methyl}amine

1) To a solution of tert-butyl{[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (300 mg, of 0.74 mmol) in toluene (5 ml) was added oxide dibutyrate (37 mg, 0.15 mmol) and trimethylsilyl (292 ml, 2.2 mmol) and the mixture was stirred at 80°C for 3 days. Was added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(1H-tetrazol-5-ylmethyl)pyridine-3-yl]methyl}carbamate (229 mg, yield 69%) as a white powder.

1H-NMR (CDCl3) δ: from 0.90 (6H, d, J=6.6 Hz), of 1.36 (9H, s), 2,08-2,11 (1H, m)to 2.35 (3H, s), 2,42 (3H, s), and 2.83 (2H, s), a 4.03(2H, s), 4.09 to (2H, USS), 4,79 (1H, USS), 7,01 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=7,8 Hz).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(1H-tetrazol-5-ylmethyl)pyridine-3-yl]methyl}amine (181 mg, Ihad 87%) was obtained as a white powder from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(1H-tetrazol-5-ylmethyl)pyridine-3-yl]methyl}carbamate way like the way example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,15-of 2.23 (1H, m), a 2.36 (3H, s), is 2.74 (3H, s), 3,14 (2H, s), of 3.78 (2H, s), Android 4.04 (2H, s), 7,06 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 8,35 (3H, USS).

Example203

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-1,2,4-oxadiazol-5(4H)-it

1) To a solution of tert-butyl{[5-(cyanomethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (400 mg, 1.0 mmol) in ethanol (5 ml) was added sodium carbonate (420 mg, 4.0 mmol) and hydroxynonenal (210 mg, 3.0 mmol) and the mixture was stirred at 80°C for 3 days. Was added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in tetrahydrofuran (5 ml). Was added N,N'-carbonyldiimidazole (350 mg, 2.5 mmol) and the mixture was stirred at 80°C for 4 h the Reaction mixture was concentrated and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]pyridine-3-yl}methyl)carbamate (120 mg, yield 26%) as white powder.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2.06 to 2,22 (1H, m), is 2.40 (3H, s), of 2.51 (3H, s), 2,73 (2H, d, J=7,2 Hz), 3,62(2H, s), was 4.02 (2H, d, J=4.5 Hz), of 4.45 (1H, USS), 7,02 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=7,8 Hz).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}-1,2,4-oxadiazol-5(4H)-she (181 mg, yield 87%) was obtained as a white powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl]pyridine-3-yl}methyl)carbamate method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,13-of 2.21 (1H, m), 2,39 (3H, s)of 2.75 (3H, s), 3,05 (2H, USS), 3,66 (2H, s), 3,76 (2H, USS), 7,16 (2H, d, J=7.8 Hz), was 7.36 (2H, d, J=7.8 Hz), compared to 8.26 (3H, USS).

Example204

The dihydrochloride diethyl{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}phosphonate

1) Triethylphosphite (772 ml, 4.5 mmol) was added to [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (692 mg, 1,45 mmol) and the mixture was stirred at 150°C for 3 hours the Reaction mixture was allowed to cool to room temperature and was purified column chromatography on silica gel to obtain diethyl{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}phosphonate (314 mg, yield 42%) as a white powder.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), of 1.17 (6H, t, J=7.2 Hz), to 1.38 (9H, s), 2,14-of 2.24 (1H, m), is 2.40 (3H, s)to 2.66 (3H, s), 2,73 (2H, d, J=5,1 Hz), 2,96 (1H, s), 3.04 from (1H, s), 3,86 (4H, q, J=7.2 Hz), 4,00 (2H, d, J=4,8 Hz), 4,17 (1H, USS), 7,07 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=8,1 Hz).

2) Dihydrochloride diethyl{[5-(aminomethyl)-6-isobutyl-2-meth is l-4-(4-were)pyridine-3-yl]methyl}phosphonate (106 mg, yield 96%) was obtained as a white powder from diethyl{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}phosphonate method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.3 Hz), to 1.21 (6H, t, J=7.2 Hz), 2,11-to 2.18 (1H, m), 2,42 (3H, s), 2,95 (3H, s)to 3.09 (2H, s), 3,17 (2H, s), of 3.78 (2H, s), 3,82 (4H, q, J=7.2 Hz), 7,26 (2H, d, J=7.8 Hz), 7,39 (2H, d, J=7.8 Hz), 8,43 (3H, USS).

Example205

Trihydrochloride pyridine-2-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) Pyridine-2-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,21 g, yield 99%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,00 g, 2,42 mmol), hydrobromide 2-(methyl bromide)pyridine (0,92 g of 3.64 mmol) and potassium carbonate (1,00 g, 7,27 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14 was 2.25 (1H, m)to 2.35 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,2 Hz), 4,14 (2H, USS), 4,25 (1H, USS), is 5.06 (2H, s), 6.89 in (1H, d, J=7,7 Hz), 7,06 (2H, d, J=7.9 Hz), 7,13 (2H, d, J=7.9 Hz), 7,17-7,22 (1H, m), EUR 7.57 (1H, t, J=7,7 Hz), charged 8.52 (1H, d, J=4,7 Hz).

2) Trihydrochloride pyridine-2-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.23 g, yield 99%) was obtained as white solids from pyridine-2-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate(1,21 g, is 2.40 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6,4 Hz), 2,17-of 2.28 (1H, m), of 2.34 (3H, s), 2,61 (3H, s)to 2.94 (2H, d, J=6.9 Hz), 3,81 (2H, d, J=4.9 Hz), 5,20 (2H, s), 7,19 (4H, s), 7.23 percent (1H, USS), a 7.62-7,66 (1H, m), of 8.06 (1H, t, J=7,Hz), 8,39 (3H, USS), 8,68 (1H, d, J=4,GC).

Example206

The dihydrochloride benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate

1) Benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (305 mg, yield 84%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and benzylbromide (180 mg, 1.05 mmol) by the method similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8gts), to 1.38 (9H, s), 2,12-of 2.28 (1H, m), of 2.38 (3H, s), 2.49 USD (3H, s), was 2.76 (2H, d, J=6.6 Hz), 3,39 (2H, s), a 4.03 (2H, d, J=5,1 Hz), 4,20 (1H, USS), of 5.05 (2H, s), make 6.90 (2H, d, J=7,GC), 7,14 (2H, d, J=7.9 Hz), 7,19-of 7.25 (2H, m), 7,31-7,40 (3H, m).

2) Dihydrochloride benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (214,5 mg, yield 95%) was obtained as a white powder from benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (240 mg, 0,464 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6,GC), 2,11-of 2.27 (1H, m), of 2.38 (3H, s), 2,78 (3H, s)and 3.15 (2H, s), of 3.78 (2H, d, J=5,1 Hz), 5,04 (2H, s), 7,10 (2H, d, J=8,1 Hz), 7,20 was 7.45 (7H, m), 8,40 (3H, USS).

Example

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide

1) tert-Butyl{[5-({[4-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (360 mg, yield 72%) was obtained as a white solid from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.50 g, 0,935 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13 was 2.25 (1H, m), of 2.38 (3H, s)to 2.65 (3H, s), was 2.76 (2H, d, J=7,4 Hz), 3,85 (2H, s), Android 4.04 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 7,05 (2H, d, J=7,4 Hz), 7,12 (2H, d, J=8.5 Hz), 7,19 (2H, d, J=7,Hz), to 7.64 (2H, d, J=8,5Hz).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide (253 mg, yield 74%) was obtained as a white solid from tert-butyl{[5-({[4-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (360 mg, 0,674 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6,5 Hz), 2,13-2,22 (1H, m), is 2.37 (3H, s), of 2.86 (3H, USS), 3,14 (2H, USS), of 3.78 (2H, d, J=4,GC), to 3.99 (2H, s), 7,22 (2H, d, J=8,5Hz), 7,26 (2H, d, J=8,1 Hz), 7,33 (2H, d, J=8,5Hz), 7,37 (1H, USS), 7,98 (1H, USS), 8,39 (3H, USS).

Example208

The dihydrochloride methyl-2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate

1) Methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobut the-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (1.19 g, yield 86%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol) and methyl-2-mercaptobenzoic (422 mg, 2.51 mmol) in a manner similar to the method of example 183-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,GC), of 1.39 (9H, s), 2,12-of 2.26 (1H, m)to 2.35 (3H, s)to 2.66 (3H, s)of 2.75 (2H, d, J=7,4 Hz), of 3.77 (2H, s)to 3.89 (3H, s), a 4.03 (2H, d, J=4,Hz), 4,19 (1H, USS), 7,05 (1H, d, J=8,1 Hz), 7,09-7,13 (3H, m), 7,17 (2H, d, J=8,1 Hz), 7,32-7,38 (1H, m), to 7.93 (1H, DD, J=7,7, 1.5 Hz).

2) Dihydrochloride methyl-2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (165 mg, yield 91%) was obtained as a white solid from methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (190 mg, 0,346 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,13 was 2.25 (1H, m), of 2.34 (3H, s), 2,77 (3H, USS), 2,98 (2H, USS), 3,69 is 3.76 (2H, m), of 3.80 (3H, s), a 3.87 (2H, s), 7,22-7,27 (4H, m), 7,31 (2H, d, J=8,5Hz), 7,47-7,52 (1H, m), 7,87 (1H, DD, J=7,7, 1.5 Hz), 8,18 (3H, USS).

Example209

2-({[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid

1) 2-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0,86 g, yield 88%) was obtained as a white solid from methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)PI the one-3-yl]methyl}thio)benzoate (1,00 g, 1.82 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.24 (1H, m), is 2.37 (3H, USS), 2,73 (3H, USS), 2,90 (2H, d, J=7,0 Hz), of 3.77 (2H, s), of 4.05 (2H, d, J=4.5 Hz), 4,32 (1H, USS), 7,01-7,10 (3H, m), 7,16-7,21 (3H, m), 7,30 and 7.36 (1H, m), 7,94-of 7.97 (1H, m).

2) 2-({[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (274 mg, yield 99%) was obtained as a white solid from 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.29 grams, 0,542 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,15-of 2.24 (1H, m), of 2.34 (3H, s), of 2.81 (3H, USS), 3,03 (2H, USS), 3,66-of 3.85 (4H, m), 7,19-to 7.35 (6H, m), 7,44 is 7.50 (1H, m), 7,88 (1H, d, J=7.5 Hz), 8,23 (3H, USS).

Example210

The dihydrochloride of 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide

1) tert-Butyl{[5-({[2-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,23 g, yield 48%) was obtained as a white solid from 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0,48 g, 0,898 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,14-of 2.26 (1H, m), is 2.40 (3H, s)of 2.64 (3H, s)of 2.75 (2H, d, J=7,4 Hz), 3,82 (2H, s), 4.00 points (2H, d, J=5.3 Hz), 4,27 (1H, USS), of 5.39 (1H, USS), of 6.68 (1H, USS), of 6.99 (2H,, d, J=7.9 Hz), 7,9-7,34 (5H, m), 7,75 for 7.78 (1H, m).

2) of the Dihydrochloride of 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide (218 mg, yield 99%) was obtained as a white solid from tert-butyl{[5-({[2-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,23 g, 0,431 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,10-of 2.24 (1H, m), of 2.38 (3H, s), and 2.83 (3H, s)3,18 (2H, USS), with 3.79 (2H, d, J=5,1 Hz), 3,86 (2H, s), 7,16 (2H, d, J=7,7 Hz), 7.23 percent and 7.36 (6H, m), 7,42 (1H, USS), of 7.48 (1H, DD, J=of 7.4 and 1.4 Hz), to 7.84 (1H, OSS), to 8.41 (3H, USS).

Example211

The dihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate

1) Methyl-3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (1.35 g, yield 82%) was obtained as a brown solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.20 g, a 3.01 mmol) and methyl-3-mercaptobenzoic (507 mg, a 3.01 mmol) in a manner similar to the method of example 183-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.24 (1H, m), of 2.38 (3H, s)of 2.64 (3H, s)of 2.75 (2H, d, J=7,4 Hz), 3,83 (2H, s), 3,90 (3H, s), was 4.02 (2H, d, J=5,1 Hz), 4,22 (1H, USS), of 7.00 (2H, d, J=8,1 Hz), 7,18 (2H, d, J=7,7 Hz), 7,28-7,30 (1H, m), 7,76-7,79 (1H, m), 7,80-to 7.84 (1H, m).

2) Dihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (28 mg, yield 87%) was obtained as a white solid from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (324 mg, 0,590 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,11-of 2.23 (1H, m), a 2.36 (3H, s)of 2.75 (3H, s), of 2.97 (2H, USS), 3,74 (2H, d, J=4.5 Hz), 3,85 (3H, s), of 3.96 (2H, s), 7,19 (2H, d, J=7,4 Hz), 7,29 (2H, d, J=7.9 Hz), the 7.43 (2H, d, J=5,1 Hz), the 7.65 (1H, s), 7,79-7,83 (1H, m), 8,18 (3H, USS).

Example212

The dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid

1) 3-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.73 g, yield 73%) was obtained as a white solid from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoate (0,90 g of 1.64 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,13-of 2.26 (1H, m), of 2.38 (3H, s), 2,68 (3H, s), and 2.79 (2H, d, J=7,0 Hz), 3,85 (2H, s), Android 4.04 (2H, d, J=4.9 Hz), 4,24 (1H, USS), of 7.00 (2H, d, J=7,2 Hz), 7,19 (2H, d, J=7.9 Hz), 7,30-to 7.35 (2H, m), to 7.84 (1H, USS), 7,89 (1H, USS).

2) of the Dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (167 mg, yield 80%) was obtained as a white solid from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-the l]methyl}thio)benzoic acid (0,22 g, 0,441 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-2,22 (1H, m), is 2.37 (3H, s)2,84 (3H, USS), 3,10 (2H, USS), 3,76 (2H, d, J=5,1 Hz), of 3.97 (2H, s), 7,21 (2H, d, J=7.9 Hz), 7,30 (2H, d, J=7.9 Hz), 7,41-7,42 (2H, m), the 7.65 (1H with), scored 8.38 (3H, USS).

Example213

The dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide

1) tert-Butyl{[5-({[3-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (460 mg, yield 92%) was obtained as a white solid from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzoic acid (0.50 g, 0,935 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,16-of 2.27 (1H, m), of 2.38 (3H, s)to 2.65 (3H, s)of 2.75 (2H, d, J=7,2 Hz), a-3.84 (2H, s), was 4.02 (2H, d, J=5,1 Hz), 4,24 (1H, USS), of 6.99 (2H, d, J=7.9 Hz), 7,19 (2H, d, J=7,7 Hz), 7,25-7,31 (2H, m), 7,49-7,53 (1H, m), 7,56-to 7.59 (1H, m).

2) of the Dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)benzamide (439 mg, quantitative) was obtained as a white solid from tert-butyl{[5-({[3-(aminocarbonyl)phenyl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (460 mg, 0,862 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,13-2,22 (1H, m), of 2.38 (3H, s), of 2.86 (3H, s), 3,19 (2H, d, J=6.6 Hz), of 3.78 (2H, d, J=4.9 Hz), 3,98 (2H, s), 7.23 percent (2H, the, J=8.1 Hz), 7,31-7,39 (4H, m), 7,45 (1H, USS), of 7.70 (1H, USS), of 7.75 (1H, d, J=7,4 Hz), of 8.04 (1H, USS), 8,46 (3H, USS).

Example214

The dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid

1) To a solution of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.50 g, 1.05 mmol), methyl-4-hydroxybenzoate (0.16 g, 1.05 mmol) and triphenylphosphine (0.36 g, 1.37 mmol) in tetrahydrofuran (10 ml) was added a 40% solution of 0.60 ml, 1.37 mmol) of diethylazodicarboxylate in toluene and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (380 mg, yield 68%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,16-of 2.27 (1H, m), of 2.34 (3H, s), 2,62 (3H, s), 2,80 (2H, d, J=7,4 Hz), a 3.87 (3H, s), 4,08 is 4.13 (2H, m), 4,30 (1H, USS), and 4.68 (2H, s), to 6.80 (2H, d, J=8,9 Hz),? 7.04 baby mortality (2H, d, J=7.9 Hz), 7,16 (2H, d, J=7,7 Hz), to 7.93 (2H, d, J=8,9 Hz).

2) 4-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (300 mg, yield 81%) was obtained as a white solid from methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (80 mg, 0,713 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-to 2.29 (1H, m)to 2.35 (3H, s)to 2.66 (3H, USS), 2,84 (2H, USS), 4,08-to 4.14 (2H, m), 4,22-of 4.25 (1H, m), 4,70 (2H, s), PC 6.82 (2H, d, J=8,9 Hz),? 7.04 baby mortality (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7.9 Hz), to 7.99 (2H, d, J=8,9 Hz).

3) of the Dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (267 mg, yield 94%) was obtained as a white solid from 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (0,30 g, 0,578 mmol) in a manner similar to the method of example 2-3).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), of 2.34 (3H, s), 2,82 (3H, USS), 3,11 (2H, USS), 3,83 (2H, d, J=5.3 Hz), 4,79 (2H, s), 6,93 (2H, d, J=8,9 Hz), 7,26 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=8.1 Hz), the 7.85 (2H, d, J=8,9 Hz), 8,35 (3H, USS).

Example215

The dihydrochloride methyl-4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate

The dihydrochloride methyl-4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (281 mg, yield 99%) was obtained as a white solid from methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (0.30 mg, 0,563 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m), of 2.33 (3H, s), 2,82 (3H, USS), 3,11 (2H, USS), 3,81-a 3.83 (5H, m), 4,80 (2H, s), of 6.96 (2H, d, J=8,9 Hz), 7,26 (2H, q, j =7.9 Hz), 7,30 (2H, d, J=8.1 Hz), 7,87 (2H, d, J=8,9 Hz), scored 8.38 (3H, USS).

Example216

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine

1) To a solution of p-tolualdehyde (8.5 g, to 78.3 mmol) and acetone (10 ml) in water (200 ml) was added sodium hydroxide (3.13 g, to 78.3 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 4-(4-were)but-3-EN-2-it (9,2 g, yield 80%) as oil. The oil obtained (1.0 g, 6,24 mmol) was dissolved in ethanol (20 ml) was added 3-amino-5-metrex-3-enitel (0,93 g, 7,49 mmol) and sodium hydroxide (0.3 g, 7,49 mmol). The mixture was heated at the boil under reflux for 2 hours, the Reaction mixture was diluted with ethyl acetate, washed sequentially with a saturated aqueous solution of ammonium chloride and a saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a residue. The obtained residue was obtained 2-isobutyl-6-methyl-4-(4-were)nicotinamide (0.45 g, yield 27%) as a yellow oil by the method similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6.6 Hz), 2,20-of 2.33 (1H, m), 2,43 (3H, s), 2.63 in (3H, s), 2,96 (2H, d, J=7,4 Hz), 7,11 (1H, s), 7,31 (2H, the, J=7.9 Hz), 7,47 (2H, d, J=8,3 Hz).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine (456 mg, yield 78%) was obtained as a white solid from 2-isobutyl-6-methyl-4-(4-were)nicotinanilide (0.45 g, 1.70 mmol) in a manner similar to the method of example 108-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.4 Hz), 2,13-2,22 (1H, m), is 2.41 (3H, s), 2,72-2,82 (3H, m), 3,05-3,18 (2H, m), as 4.02-4,11 (2H, m), 7,41 (4H, s), to 7.67 (1H, USS), of 8.47-8,58 (3H, m).

Example217

4-Methylbenzenesulfonate ({2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine

1) To a solution of 4-methylbenzenesulfonate sodium (9.00 g, and 50.5 mmol) in ethanol (50 ml) was added bromoacetone (6.9 g, 50 mmol) and the mixture was heated at the boil under reflux for 30 minutes, the Reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain 1-[(4-were)sulfonyl]acetone (8.0 g, 75%yield) as a colorless oil.

1H-NMR (CDCl3) δ: 2,41 (3H, s)to 2.46 (3H, s), 4,14 (2H, s), 7,37 (2H, d, J=8,2 Hz), to 7.77 (2H, d, J=8,2 Hz).

2) a Mixture of 1-[(4-were)sulfonyl]acetone (2.0 g, 9.4 mmol), p-tolualdehyde (1.1 g, 9.4 mmol), piperidine (0,093 ml of 0.94 mmol), acetic acid (0,11 ml, 1.9 mmol) and toluene (100 ml) is agrawala boiling under reflux, using the trap Dean-stark for 3 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 4-(4-were)-3-[(4-were)sulfonyl]but-3-EN-2-it is in the form of the crude product (3.5 g). A mixture of the crude product (1.73 g), 3-amino-5-metrex-3-onitrile (0.65 g, 5,23 mmol) and ethanol (50 ml) was heated at the boil under reflux for 12 hours the Reaction mixture was allowed to cool to room temperature and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel and the obtained solid substance was recrystallized from a mixture of diisopropyl ether-ethyl acetate to obtain 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]-1,4-dihydropyridines-3-carbonitrile (1.3 g, yield 64%) as a white powder.

TPL: 135-137°C

3) 2-Isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]nicotinamide (0,77 g, yield 68%) was obtained as a white powder from 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]-1,4-dihydropyridines-3-carbonitrile (1.1 g, 2.7 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 2.20 to 2.35 (1H, m), of 2.38 (3H, s), 2,39 (3H, s), 2.91 in (2H, d, J=7,2 Hz), of 3.07 (3H, s)6,86 (2H, d, J=8.1 Hz), was 7.08 (4H, d, J=8.1 Hz), 7.23 percent (2H, the, J=8,1 Hz).

4) ({2-Isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0.64 g, yield 93%) was obtained as colorless oil from 2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]nicotinanilide (0,69 g, 1.6 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), 1,41 (2H, USS), of 2.20 to 2.35 (1H, m), of 2.38 (6H, s), and 2.79 (2H, d, J=7,2 Hz), 2,96 (3H, s), 3,40 (2H, s)6,76 (2H, d, J=8.1 Hz), 7,03 (2H, d, J=8,3 Hz), to 7.09 (2H, d, J=8.1 Hz), 7,27 (2H, d, J=8,3 Hz).

5) ({2-Isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0.64 g, 1.5 mmol) was dissolved in ethanol (5 ml) and added dropwise with stirring a solution of hydrate p-toluensulfonate acid (to 0.29 g, 1.5 mmol) in ethanol (5 ml) at room temperature. The mixture was stirred at room temperature for 10 minutes the Precipitate was collected by filtration, washed with cold ethanol and dried to obtain 4-methylbenzenesulfonate ({2-isobutyl-6-methyl-4-(4-were)-5-[(4-were)sulfonyl]pyridine-3-yl}methyl)amine (0,57 g, yield 63%) as a white powder.

1H-NMR (DMSO-d6) δ: of 0.94 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m)to 2.29 (3H, s), is 2.37 (6H, s), 2,78 (2H, d, J=7,0 Hz), 2,84 (3H, s), of 3.57 (2H, s), 6.87 in (2H, d, J=7.9 Hz), 7,11 (4H, d, J=8.5 Hz), 7,25-7,30 (4H, m), 7,47 (2H,, d, J=7.9 Hz), 7,76 (3H, USS).

Example218

{[2-Isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)pyridine-3-yl]methyl}amine

1) a Mixture of 1-(methylsulphonyl)acetone (3,68 g,27 mmol), p-tolualdehyde (3,24 g, 27 mmol), piperidine (of 0.26 ml, 2.7 mmol), acetic acid (0.31 in ml, 5.4 mmol) and toluene (200 ml) was heated at boiling under reflux, using a trap Dean-stark, within 12 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in methanol (20 ml). Was added 3-amino-5-metrex-3-enitel (4.3 g, 35 mmol) and the mixture was heated at the boil under reflux for 6 hours the Reaction mixture was concentrated under reduced pressure and the residue was purified column chromatography on silica gel to obtain 2-isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)-1,4-dihydropyridines-3-carbonitrile (6,38 g, yield 68%) as a yellow oil.

1H-NMR (CDCl3) δ: of 0.95 (3H, d, J=6.6 Hz), a 1.01 (3H, d, J=6.6 Hz), 2,18 was 2.25 (1H, m), 2,32 (3H, s)to 2.35 (3H, s), is 2.40 (3H, s), 2,44 (1H, s), 3.04 from (1H, s), 4,69 (1H, s)5,80 (1H, s), 7,14 (2H, d, J=8.1 Hz), 7,21 (2H,, d, J=8,3 Hz).

2) 2-Isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)nicotinamide (4,14 g, yield 65%) was obtained as a white solid from 2-isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)-1,4-dihydropyridines-3-carbonitrile (6,38 g of 18.6 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6.8 Hz), 2,23-is 2.37 (1H, m), is 2.44 (3H, s), 2,95 (2H, d, J=7 Hz), of 3.05 (3H, s), from 7.24 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=7.9 Hz).

3) {[2-Isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)pyridine-3-yl]methyl}amine (0,81 g, 75%yield) was obtained as a white solid from 2-isobutyl-6-methyl-4-(4-were)-5-(methylsulphonyl)nicotinanilide (1.06 g, to 3.09 mmol)in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.8 Hz), 2,22-of 2.36 (1H, m), 2,43 (3H, s), 2,80 (3H, s), 2,82 (2H, d, J=7,4 Hz), 2,96 (3H, s), 3,50 (2H, s), 7,12 (2H, d, J=7.9 Hz), 7,26 (2H, d, J=7,7 Hz).

Example219

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (730 mg, yield 72%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.75 g, 1,89 mmol) and methyl-3-hydroxybenzoate (0.29 grams, 1,90 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m)to 2.35 (3H, s), 2,62 (3H, s), and 2.79 (2H, d, J=7,2 Hz), with 3.89 (3H, s), 4,07-4,11 (2H, m), of 4.67 (2H, s), 6,98-7,02 (1H, m), 7,05 (2H, d, J=7.9 Hz), 7,16 (2H, d, J=7,7 Hz), 7,29-to 7.32 (1H, m), 7,42-the 7.43 (1H, m), 7,60-7,63 (1H, m).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (116 mg, yield 85%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-m is Tyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (144 mg, 0,270 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), of 2.34 (3H, s), and 2.83 (3H, USS), 3,11 (2H, USS), 3,83 (5H, s), rate 4.79 (2H, s), to 7.15 (1H, DD, J=7,8 and 2.2 Hz), 7,27 (2H, d, J=8,3 Hz), 7,29-to 7.35 (3H, m), 7,42 (2H, t, J=7.9 Hz), 7,56 (1H, d, J=7,7 Hz), scored 8.38 (3H, USS).

Example220

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid

1) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (460 mg, yield 80%) was obtained as colorless oil from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (0,58 g, 1.10 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.28 (1H, m), of 2.34 (3H, s)to 2.65 (3H, s), 2,82 (2H, d, J=7,2 Hz), 4,11 (2H, USS), 4,28 (1H, USS), and 4.68 (2H, s), 7.03 is-7,07 (3H, m), 7,16 (2H, d, J=7.9 Hz), 7,33 (1H, t, J=8.0 Hz), 7,47 (1H, OSS), to 7.64-of 7.70 (1H, m).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (128 mg, yield 99%) was obtained as a white solid from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (136 mg, 0,262 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.2 Hz), 2,18-of 2.27 (1H, m), of 2.34 (3H, s), 2,73-and 2.79 (3H, m), 3.04 from (2H, USS), 3,81 (2H, OSS), was 4.76 (2H, is), 7,11 (2H, d, J=8.1 Hz), 7,21-7,31 (5H, m), 7,38 (1H, t, J=7,7 Hz), 7,54 (1H, d, J=7.5 Hz), 8,27 (3H, USS).

Example221

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (700 mg, yield 70%) was obtained as a white solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.75 g, 1,89 mmol) and methyl 2-hydroxybenzoate (0.29 grams, 1,90 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), a 2.36 (3H, s)to 2.67 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3,81 (3H, s), 4.09 to (2H, d, J=4.0 Hz), 4,23 (1H, USS), 4,71 (2H, s), of 6.66 (1H, d, J=8,3 Hz), 6,93-6,98 (1H, m),? 7.04 baby mortality (2H, d, J=8.1 Hz), 7,16 (2H, d, J=7,7 Hz), 7,29-to 7.35 (1H, m), 7,72 (1H, DD, J=7,6, 1.8 Hz).

2) Dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (42,3 mg, yield 56%) was obtained as a white solid from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (78,8 mg, 0,148 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-to 2.29 (1H, m), a 2.36 (3H, s), and 2.83 (3H, USS), of 3.07 (2H, USS), 3,74 (3H, s), 3,83 (2H, d, J=4,7 Hz), 4,78 (2H, s)6,91 (1H, d, J=8.5 Hz), 7,03 (2H, t, J=7.4 Hz), 7,25 (2H, d, J=7.9 Hz), 7,30 (2H, d, J=8.1 Hz), 7,42-of 7.48 (1H, m), of 7.64 (1H, DD, J=7,6, and 1.6 Hz), 8,30 (3H, USS).

<> Example222

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid

1) 2-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (140 mg, yield 23%) was obtained as a white solid from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoate (0,62 g at 1.17 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2.21 are of 2.30 (1H, m), of 2.34 (3H, s)to 2.65 (3H, s), of 2.81 (2H, d, J=7,4 Hz), 4,10 (2H, d, J=5.3 Hz), to 4.92 (2H, s), 6,83 (1H, d, J=8,3 Hz), 7,01 (2H, d, J=8.1 Hz), 7,10-to 7.15 (1H, m), 7,17 (2H, d, J=7,7 Hz), 7,44 is 7.50 (1H, m), 8,17 (1H, DD, J=7,8, 1.8 Hz).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (103 mg, yield 77%) was obtained as a white solid from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (0.14 g, 0,270 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m), is 2.37 (3H, s), 2,89 (3H, USS), of 3.13 (2H, USS), a-3.84 (2H, d, J=4,7 Hz), 4,78 (2H, s)6,86 (1H, d, J=8.5 Hz), 7,02 (1H, t, J=7.4 Hz), 7,27 (2H, d, J=7.9 Hz), to 7.32 (2H, d, J=8.1 Hz), 7,38-7,44 (1H, m), to 7.61 (1H, DD, J=7,5) and 1.7 Hz), 8,39 (3H, USS).

Example223

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]benzamide

To races is the thief of tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) in tetrahydrofuran (3 ml) was added benzoyl chloride (88 ml, 0.75 mmol) and then triethylamine (140 μl, 1.0 mmol). The mixture was stirred for 30 minutes was Added to the reaction mixture, a saturated aqueous solution of sodium hydroxide (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in ethyl acetate (1 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h the Solvent is evaporated under reduced pressure and the obtained residue was led from hexane to obtain the dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]benzamide (203 mg, yield 96%) as a white powder.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,20 of-2.32 (1H, m), 2,31 (3H, s)of 2.64 (3H, s), 3,11 (2H, s), a 3.87 (2H, s), 7,17-7,66 (9H, m), 8,49 (3H, USS), 10,13 (1H, USS).

Example224

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-phenylacetamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-phenylacetamide (208 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-tbutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and phenylacetylene (100 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 1,98-of 2.26 (1H, m), is 2.40 (3H, s)of 2.50 (3H, s), 3.04 from (2H, s), 3,40 (2H, s), of 3.78 (2H, s), 6,94-6,97 (2H, m), 7,12-7,53 (7H, m), 8,44 (3H, USS), for 9.90 (1H, USS).

Example225

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-phenylpropanamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-phenylpropanamide (208 mg, yield 92%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and hydrocinnamaldehyde (111 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,15-of 2.23 (1H, m), of 2.33 (2H, t, J=7.2 Hz), is 2.37 (6H, s), 2.63 in (2H, t, J=7.2 Hz), to 2.94 (2H, USS), with 3.79 (2H, s), 7,10-7,29 (9H, m), compared to 8.26 (3H, USS), 9,43 (1H, USS).

Example226

The dihydrochloride (2E)-N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-phenylacetamido

The dihydrochloride (2E)-N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-phenylacetamide (208 mg, yield 92%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and cinnamoylcocaine (125 mg, 0.75 in mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,15-of 2.28 (1H, m), of 2.34 (3H, s), 2,55 (H, C)to 3.02 (2H, USS), 3,83 (2H, USS), 6,63 (1H, d, J=15.6 Hz), 7,16-of 7.23 (2H, m), 7,28-to 7.32 (2H, m), 7,39-7,46 (4H, m), 7,52-7,56 (2H, m), at 8.36 (3H, USS), 9,76 (1H, USS).

Example227

The dihydrochloride of ethyl[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were) pyridine-3-yl]amino}carbonyl)oxy]acetate

1) Ethyl[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]acetate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethylhydroxylamine(104 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):514

2) Dihydrochloride ethyl[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]acetate (202 mg, yield 45%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.3 Hz), of 1.18 (3H, t, J=7.2 Hz), 2,11-to 2.29 (1H, m), of 2.38 (3H, s), of 2.86 (3H, s), of 3.77 (2H, USS), 3,91 (2H, USS), of 4.12 (2H, q, J=7.2 Hz), to 4.52 (2H, s), to 7.15 (2H, d, J=7.8 Hz), 7,29 (2H, d, J=7.8 Hz), 8,21 (3H, USS), 9,12 (1H, USS).

Example228

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N'-benzyladenine

1) tert-Butyl{[5-{[(benzylamino)carbonyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-m is terphenyl)nicotinic acid (412 mg, 1.0 mmol) and benzylamine (218 ml, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):517

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N'-benzyladenine (181 mg, yield 40%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.3 Hz), 2,09-2,22 (1H, m), is 2.41 (3H, s)of 2.50 (3H, s), 2,65 (2H, USS), 3,81 (2H, USS), 4,19(2H, USS), 7,11-to 7.35 (9H, m), 8,43 (3H, USS).

Example229

The dihydrochloride methyl-4-{[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]methyl}benzoate

1) Methyl-4-{[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]methyl}benzoate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and methyl-4-hydroxymethylbenzene (250 mg, 1.5 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):576

2) Dihydrochloride methyl-4-{[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]methyl}benzoate (195 mg, yield 38%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.3 Hz), 2,14-of 2.23 (1H, m), 2,39 (3H, s)to 2.55 (3H, s), of 2.97 (2H, USS), of 3.78 (2H, USS), a 3.87 (3H, s), 5,09 (2H,USS), 7,14-7,29 (6H, m), 7,92 (2H, d, J=8,4 Hz), 8,30 (3H, USS), 9,19 (1H, USS).

Example230

The dihydrochloride of 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid

1) To a solution of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.70 g, 4,12 mmol) in N,N-dimethylformamide (15 ml) was added methyl-3-(methyl bromide)benzoate (0,79 g of 3.43 mmol) and potassium carbonate (0.71 g, 5,15 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate and the mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with 3-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.80 g, yield 94%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), of 2.33 (3H, s), of 2.53 (3H, s), 2,77 (2H, d, J=7,4 Hz), of 3.94 (3H, s), of 4.13 (2H, USS), 4,20 (1H, USS), of 4.95 (2H, s), 7,01 (2H, d, J=8.1 Hz), to 7.09 (2H,, d, J=7.9 Hz), 7,22 (1H, d, J=7,7 Hz), 7,35 (1H, t. J=7,7 Hz), 7,83 (1H, s), 7,98 (1H, d, J=7,7 Hz).

2) 3-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (1,43 g, yield 87%) was obtained as colorless oil from 3-(methoxycarbonyl)benzyl-5-{[(is pet-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,69 g, a 3.01 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13 was 2.25 (1H, m), of 2.34 (3H, s)to 2.55 (3H, s), 2,80 (2H, d, J=7,4 Hz), 4,11-4,16 (2H, m), 4,22 (1H, OSS), to 4.98 (2H, s), 7,02 (2H, d, J=7.9 Hz), 7,11 (2H, d, J=7,7 Hz), 7,26-7,30 (1H, m), 7,39 (1H, t. J=7,7 Hz), 7,89 (1H, s), of 8.04 (1H, d, J=7.5 Hz).

3) of the Dihydrochloride of 3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (293 mg, yield 60%) was obtained as a white solid from 3-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]benzoic acid (0.50 g, 0,927 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16 was 2.25 (1H, m), 2,32 (3H, s)to 2.54 (3H, s), 2,90 (2H, d, J=6.6 Hz), 3,81 (2H, d, J=5,1 Hz), 5,04 (2H, s), 7,13 (2H, d, J=8.5 Hz), 7,17 (2H, d, J=8,3 Hz), 7,26-7,30 (1H, m,), 7,44 (1H, t. J=7,6 Hz), 7,73-7,74 (1H, m), 7,89-a 7.92 (1H, m), 8,30 (3H, USS).

Example231

The dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid

1) To a solution of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.10 g, to 2.67 mmol) in N,N-dimethylformamide (15 ml) was added 2-bromobenzylamine (0,61 g, 2,43 mmol) and potassium carbonate (0.51 g, 3.65 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution, and the left the house taking over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 2-bromobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.23 g, yield 87%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,14 was 2.25 (1H, m)to 2.35 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,2 Hz), 4,11-4,13 (2H, m), 4,22 (1H, USS), of 5.05 (2H, s), 7,02-7,05 (3H, m), 7,11 (2H, d, J=7.9 Hz), 7,16-7,21 (2H, m), 7,51-rate of 7.54 (1H, m).

2) 2-Bromobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,23 g, 2,12 mmol), triethylamine (0,59 ml, 4,24 mmol) and dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (174 mg, 0,212 mmol) was dissolved in methanol (5 ml)-N,N-dimethylformamide (15 ml) and the resulting mixture was stirred in an atmosphere of co carbon for 14 hours, the Reaction mixture was diluted with ethyl acetate (100 ml) and the mixture was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain 2-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.88 g, yield 74%) as a yellow oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m)to 2.35 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,2 Hz), 387 (3H, C), 4,11-4,16 (2H, m), is 4.21 (1H, USS), of 5.39 (2H, s), 7,01-7,06 (3H, m), 7,11 (2H, d, J=7.9 Hz), 7,32-7,42 (2H, m), 7,93-of 7.96 (1H, m).

3) 2-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (0.75 g, yield 89%) was obtained as colorless oil from 2-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.88 g, 1.54 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,12-of 2.21 (1H, m), a 2.36 (3H, s)to 2.54 (3H, s), and 2.83 (2H, d, J=7,2 Hz), 4,13-4,18 (2H, m), 4,25 (1H, USS), 5,38 (2H, s), 7,01? 7.04 baby mortality (3H, m), 7,11 (2H, d, J=7.5 Hz), 7,38-7,46 (2H, m), 8,06-of 8.09 (1H, m).

4) of the Dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]benzoic acid (278 mg, yield 65%) was obtained as a white solid from 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]benzoic acid (0.45 g, 0,823 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m)to 2.35 (3H, s)2,84 (2H, d, J=7,2 Hz), 3,82 (2H, d, J=5.3 Hz), 5,32 (2H, s), 6,97-7,00 (1H, m), 7,18 (2H, d, J=8,3 Hz), 7,24 (2H, d, J=7.9 Hz), 7,41-7,51 (2H,, m), 7,87-to $ 7.91 (1H, m), 8,19 (3H, USS).

Example232

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-METI the-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate (230 mg, yield 89%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and chloride nanometrology ester of terephthalic acid (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,22-2,31 (1H, m), 2,31 (3H, s)to 2.54 (3H, s), 2,95 (2H, USS), 3,85 (2H, USS), a 3.87 (3H, s), 7,20-7,27 (4H, m), 7,72 (2H, d, J=8,4 Hz), to 7.99 (2H, d, J=8,4 Hz), compared to 8.26 (3H, USS), 10,13 (1H, USS).

Example233

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (248 mg, yield 98%) was obtained as a white powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate (260 mg, 0.48 mmol) in a manner similar to the method of example 36-1).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), of 1.35 (9H, s), 2,18-to 2.29 (1H, m)to 2.29 (3H, s)at 2.59 (3H, s), is 2.88 (2H, USS), 3,99 (2H, USS), 7,14 (1H, s), 7,20 (4H, s), of 7.70 (2H, d, J=8,4 Hz), of 7.97 (2H, d, J=8,4 Hz), 10,13 (1H, USS).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (230 mg, yield 99%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzo Inoi acid (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,22 of-2.32 (1H, m), 2,31 (3H, s)to 2.55 (3H, s), 2,96 (2H, USS), 3,83 (2H, USS), 7,20-7,27 (4H, m), of 7.70 (2H, d, J=8.1 Hz), of 7.96 (2H, d, J=8.1 Hz), compared to 8.26 (3H, USS), 10,11 (1H, USS).

Example234

The dihydrochloride methyl(4-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)acetate

1) Methyl(4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)acetate (0.36 g, yield 61%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0,44 g, 1,1 mmol) and methyl-4-hydroxyphenylacetate (0.18 g, 1.1 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: of 1.03 (9H, s)to 1.37 (9H, s), a 2.36 (3H, s), 2,61 (3H, s), 2,87 (2H, s), 3,55 (2H, s), 3,68 (3H, s), 4,05-of 4.25 (3H, m), 4,59 (2H, s)6,76 (2H, d, J=8.5 Hz), 7,05 (2H, d, J=8.5 Hz), 7,14 (2H, d, J=8.5 Hz), 7,17 (2H, d, J=8,5 Hz).

2) Dihydrochloride methyl(4-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)acetate (0,088 g, yield 74%) was obtained as a white powder from methyl(4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)acetate (of 0.13 g, 0.22 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,04 (9H, s)to 2.35 (3H, s), 2,77 (3H, USS), 3,14 (2H, OSS), to 3.58 (2H, d, J=7,0 Hz)and 3.59 (3H, s), a 3.87 (2H, s), of 4.66 (2H, s), to 6.80 (2H, d, J=8.7 Hz), 7,14 (2H, d, J=87 Hz), of 7.25 (2H, d, J=7,7 Hz), 7,31 (2H, d, J=7,7 Hz), to 8.20 (3H, USS).

Example235

The dihydrochloride methyl-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,3-oxazol-4-carboxylate

1) Methyl-N-{[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}serinate (lower than the 5.37 g, yield 87%) was obtained as colorless oil from 5-cyano-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (5,00 g, and 11.2 mmol) and hydrochloride complex serine methyl ester (2,09 g, a 13.4 mmol) in a manner similar to the method of example 195-2).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=5.7 Hz), 2,15-of 2.26 (1H, m), of 2.38 (3H, s), to 2.57 (3H, s), 2,80 (2H, d, J=7,0 Hz), 3,36-of 3.42 (1H, m), 3,61 at 3.69 (1H, m), of 3.73 (3H, s), 4,19-the 4.29 (2H, m), 4,43-to 4.52 (2H, m), of 5.03 (2H, s), 6,21 (1H, d, J=7,0 Hz), 7,12-7,17 (2H, m), 7,17-7,22 (2H, m), 7,29-7,38 (5H, m).

2) Solution of methyl N-{[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}Serenata (lower than the 5.37 g, 9,81 mmol) in dichloromethane (50 ml) was cooled to -78°C and added diethylaminoacetate (1,72 ml of 11.8 mmol). The mixture was stirred at the same temperature for 1 h was Added potassium carbonate (1,36 g, 14.7 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 2-[-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4,5-dihydro-1,3-oxazol-4-carboxylate (3,59 g, yield 69%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), 2,15-of 2.26 (1H, m), is 2.37 (3H, s), to 2.57 (3H, s), of 2.81 (2H, d, J=7,2 Hz), 3,71 (3H, s), 4,11-4,16 (1H, m)to 4.23 (2H, d, J=5,5 Hz)to 4.33 (1H, DD, J=8,8, 7,4 Hz), 4,59 with 4.65 (1H, m), to 5.03 (2H, s), 7,05 (2H, d, J=8.5 Hz), 7,13-7,21 (2H, m), 7,29-7,38 (5H, m).

3) Solution of methyl-2-[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4,5-dihydro-1,3-oxazol-4-carboxylate (0,83 g, 2,12 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (1,11 ml, 7,42 mmol) in dichloromethane (10 ml) was cooled to 0°C and added bromotrichloromethane (0,73 ml, 7,42 mmol). The mixture was stirred at the same temperature for 1 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 2-[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,3-oxazol-4-carboxylate (520 mg, yield 63%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.03 (6H, d, J=6.8 Hz), 2,24-of 2.34 (4H, m), 2,59 (3H, s)of 3.00 (2H, d, J=7,4 Hz)to 3.92 (3H, s), 7,11 (2H, d, J=8.5 Hz), 7,16 (2H, d, J=8,3 Hz), 8,08 (1H, s).

4) Dihydrochloride methyl-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,3-oxazol-4-carboxylate (456 mg, yield 73%) was obtained as a white solid from methyl-2-[5-cyano-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,3-oxazol-4-carboxylate (0.52 in the, of 1.34 mmol) in a manner similar to the method of example 108-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2.21 are of 2.30 (4H, m), 2,45-2,48 (3H, m), 2,90-to 3.02 (2H, m), of 3.78 (3H, s), 3,85 (2H, d, J=4,7 Hz), 7,11 (2H, DD, J=8,1, 2,1 Hz), 7,20 (2H, d, J=8.1 Hz), 8,30-of 8.47 (3H, m), 8,77 (1H, d, J=1.5 Hz).

Example236

The dihydrochloride of 2-(4-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)ndimethylacetamide

1) tert-Butyl{[5-{[4-(2-amino-2-oxoethyl)phenoxy]methyl}-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.14 g, yield 47%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0,22 g, of 0.53 mmol) and 4-hydroxyphenylacetamide (of 0.081 g of 0.53 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 1,04 (9H, s)to 1.37 (9H, s), a 2.36 (3H, s), 2,62 (3H, s), is 2.88 (2H, s), 3,51 (2H, s), 4,10-of 4.25 (3H, m), br4.61 (2H, s), to 5.35 (2H, USS), 6,75-to 6.80 (2H, m), 7,05 (2H, d, J=7.9 Hz), 7,10-7,20 (4H, m).

2) of the Dihydrochloride of 2-(4-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}phenyl)ndimethylacetamide (0,098 g, yield 92%) was obtained as pale yellow powder from tert-butyl{[5-{[4-(2-amino-2-oxoethyl)phenoxy]methyl}-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (0.11 g, 0.20 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.05 (9H, s), a 2.36 (3H, s), and 2.79 (3H, USS), 3,05-of 3.25 (2H, m), or 3.28 (2H, s), 3,88 (2H, USS), of 4.66 (2H, s), 6,79 (2H, d, J=8.5 Hz), 6,83 (1H, USS), 7,14 (2H, d, J=8.5 Hz), 7,26 (2H, d, J=7,4 Hz), 7,33 2H, d, J=7,4 Hz), 7,42 (1H, USS), 8,19 (3H, USS).

Example237

Methyl(4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}phenyl)acetate

1) Methyl(4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}phenyl)acetate (570 mg, yield 83%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (500 mg, 1.25 mmol) and methyl(4-hydroxyphenyl)acetate (250 mg and 1.51 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.30 (1H, m), a 2.36 (3H, s), 2,62 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3,51 (2H, s), of 3.56 (3H, s), 4,10 (2H, d, J=4,7 Hz), 4,20 (1H, s), br4.61 (2H, s), 6,78 (2H,, d, J=8.5 Hz), 7,06 (2H, d, J=8.5 Hz), 7,12-7,20 (4H, m).

2) Methyl(4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}phenyl)acetate (570 mg, 1.04 mmol) was dissolved in triperoxonane acid (10 ml) and the mixture was stirred for 1 h, the Reaction mixture was concentrated under reduced pressure and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain methyl(4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}phenyl)AC is Tata (300 mg, yield 65%) as a colourless oil.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,18 was 2.25 (1H, m), of 2.34 (3H, s), 2,60 (3H, s), is 2.88 (2H, d, J=7,4 Hz), 3,30 (2H, d, J=5.3 Hz), 3,61 (3H, s), 4,20 (2H, d, J=4,7 Hz), 4,60 (2H, s)6,70 (2H, d, J=8.5 Hz), 6,79 (2H, d, J=8.5 Hz), 7,05 (2H, d, J=8,3 Hz), to 7.15 (2H, d, J=8,3 Hz).

Example238

The dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid

The dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (230 mg, yield 89%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and chloride nanometrology ester of isophthalic acid (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,18-2,31 (1H, m), 2,31 (3H, s), 2,60 (3H, s), 3.04 from (2H, USS), 3,85 (2H, USS), 7,25 (4H, s), EUR 7.57 (1H, t, J=7.8 Hz), 7,86 (1H, d, J=7.8 Hz), 8,07 (1H, d, J=7.8 Hz), 8,16 (1H, ), at 8.36 (3H, USS), 10,19 (1H, USS).

Example239

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-indole-2-carboxylate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-indole-2-carboxylate (0,41 g, yield 52%) was obtained as a pale-yellow solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carb is ATA (0,60 g, for 1.49 mmol) and methyl-3-hydroxyindole-2-carboxylate (0.26 g, of 1.36 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.37 (9H, s), 2,17-of 2.26 (1H, m), is 2.37 (3H, s), 2,77 (2H, d, J=7,2 Hz), of 2.86 (3H, s), 3,82 (3H, s), 4.00 points (2H, d, J=4.5 Hz), 4.09 to (1H, OSS), to 5.03 (2H, s), 6,74-6,89 (4H, m), 7,09 (2H, d, J=7.9 Hz), 7,21-7,31 (2H, m), of 8.28 (1H, USS).

2) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-indole-2-carboxylate (0.26 g, of 1.36 mmol) was dissolved in 4n. an ethyl acetate solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The obtained yellow solid was recrystallized from a mixture of ethyl acetate-hexane to obtain methyl 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-indole-2-carboxylate (256 mg, yield 75%) as pale yellow crystals.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 2,17-of 2.30 (1H, m), of 2.38 (3H, s), and 2.79 (2H, d, J=7,4 Hz), of 2.86 (3H, s), 3,51 (2H, s), 3,83 (3H, s), 5,02 (2H, s), 6,77-to 6.88 (4H, m), 7,10 (2H, d, J=7,7 Hz), 7,22-7,28 (2H, m), of 8.27 (1H, USS).

Example240

4-Cyanobenzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 4-Cyanobenzyl-5-{[(tert-butoxycarbonyl the l)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,32 g, yield 86%) was obtained as a yellow oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.10 g, 5,10 mmol) and 4-cyanobenzaldehyde (1,00 g, 5,10 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,17-of 2.26 (1H, m), is 2.37 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,2 Hz), 4,11-4,13 (2H, m), 4,20 (1H, OSS), to 4.98 (2H, s), 7,01 (2H, d, J=8.1 Hz), 7,10 (4H, d, J=8.1 Hz), 7,54 (2H, d, J=8,3 Hz).

2) 4-Cyanobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.52 g, 0,985 mmol) was dissolved in triperoxonane acid (10 ml) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate to obtain 4-cyanobenzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,42 g, yield 99%) as a yellow oil.

1H-NMR (CDCl3) δ: from 0.90 (6H, d, J=6.6 Hz), 2,08-2,17 (1H, m), 2,32 (3H, s)to 2.54 (3H, s), 2,70 (2H, d, J=7,0 Hz), of 3.97 (2H, s), 4,99 (2H, s)to 7.00 (2H, d, J=8.1 Hz), 7,08-7,14 (4H, m), 7,54 (2H, d, J=8,3 Hz).

Example241

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cinoxacin-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cinoxacin-2-carboxamide (137 mg, yield 50%) was obtained in the form of below the powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and cinoxacin-2-carbonylchloride (144 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: of 1.02 (6H, d, J=6.6 Hz), 2,22-to 2.29 (1H, m), of 2.23 (3H, s)of 2.64 (3H, s), 3,06 (2H, USS), 3,86 (2H, USS), 7,22 (2H, d, J=8.1 Hz), 7,29 (2H, d, J=8.1 Hz), of 7.96-of 8.04 (2H, m), 8,11-of 8.28 (2H, m), 8,39 (3H, USS), 9,34 (1H, s), 10,50 (1H, USS).

Example242

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,5-dimethylfuran-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,5-dimethylfuran-3-carboxamide (215 mg, yield 90%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 2,5-dimethylfuran-3-carbonylchloride (119 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,17 (3H, s), 2,17-to 2.29 (1H, m)to 2.29 (3H, s), of 2.34 (3H, s)to 2.54 (3H, s)to 2.99 (2H, USS), 3,82 (2H, d, J=5,1 Hz), and 6.25 (1H, s), 7,20 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8,1 Hz), of 8.28 (3H, OSS), to 9.32 (1H, USS).

Example243

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methylthiophene-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methylthiophene-2-carboxamide (215 mg, yield 90%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 3-methylthiophene-2-the carb is melhorada (120 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), of 2.08 (3H, s), 2,09 is 2.33 (1H, m), of 2.34 (3H, s), of 2.51 (3H, s), 2.91 in (2H, USS), 3,82 (2H, USS), 6,89 (1H, d, J=5,1 Hz), 7,19 (2H, d, J=7.8 Hz), 7,27 (2H, d, J=7.8 Hz), 7,55 (1H, d, J=5,1 Hz), 8,17 (3H, USS), 9,37 (1H, USS).

Example244

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1-benzothiophen-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1-benzothiophen-2-carboxamide (215 mg, yield 90%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 1-benzothiophen-2-carbonylchloride (150 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,20-of 2.28 (1H, m), of 2.28 (3H, s), 2,60 (3H, s)of 3.00 (2H, USS), a-3.84 (2H, d, J=5.4 Hz), 7,25 (4H, s), 7,41-to 7.50 (2H, m), to $ 7.91 (1H, d, J=6.9 Hz), 8,00 (1H, d, J=6.9 Hz), of 8.04 (1H with), with 8.33 (3H, USS), 10,34 (1H, USS).

Example245

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methyl-1-benzofuran-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methyl-1-benzofuran-2-carboxamide (213 mg, yield 90%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 3-methyl-1-benzofuran-2-carbonylchloride (150 mg, 0.75 mm is l) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,16-to 2.29 (1H, m)to 2.29 (3H, s)to 2.41 (3H, s), 2,60 (3H, s), 3,03 (2H, USS), 3,83 (2H, USS), 7,25 (4H, s), 7,35 (1H, t, J=6.9 Hz), 7,49 (1H, t, J=6.9 Hz), 7,56 (1H, d, J=6,9 Hz), 7,73 (1H, d, J=6.9 Hz), 8,35 (3H, USS), 10,08 (1H, USS).

Example246

The dihydrochloride methyl[4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]acetate

1) Methyl[4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]acetate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and methyl(2-oxopiperidin-1-yl)acetate (344 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):582

2) Dihydrochloride methyl[4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]acetate (271 mg, yield 49%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.3 Hz), 1,99-of 2.28 (1H, m), is 2.37 (3H, s)of 2.50 (3H, s), 2,60 (2H, USS), 3,14 (2H, t, J=5,1 Hz), of 3.46 (2H, t, J=5,1 Hz), 3,66 (3H, s), 3,81 (4H, USS), 4,08 (2H, s), 7,17 (2H, d, J=7,8 Hz), 7,29 (2H, d, J=7.8 Hz), 8,43 (3H, USS).

Example247

[5-(Methoxycarbonyl)pyridine-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) To a solution of 5-{[(tert-butoxycarbonyl is)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.85 g, 4,48 mmol), methyl-6-(hydroxymethyl)nicotinate (0.68 g, 4.07 mmol) and triphenylphosphine (1.39 g, from 5.29 mmol) in tetrahydrofuran (20 ml) was added a 40% toluene solution of diethylazodicarboxylate (2,3 ml of 5.29 mmol) and the mixture was stirred at room temperature for 30 minutes the Solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain [5-(methoxycarbonyl)pyridine-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (to 2.29 g, yield 99%) as a white solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.26 (1H, m)to 2.35 (3H, s), 2,58 (3H, s), and 2.79 (2H, d, J=7,2 Hz), of 3.96 (3H, s), 4,13-to 4.15 (2H, m), is 4.21 (1H, USS), 5,11 (2H, s), to 6.88 (1H, d, J=8.5 Hz), 7,06 (2H, d, J=8.1 Hz), 7,13 (2H, d, J=7.9 Hz), 8,14 (1H, DD, J=8,2, 2.2 Hz), 9,10 (1H, DD, J=2,1, 0,75 Hz).

2) [5-(Methoxycarbonyl)pyridine-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,37 g, 0,659 mmol) was dissolved in 4n. an ethyl acetate solution of hydrogen chloride (10 ml) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain [5-(methoxycarbonyl)pyridine-2-yl]methyl-5-(amino shall ethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (142 mg, yield 46%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 2,17-to 2.29 (1H, m)to 2.35 (3H, s), to 2.57 (3H, s), of 2.81 (2H, d, J=7,4 Hz), the 3.65 (2H, s), of 3.96 (3H, s), 5,11 (2H, s), 6.89 in (1H, d, J=8,3 Hz), 7,10-7,16 (4H, m)to 8.14 (1H, DD, J=of 8.2 and 2.2 Hz), 9,10 (1H, d, J=1.3 Hz).

Example248

Trihydrochloride 6-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]nicotinic acid

1) 6-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]nicotinic acid (1.08 g, yield 58%) was obtained as a colourless oil [5-(methoxycarbonyl)pyridine-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.90 g, to 3.38 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (9H, s), and 2.27 to 2.35 (4H, m)2,60 (3H, s), of 2.81 (2H, d, J=7,2 Hz), 4,14-to 4.15 (2H, m), 4,25 (1H, USS), 5,14 (2H, s), 6,88-to 6.95 (1H, m), 7,06-7,19 (4H, m), 8,19 (1H, DD, J=8,2 and 2.2 Hz), 9,16 (1H, s).

2) Trihydrochloride 6-[({[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]nicotinic acid (413 mg, yield 81%) was obtained as a white solid from 6-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]nicotinic acid (0.50 g, 0,913 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,18-of 2.28 (1H, m), of 2.33 (3H, s), 2.63 in (3H, USS), 2,90-of 2.97 (2H, is), is 3.82 (2H, d, J=5,1 Hz), further 5.15 (2H, s), 7,03 (1H, d, J=8.1 Hz), 7,17-of 7.23 (4H, m), 8,17 (1H, DD, J=8,2, 2.0 Hz), scored 8.38 (3H, USS), 8,98 (1H, d, J=1.5 Hz).

Example249

[5-(Aminocarbonyl)pyridine-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) [5-(Aminocarbonyl)pyridine-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (222 mg, yield 38%) was obtained as colorless oil from 6-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]nicotinic acid (0,58 g, 1.06 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.26 (1H, m), a 2.36 (3H, s), 2,58 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,13-to 4.15 (2H, m), 4,22 (1H, USS), 5,10 (2H, s), 6,92 (1H, d, J=7.9 Hz), 7,07 (2H, d, J=8.1 Hz), 7,14 (2H, d, J=7.9 Hz), 8,03 (1H, DD, J=8,3, 2.3 Hz), 8,89 (1H, d, J=2.3 Hz).

2) [5-(Aminocarbonyl)pyridine-2-yl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (159 mg, yield 87%) was obtained as a colourless oil [5-(aminocarbonyl)pyridine-2-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,22 g, 0,406 mmol) in a manner similar to the method of example 247-2).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), 2,15-2,31 (1H, m), a 2.36 (3H, s), to 2.57 (3H, s), of 2.81 (2H, d, J=7,4 Hz), the 3.65 (2H, s), 5,10 (2H, s)6,94 (1H, d, J=7,7 Hz), 7,11-7,17 (4H, m), 8,03 (1H, DD, J=8,1, 2.3 Hz), 8,89 (1H, d, J=2.3 Hz).

Example250

Tetrahydrochloride ethyl-4-{[5-(aminomethyl)-6-isobutyl--methyl-4-(4-were)pyridine-3-yl]methoxy}-2-ethylpyrimidine-5-carboxylate

1) Ethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-ethylpyrimidine-5-carboxylate (308 mg, yield 40%) was obtained as a white solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,53 g of 1.33 mmol) and ethyl-2-ethyl-4-hydroxypyrimidine-5-carboxylate (0.26 g, of 1.33 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.8 Hz), 1,20-of 1.29 (6H, m)of 1.39 (9H, s), 2,19-of 2.28 (1H, m), of 2.34 (3H, s)to 2.67 (3H, s), 2,75-and 2.83 (4H, m), 4,10 (2H, d, J=4.9 Hz), 4,27-4,34 (3H, m), with 5.22 (2H, s), 7,06 (2H, d, J=8,1 Hz), 7,14 (2H, d, J=7.9 Hz), 8,86 (1H, s).

2) Tetrahydrochloride ethyl-4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-ethylpyrimidine-5-carboxylate (269 mg, yield 80%) was obtained as a white solid from ethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-ethylpyrimidine-5-carboxylate (308 mg, 0,536 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 1,19 (3H, t, J=7.5 Hz), 1,25 (3H, t, J=7,1 Hz), 2,14-of 2.23 (1H, m), 2,43 (3H, s), 2,58-to 2.67 (2H, m), 2,81-of 2.97 (3H, m), of 3.13 (2H, OSS), to 3.73-a 3.83 (2H, m), 4,22 (2H, t, J=7,0 Hz)that was 4.42 (2H, s), 7,25-7,31 (2H, m), 7,38-the 7.43 (2H, m), 8,43 (3H, USS), 8,46 (1H, s).

Example251

The dihydrochloride of 4-(1H-tetrazol-5-yl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) a Solution of 4-cyanobenzyl-5-{[(tert-butoxycarbonyl)and the Ino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.28 g, 2,43 mmol) and azide anti - (2,3 ml, 8,49 mmol) in toluene (7.5 ml) was heated at boiling under reflux in an argon atmosphere for 3 hours the Solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 4-(1H-tetrazol-5-yl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.23 g, yield 88%) as a colorless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.24 (1H, m), of 2.25 (3H, s)to 2.54 (3H, s), and 2.83 (2H, d, J=7,2 Hz), 4,18 (2H, d, J=4.9 Hz), 4,32 (1H, OSS), to 5.00 (2H, s), 7,01 (2H, d, J=7.9 Hz), 7,07 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=8.1 Hz), 8,03 (2H, d, J=8,1 Hz).

2) Dihydrochloride 4-(1H-tetrazol-5-yl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (688 mg, yield 95%) was obtained as a white solid from 4-(1H-tetrazol-5-yl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.75 g, of 1.33 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), is 2.30 (3H, s)to 2.54 (3H, s), 2,87 (2H, d, J=6.8 Hz), 3,81 (2H, d, J=5.5 Hz), to 5.08 (2H, s), 7,14-of 7.25 (6H, m), 8,02 (2H, d, J=8.1 Hz), by 8.22 (3H, USS).

Example252

The dihydrochloride of 5-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-2-carboxylic acid

1) [5-(Methoxycarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-m is Tyl-4-(4-were)nicotinate (2.37 g, yield 88%) was obtained as a yellow oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.00 g, is 4.85 mmol) and methyl-5-(chloromethyl)furan-2-carboxylate (0.85 grams, is 4.85 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.24 (1H, m)to 2.35 (3H, s), 2,52 (3H, s), 2,77 (2H, d, J=7,2 Hz), 3,91 (3H, s), 4,11 (2H, d, J=5,1 Hz), 4,19 (1H, USS), 4,94 (2H, s), 6,24 (1H, d, J=3,6 Hz), of 7.00 (2H, d, J=8.1 Hz), 7,06 (1H, d, J=3.6 Hz), 7,11 (2H, d, J=7.9 Hz).

2) 5-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-2-carboxylic acid (1,95 g, yield 95%) was obtained as a white solid from [5-(methoxycarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2,11 g, a 3.83 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14 was 2.25 (1H, m), a 2.36 (3H, s), of 2.53 (3H, s), of 2.86 (2H, d, J=7.0 Hz), 4.09 to 4,18 (2H, m), 4.26 deaths (1H, OSS), at 4.99 (2H, s), 6,32 (1H, d, J=3,4 Hz), 7,03 (2H, d, J=8.1 Hz), 7,10-to 7.18 (3H, m).

3) Dihydrochloride 5-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-2-carboxylic acid (460 mg, yield 79%) was obtained as a white solid from 5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-2-carboxylic acid (0,61 g to 1.14 mmol) in a manner similar what about the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), of 2.33 (3H, s), 2,90 (2H, USS), 3,80 (2H, d, J=5.3 Hz), of 5.05 (2H, s), 6,46 (1H, d, J=3,4 Hz), 7,11-7,14 (3H, m), 7,17 (2H, d, J=8.1 Hz), 8,29 (3H, USS).

Example253

The dihydrochloride [5-(aminocarbonyl)-2-furyl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) [5-(Aminocarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (520 mg, yield 69%) was obtained as colorless oil from 5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]-furan-2-carboxylic acid (0.75 g, of 1.40 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14-of 2.27 (1H, m)to 2.35 (3H, s), 2,52 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,06 is 4.13 (2H, m), 4,19 (1H, USS), 4,94 (2H, s), the 5.45 (1H, USS), 6,16 (1H, USS), 6,27 (1H, d, J=3,4 Hz), 6,98 (2H, d, J=8.1 Hz),? 7.04 baby mortality (1H, d, J=3.6 Hz), to 7.09 (2H, d, J=7.9 Hz).

2) Dihydrochloride [5-(aminocarbonyl)-2-furyl]methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (471 mg, yield 95%) was obtained as a white solid from [5-(aminocarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.52 g, 0,971 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14-of 2.27 (1H, m), of 2.34 (3H, s), is 2.88 (2H, USS), 3,80 (2H, d, J=5.5 Hz), 5,02 (2H, s), to 6.39 (2H, d, J=3,4 Hz), 7,06 (1H, d, J=3,4 Hz), 7,12 (2H, d, J=7.9 Hz), 718 (2H, d, J=8,3 Hz), the 7.43 (1H, USS), 7,73 (1H, USS), 8,28 (3H, USS).

Example254

The dihydrochloride methyl-3-{[[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl](methyl)amino]carbonyl}benzoate

To a mixture of 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (212 mg, 0.4 mmol), potassium carbonate (138 mg, 1.0 mmol) and N,N-dimethylformamide (5 ml) was added methyliodide (282 mg, 2.0 mmol) and the mixture was stirred at room temperature for 8 hours was Added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in ethyl acetate (1 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (1 ml) and the mixture was stirred at room temperature for 1 h the Solvent is evaporated under reduced pressure and the obtained residue was led from hexane to obtain dihydrochloride methyl-3-{[[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl](methyl)amino]carbonyl}benzoate (203 mg, yield 95%) as a white powder.

EIMC(M+1):460

Example255

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-Mei is phenyl)pyridine-3-yl]isophthalamide

1) tert-Butyl{[5-{[3-(aminocarbonyl)benzoyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (248 mg, yield 98%) was obtained as a white powder from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (260 mg, 0.48 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,20-2,31 (1H, m), of 2.33 (3H, s), 2.49 USD (3H, s), 2,78 (2H, USS), of 4.13 (2H, USS), and 4.40 (1H, USS), 5,79 (1H, USS), 6,38 (1H, USS), 7,03 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=8.1 Hz), 7,7,39 was 7.45 (1H, USS), 7,60-7,63 (1H, m), 7,88-a 7.92 (2H, m).

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isophthalamide (233 mg, yield 99%) was obtained as a white powder from tert-butyl{[5-{[3-(aminocarbonyl)benzoyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.3 Hz), 2,22-of 2.30 (1H, m), is 2.30 (3H, s), of 2.51 (3H, s), 2,89 (2H, USS), a-3.84 (2H, USS), of 7.23 (4H, s), 7,56 (1H, t, J=7.8 Hz), 7,83 (2H, d, J=7.8 Hz), of 8.06 (2H, d, J=7.8 Hz), 8,14 (1H, ), 8,16 (3H, USS), 10,04 (1H, USS).

Example256

The dihydrochloride of 4-[2-oxo-2-(2-oxo-2-phenylethane)ethyl]benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 4-[2-Oxo-2-(2-oxo-2-phenylethane)ethyl]benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.85 g, yield 86%) was obtained in the form of bescoto the oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (2.00 g, is 4.85 mmol) and phenacyl-4-(methyl bromide)phenylacetate (1,69 g is 4.85 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.24 (1H, m), of 2.38 (3H, s), 2,52 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,82 (2H, s), 4,11-4,16 (2H, m), is 4.21 (1H, USS), 4,91 (2H, s), are 5.36 (2H, s), 7,02-7,05 (4H, m)to 7.15 (2H, d, J=7,7 Hz), 7,26-7,29 (2H, m), 7,46-7,51 (2H, m), 7,58-to 7.64 (1H, m), 7,88-to $ 7.91 (2H, m).

2) of the Dihydrochloride of 4-[2-oxo-2-(2-oxo-2-phenylethane)ethyl]benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (117 mg, yield 45%) was obtained as a white solid from 4-[2-oxo-2-(2-oxo-2-phenylethane)ethyl]benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.27 g, 0,398 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), of 2.38 (3H, s), and 2.83 (2H, USS), 3,81 (2H, d, J=5.3 Hz), 3,85 (2H, s), of 4.95 (2H, s), of 5.53 (2H, s), 7,02 (2H, d, J=8.1 Hz), to 7.15 (2H, d, J=7.5 Hz), 7,26 (4H, t, J=7,72), 7,56 (2H, d, J=7.9 Hz), to 7.67-7,72 (1H, m), 7,92-7,98 (2H, m), 8,17 (3H, USS).

Example257

The dihydrochloride of 4-(2-methoxy-2-oxoethyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) {4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (1.65 g, yield 77%) was obtained as colorless oil from 4-[2-oxo-2-(2-oxo-2-phenylethane)ethyl]benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (2.58 g, of 3.80 mmol who) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14-of 2.23 (1H, m), is 2.37 (3H, s), 2,52 (3H, s), 2,77 (2H, d, J=7,2 Hz), the 3.65 (2H, s), 4.09 to to 4.16 (2H, m), is 4.21 (1H, USS), the 4.90 (2H, s), 7,00-7,06 (4H, m), 7,13 (2H, d, J=7.9 Hz), 7,21 (2H, d, J=8,1 Hz).

2) To a mixture of {4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (0.65 g, of 1.16 mmol), potassium carbonate (0.32 g, 2.32 mmol) and N,N-dimethylformamide (15 ml) was added methyliodide (197 mg, of 1.39 mmol) and the mixture was stirred at room temperature for 1 h the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain 4-(2-methoxy-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.56 g, yield 84%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.26 (1H, m), of 2.38 (3H, s), 2,52 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,62 (2H, s), 3,70 (3H, s), 4,12-4,13 (2H, m), 4,20 (1H, USS), the 4.90 (2H, s), 7,01? 7.04 baby mortality (4H, m), 7,14 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=8,1 Hz).

3) Dihydrochloride 4-(2-methoxy-2-oxoethyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (483 mg, yield 90%) was obtained as a white solid from 4-(2-methoxy-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-Isobe the Il-2-methyl-4-(4-were)nicotinate (0,56 g, 0,974 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,14-of 2.26 (1H, m), is 2.37 (3H, s), 2,79-is 2.88 (2H, m), 3,62 (3H, s), of 3.69 (2H, s), 3,81 (2H, d, J=5.3 Hz), 4,94 (2H, s)to 7.00 (2H, d, J=8.1 Hz), 7,13-7,24 (6H, m), 8,21 (3H, USS).

Example258

The dihydrochloride {4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid

The dihydrochloride {4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (348 mg, yield 73%) was obtained as a white solid from {4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (0.50 g, 0,892 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), is 2.37 (3H, s), of 2.53 (3H, s), 2,90 (2H, d, J=5.8 Hz), of 3.57 (2H, s), 3,82 (2H, d, J=5.3 Hz), of 4.95 (2H, s), of 6.99 (2H, d, J=8.1 Hz), to 7.15 (2H, d, J=8.1 Hz), then 7.20 (2H, d, J=8.1 Hz), 7.23 percent (2H, d, J=8.1 Hz), 8,30 (3H, USS).

Example259

The dihydrochloride of 4-(2-amino-2-oxoethyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 4-(2-Amino-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (360 mg, yield 72%) was obtained as colorless oil from {4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid is (0.50 g, 0,892 mmol) in a manner similar to the method of example 3-1).

H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.26 (1H, m), 2,39 (3H, s), 2,52 (3H, s), 2,77 (2H, d, J=7,4 Hz)to 3.58 (2H, s), 4,12-4,13 (2H, m), is 4.21 (1H, USS), 4,91 (2H, s), 5,31 (2H, USS),? 7.04 baby mortality-7,06 (4H, m), 7,16 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=8,1 Hz).

2) Dihydrochloride 4-(2-amino-2-oxoethyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (231 mg, yield 67%) was obtained as a white solid from 4-(2-amino-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.36 g, 0,643 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,14 was 2.25 (1H, m), of 2.38 (3H, s), of 2.86 (2H, USS), 3,37 (2H, s), 3,81 (2H, d, J=5.5 Hz), is 4.93 (2H, s), to 6.88 (1H, USS), 6,98 (2H, d, J=8.1 Hz), 7,13-of 7.25 (6H, m), 7,49 (1H, USS), 8,21 (3H, USS).

Example260

The dihydrochloride of 4-(methylsulphonyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 4-(Methylsulphonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (530 mg, yield 73%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (495 mg, 1.20 mmol) and 1-(methyl bromide)-4-(methylsulphonyl)benzene (300 mg, 1.20 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), of 2.38 (3H, s)to 2.55 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3.04 from (3H, s), 4,12-4,13 (2H, m), 4,21 1H, OSS), free 5.01 (2H, s),? 7.04 baby mortality (2H, d, J=8.1 Hz), 7,14 (2H, d, J=7.9 Hz), 7,19 (2H, d, J=8,3 Hz), 7,83 (2H, d, J=8,5 Hz).

2) Dihydrochloride 4-(methylsulphonyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (466 mg, yield 92%) was obtained as a white solid from 4-(methylsulphonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,53 g, 0,913 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,15-of 2.26 (1H, m), a 2.36 (3H, s), 2,54-of 2.58 (3H, m), 2,87-of 2.97 (2H, m), up 3.22 (3H, s), 3,81 (2H, d, J=5,1 Hz), 5,11 (2H, s), 7,15-7,28 (6H, m), to 7.84 (2H, d, J=8,3 Hz), 8,23-8,40 (3H, m).

Example261

The dihydrochloride ethyl-3-[4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]propionate

1) Ethyl-3-[4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]propionate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl(2-oxopiperidin-1-yl)propionate (250 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):610

2) Dihydrochloride ethyl-3-[4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)-2-oxopiperidin-1-yl]propionate (278 mg, yield 49%) was obtained as a white powder from the oil obtained in the above stage 1), spoorendonk method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.3 Hz), 1,19 (3H, t, J=7.2 Hz), 2,14-of 2.23 (1H, m), is 2.37 (3H, s)of 2.64 (2H, s), 3,06 (4H, USS), 3,37-3,47 (4H, m), 3,74 (2H, s), 3,83 (2H, USS), 4,06 (2H, q, J=7.2 Hz), 7,18 (2H, d, J=7,8 Hz), 7,29 (2H, d, J=7.8 Hz), 8,40 (3H, USS).

Example262

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-methoxybenzamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-methoxybenzamide (209 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 2-methoxybenzylamine (128 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-to 2.29 (1H, m), a 2.36 (3H, s), 2,61 (3H, s), 3,03 (2H, s), of 3.69 (3H, s), a-3.84 (2H, USS), 6,98 (1H, t, J=7.5 Hz), was 7.08 (1H, d, J=8.1 Hz), 7,24 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), 7,39-7,49(2H, m), 8,32 (3H, USS), of 9.55 (1H, USS).

Example263

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-fermentated

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-fermentated (204 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 2-tormentilla (122 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2.21 are of 2.28 (1H, m), is 2.37 (3H, s), 2,55 (3, C)2,92 (2H, s), a-3.84 (2H, s), 7,13-to 7.32 (7H, m), 7,49-rate of 7.54 (1H, m), to 8.20 (3H, USS), 9,86 (1H, USS).

Example264

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methoxybenzamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-methoxybenzamide (196 mg, yield 80%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 3-methoxybenzylamine (128 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,19-2,31 (1H, m), 2,32 (3H, s), 2,58 (3H, s), to 3.02 (2H, in), 3.75 (3H, s), 3,85 (2H, USS), 7,08-7,10 (2H, m), 7,18 and 7.36 (6H, m), with 8.33 (3H, USS), 9,96 (1H, USS).

Example265

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-fermentated

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-fermentated (186 mg, yield 78%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 3-tormentilla (122 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,18-of 2.36 (1H, m), 2,31 (3H, s), 2,62 (3H, s), is 3.08 (2H, s), 3,86 (2H, s), 7,26 (4H, s), 7,38-7,42 (2H, m), 7,50 (2H, s), to 8.41 (3H, USS), 10,22 (1H, USS).

Example266

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-IU oxybenzone

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-methoxybenzamide (209 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-methoxybenzylamine (128 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,19-of 2.26 (1H, m), 2,31 (3H, s), 2.63 in (3H, s), of 3.12 (2H, s), with 3.79 (3H, s), a 3.87 (2H, USS), of 6.96 (1H, t, J=9.0 Hz), 7,25 (4H, s), to 7.67 (2H, d, J=9.0 Hz), 8,43 (3H, USS), 9,92 (1H, USS).

Example267

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-fermentated

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-fermentated (204 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-tormentilla (122 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,14-2,31 (1H, m), 2,31 (3H, s), 2,62 (3H, s), is 3.08 (2H, s), 3,85 (2H, s), 7,25-7,30 (6H, m), 7,70 to 7.75 (2H, m), to 8.41 (3H, USS), 10,14 (1H, USS).

Example268

The dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (540 mg, Ihad 86%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, at 1.17 mmol) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-she (209 mg, of 1.41 mmol) in a manner similar to the method of example 176-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), and 2.14 (3H, s), 2,16-of 2.28 (1H, m), is 2.40 (3H, s), 2.49 USD (3H, s)of 2.75 (2H, d, J=7,4 Hz), 3,40 (2H, s), Android 4.04 (2H, d, J=5,1 Hz), is 4.21 (1H, OSS), was 4.76 (2H, s), 6,93 (2H,, d, J=7.9 Hz), 7,21 (2H, d, J=7.9 Hz).

2) Dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (500 mg, yield 99%) was obtained as a white powder from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (530 mg, 0,984 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), of 2.15 (3H, s), 2,18 was 2.25 (1H, m), 2,39 (3H, s), is 2.88 (3H, s), 3,29 (2H, d, J=7,2 Hz), 3,54-of 3.64 (4H, m), 4,94 (2H, s), 7,16 (2H, d, J=7.9 Hz), 7,33 (2H, d, J=7.9 Hz), 8,63 (3H, USS).

Example269

The dihydrochloride of 2-[4-(methoxycarbonyl)phenyl]ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 2-[4-(Methoxycarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.77 g, yield 70%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.80 g, 4,37 mmol) and methyl-4-(2-bromacil)benzoate (1.06 g, 4,37 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 16-2,28 (1H, m), is 2.37 (3H, s)to 2.46 (3H, s)to 2.66 (2H, t, J=7.0 Hz), 2,77 (2H, d, J=7,4 Hz), 3,91 (3H, s), 4,11-to 4.15 (4H, m), 4,22 (1H, USS), 7,02 (2H, d, J=8.1 Hz), to 7.15 (4H, d, J=8,3 Hz), 7,95 (2H, d, J=8,5 Hz).

2) of the Dihydrochloride of 2-[4-(methoxycarbonyl)phenyl]ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (291 mg, yield 82%) was obtained as a white solid from 2-[4-(methoxycarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0,37 g, mmol 0,644) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.8 Hz), 2,14-of 2.27 (1H, m)to 2.35 (3H, s), 2,42 (3H, USS), 2,73 (2H, d, J=6.4 Hz), only 2.91 (2H, USS), 3,81 (2H, d, J=5.3 Hz), 3,85 (3H, s)to 4.17 (2H, t, J=6.5 Hz), 7,12 (2H, d, J=6.8 Hz), 7,22 (2H, d, J=7.9 Hz), 7,29 (2H, d, J=8,3 Hz), 7,89 (2H, d, J=8,3 Hz), 8.34 per (3H, USS).

Example270

The dihydrochloride of 4-[2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid

1) 4-[2-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (1,30 g, yield 95%) was obtained as colorless oil from 2-[4-(methoxycarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.40 g, 2,44 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,16-of 2.27 (1H, m), is 2.37 (3H, s), is 2.44 (3H, s), 2,70 (2H, d, J=6.9 Hz), and 2.79 (2H, d, J=7,2 Hz), 4,11-4,18 (4H, m), 4,24 (1H, USS), 7,02 (2H, d, J=7.9 Hz), 7,15-7,20 (4H, m), 8,01 (2H, the, J=8,3 Hz).

2) of the Dihydrochloride of 4-[2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (359 mg, yield 94%) was obtained as a white solid from 4-[2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (0.40 g, 0,713 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14 was 2.25 (1H, m)to 2.35 (3H, s), 2,42 (3H, s), a 2.71 (2H, t, J=6.5 Hz), 2,87 (2H, d, J=7,0 Hz), 3,80 (2H, d, J=5.3 Hz), of 4.16 (2H, t, J=6.5 Hz), 7,11 (2H, d, J=8.1 Hz), 7,21-7,26 (4H, m), 7,87 (2H, d, J=8.1 Hz), 8,28 (3H, USS).

Example271

The dihydrochloride of 2-[4-(aminocarbonyl)phenyl]ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 2-[4-(Aminocarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (598 mg, yield 99%) was obtained as colorless oil from 4-[2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (0,60 g, 1.07 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,16-of 2.27 (1H, m), is 2.37 (3H, s), 2,47 (3H, s)to 2.66 (2H, t, J=7,1 Hz), 2,78 (2H, d, J=7,2 Hz), 4.09 to to 4.15 (4H, m), 4,24 (1H, USS), 5,67 (1H, USS), the 6.06 (1H, USS), 7,02 (2H, d, J=7.9 Hz), 7,15-7,19 (4H, m), 7,73 (2H, d, J=8,1 Hz).

2) of the Dihydrochloride of 2-[4-(aminocarbonyl)phenyl]ethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotine is a (508 mg, yield 90%) was obtained as a white solid from 2-[4-(aminocarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (598 mg, 1.06 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16 was 2.25 (1H, m), a 2.36 (3H, s), 2,42 (3H, OSS), to 2.67 (2H, t, J=6.4 Hz), 2,87 (2H, USS), 3,81 (2H, d, J=5,5 Hz)to 4.16 (2H, t, J=6.5 Hz), 7,11 (2H, d, J=7,7 Hz), 7.18 in-to 7.25 (4H, m), 7,32 (1H, USS), 7,81 (2H, d, J=8,3 Hz), 7,95 (1H, USS), of 8.27 (3H, USS).

Example272

3-{[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzamide

1) tert-Butyl{[5-{[3-(aminocarbonyl)phenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (240 mg, yield 80%) was obtained as a white solid from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzoic acid (0,30 g, 0,578 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2.21 are of 2.28 (1H, m)to 2.35 (3H, s), 2,62 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 4.09 to-4,11 (2H, m), 4,22 (1H, USS), and 4.68 (2H, s), of 5.55 (1H, USS), 6,01 (1H, USS), of 6.96-7,01 (1H, m),? 7.04 baby mortality (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7,7 Hz), 7,29-to 7.32 (2H, m), 8,02 (1H, s).

2) 3-{[5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}benzamide (166 mg, yield 85%) was obtained as a white solid from tert-butyl{[5-{[3-(aminocarbonyl)phenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (240 m is, 0,463 mmol) in a manner similar to the method of example 239-2).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.8 Hz), 2.21 are of 2.30 (1H, m), a 2.36 (3H, s), 2,61 (3H, s), of 2.81 (2H, d, J=7,2 Hz), of 3.60 (2H, s), and 4.68 (2H, s)5,52 (1H, USS), the 6.06 (1H, USS), of 6.96-7,00 (1H, m), to 7.09 (2H, d, J=7.9 Hz), 7.18 in (2H, d, J=7.9 Hz), 7,25-7,31 (3H, m).

Example273

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoate (720 mg, yield 52%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.0 in g, 2.51 mmol) and methyl 2-hydroxy-5-methylbenzoate (500 mg, a 3.01 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.26 (1H, m), and 2.27 (3H, s), is 2.37 (3H, s)to 2.67 (3H, s), 2,78 (2H, d, J=7,2 Hz), 3,80 (3H, s), 4.09 to (2H, d, J=4.9 Hz), 4,20 (1H, USS), and 4.68 (2H, s), 7,02-7,06 (3H, m), 7,11 (1H, DD, J=8,5, 1.9 Hz), 7,16 (2H, d, J=7,7 Hz), 7,52 (1H, d, J=1.9 Hz).

2) Dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoate (100 mg, yield 70%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoate (150 mg, 0,274 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (6H, d, J=6.2 Hz), 2,18-of 2.24 (1H, m), 2,24 (3H, s), is 2.37(3H, C)to 2.99 (3H, s), 3,29 (2H, d, J=7,2 Hz), 3,70 is 3.76 (5H, m), 4,78 (2H, s), is 6.78 (1H, d, J=8.5 Hz), 7,17-7,40 (5H, m), 7,46 (1H, s), 8,63 (3H, USS).

Example274

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoate (0,80 g, 71%yield) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,80 g, 2.0 mmol) and methyl-5-chlorosalicylic (0.56 g, 3.0 mmol) in a manner similar to the method of example 106-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.30 (1H, m), is 2.37 (3H, s)to 2.66 (3H, s), 2,78 (2H, d, J=7,2 Hz), 3,81 (3H, s), 4.09 to (2H, d, J=4.9 Hz), 4,15-of 4.25 (1H, m), 4,69 (2H, s), to 6.57 (1H, d, J=the 8.9 Hz), 7,03 (2H, d, J=8.0 Hz), 7,17 (2H, d, J=8.0 Hz), 7,26 (1H, DD, J=2.7, and a 8.9 Hz), 7,69 (1H, d, J=2.7 Hz).

2) a Mixture of methyl 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoate (0,19 g, 0.33 mmol) and methanolic solution of hydrogen chloride (4 ml) was stirred at room temperature for 3 hours the Reaction mixture was concentrated under reduced pressure and the obtained solid is washed with diisopropyl ether to obtain dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoate (0.17 g, yield 96%) as a white powder.

1H-NMR (DMSO-d 6) δ: 0,99 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m)to 2.35 (3H, s), is 3.08 (3H, USS), is 3.08 (2H, OSS in), 3.75 (3H, s), 3,82 (2H, d, J=4.5 Hz), 4,79 (2H, s), 6,97 (1H, d, J=9.0 Hz), 7,24 (2H, d, J=7.9 Hz), 7,29 (2H, d, J=7.9 Hz), 7,52 (1H, DD, J=2,8, 9.0 Hz), the 7.65 (1H, d, J=2,8 Hz), 8,35 (3H, USS).

Example275

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methoxybenzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methoxybenzoate (0,70 g, yield 62%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,80 g, 2.0 mmol) and methyl-5-metoxisalicilice (0.55 g, 3.0 mmol) in a manner similar to the method of example 106-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.30 (1H, m), of 2.38 (3H, s), 2,69 (3H, s), 2,78 (2H, d, J=7,2 Hz), of 3.77 (3H, s), 3,81 (3H, s), 4.09 to (2H, d, J=4,7 Hz), 4,15-4,30 (1H, m), and 4.68 (2H, s), 6,50 (1H, d, J=9.0 Hz), 6,85 (1H, DD, J=3.2, and 9.0 Hz), 7,01 (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7.9 Hz), 7,24 (1H, d, J=3.2 Hz).

2) Dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methoxybenzoate (0.20 g, yield 96%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methoxybenzoate (0,23 g, 0.40 mmol) in a manner similar to the method of example 274-2).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m), is 2.37 (3H, s), 2,73 (3H, USS), with 2.93 (2H, USS), and 3.72 (H, C)to 3.73 (3H, s), with 3.79 (2H, d, J=4.9 Hz), 4,69 (2H, USS), 6,77 (1H, d, J=9.0 Hz), 7,01 (1H, DD, J=3.2, and 9.0 Hz), 7,14 (1H, d, J=3.2 Hz), 7,20 (2H, d, J=7.8 Hz), 7,29 (2H, d, J=7.8 Hz), 8,11 (3H, USS).

Example276

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoic acid

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoate (0,81 g, yield 72%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,80 g, 2.0 mmol) and methyl-4-metoxisalicilice (0.55 g, 3.0 mmol) in a manner similar to the method of example 106-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.30 (1H, m), a 2.36 (3H, s), 2,68 (3H, s), 2,78 (2H, d, J=7,2 Hz in), 3.75 (3H, s), of 3.77 (3H, s), 4.09 to (2H, d, J=4,7 Hz), 4,20-of 4.25 (1H, m), and 4.68 (2H, s), 6,14 (1H, d, J=2.4 Hz), 6.48 in (1H, DD, J=2,4, and 8.7 Hz), 7,00-7,10 (2H, m), 7,15-7,20 (2H, m), 7,79 (1H, d, J=8.7 Hz).

2) 2-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoic acid (0,19 g, yield 37%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoate (0.51 g, of 0.91 mmol) in a manner similar to the method of example 36-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6,8 Hz)of 1.39 (9H, s), of 2.15 to 2.35 (1H, m)to 2.35 (3H, s)of 2.64 (3H, s), of 2.81 (2H, d, J=7,2 Hz), 3,82 (3H, s), 4.09 to (2H, d, J=4.9 Hz), 4,15-4,30 (1H, m), to 4.87 (2H, s), 6,30 (1H, is, J=2.3 Hz), 6,63 (1H, DD, J=2,3, and 8.9 Hz), 7,00 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=7.9 Hz), to 8.12 (1H, d, J=8,9 Hz), 10,42 (1H, USS).

3) a Mixture of 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoic acid (0.15 g, 0.28 mmol) and 6N. hydrochloric acid (4 ml) was stirred at room temperature for 6 hours the Reaction mixture was concentrated under reduced pressure and the obtained solid was washed with acetonitrile to obtain the dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoic acid (0.12 g, yield 81%) as a white powder.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,10-of 2.30 (1H, m), is 2.37 (3H, s), of 2.86 (3H, USS), 3,06 (2H, OSS), to 3.73 (3H, s), 3,82 (2H, OSS), was 4.76 (2H, USS), of 6.31 (1H, d, J=2.1 Hz), 6,60 (1H, DD, J=2,1, to 8.7 Hz), 7,26 (2H, d, J=7,2 Hz), 7,32 (2H, d, J=7,2 Hz), to 7.68 (1H, d, J=8.7 Hz), 8,28 (3H, USS).

Example277

Trihydrochloride methyl-6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinate

1) a Mixture of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.50 g, 3,76 mmol), triethylamine (1,05 ml, 7,52 mmol) and tetrahydrofuran (50 ml) was cooled to 0°C was added dropwise methanesulfonanilide (647 mg, the 5.65 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into a saturated aqueous solution of hydrocarbon is the sodium and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate in the form of a crude product. The crude product was added to a solution of (5-bromopyridin-2-yl)methanol (848 mg, 4,51 mmol) and sodium hydride (60% in oil, 226 mg, the 5.65 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at 60°C for 1 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl{[5-{[(5-bromopyridin-2-yl)methoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.35 g, yield 63%) as a white solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.24 (1H, m), is 2.41 (3H, s)to 2.65 (3H, s)of 2.75 (2H, d, J=7,4 Hz)4,06 (2H, d, J=4,9 Hz)to 4.23 (2H, s), 4,39 (2H, s), 7,01 (2H, d, J=7.9 Hz), 7,16-7,20 (3H, m), 7,73 (1H, DD, J=8,4, 2.4 Hz), 8,54 (1H, d, J=2.1 Hz).

2) Methyl-6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinate (1,15 g, yield 88%) was obtained as a yellow oil from tert-butyl{[5-{[(5-bromopyridin-2-yl)methoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.5 g, is 2.37 mmol) in a manner similar to the method of example 231-2).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), is 2.40 (3H, s)to 2.67 (3H, s), was 2.76 (2H, d, J=7,2 Hz), of 3.95 (3H, s)4,06 (2H, d, J=4.9 Hz), 4,20 (1H, USS), 4,27 (2H, s), 4,50 (2H, s), 7,02 (2H,, d, J=7.9 Hz), 7,19 (2H, d, J=7,7 Hz), was 7.36 (1H, d, J=8.1 Hz), 8,21 (1H, DD, J=8,1, 2,1 Hz), the remaining 9.08 (1H, d, J=1.7 Hz).

3) Trihydrochloride methyl-6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinate (114 mg, yield 58%) was obtained as a white solid from methyl-6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinate (0,19 g, 0,347 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-2,22 (1H, m), of 2.38 (3H, s), 3,14 (2H, USS), 3,81 (2H, d, J=5.3 Hz), 3,90 (3H, s), the 4.29 (2H, s), 4,51 (2H, s), 7.23 percent (2H, d, J=7.9 Hz), 7,32 (2H, d, J=7.9 Hz), 7,38 (1H, d, J=8.1 Hz), of 8.25 (1H, DD, J=8,1, 2.2 Hz), scored 8.38 (3H, USS), 8,98 (1H, d, J=1.5 Hz).

Example278

Trihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinic acid

1) 6-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinic acid (760 mg, yield 81%) was obtained as colorless oil from methyl-6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinate (0.96 g, a 1.75 mmol) in a manner similar to the method of example 9-1).

1H-YAM who (CDCl 3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14-of 2.26 (1H, m), 2,39 (3H, s), a 2.71 (3H, s), 2,85 (2H, d, J=7,2 Hz), 4,05-4,10 (2H, m), 4,29 (3H, OSS), to 4.52 (2H, s), 7,03 (2H, d, J=7.9 Hz), 7,38 (1H, d, J=8.1 Hz), 8,29 (1H, DD, J=8,2, 1.8 Hz), to 9.15 (1H, d, J=1.5 Hz).

2) Trihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinic acid (259 mg, yield 90%) was obtained as a white solid from 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinic acid (0.28 g, 0,525 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.4 Hz), 2,11-2,22 (1H, m), 2,39 (3H, s)to 2.94 (3H, USS), 3,13-up 3.22 (2H, m), 3,81 (2H, USS), the 4.29 (2H, USS), 4,51 (2H, s), 7,19-of 7.25 (2H, m), 7,30 and 7.36 (3H, m), 8,19-8,24 (1H, m), 8,43 (3H, USS), 8,93-8,96 (1H, m).

Example279

The dihydrochloride methyl-2-{2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ethyl}benzoate

1) To a solution of tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.36 g, 0,908 mmol) and diethyl(2-bromobenzyl)phosphonate (363 mg, 1.18 mmol) in N,N-dimethylformamide (10 ml) was added sodium methoxide (165 mg, 4,08 mmol) and the mixture was stirred at room temperature for 1 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column of HRO what ecografia on silica gel to obtain tert-butyl{[5-[(E)-2-(2-bromophenyl)vinyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (390 mg, yield 78%) as a white solid.

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.30 (1H, m), 2,39 (3H, s), of 2.72 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,11 (2H, d, J=5,1 Hz), 4,24 (1H, USS), 6,55 (1H, d, J=16.6 Hz), 6,78 (1H, d, J=16.6 Hz), 7,02 (2H, d, J=7.9 Hz), 7,05-was 7.08 (1H, m), 7,15-to 7.18 (2H, m), 7,22 (2H, d, J=7,7 Hz)to 7.50 (1H, d, J=7.5 Hz).

2) Methyl-2-{(E)-2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]vinyl}benzoate (280 mg, yield 74%) was obtained as a yellow oil from tert-butyl{[5-[(E)-2-(2-bromophenyl)vinyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (390 mg, 0,907 mmol) in a manner similar to the method of example 231-2).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.27 (1H, m), 2,39 (3H, s), is 2.74 (3H, s), 2,78 (2H, d, J=7,4 Hz)to 3.89 (3H, s), 4,11 (2H, d, J=5.3 Hz), 4,24 (1H, USS), 6,47 (1H, d, J=16,8 Hz), 7,02 (2H, d, J=7.9 Hz), 7,13 (1H, d, J=7.5 Hz), 7,20-7,29 (4H, m), 7,35-7,40 (1H, m), 7,86 (1H, DD, J=7,8, and 1.4 Hz).

3) a Mixture of methyl-2-{(E)-2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]vinyl}benzoate (0.28 g, of 0.53 mmol), 10% palladium on carbon (57 mg, 0,053 mmol) and methanol (10 ml) was stirred in a hermetically sealed tube in an atmosphere of hydrogen at 0.5 MPa at room temperature for 3 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel with obtaining methyl-2-{2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-tbutyl-2-methyl-4-(4-were)pyridine-3-yl]ethyl}benzoate (250 mg, yield 88%) as a white solid.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14-of 2.23 (1H, m), 2,43 (3H, s), 2,60 (3H, s), 2,62 of 2.68 (2H, m), 2,73 (2H, d, J=7,4 Hz), 2.91 in-2,96 (2H, m), 3,82 (3H, s)to 4.01 (2H, d, J=5,1 Hz), is 4.21 (1H, USS)that is 6.54 (1H, DD, J=7,4, 1.2 Hz), 6,94 (2H, d, J=8.1 Hz), 7,15-of 7.25 (4H, m), to 7.77 (1H, DD, J=7,6, 1,6 Hz).

4) Dihydrochloride methyl-2-{2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ethyl}benzoate (201 mg, yield 84%) was obtained as a white solid from methyl-2-{2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ethyl}benzoate (0.25 g, 0,471 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.20 (1H, m), of 2.45 (3H, s), 2,63-of 2.72 (2H, m), 2,83-2,90 (5H, m), 2.91 in-2,96 (2H, m), 3,18 (2H, OSS), to 3.73-a-3.84 (5H, m), of 6.65 (1H, d, J=7,4 Hz), 7,26 (2H, d, J=7,7 Hz), 7,31 (1H, DD, J=7,4, and 1.4 Hz), 7,35 (1H, DD, J=7,4, 1.8 Hz), 7,42 (2H, d, J=7.9 Hz), of 7.75 (1H, DD, J=7,5, 1.5 Hz), 8,46 (3H, USS).

Example280

The dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate

1) Methyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (258 mg, yield 64%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and methyl-4-(methyl bromide)benzoate (209 mg, 0,914 mmol) in a manner similar to the method of example 169-1).

sup> 1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,17-of 2.26 (1H, m), of 2.38 (3H, s), 2.49 USD (3H, s), 2,77 (2H, d, J=7,0 Hz), 3,42 (3H, s), 3,93 (3H, s), a 4.03 (2H, d, J=5,1 Hz), 5,09 (2H, s), 6,92 (2H, d, J=8,1 Hz), 7,16 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 8,01 (2H, d, J=8,1 Hz).

2) Dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (60 mg, yield 92%) was obtained as a white powder from methyl 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (68.6 mg, 0,119 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,17-of 2.23 (1H, m), of 2.38 (3H, s), 2,85 (3H, s)of 3.25 (2H, d, J=6.8 Hz), 3,63 (2H, s), with 3.79 (2H, d, J=4.5 Hz), a 3.87 (3H, s)to 5.13 (2H, s), 7,13 (2H, d, J=7.9 Hz), 7,30 (2H, d, J=7.9 Hz), 7,39 (2H, d, J=8,3 Hz), of 7.97 (2H, d, J=8,3 Hz), 8,63 (3H, USS).

Example281

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoic acid

1) 2-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoic acid (450 mg, yield 86%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoate (537 mg, 0,982 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.30 (1H, m), 2,32 (3H, s), of 2.34 (3H, s)of 2.64 (3H, s), 2,80 (2H, d, J=7,4 Hz), 4,10 (2H, d, J=4.9 Hz), 4,20 (H, C)4,88 (2H, s), 6,72 (1H, d, J=8.5 Hz), 7,01 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=8.1 Hz), 7.23 percent-of 7.25 (1H, m), of 7.97 (1H, d, J=2.26 and Hz).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoic acid (150 mg, yield 94%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoic acid (168 mg, 0,316 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.02 (6H, d, J=6.6 Hz), 2,18-of 2.30 (1H, m), 2,24 (3H, s), of 2.38 (3H, s)of 3.00 (3H, s), 3,30 (2H, d, J=6.8 Hz), a 3.87 (2H, d, J=2.6 Hz), 4,78 (2H, s), 6,72 (1H, d, J=8.5 Hz), 7,20-7,22 (1H, m), 7,30-7,34 (4H, m), the 7.43 (1H, d, J=1.5 Hz), 8,63 (3H, USS).

Example282

The dihydrochloride methyl-3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate

1) Methyl-3-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (401 mg, yield 64%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (466 mg, of 1.09 mmol) and methyl-3-(methyl bromide)benzoate (325 mg, of 1.42 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,17-of 2.26 (1H, m), a 2.36 (3H, s), 2,48 (3H, s), is 2.74 (2H, d, J=7,4 Hz)to 3.41 (2H, s), 3,93 (3H, s), a 4.03 (2H, d, J=4.9 Hz), 4,20 (1H, OSS), to 5.08 (2H, s), 6.90 to-6,93 (2H, m), 7,14 (2H, d, J=7,7 Hz), 7,40-7,44 (2H, m), to 7.93 (1H, d, J=0.8 Hz), 7,98 shed 8.01 (1H, m).

2)Dihydrochloride methyl-3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (80 mg, yield 99%) was obtained as a white powder from methyl 3-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}oxy)methyl]benzoate (to 84.6 mg, 0.147 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), a 2.36 (3H, s), is 2.88 (3H, s), 3,30 (2H, d, J=6.8 Hz), of 3.60 (2H, s), 3,80 (2H, d, J=3.8 Hz), 3,88 (3H, s)to 5.13 (2H, s), 7,12 (2H, d, J=7.9 Hz), 7,27 (2H, d, J=7.9 Hz), 7,56-of 7.60 (2H, m), 7,89 (1H, s), 7,95-7,98 (1H, m), 8,63 (3H, USS).

Example283

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzamide

1) tert-Butyl{[5-{[2-(aminocarbonyl)-5-methoxyphenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.31 g, yield 82%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzoic acid (0,38 g of 0.68 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.30 (1H, m), a 2.36 (3H, s), 2.63 in (3H, s), 2,80 (2H, d, J=7,2 Hz), 3,80 (3H, s), 4,10 (2H, d, J=5,1 Hz), 4,20-of 4.25 (1H, m), and 4.75 (2H, s), 5,51 81H, USS), 6,26 (1H, d, J=2.3 Hz), to 6.58 (1H, DD, J=2,3, and 8.9 Hz), 7,00 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=7.9 Hz), 7,41 (1H, USS), 8,18 (1H, d, J=8,9 Hz).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-methoxybenzamide (0,22 g, yield 91%) was obtained as a white powder from tert-butyl{[5-{[2-(aminocarbonyl)-5-metoxy is noxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.25 g, 0.46 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,10-of 2.30 (1H, m)to 2.35 (3H, s), 2,78 (3H, USS), a 3.01 (2H, USS), 3,74 (3H, s), 3,80 (2H, d, J=5,1 Hz), 4,82 (2H, s), 6.42 per (1H, d, J=2.2 Hz), 6,63 (1H, DD, J=2,2, 8.7 Hz), 7,14 (2H,, USS), 7,15-to 7.35 (4H, m), 7,74 (1H, d, J=8.7 Hz), 8,28 (3H, USS).

Example284

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-aftout (1.07 g, yield 73%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.0 in g, 2.51 mmol) and methyl-3-hydroxy-2-naphthoate (609 mg, a 3.01 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,18-2,31 (1H, m), of 2.34 (3H, s), 2,70 (3H, s), and 2.79 (2H, d, J=7,4 Hz), a 3.87 (3H, s), 4,11 (2H, d, J=4,7 Hz), 4,20 (1H, OSS), to 4.81 (2H, s)6,91 (1H, s), to 7.09 (2H,, d, J=7.9 Hz), 7,16 (2H, d, J=7.9 Hz), 7,34-7,38 (1H, m), 7,46 is 7.50 (1H, m), 7,58 to 7.62 (1H, m), 7,79 (1H, d, J=8.1 Hz), by 8.22 (1H, s).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoate (178 mg, yield 84%) was obtained as a white powder from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2 naphthoate (220 mg, 0,378 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.05 (6H, d, J=6.2 Hz), ,18-2,33 (1H, m)of 2.34 (3H, s), 3,06 (3H, s)to 3.36 (2H, d, J=6.0 Hz), of 3.84 (3H, s), 3,91 (2H,s), 4,96 (2H, s), 7,35-7,45 (6H, m), 7,58 (1H, t, J=7,35 Hz), 7,79 (1H, d, J=8.1 Hz), 7,98 (1H, d, J=7.9 Hz), 8,32 (1H, ), 8,63 (3H, USS).

Example285

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoic acid

1) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoic acid (860 mg, yield 100%) was obtained as a white powder from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoate (817 mg, of 1.40 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 1.02 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,20-of 2.30 (1H, m), 2,32 (3H, s), of 2.81 (3H, s), 2,97 (2H, d, J=6.4 Hz), 4,15 (2H, d, J=3.0 Hz), 4,20 (1H, USS), free 5.01 (2H, s), 7,06 (3H, d, J=7,7 Hz), 7,18 (2H, d, J=7,7 Hz), 7,40-of 7.48 (1H, m), 7,52-7,58 (1H, m), 7,62-to 7.68 (1H, m), 7,89 (1H, d, J=8.1 Hz), 8,67 (1H, s).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoic acid (300 mg, yield 98%) was obtained as a white powder from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoic acid (320 mg, 0,563 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.4 Hz), 2,17-to 2.29 (1H, m), of 2.33 (3H, s), of 2.81 (3H, s), 2,90 (2H, s), 3,83 (2H, s), a 4.86 (2H, s), 7,24 (1H, s), 7,26-7,33 (4H, m), 7,41 (1H, t, J=7.5 Hz), 7,53 (1H, t, J=7.5 Hz), 7,75 (1H, d, J=8.1 Hz), 7,94 (1H, d, J =8.1 Hz), charged 8.52 (1H, s), 8,63(3H, OSS).

Example286

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzamide

1) tert-Butyl{[5-{[2-(aminocarbonyl)-4-methylphenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (250 mg, yield 91%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzoic acid (276 mg, 0,518 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.28 (1H, m), 2,31 (3H, s)to 2.35 (3H, s)of 2.64 (3H, s), of 2.81 (2H, s), 4,11 (2H, s), 4,20 (1H, s), was 4.76 (2H, s), of 6.66 (1H, d, J=8.5 Hz), 7,00 (2H, d, J=8.1 Hz), 7,17 (2H, d, J=8.1 Hz), 7,55 (2H, s), 8,00 (2H, s).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-methylbenzamide (200 mg, yield 92%) was obtained as a white powder from tert-butyl{[5-{[2-(aminocarbonyl)-4-methylphenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (230 mg, 0,433 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.4 Hz), 2,10-of 2.30 (4H, m), a 2.36 (3H, s), 2,96 (3H, s), with 3.27 (2H, d, J=7,0 Hz), 3,86 (2H, d, J=4.5 Hz), 4.72 in-4,84 (2H, m), 6,76 (1H, d, J=8.5 Hz), to 7.15 (1H, DD, J=8,5, 1.9 Hz), 7,25-7,38 (4H, m), 7,42 (1H, d, J=1.9 Hz), 8,64 (3H, USS).

Example287

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ndimethylacetamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl--(4-were)pyridine-3-yl]ndimethylacetamide (198 mg, yield 95%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and acetylchloride (53 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), of 1.76 (3H, s), 2,13-2,22 (1H, m), 2,39 (3H, s)to 2.55 (3H, s), to 3.02 (2H, USS), 3,82 (2H, s), 7,17 (2H, d, J=7.5 Hz), 7,33 (2H, d, J=7.5 Hz), 8,31 (3H, USS), 9,50 (1H, USS).

Example288

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propanamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]propanamide (195 mg, yield 93%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and propionitrile (65 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: of 0.82 (3H, t, J=6.9 Hz), and 0.98 (6H, d, J=6.6 Hz), 2,02 (2H, q, J=6.9 Hz), 2,08 of-2.32 (1H, m), of 2.38 (3H, s)to 2.55 (3H, s), 3,06 (2H, USS), 3,83 (2H, s), 7,17 (2H, d, J=7.8 Hz), 7,32 (2H, d, J=7.8 Hz), of 8.37 (3H, USS), 9,49 (1H, USS).

Example289

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,2-dimethylpropanamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,2-dimethylpropanamide (184 mg, yield 72%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) is of pivaloate (92 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,89 (9H, s), and 0.98 (6H, d, J=6.6 Hz), 2,12-of 2.24 (1H, m), a 2.36 (3H, s), of 2.51 (3H, s), of 2.97 (2H, USS), 3,81 (2H, s), 7,14 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8.1 Hz), 8,28 (3H, USS), of 8.95 (1H, USS).

Example290

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclopropanecarboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclopropanecarboxamide (170 mg, yield 85%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and cyclopropanecarbonitrile (68 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,58-0,67 (4H, m), and 0.98 (6H, d, J=6.6 Hz), 1,51 is 1.58 (1H, m), 2,17-of 2.26 (1H, m), 2,39 (3H, s)to 2.54 (3H, s), to 3.02 (2H, USS), 3,81 (2H, s), 7,16 (2H, d, J=7.5 Hz), 7,32 (2H, d, J=7.5 Hz), 8,32 (3H, USS), to 9.70 (1H, USS).

Example291

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclopentanecarboxylic

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclopentanecarboxylic (137 mg, yield 62%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and cyclopentanecarbonitrile (68 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J6,6 Hz), 1,30-of 1.62 (9H, m), 2,15-of 2.24 (1H, m), of 2.38 (3H, s)of 2.50 (3H, s), to 3.02 (2H, USS), 3,81 (2H, s), to 7.15 (2H, d, J=7.8 Hz), 7,30 (2H, d, J=7.8 Hz), 8,32 (3H, USS), 9,39 (1H, USS).

Example292

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyridine-2-carboxamide

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyridine-2-carboxamide (218 mg, yield 91%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and pyridine-2-carbonylchloride (106 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,20-of 2.28 (1H, m), of 2.28 (3H, s)of 2.64 (3H, s), 3,14 (2H, USS), 3,86 (2H, s), 7,20-7,27 (4H, m), 7,06-the 7.65 (1H, m), 7,94-8,02 (2H, m), 8,43 (3H, USS), 8,61 (1H, d, J=4,8 Hz), 10,33 (1H, s).

Example293

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]nicotinamide

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]nicotinamide (225 mg, yield 94%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and nicotinanilide (106 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: of 1.02 (6H, d, J=6.6 Hz), 2,23-2,31 (1H, m), 2,31 (3H, s), 2,73 (3H, s), 3,19 (2H, USS), 3,90 (2H, s), 7,28 (4H, s), 7,73 for 7.78 (1H, m), 8,35 (2H, d, J=8.1 Hz), 8,53 (3H, USS), cent to 8.85 (1H, d, J=3.6 Hz), 8,94 (1H, s)10,90 (1H, USS).

p> Example294

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isonicotinamide

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isonicotinamide (215 mg, yield 91%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and isonicotinohydrazide (106 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,22-2,31 (1H, m), 2,31 (3H, s), 2,70 (3H, s), 3,51 (2H, USS), 3,88 (2H, s), 7,28 (4H, s), 7,87 (2H, d, J=6.0 Hz), 8,51 (3H, USS), 8,88 (2H, d, J=6.0 Hz), 11,20 (1H, USS).

Example295

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(phenoxymethyl)pyridine-3-yl]methyl}amine

1) tert-Butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(phenoxymethyl)pyridine-3-yl]methyl}carbamate (270 mg, yield 56%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.40 g, 1.00 mmol) and phenol (or 94.5 mg, 1.00 and mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.27 (1H, m), a 2.36 (3H, s), 2.63 in (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,10 (2H, d, J=5.7 Hz), 4,22 (1H, OSS), to 4.62 (2H, s), 6,78-PC 6.82 (2H, m), 6,93 (1H, t, J=the 7.4 Hz), 7,05 (2H, d, J=8.1 Hz), 7,17 (2H, d, J=7,7 Hz), 7,21-7,24 (2H, m).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(phenoxymethyl)pyridine-3-yl]methyl}amine (132 mg, yield 51%) received is in the form of a colorless oil from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(phenoxymethyl)pyridine-3-yl]methyl}carbamate (0.27 g, 0,569 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m)to 2.35 (3H, s), 2,82 (3H, USS), of 3.12 (2H, USS), 3,83 (2H, d, J=4.9 Hz), 4,70 (2H, s), 6,85 (2H, d, J=7.9 Hz), to 6.95 (1H, t, J=7.4 Hz), 7.23 percent-7,33 (6H, m), scored 8.38 (3H, USS).

Example296

Trihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinamide

1) tert-Butyl{[5-({[5-(aminocarbonyl)pyridine-2-yl]methoxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (370 mg, yield 77%) was obtained as a white solid from 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinic acid (0,48 g, 0,899 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.23 (1H, m), is 2.40 (3H, s)to 2.67 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,07 (2H, d, J=5,1 Hz)to 4.23 (1H, USS), 4,27 (2H, s), of 4.49 (2H, s), 7,03 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=7,7 Hz), 7,38 (1H, d, J=7.9 Hz), 8,08 (1H, DD, J=8,1, 2.3 Hz), of 8.90 (1H, d, J=2.3 Hz).

2) Trihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}methyl)nicotinamide (282 mg, yield 75%) was obtained as a white solid from tert-butyl{[5-({[5-(aminocarbonyl)pyridine-2-yl]methoxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,37 g, 0,695 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.24 (1H, m), 2,39 (3H, s),of 2.97 (3H, OSS), 3,23 (2H, d, J=5.8 Hz), 3,82 (2H, d, J=5.3 Hz), 4,30 (2H, s)to 4.52 (2H, s), 7,25 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), 7,39-7,42 (1H, m), to 7.61-of 7.69 (1H, m), 8,27-8,30 (1H, m), and 8.50 (3H, USS), 8,99 (1H, USS).

Example297

The dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalic acid

1) Dimethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalate (1.12 g, 75%yield) was obtained as a white solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol) and dimethyl-4-hydroxyisophthalate (528 mg, 2.51 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,19-2,31 (1H, m)to 2.35 (3H, s)to 2.66 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3,83 (3H, s)to 3.89 (3H, s), 4,06-4,11 (2H, m)to 4.23 (1H, USS), of 4.77 (2H, s)of 6.71 (1H, d, J=8,9 Hz), 7,05 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=7.9 Hz), 8,01 (1H, DD, J=8,7, and 2.3 Hz), to 8.41 (1H, d, J=2.3 Hz).

2) 4-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalic acid (310 mg, yield 90%) was obtained as white solids from dimethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalate (0.36 g, 0,609 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 1.03 (6H, d, J=6,4 Hz)to 1.37 (9H, s)to 2.35 (3H, s), 2,96 (3H, USS), of 3.13 (2H, OSS), to 4.16 (2H, USS), 4,94 (2H, USS), 6,76 (1H, USS), 7,07 (2H, USS), ,22 (2H, d, J=7,7 Hz), 8,01 (1H, USS), 8,53 (1H, USS).

3) of the Dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalic acid (256 mg, yield 86%) was obtained as a white solid from 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}isophthalic acid (0.31 g, 0,551 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,16-of 2.28 (1H, m)to 2.35 (3H, s), 2,85 (3H, USS), is 3.08 (2H, USS), 3,83 (2H, USS), a 4.86 (2H, s), 7,01 (1H, d, J=8,9 Hz), 7,27 (2H, d, J=8.1 Hz), 7,31 (2H, d, J=7,7 Hz), of 7.97 (1H, DD, J=8,7, and 2.3 Hz), 8,18 (1H, d, J=2.1 Hz), 8.34 per (3H, USS).

Example298

The dihydrochloride methyl-2-{(E)-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]vinyl}benzoate

The dihydrochloride methyl-2-{(E)-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]vinyl}benzoate (to 31.4 mg, yield 33%) was obtained as a white solid from methyl-2-{(E)-2-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]vinyl}benzoate (0.10 g, 0,189 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.4 Hz), 2,16-of 2.28 (1H, m), of 2.38 (3H, s), of 2.86 (3H, USS), 3,06 (2H, USS), 3,83-3,88 (5H, m), 6,53 (1H, d, J=16,8 Hz), 7,17 (1H, d, J=16,8 Hz), 7,24 (2H, d, J=7,7 Hz), 7,29 (1H, d, J=7,7 Hz), to 7.35 (2H, d, J=7.9 Hz), 7,40 (1H, t, J=7.5 Hz), 7,53 (1H, t, J=7.5 Hz), 7,79 (1H, DD, J=7,8, 1.2 Hz), 8,32 (3H, USS).

Example299

The dihydrochloride of 4-[1-({[5-(aminomethyl)-6-isobutyl-2-meth is l-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid

1) 1-[4-(Methoxycarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,02 g, yield 73%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,00 g, 2,42 mmol) and methyl-4-(1-hydroxyethyl)benzoate (486 mg, 2,42 mmol) in a manner similar to the method of example 247-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,25 (3H, d, J=7,0 Hz)of 1.39 (9H, s), 2,16-of 2.24 (1H, m), of 2.33 (3H, s), 2,48 (3H, s), 2,78 (2H, d, J=7,4 Hz)to 3.92 (3H, s), 4,11-4,16 (2H, m), 4,22 (1H, USS), 5,73-5,79 (1H, m), of 6.96-6,99 (1H, m),? 7.04 baby mortality-to 7.09 (2H, m), 7,13-7,17 (3H, m), to 7.93 (2H, d, J=8,3 Hz).

2) 4-[1-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (950 mg, yield 95%) was obtained as colorless oil from 1-[4-(methoxycarbonyl)phenyl]ethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,02 g, 1.77 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.26 (3H, d, J=6,8 Hz)of 1.39 (9H, s), 2,15-of 2.26 (1H, m), of 2.34 (3H, s)of 2.50 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 4,11-4,16 (2H, m), 4,24 (1H, USS), 5,79 (1H, q, J=6.6 Hz), 7,00-7,13 (4H, m), 7,18 (2H, d, J=8.1 Hz), to 7.99 (2H, d, J=8,3 Hz).

3) of the Dihydrochloride of 4-[1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (259 mg, yield 93%) was obtained as a white solid from 4-[1-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-tbutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)ethyl]benzoic acid (0,30 g, 0,522 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6,8 Hz)to 1.22 (3H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), of 2.33 (3H, s), 2,47 (3H, USS), is 2.88 (2H, d, J=5.7 Hz), 3,81 (2H, d, J=5.5 Hz), USD 5.76 (1H, q, J=6.6 Hz), 7,11-of 7.25 (6H, m), 8,27 (3H, USS).

Example300

The dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]amine

1) tert-Butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (1,37 g, yield 70%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.50 g, mmol 3,76) and 2-(methylthio)phenol (573 mg, 3,76 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-2,31 (1H, m), a 2.36 (3H, s), is 2.37 (3H, s), 2,69 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4.09 to-4,11 (2H, m), is 4.21 (1H, USS), and 4.68 (2H, s), to 6.57 (1H, DD, J=7,9, 1.3 Hz), 6,91? 7.04 baby mortality (2H, m), 7,06 for 7.12 (3H, m), 7,17 (2H, d, J=7,7 Hz).

2) Dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]amine (112 mg, yield 69%) was obtained as a white solid from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (0.17 mg, 0,326 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m)to 2.35 (3H, s), a 2.36 (3H, s), is 2.88 (3H, USS)and 3.15 (2H, USS), 3,83 (2H, USS), and 4.75 (2H, s), to 6.57 (1H, d, J=6.8 Hz), of 6.96-7,07 (2H, m), 13-7,16 (1H, m), 7,28 (2H, d, J=8,3 Hz), 7,32 (2H, d, J=7,4 Hz), to 8.41 (3H, USS).

Example301

The dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulphonyl)phenoxy]methyl}pyridine-3-yl)methyl]amine

1) tert-Butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulphonyl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (330 mg, yield 81%) was obtained as a white solid from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (0,38 g, at 0.730 mmol) in a manner similar to the method of example 91-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2.21 are of 2.30 (1H, m)to 2.35 (3H, s)to 2.67 (3H, s), and 2.79 (2H, d, J=7,4 Hz), is 3.08 (3H, s), 4,11 (2H, d, J=5,1 Hz), 4,27 (1H, USS), 4,79 (2H, s)6,76 (1H, d, J=8,1 Hz), 7,06-7,10 (3H, m), 7,18 (2H, d, J=7.9 Hz), 7,45 is 7.50 (1H, m), of 7.97 (1H, DD, J=7,7, 1,7 Hz).

2) Dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulphonyl)phenoxy]methyl}pyridine-3-yl)methyl]amine (227 mg, yield 59%) was obtained as a white solid from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulphonyl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (0.33 g, 0,597 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.4 Hz), 2,17-of 2.28 (1H, m)to 2.35 (3H, s)2,84 (3H, USS), 3,05-3,17 (5H, m), a-3.84 (2H, d, J=4,7 Hz), to 4.87 (2H, s), 7,11 (1H, d, J=8,3 Hz), 7,18 (1H, t, J=7,6 Hz), 7,28-7,33 (4H, m), 7,60-7,66 (1H, m), 7,81 (1H, DD, J=7,7, 1.7 Hz), 8,40 (3H, USS).

Example302

The dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(matilal the Nile)phenoxy]methyl}pyridine-3-yl)methyl]amine

1) To a mixed solution of tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylthio)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (0,47 g, 0,902 mmol) in methanol (10 ml) and water (10 ml) was added periodate sodium (377 mg, of 1.76 mmol) and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulfinyl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (164 mg, yield 33%) as a yellow oil.

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2.21 are to 2.29 (1H, m)to 2.35 (3H, s), 2,61 (3H, s), 2,69 (3H, s), 2,80 (2H, d, J=7,4 Hz), 4.09 to-4,11 (2H, m)to 4.23 (1H, USS), 4,59 (1H, d, J=10.0 Hz), a 4.83 (1H, d, J=10,0 Hz), of 6.71 (1H, d, J=8.1 Hz), 6,95-6,98 (1H, m), 7,02-7,05 (1H, m), 7,16-7,21 (3H, m), 7,32-7,38 (1H, m), 7,82 (1H, DD, J=7,7, 1,7 Hz).

2) Dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulfinyl)phenoxy]methyl}pyridine-3-yl)methyl]amine (97,4 mg, yield 62%) was obtained as a white solid from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(methylsulfinyl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (164 mg, 0,306 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6,6 Hz, 2,17-of 2.27 (1H, m), of 2.34 (3H, s), 2.63 in (3H, s), 2,77 (3H, USS), 3,06 (2H, USS), 3,82 (2H, USS), 4,70 (1H, d, J=a 10.6 Hz), the 4.90 (1H, d, J=10,7 Hz), of 6.99 (1H, d, J=8.1 Hz), 7,20-7,33 (5H, m), 7,42-7,47 (1H, m), of 7.64 (1H, DD, J=7,5) and 1.7 Hz), 8,31 (3H, USS).

Example303

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthalide

1) tert-Butyl{[5-({[3-(aminocarbonyl)-2-naphthyl]oxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (230 mg, yield 46%) was obtained as a white powder from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthoic acid (500 mg, 0,879 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,89 (6H, d, J=6.6 Hz), of 1.35 (9H, s), 2,07-2,22 (1H, m), of 2.28 (3H, s), and 2.79 (3H, s), 2,87 (2H, d, J=7,2 Hz), 4,14-is 4.21 (3H, m), of 4.95 (2H, s),? 7.04 baby mortality (1H, s), 7,08-7,21 (4H, m), 7,42-7,52 (1H, m), 7,63 (1H, d, J=7.5 Hz), 7,74 (1H, d, J=7.5 Hz), 7,81 (1H, d, J=8.1 Hz), 8,67 (1H, s), 11,73 (2H, s).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-naphthalide (200 mg, yield 91%) was obtained as a white powder from tert-butyl{[5-({[3-(aminocarbonyl)-2-naphthyl]oxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (230 mg, 0,405 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.4 Hz), 2,17-of 2.30 (1H, m), 2,32 (3H, s), of 2.51 (3H, s), of 2.81 (2H, s), 3,83 (2H, s), 4,88 (2H, s), 7,25-7,33 (4H, m), 7,40 (1H, t, J=7.5 Hz), to 7.50 (1H, t, J=7.5 Hz), of 7.75 (1H, d, J=8.1 Hz), 7,92 (1H, d, J =7.9 Hz), to 8.12 (1H, s), 8,42 (1H, s), or 8.6 (3H, OSS).

Example304

5-(Aminomethyl)-6-isobutyl-2-methyl-4-(4-were)-N-phenyldiamine

To a solution of 5-({[(benzyloxy)carbonyl]amino}methyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (523 mg, 1,17 mmol) in tetrahydrofuran (5 ml) was added oxalicacid (120 μl, 1.4 mmol) and then one drop of N,N-dimethylformamide. The reaction solution was stirred for 3 h, then the reaction mixture was concentrated. The residue was dissolved in tetrahydrofuran (5 ml). Added aniline (91 μl, 1.0 mmol) and triethylamine (210 μl, 1.5 mmol) and the mixture was stirred for 30 minutes was Added to the reaction mixture water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the oil in ethanol (5 ml) was added 10% palladium on carbon (50 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 3 hours, the Reaction mixture was filtered and the filtrate was concentrated. The resulting oil was led from a mixture of hexane and diethyl ether to obtain 5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)-N-fenilcetonuria (320 mg, yield 83%) as a white powder.

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), 2,172,31 (1H, m)of 2.34 (3H, s)to 2.65 (3H, s), 2,82 (2H, d, J=7.5 Hz), of 3.69 (2H, s), 6,93 (1H, USS),? 7.04 baby mortality-7,26 (9H, m).

Example305

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate

1) Ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (3,23 g, yield 79%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (3.00 g, 7,52 mmol) and ethyl-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (1.28 g, 7,52 mmol) in a manner similar to the method of example 183-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.28 (3H, t, J=7,1 Hz)of 1.39 (9H, s), 2,17-of 2.26 (1H, m), a 2.36 (3H, s)to 2.66 (3H, s), 2,77 (2H, d, J=7,4 Hz)to 3.67 (3H, s)4,08 (2H, d, J=4,7 Hz), 4,19-4.26 deaths (3H, m), the 4.90 (2H,with), 7,10 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=8.1 Hz), to 7.61 (1H, s).

2) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (1,58 g, 51%yield) was obtained as a white solid from ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (3,23 g, 5,86 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,15-of 2.28 (1H, m), a 2.36 (3H, s)to 2.66 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 3,71 (3H, s), Android 4.04-4.09 to (2H, m)to 4.23 (1H, OSS), to 4.98 (2H, s), 7,05 (2H, d, J=8.1 Hz), 7,9 (2H, d, J=7,7 Hz), 7,69 (1H, s).

3) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.50 g, 0,957 mmol) was dissolved in N,N-dimethylformamide (5 ml) and methyliodide (176 mg, 1,24 mmol) was added potassium carbonate (0.20 g, 1.44 mmol). The mixture was stirred at room temperature for 1 h To the reaction mixture were added ethyl acetate and the mixture was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (470 mg, yield 91%) as a white solid.

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.26 (1H, m), a 2.36 (3H, s)to 2.66 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,68 (3H, s), 3,76 (3H, s)4,08 (2H, d, J=4,7 Hz)to 4.23 (1H, USS), the 4.90 (2H, s), 7,10 (2H,, d, J=7.9 Hz), 7,16 (2H, d, J=7.9 Hz), a 7.62 (1H, s).

4) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (382 mg, yield 85%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (0,47 g, 0,876 mmol) in a manner similar to the way the application is and 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,14-of 2.28 (1H, m), of 2.38 (3H, s), 2,90 (3H, USS), and 3.16 (2H, USS), the 3.65 (3H, s), 3,66 (3H, s), 3,82 (2H, d, J=5,1 Hz), the 4.90 (2H, s), 7,27 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8,1 Hz), of 8.09 (1H, s), to 8.41 (3H, USS).

Example306

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (268 mg, yield 94%) was obtained as a white solid from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0,30 g, 0,574 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,14 was 2.25 (1H, m), 2,39 (3H, s), is 2.88 (3H, USS), 3,14 (2H, OSS), to 3.64 (3H, s), 3,82 (2H, d, J=4,7 Hz), to 4.87 (2H, s), 7,28 (2H, d, J=7.9 Hz), 7,34 (2H, d, J=8.1 Hz), 8,00 (1H, ), scored 8.38 (3H, USS).

Example307

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxamide

1) tert-Butyl{[5-({[4-(aminocarbonyl)-1-methyl-1H-pyrazole-3-yl]oxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (307 mg, yield 61%) was obtained as colorless oil from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.50 g, 0,957 the mol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), is 2.37 (3H, s)to 2.65 (3H, s), and 2.79 (2H, d, J=7,4 Hz), of 3.69 (3H, s), 4.09 to (2H, d, J=4.9 Hz), 4,22 (1H, OSS), to 4.98 (2H, s), and 5.30 (1H, OSS), to 6.43 (1H, USS), 7,01 (2H, d, J=8.1 Hz), 7,20 (2H, d, J=7,7 Hz), 7,69 (1H, s).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxamide (253 mg, yield 87%) was obtained as a white solid from tert-butyl{[5-({[4-(aminocarbonyl)-1-methyl-1H-pyrazole-3-yl]oxy}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (307 mg, 0,588 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,14-of 2.27 (1H, m), of 2.38 (3H, s), with 2.93 (3H, USS), 3,17 (2H, USS), 3,63 (3H, s), 3,82 (2H, d, J=4,7 Hz), is 4.93 (2H, s), 6,37 (1H, OSS), was 7.08 (1H, USS), 7,29 (2H, d, J=7.9 Hz), 7,35 (2H,, d, J=8.1 Hz), to $ 7.91 (1H, s), 8,42 (3H, USS).

Example308

The dihydrochloride (3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetic acid

1) To a solution of tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol), methyl(3-hydroxy-1-methyl-1H-pyrazole-4-yl)acetate (0,43 g, 2.51 mmol) and tributylphosphine (0,61 g, a 3.01 mmol) in tetrahydrofuran (20 ml) was added 1,1'-(azodicarbon)dipiperidino (0,76 g, a 3.01 mmol) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was filtered and the solvent in the filtrate of the flash steam is piss off under reduced pressure. The obtained residue was purified column chromatography on silica gel to obtain methyl(3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetate (1.20 g, yield 86%) as a colourless oil. Then received (3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetic acid (173 mg, yield 15%) as a white solid from methyl(3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetate (1.20 g, to 2.18 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,12-of 2.30 (1H, m), a 2.36 (3H, s), 2,62 (3H, s), 2,80 (2H, d, J=7,2 Hz), the 3.35 (2H, s), 3,66 (3H, s), of 4.05-4.09 to (2H, m), 4,27 (1H, USS), 4,84 (2H, s), 7,03 (2H, d, J=7.9 Hz), 7,12 (1H, s), 7,18 (2H, d, J=7,7 Hz).

2) Dihydrochloride (3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetic acid (84,2 mg, 51%yield) was obtained as a white solid from (3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-yl)acetic acid (173 mg, 0,323 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), of 2.38 (3H, s), was 2.76 (3H, USS), of 3.00 (2H, USS)and 3.15 (2H, s)to 3.58 (3H, s), of 3.77-a-3.84 (2H, m), was 4.76 (2H, s), 7.23 percent (2H, d, J=7,7 G is), 7,33 (2H, d, J=7.5 Hz), 7,37 (1H, s), 8,18 (3H, USS).

Example309

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-(1H-tetrazol-5-yl)benzamide

To a solution of tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (383 mg, 1.0 mmol) in tetrahydrofuran (5 ml) was added 3-cyanobenzoate (245 mg, 1.5 mmol) and then triethylamine (280 ml, 2.0 mmol). The mixture was stirred for 18 hours To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in dimethyl sulfoxide (3 ml) was added sodium azide (97 mg, 1.5 mmol) and ammoniacal (312 mg, 2.0 mmol) and the mixture was stirred at 100°C for 3 hours was Added to the reaction mixture distilled water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in ethyl acetate (2 the l) was added 4n. an ethyl acetate solution of hydrogen chloride (2 ml) and the resulting mixture was stirred at room temperature for 3 hours the Solvent is evaporated under reduced pressure and the obtained residue was led from hexane to obtain the dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-(1H-tetrazol-5-yl)benzamide (86 mg, yield 16%) as a white powder.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.27 (1H, m), and 2.27 (3H, s), 2,52 (3H, s), with 2.93 (2H, s), 3,83 (2H, s), 7,22 (4H, s), to 7.64 (1H, t, J=7.8 Hz), 7,76 (1H, d, J=7.8 Hz), 8,16 (4H, OSS), to 8.34 (1H, USS), 10,10 (1H, USS).

Example310

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoate (600 mg, yield 44%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1.0 in g, 2.51 mmol) and methyl 2-hydroxy-3-methylbenzoate (500 mg, a 3.01 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), of 1.80 (3H, s), 2,15-of 2.28 (1H, m), of 2.34 (3H, s), 2,70 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,66 (3H, s), of 3.97 (2H, d, J=4.9 Hz), 4,20 (1H, OSS), was 4.76 (2H, s), of 6.52 (2H,, d, J=7.9 Hz), of 6.99 (2H, d, J=7.9 Hz), 7,01-7,06 (1H, m), 7,19 (1H, DD, J=7,4, 1.0 Hz), 7,44 (1H, DD, J=7,7, 1.0 Hz). 2)

2) Dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-IU is ylphenyl)pyridine-3-yl]methoxy}-3-methylbenzoate (215 mg, yield 94%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoate (240 mg, 0,439 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.4 Hz), equal to 1.82 (3H, s), 2,14-to 2.29 (1H, m), a 2.36 (3H, s), to 3.02 (3H, s), and 3.31 (2H, d, J=6,8 Hz)to 3.67 (3H, s), of 3.78 (2H, d, J=2,45 Hz), to 4.81 (2H, s), 6.89 in (2H, d, J=7,7 Hz), 7,11-7,20 (3H, m), 7,33 (1H, d, J=7,0 Hz), the 7.43 (1H, d, J=7,0 Hz), 8,63 (3H, USS).

Example311

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-cyclopropylacetic

1) a Mixture of [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (200 mg, 0,469 mmol), cyclopropylamine (80 mg, of 1.41 mmol), 1-hydroxy-1H-benzotriazole (215 mg, of 1.41 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (270 mg, of 0.65 mmol) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours, the Reaction mixture was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[2-(cyclopropylamino)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (150 mg, yield 69%) as a white powder.

1H-NMR (CDCl3) δ: 0,33-0,9 (2H, m)to 0.97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), of 1.80 (3H, s), 2,13-to 2.29 (1H, m), is 2.40 (3H, s)to 2.54 (3H, s), 2.57 m-of 2.64 (1H, m)of 2.75 (2H, d, J=7,4 Hz), 3,23 (2H, s), of 4.05 (2H, s), 4,20 (1H, USS), 6,94 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7.9 Hz).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-cyclopropylacetylene (100 mg, yield 89%) was obtained as a white powder from tert-butyl{[5-[2-(cyclopropylamino)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (120 mg, mmol 0,258) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,34 (2H, s), or 0.57 (2H, d, J=5.5 Hz), 0,99 (6H, d, J=6.2 Hz), 2,11-of 2.25 (1H, m), is 2.41 (3H, s), 2,53-of 2.58 (1H, m), of 2.81 (2H, s), 3,24 (2H, s), 3,6-3,9 (5H, m), 7,20 (2H, d, J=7,7 Hz), 7,37 (2H, d, J=7,7 Hz), 8,08 (1H, d, J=3,4 Hz), 8,56 (3H, USS).

Example312

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}amine

1) tert-Butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}carbamate (50 mg, yield 22%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (200 mg, 0,469 mmol) and research (123 mg, of 1.41 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,09-of 2.27 (1H, m), is 2.41 (3H, s)of 2.50 (3H, s), 2,73 (2H, d, J=7,4 Hz), 3,17 (2H, d, J=4,1 Hz), 3,30 (2H, s)to 3.41 (2H, d, J=4,1 Hz), of 3.56 (4H, DD, J=16.5, and a 4.1 Hz), Android 4.04 (2H, d, J=4.52 Hz), 4,20 (1H, USS), 6,98 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz).

2) Dihydro what lorid {[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}amine (40 mg, yield 94%) was obtained as a white powder from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}carbamate (45 mg, 0,0908 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,09-of 2.30 (1H, m), is 2.41 (3H, s)of 2.50 (3H, s), and 2.79 (2H, s), 3,09-3,42 (10H, m), 3,82 (2H, d, J=3.8 Hz), 7,16 (2H, d, J=7,7 Hz), 7,39 (2H, d, J=7,7 Hz), charged 8.52 (3H, USS).

Example313

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-benzylated

1) tert-Butyl{[5-[2-(benzylamino)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (150 mg, yield 62%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (200 mg, 0,469 mmol) and benzylamine (151 mg, of 1.41 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,12-of 2.27 (1H, m), is 2.37 (3H, s), of 2.56 (3H, s), is 2.74 (2H, d, J=7,2 Hz), 3,32 (2H, s), was 4.02 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 4,34 (2H, d, J=5.8 Hz), the 5.45 (1H, USS), to 6.88 (2H, d, J=7.9 Hz), 7,10-7,20 (4H, m), 7,25-to 7.35 (3H, m).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-benzylcyanide (125 mg, yield 100%) was obtained as a white powder from tert-butyl{[5-[2-(benzylamino)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (130 mg, mmol 0,252) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d ) δ: 0,99 (6H, d, J=6.4 Hz), 2,07-of 2.28 (1H, m), is 2.40 (3H, s), and 2.83 (3H, s), or 3.28 (2H, d, J=7,0 Hz), 3,42 (2H)3,81 (2H, d, J=3.0 Hz), is 4.21 (2H, d, J=5.7 Hz), 7,10-7,44 (9H, m), charged 8.52 (3H, USS).

Example314

The dihydrochloride [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(1H-tetrazol-5-yl)phenoxy]methyl}pyridine-3-yl)methyl]amine

1) tert-Butyl{[5-[(2-cianfrocca)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (586 mg, yield 70%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,67 g, by 1.68 mmol) and 2-hydroxybenzonitrile (221 mg, of 1.85 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), of 2.34 (3H, s)to 2.66 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 4.09 to-4,11 (2H, m), 4.26 deaths (1H, OSS), to 4.73 (2H, s)6,76 (1H, d, J=8.5 Hz), of 6.96-7,01 (2H, m), to 7.09 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=7.9 Hz), 7,40-7,46 (1H, m), 7,50-7,56 (1H, m).

2) tert-Butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(1H-tetrazol-5-yl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (400 mg, yield 63%) was obtained as a white solid from tert-butyl{[5-[(2-cianfrocca)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (586 mg, 1,17 mmol) in a manner similar to the method of example 251-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.28 (1H, m), 2,32 (3H, s)at 2.59 (3H, s), 2,82 (2H, d, J=7,4 Hz), 4.09 to-4,13 (2H, m), or 4.31 (1H, OSS), to 4.92 (2H, s), 6,91-to 6.95 (3H, m), 7,12 (2H, d, J=7,7 Hz), to 7.18 (1H, t, J=7,6 Hz), 7,43-7,49 (1H, m), 8,42 (2H, DD, J=7,9, 1,7 Hz).

3) DigiTech orig [(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(1H-tetrazol-5-yl)phenoxy]methyl}pyridine-3-yl)methyl]amine (327 mg, yield 86%) was obtained as a white solid from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[2-(1H-tetrazol-5-yl)phenoxy]methyl}pyridine-3-yl)methyl]carbamate (400 mg, 0,737 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,17-to 2.29 (4H, m), is 2.88 (3H, USS), and 3.16 (2H, USS), 3,80 (2H, USS), 4,89 (2H, s), 7.03 is-7,10 (3H, m), 7,13-7,17 (3H, m), 7,46-7,52 (1H, m), 7,87 (1H, d, J=7,7 Hz), to 8.41 (3H, USS).

Example315

The dihydrochloride of 5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-1,3-thiazolidine-2,4-dione

1) a Mixture of tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (600 mg and 1.51 mmol), 1,3-thiazolidin-2,4-dione (177 mg and 1.51 mmol), piperidine (0,015 ml) and ethanol (10 ml) was stirred with heating at 80°C for 3.5 days. Allowing the mixture to cool to room temperature, evaporated under reduced pressure the solvent. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (400 mg, yield 53%) as a white powder.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,12-2,31 (1H, m), of 2.38 (3H, s)of 2.50 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,12 (2H, d, J=5,1 Hz), 4,20 (1H, USS), of 6.96 (2H, d, J=8.1 Hz), 7,19 (2H, d, J=8.1 Hz), 7,51 (1H, s).

2) Dihydrochloride 5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-1,3-thiazolidine-2,4-dio is a (155 mg, yield 100%) was obtained as a white powder from tert-butyl{[5-[(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (157 mg, 0,316 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,14-to 2.29 (1H, m), is 2.37 (3H, s), of 2.51 (3H, s), is 3.08 (2H, d, J=6.4 Hz), 3,83 (2H, d, J=4,7 Hz), 7.23 percent (2H, d, J=8.1 Hz), 7,28-7,40 (3H, m), 8,49 (3H, USS).

Example316

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoic acid

1) 2-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoic acid (280 mg, yield 93%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoate (300 mg, 0,563 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ with 1.07 (6H, d, J=6,4 Hz)to 1.38 (9H, s)a 1.96 (3H, s), 2,24 of-2.32 (1H, m), a 2.36 (3H, s), 3,14 (3H, s), and 3.31 (2H, d, J=6.8 Hz), 4,06 (2H, d, J=4.3 Hz), 4,20 (1H, USS), a 4.83 (2H, s), 6,60 (2H, d, J=7.5 Hz,), 7,02-7,13 (3H, m), 7,19-7,24 (1H, m), 7,45-rate of 7.54 (1H, m).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoic acid (55 mg, yield 100%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoyl acid (58,4 mg, 0,110 mmol) by the method p is like the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6,4 Hz)to 1.79 (3H, s), 2,14-of 2.28 (1H, m), a 2.36 (3H, s), of 2.97 (3H, s), 3,26 (2H, d, J=6.8 Hz), of 3.77 (2H, d, J=4.0 Hz), to 4.81 (2H, s), 6,93 (2H, d, J=7.9 Hz), to 7.09 (1H, t, J=7.5 Hz), 7,19 (2H, d, J=7.9 Hz), 7,29 (1H, d, J=6.6 Hz), 7,38-7,46 (1H, m), to 8.57 (3H, USS).

Example317

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzamide

1) 2-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoyl acid (0.54 g, yield 97%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzoate (or 0.57 g, 1.0 mmol) by a method similar to the method of example 43-1).

1H-NMR (CDCl3) δ: was 1.04 (6H, d, J=6.6 Hz), of 1.37 (9H, s), of 2.20 to 2.35 (1H, m), is 2.40 (3H, s)of 3.00 (3H, s), 3,21 (2H, d, J=5,2 Hz), 4,17 (2H, d, J=5.8 Hz), 4,50 with 4.65 (1H, m), 4,88 (2H, s), 6,62 (1H, d, J=8,9 Hz), 7,05 (2H,, d, J=7.8 Hz), 7,25 (2H, d, J=7.8 Hz), 7,33 (1H, DD, J=2,6, a 8.9 Hz), of 7.90 (1H, d, J=8,9 Hz).

2) tert-Butyl{[5-{[2-(aminocarbonyl)-4-chlorophenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.20 g, yield 71%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorbenzoyl acid (0.28 g, 0.51 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), of 2.15 to 2.35 (1H, m), a 2.36 (3H, s), 2.63 in (3H, s), 2,80 (2H, d, J=7,4 Hz), 4,10 (2H, d, J=5,1 Hz), 4,15-4,30(1H, m), of 4.77 (2H, s), the 5.65 (1H, USS), 6,69 (1H, d, J=8,9 Hz), of 6.99 (2H, d, J=7.9 Hz), 7,18 (2H, d, J=7.9 Hz), 7,31 (1H, DD, J=2,8, and 8.9 Hz), of 7.48 (1H, USS), 8,18 (1H, d, J=2,8 Hz).

3) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorobenzamide (0.16 g, yield 99%) was obtained as a white powder from tert-butyl{[5-{[2-(aminocarbonyl)-4-chlorophenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.17 g, 0.31 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), of 2.15 to 2.35 (1H, m), a 2.36 (3H, s)2,84 (3H, USS), is 3.08 (2H, USS), 3,82 (2H, d, J=2.6 Hz), 4,79 (2H, s), 6,83 (1H, d, J=9.0 Hz), 7,25 (2H, d, J=7.9 Hz), 7,31 (2H, d, J=7.9 Hz), 7,41 (1H, DD, J=2.7, and 9.0 Hz), 7,52 (2H, USS), 7,55 (1H, d, J=2.7 Hz), at 8.36 (3H, USS).

Example318

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorbenzoyl acid

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorbenzoyl acid (0.16 g, yield 85%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-5-chlorbenzoyl acid (0.20 g, 0.36 mmol) in a manner similar to the method of example 276-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,15-of 2.30 (1H, m), a 2.36 (3H, s), and 2.83 (3H, OSS), was 3.05 (2H, USS), 3.75 to 3,90 (2H, m), of 4.77 (2H, USS), 6,92 (1H, d, J=8,9 Hz), 7,24 (2H, d, J=7.8 Hz), 7,31 (2H, d, J=7.8 Hz), 7,47 (1H, DD, J=2,8, and 8.9 Hz), to 7.61 (1H, d, J=2,8 Hz), 8,30 (3H, USS).

Example

The dihydrochloride of 4'-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]biphenyl-4-carboxylic acid

1) 4-Bromobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1.92 g, yield 75%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,82 g, to 4.41 mmol) and 4-bromobenzylamine (1.10 g, to 4.41 mmol) method like way of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.26 (1H, m), of 2.38 (3H, s), of 2.53 (3H, s), 2,77 (2H, d, J=7,2 Hz), 4,11 (2H, d, J=4.9 Hz), 4,19 (1H, USS), 4,89 (2H, s)6,91 (2H, d, J=8.5 Hz), of 6.99 (2H, d, J=8.1 Hz), to 7.09 (2H, d, J=7,7 Hz), 7,39 (2H, d, J=8,5 Hz).

2) a Solution of 4-bromobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,09 g of 1.87 mmol), [4-(methoxycarbonyl)phenyl]Bronevoy acid (675 mg, 3.75 mmol), potassium carbonate (388 mg, of 2.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (216 mg, 0,187 mmol) in dioxane (15 ml) and water (2.5 ml) was stirred in an argon atmosphere for 12 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining [4'-(methoxycarbonyl)biphenyl-4-yl]methyl-5-{[(tert-butoxycarbonyl)aminomethyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (570 mg, yield 48%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,17-of 2.26 (1H, m)to 2.29 (3H, s)to 2.55 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3,91 (3H, s)to 4.16 (2H, d, J=4.5 Hz), 4,60 (1H, OSS), to 4.98 (2H, s), 7,07 (2H, d, J=8,1 Hz), 7,12-7,16 (4H, m), 7,53 (2H, d, J=8,3 Hz), to 7.64 (2H, d, J=8.7 Hz), 8,10 (2H, d, J=8,5 Hz).

3) 4'-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]biphenyl-4-carboxylic acid (380 mg, yield 68%) was obtained as a white solid from [4'-(methoxycarbonyl)biphenyl-4-yl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (570 mg, 0,895 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.26 (1H, m), of 2.34 (3H, s), of 2.56 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,11-4,16 (2H, m)to 4.23 (1H, OSS), at 4.99 (2H, s), 7,05 (2H, d, J=7.9 Hz), 7,13-to 7.18 (4H, m), at 7.55 (2H, d, J=8,3 Hz), to 7.68 (2H, d, J=8.5 Hz), 8,18 (2H, d, J=8,3 Hz).

4) of the Dihydrochloride of 4'-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]biphenyl-4-carboxylic acid (255 mg, yield 70%) was obtained as a white solid from 4'-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]biphenyl-4-carboxylic acid (380 mg, 0,610 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,15-of 2.26 (1H, m), of 2.33 (3H, s), to 2.57 (3H, USS), of 2.92 (2H, USS), 3,82 (2H, d, J=4.3 Hz), 5,04 (2H, s), 7,18 (4H, d, J=8,3 Hz),7,24 (2H, d, J=8.1 Hz), to 7.68 (2H, d, J=8,3 Hz), 7,82 (2H, d, J=8.5 Hz), of 8.04 (2H, d, J=8.5 Hz), 8.34 per (3H, USS).

Example320

Trihydrochloride pyridine-4-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) Pyridine-4-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (322 mg, yield 53%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.50 g, to 1.21 mmol), hydrochloride of 4-(chloromethyl)pyridine (0,20 g to 1.21 mmol) and potassium carbonate (0,42 g, 3.0 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.27 (1H, m), a 2.36 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4,14 (2H, d, J=4.9 Hz), 4,42 (1H, USS), 4,94 (2H, s), 6.89 in (2H, d, J=5.8 Hz),? 7.04 baby mortality (2H, d, J=8.1 Hz), 7,12 (2H, d, J=7.9 Hz), 8,48 (2H, d, J=5.3 Hz).

2) Trihydrochloride pyridine-4-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (260 mg, yield 79%) was obtained as white solids from pyridine-4-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (322 mg, 0,639 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,19-of 2.27 (1H, m), of 2.33 (3H, s), to 2.57 (3H, USS), 2,89 (2H, USS), 3,81 (2H, d, J=5.5 Hz), from 5.29 (2H, s), 7,17-7,24 (4H, m), 7,60 (2H, USS), 8,35 (3H, USS), 8,83-8,84 (2H, USS).

Example321

Trihydrochloride pyridine-3-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphen is)nicotinate

1) Pyridine-3-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (454 mg, yield 74%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.50 g, to 1.21 mmol), hydrobromide 3-(methyl bromide)pyridine (0,46 g, is 1.81 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.24 (1H, m), a 2.36 (3H, s)to 2.54 (3H, s), 2,77 (2H, d, J=7,4 Hz), 4,12 (2H, d, J=4,1 Hz), 4,20 (1H, USS), 4,94 (2H, s), of 6.99 (2H, d, J=8.1 Hz), to 7.09 (2H, d, J=7.9 Hz), 7,17-7,21 (1H, m), 7,32-7,37 (1H, m), a 8.34 (1H, d, J=1.7 Hz), 8,55 (1H, DD, J=4,8, 1,6 Hz).

2) Trihydrochloride pyridine-3-ylmethyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (183 mg, yield 39%) was obtained as white solids from pyridine-3-ylmethyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (454 mg, of 0.903 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.8 Hz), 2,17-of 2.26 (1H, m), 2,31 (3H, s)at 2.59 (3H, s), with 2.93 (2H, d, J=6.0 Hz), of 3.78 (2H, d, J=5.5 Hz), with 5.22 (2H, s), 7,12 (4H, s), 7,95 (1H, t, J=6,7 Hz)to 8.14 (1H, d, J=7.9 Hz), to 8.41 (3H, USS), 8,67 (1H, s), of 8.90 (1H, d, J=5,5 Hz).

Example322

The dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methoxybenzoate

1) Methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]IU the oxy}-3-methoxybenzoate (0,62 g, yield 55%) was obtained as a white powder from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0,80 g, 2.0 mmol) and methyl-3-metoxisalicilice (0.55 g, 3.0 mmol) in a manner similar to the method of example 106-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.30 (1H, m), of 2.34 (3H, s), 2,73 (3H, s)of 2.75 (2H, d, J=7,4 Hz), of 3.54 (3H, s)to 3.64 (3H, s), of 3.97 (2H, d, J=5,1 Hz), 4,20-4,30 (1H, m), a 4.86 (2H, s), 6,60 (2H, d, J=8.1 Hz), 6,85 (1H, DD, J=1.5 and 8.1 Hz), 7,01 (2H, d, J=8.1 Hz), 7,06 (1H, d, J=8.1 Hz), 7,14 (1H, DD, J=1.5 and 8.1 Hz).

2) Dihydrochloride methyl-2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methoxybenzoate (0.12 g, yield 66%) was obtained as a white powder from methyl-2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3 methoxybenzoate (0,19 g, 0.34 mmol) in a manner similar to the method of example 274-2).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,10-of 2.30 (1H, m), is 2.37 (3H, s)to 2.94 (3H, USS), 3,00-3,20 (2H, m), 3,51 (3H, s), 3,63 (3H, s), and 3.72 (2H, USS), 4,88 (2H, USS), 6,77 (2H, d, J=7.9 Hz), 7,00-7,22 (3H, m), 7,17 (2H, d, J=7.9 Hz), 8,27 (3H, USS).

Example323

The dihydrochloride methyl-2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoate

1) Methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoate (1,46 g, yield 63%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentyl is pyridin-3-yl]methylmethanesulfonate (2.0 g, 4.7 mmol) and methylthioadenosine (757 mg, 45 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), of 2.34 (3H, s)to 2.65 (3H, s), and 2.83 (2H, s)to 3.89 (3H, s)4,07 (2H, d, J=4.9 Hz), 4,17 (1H, USS),? 7.04 baby mortality-to 7.18 (6H, m), 7,32-7,38 (1H, m), to $ 7.91-of 7.95 (1H, m).

2) Dihydrochloride methyl-2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoate (254 mg, yield 89%) was obtained in powder form from methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoate (300 mg, of 0.533 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s), of 2.34 (3H, s), and 2.83 (3H, s)3,18 (2H, USS), of 3.80 (3H, s), 3,88 (2H, s), of 4.00 (2H, s), 7.23 percent-to 7.32 (6H, m), 7,47-7,52 (1H, m), a 7.85-7,88 (1H, m), 8,21 (3H, USS).

Example324

The dihydrochloride of 2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoic acid (897 mg, yield 92%) was obtained as a white solid from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoate (1.0 g, 1.78 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 1,12 (9H, s)to 1.38 (9H, s), of 2.38 (3H, s)to 3.09 (3H, s), 3,47 (2H, s), with 3.79 (2H, s), 4,14 (2H, d, J=4.3 Hz), to 4.52 (1H, USS), 6,85-6,92 (2H, m), 7,08-7,13 (1H, m), 7,19-7,21 (2H, m), 7,29-7,33 (1H, m), 7,37-7,41 (1H, m), 7,94-of 7.97 (1H, m).

2) the Dihydrochloride of 2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoic acid (158 mg, yield 83%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoic acid (200 mg, 0,364 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s), of 2.34 (3H, s), of 2.81 (3H, s)and 3.15 (2H, USS), of 3.80 (2H, s), 3,85 (2H, s), 7,19-7,33 (6H, m), 7,44-7,49 (1H, m), 7,86-7,89 (1H, m), 8,17 (3H, USS).

Example325

The dihydrochloride of 2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzamide

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzamide (349 mg, yield 70%) was obtained as a white solid from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzoic acid (500 mg, 0,911 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), 2,39 (3H, s), 2.63 in (3H, s), and 2.83 (2H, s), 3,81 (2H, s), Android 4.04 (2H, d, J=5,1 Hz), 4,24 (1H, USS), the 5.45 (1H, USS), of 6.68 (1H, USS), of 6.96-6,99 (2H, m), 7.18 in-7,22 (3H, m), 7,28-7,32 (2H, m), 7,75 for 7.78 (1H, m).

2) of the Dihydrochloride of 2-({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzamide (160 mg, yield 84%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methyl}thio)benzamide (200 mg,, 0,365 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, what), is 2.37 (3H, s), was 2.76 (3H, s), 3,17 (2H, USS), 3,75-of 3.85 (4H, m), 7,14-to 7.35 (7H, m), 7,40 (1H, s), 7,50-of 7.48 (1H, m), 7,81 (1H, s), to 8.20 (3H, USS).

Example326

The dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzamide

1) tert-Butyl{[5-{[2-(aminocarbonyl)-6-methylphenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (190 mg, yield 95%) was obtained as a white powder from 2-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzoic acid (200 mg, the 0.375 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: of 1.05 (6H, d, J=6.2 Hz), of 1.40 (9H, s)of 1.93 (3H, s), 2,21 of-2.32 (1H, m), a 2.36 (3H, s), a 3.01 (3H, s), and 3.16 (2H, d, J=6.8 Hz), Android 4.04 (2H, s), 4,20 (1H, OSS), to 4.81 (2H, s)5,80 (1H, USS), 6,40 (1H, USS), 6,65 (2H, s), 7,02-of 7.23 (4H, m), 7,56 (1H, s).

2) of the Dihydrochloride of 2-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-3-methylbenzamide (100 mg, yield 70%) was obtained as a white powder from tert-butyl{[5-{[2-(aminocarbonyl)-6-methylphenoxy]methyl}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (150 mg, 0,282 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6,4 Hz)of 1.76 (3H, s), 2,13-to 2.29 (1H, m), is 2.37 (3H, s), 2,96 (3H, s), 3,21 (2H, d, J=6.6 Hz), 3,76 (2H, d, J=4.9 Hz), 4,78 (2H, s), 7,01 (2H, d, J=7.9 Hz),? 7.04 baby mortality-was 7.08 (1H, m), 7,15-7,26 (4H, m), 7,34 (1H, USS), 7,53 (1H, USS), charged 8.52 (3H, USS).

Example327

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-m is terphenyl)pyridine-3-yl]-N-phenylacetamide

1) tert-Butyl{[5-(2-aniline-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (220 mg, yield 94 %) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (200 mg, 0,469 mmol) and aniline (150 mg, of 1.41 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-to 2.29 (1H, m), is 2.40 (3H, s), 2.63 in (3H, s), 2,77 (2H, d, J=7,2 Hz), 3,66 (3H, s)4,06 (2H, d, J=4,Hz), 4,20 (1H, USS), 7,02 (2H, d, J=7.9 Hz), 7,06-7,14 (1H, m), from 7.24 (2H, d, J=7.9 Hz), 7,27-7,39 (4H, m).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-phenylacetamide (200 mg, yield 100%) was obtained as a white powder from tert-butyl{[5-(2-aniline-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (210 mg, 0,419 mmol) method like the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=5.5 Hz), 2,13-of 2.28 (1H, m), of 2.38 (3H, s), 2,85 (3H, s)of 3.25 (2H, s), 3,62 (2H, s), 3,83 (2H, s),? 7.04 baby mortality (1H, t, J=6,7 Hz), 7,15-7,42 (6H, m)to 7.50 (2H, d, J=7,4 Hz), 8,53 (3H, USS), 10,20 (1H, s).

Example328

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclohexanecarboxylic

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]cyclohexanecarboxylate (230 mg, yield 98%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate 192 mg, 0.5 mmol) and cyclohexanecarbonitrile (100 ml, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 1,00-1,25 (6H, m)of 1.41 (2H, OSS), to 1.59 (2H, USS), 2,08-2,22 (2H, m), is 2.37 (3H, s), of 2.53 (3H, s), 3,03 (2H, USS), 3,81 (2H, s), 7,14 (2H, d, J=7.8 Hz), 7,30 (2H, d, J=7.8 Hz), 8,33 (3H, USS), 9,37 (1H, USS).

Example329

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]piperidine-1-carboxamide

1) tert-Butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(piperidine-1-ylcarbonyl)amino]pyridine-3-yl}methyl)carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and piperidine (150 ml, 1.5 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):495

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]piperidine-1-carboxamide (218 mg, yield 47%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.3 Hz), 1,07-1,19 (4H, m)of 1.44 (2H, USS), 2,12-of 2.27 (1H, m), is 2.37 (3H, s), 2,60 (3H, s), 3,05 (2H, USS), 3,15 (4H, USS), 3,83 (2H, s), 7,19 (2H, d, J=7.8 Hz), 7,31 (2H, d, J=7.8 Hz), of 7.96 (1H, USS), of 8.27 (3H, USS).

Example330

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]tetrahydro-2H-Piran-4-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-IU is ylphenyl)pyridine-3-yl]tetrahydro-2H-Piran-4-carboxamide (232 mg, yield 98%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and tetrahydro-2H-Piran-4-carbonylchloride (111 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 1,00-1,25 (6H, m)of 1.41 (2H, OSS), to 1.59 (2H, USS), 2,08-2,22 (2H, m), is 2.37 (3H, s), of 2.53 (3H, s), 3,03 (2H, USS), 3,81 (2H, s), 7,14 (2H, d, J=7.5 Hz), 7,30 (2H, d, J=7.8 Hz), 8,27 (3H, USS), 9,43 (1H, USS).

Example331

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]morpholine-4-carboxamide

1) tert-Butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(morpholine-4-ylcarbonyl)amino]pyridine-3-yl}methyl)carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and research (130 ml, 1.5 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):497

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]morpholine-4-carboxamide (278 mg, yield 59%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.3 Hz), 2,10-of 2.27 (1H, m), 2,39 (3H, s), 2,70 (3H, s), 3,14 (6H, USS), 3,19 (4H, USS), 3,86 (2H, USS), 7,21 (2H, d, J=7.8 Hz), 7,34 (2H, d, J=7.8 Hz), 8,44 (4H, USS).

Example332

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)p is ridin-3-yl]piperidine-4-carboxamide

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]piperidine-4-carboxamide (246 mg, yield 98%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (210 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), the 1.44 (4H, USS), 2,15-of 2.26 (1H, m), of 2.38 (3H, s), 2,38-to 2.57 (1H, m), to 2.57 (3H, s), was 2.76 (2H, USS), of 3.07 (4H, USS), 3,81 (2H, USS), 7,17 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), to 8.41 (3H, USS), 8,80 (1H, USS), which is 9.09 (1H, USS), 9,84 (1H, USS).

Example333

Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]piperazine-1-carboxamide

1) tert-Butyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperazine-1-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and tert-butylpiperazine-1-carboxylate (140 mg, 1.5 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):596

2) Trihydrochloride N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]piperazine-1-carboxamide (250 mg, yield 97%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.3 Hz), 2,15-of 2.26 (1H, m), 2,42 (3H, s), 2,62 (2H, s), of 2.72 (3H, s), 3,05 (2H, USS), 3,42 (4H, USS), 3,82 (2H, USS), 7,19 (2H, d, J=7.5 Hz), 7,31 (2H, d, J=7.5 Hz), of 8.37 (3H, OSS), at 8.60 (1H, USS), 9,41 (2H,, USS).

Example334

The dihydrochloride (5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid

1) (5-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid (355 mg, yield 50%) was obtained as a yellow powder from tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (500 mg, of 1.26 mmol) and (4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid (241 mg, of 1.26 mmol) in a manner similar to the method of example 315-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,09-of 2.27 (1H, m), a 2.36 (3H, s)of 2.50 (3H, s), 2,8 (2H, d, J=7,4 Hz), 4,01-4,18 (4H, m), 4,20 (1H, USS), of 6.96 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=7.9 Hz), 7,38 (1H with).

2) Dihydrochloride (5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid (198 mg, yield 100%) was obtained as a yellow powder (5-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid (210 mg, 0,386 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.4 Hz), 2,17-2,31 (1H, m), a 2.36 (3H, s)to 2.55 (3H, s), 2,95 (2H, d, J=6.6 Hz), 3,80 (2H, d, J=7,4 Hz), 4,63 (2H, s), 7,22 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,55 (1H, s), 8,35 (3H, USS).

Example335

The dihydrochloride of 5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-2-thioxo-1,3-thiazolidin-4-it

1) tert-Butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(4-oxo-2-thioxo-1,3-thiazolidin-5-ilidene)methyl]pyridine-3-yl}methyl)carbamate (310 mg, yield 48%) was obtained as a yellow powder from tert-butyl{[5-formyl-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (500 mg, of 1.26 mmol) and 2-thioxo-1,3-thiazolidin-4-it (168 mg, of 1.26 mmol) in a manner similar to the method of example 315-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,15-2,31 (1H, m), is 2.37 (3H, s)of 2.50 (3H, s), 2,80 (2H, d, J=7,4 Hz), 4,13 (2H, d, J=7,4 Hz), 4,20 (1H, OSS), to 6.95 (2H, d, J=7,7 Hz), 7,20 (2H, d, J=7,7 Hz), 7,34 (1H, s).

2) Dihydrochloride 5-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylene}-2-thioxo-1,3-thiazolidin-4-it (173 mg, yield 100%) was obtained as a yellow powder from tert-butyl({2-isobutyl-6-methyl-4-(4-were)-5-[(4-oxo-2-thioxo-1,3-thiazolidin-5-ilidene)methyl]pyridine-3-yl}methyl)carbamate (200 mg, 0,390 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,11-2,31 (1H, m), a 2.36 (3H, s), 2,52 (2H, s), 2,90 (3H, s), with 3.79 (2H, s), 7,19 (2H, d, J=8.1 Hz), 7,26-7,37 (3H, m), 8,27 (3H, USS).

Example336

The dihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate

p> 1) Methyl-3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (230 mg, yield 35 %) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and methyl-3-aminobenzoate (532 mg, to 3.52 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16-2,31 (1H, m), is 2.41 (3H, s)of 2.64 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,47 (2H, s), 3,91 (3H, s)4,07 (2H, d, J=4.5 Hz), 4,20 (1H, USS), of 5.50 (1H, USS), 7,02 (2H,, d, J=7.9 Hz), 7,24 (2H, d, J=7.9 Hz), 7,38 (1H, t, J=7.9 Hz), 7,72-7,86 (3H, m).

2) Dihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (65 mg, yield 91%) was obtained as a white powder from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (to 75.2 mg, 0,134 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-of 2.30 (1H, m), a 2.36 (3H, s), of 2.53 (3H, s), 2,68 (2H, s), 2,98 (2H, s), of 3.78 (2H, s), of 3.84 (3H, s), 7,19 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), 7,44 (1H, t, J=7.9 Hz), to 7.61-7,71 (2H, m), 8,10 (3H, OSS), to 8.20 (1H, s)to 10.6 (1H, USS).

Example337

Trihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylate

1) Methyl-3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]METI the}thio)pyridine-2-carboxylate (1,43 g, 2,60 mmol) was obtained as a yellow oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (2,08 g, with 5.22 mmol) and methyl-3-mercaptopyridine-2-carboxylate (883 mg, with 5.22 mmol) in a manner similar to the method of example 183-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,14-of 2.26 (1H, m)to 2.35 (3H, s)to 2.66 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 3,76 (2H, s)to 3.99 (3H, s), a 4.03 (2H, d, J=5.3 Hz), 4,19 (1H, USS),? 7.04 baby mortality-7,07 (1H, m), 7,09 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=7,7 Hz), 7,28-7,31 (1H, m), 7,40-7,44 (1H, m), 8,43 (1H, DD, J=4,5, 1.5 Hz).

2) Trihydrochloride methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylate (161 mg, yield 80%) was obtained as a pale-yellow solid from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylate (197 mg, 0,359 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.4 Hz), 2,15-of 2.26 (1H, m)to 2.35 (3H, s), 2,89 (3H, USS), 3,18 (2H, USS), of 3.77 (2H, d, J=5,1 Hz), 3,83 (3H, s), of 3.94 (2H, s), 7,25 (2H, d, J=7.9 Hz), 7,31 (2H, d, J=8.1 Hz), 7,51 (1H, DD, J=8,3, 4.5 Hz), 7,76 (1H, d, J=8.1 Hz), 8,35-8,53 (4H, m).

Example338

Trihydrochloride 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylic acid

1) 3-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylic acid (1.19 g, yield 99%) was obtained in sidebusting oil from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylate (1.23 g, 2,24 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 1.06 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,21 of-2.32 (1H, m), is 2.37 (3H, s), of 2.97 (3H, USS), 3,17 (2H, USS), 3,81 (2H, s), 4,08 is 4.13 (2H, m), or 4.31 (1H, USS), 7,14 (2H, d, J=7.9 Hz), 7,24 (2H, d, J=8,3 Hz), 7,42-7,46 (1H, m), 7,50-7,53 (1H, m), 8,35 (1H, DD, J=4,4, 1.2 Hz).

2) Trihydrochloride 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylic acid (265 mg, yield 69%) was obtained as a pale-yellow solid from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylic acid (0,38 g, 0,709 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,13-of 2.24 (1H, m), of 2.34 (3H, s), 2,79-2,82 (3H, m), 3,05 (2H, OSS in), 3.75 (2H, USS), the 3.89 (2H, USS), 7,26 (2H, d, J=6.4 Hz), 7,31 (2H, d, J=8,3 Hz), of 7.48 (1H, DD, J=8,3, 4.5 Hz), 7,72 (1H, d, J=8,3 Hz), 8,19-at 8.36 (3H, m), 8,43 (1H, d, J=4.5 Hz).

Example339

Trihydrochloride 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxamide

1) tert-Butyl{[5-({[2-(aminocarbonyl)pyridine-3-yl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (720 mg, yield 88%) was obtained as colorless oil from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxylic acid (0,82 g, 1.53 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,8 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14-of 2.26 (1H, m), of 2.33 (3H, s)to 2.67 (3H, s)of 2.75 (2H, d, J=7,2 Hz), 3,71 (2H, s), a 4.03 (2H, d, J=4.9 Hz), 4,18 (1H, USS), 5,44 (1H, USS), 7,12-to 7.18 (4H, m), 7,25-7,29 (1H, m), 7,42 (1H, DD, J=8,3, 1.3 Hz), 7,82 (1H, USS), 8,24 (1H, DD, J=4,3, 1.3 Hz).

2) Trihydrochloride 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methyl}thio)pyridine-2-carboxamide (546 mg, yield 74%) was obtained as a pale-yellow solid from tert-butyl{[5-({[2-(aminocarbonyl)pyridine-3-yl]thio}methyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (720 mg, 1.35 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,13-of 2.26 (1H, m), of 2.34 (3H, s), 2,96 (3H, s)of 3.25 (2H, USS), with 3.79 (2H, d, J=5,1 Hz), 3,86 (2H, s), 7,29-7,40 (4H, m), 7,46 (1H, DD, J=8,1, 4.5 Hz), to 7.64 (1H, USS), of 7.69 (1H, d, J=7.5 Hz), of 8.09 (1H, OSS), at 8.36 (1H, DD, J=4,5, 1.2 Hz), 8,51 (3H, USS).

Example340

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]cyclohexanecarbonyl acid

1) a Mixture of methyl-4-(hydroxymethyl)cyclohexanecarboxylate (0.40 g, 2.32 mmol), triethylamine (0,65 ml, with 4.64 mmol) and tetrahydrofuran (10 ml) was cooled to 0°C was added dropwise methanesulfonanilide (0,27 ml of 3.48 mmol). After stirring at room temperature for 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solution is tel evaporated under reduced pressure to obtain methyl 4-{[(methylsulphonyl)oxy]methyl}of cyclohexanecarboxylate in the form of a crude product. The crude product was dissolved in N,N-dimethylformamide (15 ml) was added potassium carbonate (480 mg, of 3.48 mmol) and 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.95 g, 2.32 mmol). The mixture was stirred with heating at 70°C for 1 h, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain [4-(methoxycarbonyl)cyclohexyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (750 mg, yield 57%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,07-of 1.18 (2H, m), 1,33-1,49 (14H, m), 1,83 is 1.96 (2H, m), 2,16 was 2.25 (1H, m), 2,39 (3H, s), 2,48-of 2.56 (4H, m), 2,78 (2H, d, J=7,4 Hz)to 3.67 (3H, s), of 3.78 (2H, d, J=6.8 Hz), 4,13-to 4.17 (2H, m)to 4.23 (1H, USS), 7,07 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=7,7 Hz).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]cyclohexanecarbonyl acid (550 mg, yield 75%) was obtained as a white solid from [4-(methoxycarbonyl)cyclohexyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (750 mg, 1,32 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), 1,08 is 1.20 (2H, m), 1,33-1,68 (14H,m), 1,86 is 1.96 (2H, m), 2,15-of 2.28 (1H, m), of 2.38 (3H, s), 2,54-2,60 (4H, m), 2,78 (2H, USS), of 3.78 (2H, d, J=6.6 Hz), 4,12-4,16 (2H, m), 4,24 (1H, USS), 7,07 (2H, d, J=7.9 Hz), 7,20 (2H, d, J=7,7 Hz).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]cyclohexanecarboxylic acid (254 mg, yield 83%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]cyclohexanecarboxylic acid (320 mg, 0,579 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 1,17-of 1.42 (7H, m), 1,66-to 1.82 (2H, m), 2,14-of 2.24 (1H, m), is 2.37 (3H, s), 2,41 at 2.45 (1H, m), of 2.54 (3H, s), 2,86-of 2.97 (2H, m), 3,76 (2H, d, J=6.6 Hz), 3,83 (2H, d, J=4,7 Hz), 7,20 (2H, d, J=7.9 Hz), 7,30 (2H, d, J=8.1 Hz), 8.34 per (3H, USS).

Example341

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]thiophene-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]thiophene-2-carboxamide (171mg, 75%yield) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and thiophene-2-carbonylchloride (110 mg, 0.75 in mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,20-2,31 (1H, m), 2,31 (3H, s), 2.63 in (3H, s), of 3.07 (2H, USS), 3,86 (2H, s), 7,12 (1H, DD, J=3.3, which is 4.8 Hz), 7,25 (4H, s), 7,74 (1H, d, J=3.3 Hz), 7,79 (1H, d, J=4,8 Hz), 8,42 (3H, USS), 10,18 (1H, USS).

Note the p 342

The dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid

1) 3-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid (110 mg, yield 87%) was obtained as a white powder from methyl 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (130 mg, 0,232 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.94 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,10-of 2.27 (1H, m), a 2.36 (3H, s), 2,89-3,10 (5H, m), 3,90 (2H, d, J=5.7 Hz), 4,10 (2H, d, J=7,2 Hz), 4,20 (1H, USS), the 4.90 (1H, USS), 7,13 (2H, d, J=8.1 Hz), 7,24 (2H,, d, J=8.1 Hz), 7,32 (1H, t, J=8.0 Hz), the 7.65 (1H, d, J=7,7 Hz), 7,89 (1H, s), 8,17 (1H, s).

2) of the Dihydrochloride of 3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid (95 mg, yield 95%) was obtained as a white powder from 3-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid acid (105 mg, 0,192 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.8 Hz), 2,08 was 2.25 (1H, m), is 2.37 (3H, s), of 2.51 (3H, s), and 2.83 (2H, s), 3,20 (2H, s), 3,82 (2H, s), 7,09-7,51 (5H, m), 7,54-7,79 (2H, m)to 8.14 (1H, s), 8,44 (3H, s), 10,34 (1H, USS).

Example343

The dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoate

1) Methyl-4-[({[5-{[(tert-butoxycarbonyl)and the Ino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoate (350 mg, yield 67%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (390 mg, 0,914 mmol) and methyl-4-(aminomethyl)benzoate (553 mg, is 2.74 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,11-to 2.29 (1H, m), 2,39 (3H, s)to 2.55 (3H, s), is 2.74 (2H, d, J=7,2 Hz), the 3.35 (2H, s), 3,93 (3H, s), was 4.02 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 4,39 (2H, d, J=5.8 Hz), 5,49 (1H, USS), of 6.90 (2H, d, J=7.9 Hz), 7,16 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=8.1 Hz), to 7.99 (2H, d, J=8,1 Hz).

2) Dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoate (51 mg, yield 89%) was obtained as a white powder from methyl 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoate (60 mg, 0,105 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.27 (1H, m), is 2.40 (3H, s), of 2.81 (3H, s), 3,24 (2H, d, J=6.0 Hz), 3,44 (2H, s), 3,78-to 3.89 (5H, m), 4,28 (2H, d, J=5.5 Hz), 7,20 (2H, d, J=7.9 Hz), 7,27-7,38 (5H, m),7,94 (2H, d, J=7.9 Hz), 8,54 (3H, USS).

Example344

The dihydrochloride of 5-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylic acid

1) Methyl-5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylate (1.35 g, yield 98%) was obtained as colorless oil from 5{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,00 g, 2,43 mmol) and methyl-5-(methyl bromide)pyrazin-2-carboxylate (0.51 g, 2.21 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,17-of 2.27 (1H, m), 2,31 (3H, s), 2,58 (3H, s), and 2.79 (2H, d, J=7,2 Hz), 4,06 (3H, s), 4,12-4,16 (2H, m), 4,22 (1H, OSS), to 5.13 (2H, s), 7,02 (2H, d, J=8.1 Hz), 7,10 (2H, d, J=7.9 Hz), at 8.36 (1H, d, J=1.3 Hz), 9,19 (1H, d, J=1.3 Hz).

2) 5-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylic acid (600 mg, yield 45%) was obtained as colorless oil from methyl-5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylate (1.35 g, is 2.40 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,16-of 2.28 (1H, m), of 2.33 (3H, s)at 2.59 (3H, s), 2,82 (2H, d, J=7,4 Hz), 4,11-4,19 (2H, m), 4,24 (1H, USS), is 5.18 (2H, s),? 7.04 baby mortality (2H, d, J=7.9 Hz), 7,12 (2H, d, J=7,2 Hz), to 8.20 (1H, s), of 9.30 (1H, s).

3) Dihydrochloride 5-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylic acid (497 mg, yield 76%) was obtained as yellow solid from 5-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]pyrazin-2-carboxylic acid (600 mg, of 1.09 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m)to 2.29 (3H, s), 2,62 (3H, OSS), to 2.94 (2H, USS),3,80 (2H, d, J=4,7 Hz), 5,23 (2H, s), 7,08-to 7.18 (4H, m), scored 8.38 (3H, USS), 8,43 (1H, d, J=1.3 Hz), 9,10 (1H, d, J=1.3 Hz).

Example345

The dihydrochloride of 4-bromobenzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

The dihydrochloride of 4-bromobenzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (628 mg, yield 90%) was obtained as a white solid from 4-bromobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.73 g, of 1.26 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.8 Hz), 2,14-of 2.27 (1H, m), a 2.36 (3H, s), 2,87 (2H, USS), 3,80 (2H, d, J=5.3 Hz), equal to 4.97 (2H, s)to 7.00 (2H, d, J=8.5 Hz), 7,12 (2H, d, J=8.1 Hz), 7,19 (2H, d, J=8.1 Hz), to 7.50 (2H, d, J=8,5 Hz), compared to 8.26 (3H, USS).

Example346

The dihydrochloride {[5-[(2-bromophenoxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine

1) tert-Butyl{[5-[(2-bromophenoxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (640 mg, yield 46%) was obtained as a white solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol) and 2-bromophenol (478 mg, was 2.76 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,19-of 2.28 (1H, m), is 2.37 (3H, s), 2,69 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 4,08-4,11 (2H, m), 4,24 (1H, USS), of 4.67 (2H, s), of 6.65 (1H, DD, J=8,1, 1.3 Hz), 6,79-6,84 (1H, m), 7,07 (2H, d, J=8.1 Hz), 7,12-7,19 (3H, m), 7,51 (1H, DD, J=7,9, 1.5 Hz).

2) Dihydrochloride {[5-[(2-b is emproxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}amine (458 mg, yield 75%) was obtained as a white solid from tert-butyl{[5-[(2-bromophenoxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (640 mg, of 1.16 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,16-of 2.30 (1H, m), a 2.36 (3H, s), 2.91 in (3H, USS), 3,20 (2H, USS), 3,79-are 3.90 (2H, m), 4,79 (2H, s), 6.89 in-6,95 (2H, m), 7,25 and 7.36 (5H, m), 7,58 (1H, DD, J=7,7, 1.5 Hz), 8,48 (3H, USS).

Example347

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-methoxybenzoic acid

1) 2-Methoxy-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,15 g, yield 100%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0,80 g, 1.94 mmol) and methyl-4-(methyl bromide)-3-methoxybenzoate (503 mg, 1.94 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.24 (1H, m), of 2.34 (3H, s)to 2.54 (3H, s), 2,77 (2H, d, J=7,2 Hz), 3,85 (3H, s), 3,93 (3H, s), 4,10-4,16 (2H, m), 4,20 (1H, USS), is 5.06 (2H, s), of 6.96 (1H, d, J=7.9 Hz), 7,03 (2H, d, J=8.1 Hz), 7,10 (2H, d, J=7.9 Hz), of 7.48-7,53 (2H, m).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-methoxybenzoic acid (1.10 g, yield 97%) was obtained as colorless oil from 2-methoxy-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxy arbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,15 g, 1.94 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,16-of 2.26 (1H, m)to 2.35 (3H, s), of 2.56 (3H, s), 2,80 (2H, d, J=7,2 Hz), 3,86 (3H, s), 4,11-4,16 (2H, m)to 4.23 (1H, OSS), to 5.08 (2H, s), 6,97 (1H, d, J=7.9 Hz),? 7.04 baby mortality (2H, d, J=7,7 Hz), 7,11 (2H, d, J=7,7 Hz), 7,53 (1H, s), 7,58 (1H, d, J=7.9 Hz).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-methoxybenzoic acid (247 mg, yield 74%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-methoxybenzoic acid (0.35 g, 0,607 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6,GC), 2,17-of 2.26 (1H, m), 2,32 (3H, s)2,84 (2H, USS), with 3.79 (2H, d, J=5,GC), 3,83 (3H, s), of 5.03 (2H, s), of 6.96 (1H, d, J=7,Hz), 7,13 (2H, d, J=8,1 Hz), 7,18 (2H, d, J=8,1 Hz), 7,42 was 7.45 (1H, m), 7,46 (1H, s), 8,19 (3H, USS).

Example348

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-methoxybenzoic acid

1) 3-Methoxy-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (680 mg, yield 94%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.50 g, 1,22 mmol) and methyl-4-(methyl bromide)-2-methoxybenzoate (315 mg, 1,22 mmol) in a manner similar to the way the example is 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6,GC), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), of 2.33 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,4 Hz), 3,86 (3H, s), 3,90 (3H, s), 4,11-4,13 (2H, m), is 4.21 (1H, USS), 4,94 (2H, s), of 6.65 (1H, DD, J=8.0 a, and 1.4 Hz), to 6.75 (1H, d, J=1,1 Hz), of 6.99 (2H, d, J=8,1Hz), was 7.08 (2H, d, J=7,Hz), of 7.70 (1H, d, J=7,GC).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-methoxybenzoic acid (550 mg, yield 83%) was obtained as colorless oil from 3-methoxy-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (680 mg, 1.15 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16 was 2.25 (1H, m), of 2.33 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,4 Hz), Android 4.04 (3H, s), 4,11-4,13 (2H, m), 4,20 (1H, OSS), to 4.98 (2H, s), 6,77 (1H, d, J=9.4 Hz), 6,84 (1H, s), of 6.99 (2H, d, J=8.1 Hz), 7,07 (2H, d, J=7.9 Hz), 8,08 (1H, d, J=7.9 Hz).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-methoxybenzoic acid (240 mg, yield 85%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-methoxybenzoic acid (293 mg, 0,509 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14-of 2.26 (1H, m), of 2.33 (3H, s), 2,58 (3H, USS), with 2.93 (2H, USS), of 3.78 (3H, s), 3,81 (2H, d, J=4.5 Hz), free 5.01 (2H, s), 6,62 (1H, d, J=7.9 Hz), 6,92 (1H, d, J=0.9 Hz), 7,12-7,22 (4H, m), 7,55 1H, d, J=7,7 Hz), of 8.37 (3H, USS).

Example349

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoic acid

1) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoic acid (182 mg, yield 94%) was obtained as a white powder from methyl 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoate (200 mg, 0,349 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: to 0.92 (6H, d, J=6.6 Hz), of 1.34 (9H, s), 2,10-of 2.24 (1H, m)to 2.35 (3H, s), of 2.38 (3H, s), 2,58 (2H, s), up 3.22 (2H, s), of 3.77 (2H, d, J=3.0 Hz), 4,20 (1H, USS), 4,27 (2H, d, J=5.8 Hz), 6,74 (1H, s), to 7.09 (2H,, d, J=8.1 Hz), 7,17 (2H, d, J=8.1 Hz), 7,28 (2H, d, J=8,3 Hz), of 7.90 (2H, d, J=8,3 Hz), 8,17 (1H, s).

2) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoic acid (135 mg, yield 95%) was obtained as a white powder from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]benzoic acid (150 mg, 0,268 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,07-of 2.24 (1H, m), is 2.40 (3H, s), 2,78 (3H, s), 3,10 (2H, s)to 3.41 (2H, s), of 3.78 (2H, s), 4,27 (2H, d, J=5.7 Hz), 7,16 (2H, d, J=7.9 Hz), 7,26-7,34 (4H, m), 7,92 (2H, d, J=8,3 Hz), with 8.33 (3H, OSS), to 8.45 (1H, USS).

Example350

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-shall ethylphenyl)pyridine-3-yl]isoxazol-4-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isoxazol-4-carboxamide (173 mg, yield 76%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and isoxazol-4-carbonylchloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,20-2,31 (1H, m), of 2.53 (3H, s)to 2.94 (2H, s), 3,82 (2H, OSS), to 7.09 (1H, s), 7,20 (2H, d, J=8.1 Hz), 7,25 (2H, d, J=8.1 Hz), 8,28 (3H, USS), 8,73 (1H, USS), 10,59 (1H, USS).

Example351

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]furan-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]furan-2-carboxamide (190 mg, yield 85%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and furan-2-carbonylchloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,09-of 2.30 (1H, m), 2,32 (3H, s), 2,58 (3H, s), 3.04 from (2H, USS), 3,83 (2H, s), is 6.61 (1H, DD, J=1,8, and 3.3 Hz), 7,14 (1H, d, J=3.3 Hz), 7,21 (2H, d, J=7.8 Hz), 7,25 (2H, d, J=7,8 Hz), to 7.84 (1H, s)of 8.37 (3H, USS), 9,98 (1H, USS).

Example352

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-methylbenzamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-methylbenz the MFA (211 mg, yield 87%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-methylbenzylamine (116 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,22 of-2.32 (1H, m), 2,31 (3H, s), 2,32 (3H, s), to 2.57 (3H, s), 3,01 (2H, USS), a-3.84 (2H, s), 7,21-7,27 (6H, m), 7,55 (2H, d, J=8.1 Hz), 8,32 (3H, USS), 9,88 (1H, USS).

Example353

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-tert-butylbenzamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-tert-butylbenzamide (211 mg, yield 83%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-tert-butylbenzylamine (147 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.27 (9H, s), 2,22-2,31 (1H, m), 2,31 (3H, s), of 2.56 (3H, s), 3,01 (2H, USS), a-3.84 (2H, s), 7,21-7,26 (4H, m), 7,44 (2H, d, J=8,4 Hz), 7,60 (2H, d, J=8,4 Hz), 8,32 (3H, OSS), to 9.91 (1H, USS).

Example354

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-chlorobenzamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-chlorobenzamide (203 mg, yield 82%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg,0.5 mmol) and 4-chlorobenzylchloride (131 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,20-of 2.30 (1H, m), 2,31 (3H, s), 2,62 (3H, s), is 3.08 (2H, USS), 3,86 (2H, s), 7,25 (4H, s), 7,52 (2H, d, J=8,4 Hz), to 7.67 (2H, d, J=8,4 Hz), to 8.41 (3H, USS), and 10.20 (1H, USS).

Example355

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-cyanobenzene

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-cyanobenzene (209 mg, yield 86%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-cyanobenzaldehyde (126 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,10-2,31(1H, m), 2,31 (3H, s)at 2.59 (3H, s), to 3.02 (2H, USS), 3,85 (2H, s), 7,24 (4H, s), 7,76 (2H, d, J=8.1 Hz), 7,94 (2H, d, J=8.1 Hz), at 8.36(3H, USS), 10,36 (1H, USS).

Example356

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-cryptomelane

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-cryptomelane (209 mg, yield 86%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-triftormetilfullerenov (156 mg, 0.75 mmol) a method similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2.21 are 2,32 (1H, m), 2,31 (3H, s)to 2.55 (3H, s), 2,9 (2H, OSS), 3,83 (2H, s), 7,22 (2H, d, J=7.8 Hz), 7,26 (2H, d, J=7.8 Hz), 7,78 (2H, d, J=7.8 Hz), 7,82 (2H, d, J=7.8 Hz), 8,27 (3H, USS), of 10.21 (1H, USS).

Example357

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]furan-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]furan-3-carboxamide (190 mg, yield 85%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and furan-3-carbonylchloride (100 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2.21 are 2,32 (1H, m)to 2.55 (3H, s), 2,98 (3H, s), 3,82 (2H, USS), 6,74 (1H, s), 7,20 (2H, d, J=7.8 Hz), 7,25 (2H, d, J=7.8 Hz), 7,69 (1H, s), 8,15 (1H, s), 8,30 (3H, USS), 9,74 (1H, USS).

Example358

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]thiophene-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]thiophene-3-carboxamide (233 mg, yield 99%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and thiophene-3-carbonylchloride (110 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,20-2,31 (1H, m), 2,31 (3H, s)at 2.59 (3H, s), 3,05 (2H, USS), a-3.84 (2H, s), 7,24 (4H, s), of 7.36 (1H, DD, J=1,2, 5,1 Hz), 7,56 (1H, DD, J=5,1, 2.7 Hz), 8,10 (1H, d, J=2.7 Hz), 8,35 (3H, OSS), to 9.91 (1H, USS).

Example359

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-fermenting acid

1) 2-Fluoro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (650 mg, yield 92%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.50 g, to 1.21 mmol) and methyl-4-(methyl bromide)-3-perbenzoate (299 mg, to 1.21 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,16 was 2.25 (1H, m), of 2.33 (3H, s)to 2.54 (3H, s), 2,77 (2H, d, J=7,4 Hz), of 3.94 (3H, s), 4.09 to-4,13 (2H, m), 4,20 (1H, USS), of 5.05 (2H, s), 6,98-to 7.09 (5H, m), of 7.64-7,71 (2H, m).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-fermenting acid (450 mg, yield 71%) was obtained as colorless oil from 2-fluoro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (650 mg, 1.12 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,13 was 2.25 (1H, m), of 2.33 (3H, s), of 2.56 (3H, s), 2,80 (2H, d, J=7,2 Hz), 4.09 to to 4.16 (2H, m), 4,22 (1H, USS), 5,07 (2H, s), 7,00 for 7.12 (5H, m), 7,70-7,76 (2H, m).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-fermenting acid (329 mg, yield 76%) was obtained in view of the white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-fermenting acid (450 mg, 0,797 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.95 (6H, d, J=6.6 Hz), 2,16-of 2.23 (1H, m)to 2.29 (3H, s), of 2.86 (2H, USS), of 3.78 (2H, d, J=5.5 Hz), 5,11 (2H, s), 7,07-7,13 (4H, m), 7,18 (1H, t, J=7,6 Hz), 7,60-of 7.69 (2H, m), 8,23 (3H, USS).

Example360

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-chlorbenzoyl acid

1) 2-Chloro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (518 mg, yield 99%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.36 g, 0,873 mmol) and methyl-4-(methyl bromide)-3-chlorobenzoate (230 mg, 0,873 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,17-of 2.26 (1H, m), 2,32 (3H, s), of 2.56 (3H, s), 2,78 (2H, d, J=7,4 Hz), of 3.94 (3H, s), 4,11-4,13 (2H, m), 4,22 (1H, USS), 5,11 (2H, s), 7,02? 7.04 baby mortality (3H, m), to 7.09 (2H, d, J=8.1 Hz), 7,78 (1H, DD, J=8.0 a, 1,6 Hz), to 7.99 (1H, d, J=1.5 Hz).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-chlorbenzoyl acid (420 mg, yield 83%) was obtained as a white solid from 2-chloro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (518 mg, 0,870 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,22-2,3 (4H, m)at 2.59 (3H, USS), 2,82 (2H, USS), 4.09 to to 4.17 (2H, m), 4,25 (1H, OSS), to 5.13 (2H, s), 7,01-7,14 (5H, m), 7,83 (1H, DD, J=8.0 a, 1,6 Hz), of 8.04 (1H, d, J=1.5 Hz).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-chlorbenzoyl acid (265 mg, yield 66%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-chlorbenzoyl acid (420 mg, 0,722 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,15-of 2.24 (1H, m)to 2.29 (3H, s)to 2.54 (3H, s), of 2.86 (2H, USS), with 3.79 (2H, d, J=5.3 Hz), 5,14 (2H, s), 7,13 (4H, s), 7,16 (1H, d, J=7.9 Hz), 7,78 (1H, DD, J=7,9, 1.5 Hz), of 7.90 (1H, d, J=1.5 Hz), of 8.25 (3H, USS).

Example361

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]isophthalic acid

1) Dimethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]isophthalate (1.12 g, yield 99%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.75 g, 1.82 mmol) and dimethyl-4-(methyl bromide)isophthalate (522 mg, 1.82 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.26 (1H, m)to 2.35 (3H, s), to 2.57 (3H, s), and 2.79 (2H, d, J=7,4 Hz), 3,91 (3H, s), of 3.96 (3H, s), 4,11-4,16 (2H, m)to 4.23 (1H, USS), the 5.45 (2H, s), of 6.99 (1H, d, J=8.1 Hz), 706 (2H, d, J=8,3 Hz), 7,13 (2H, d, J=7.9 Hz), to 7.99 (1H, DD, J=8,1, 1.9 Hz), 8,59 (1H, d, J=1.9 Hz).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]isophthalic acid (750 mg, yield 68%) was obtained as colorless oil from dimethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]isophthalate (1.12 g, is 1.81 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,4 Hz)to 1.38 (9H, s), 2,23 to 2.35 (4H, m), 2,58 (3H, s), of 2.86 (2H, d, J=5,1 Hz), 4,11-is 4.21 (2H, m), 4,35 (1H, USS), of 5.48 (2H, s), 7,01-7,17 (5H, m), of 7.96-8,08 (1H, m), 8,64 is 8.75 (1H, m).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]isophthalic acid (362 mg, yield 90%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the carbonyl}oxy)methyl]isophthalic acid (420 mg, 0,711 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,16-of 2.27 (1H, m), of 2.33 (3H, s), to 2.57 (3H, USS), 2,90 (2H, USS), 3,82 (2H, d, J=5,1 Hz), 5,42 (2H, s), 7,01 (1H, d, J=8.1 Hz), 7,19 (2H, d, J=8.7 Hz), 7.23 percent (2H, d, J=8,3 Hz), of 7.97 (1H, DD, J=8,1, 1.9 Hz), 8,31 (3H, USS), 8,42 (1H, d, J=1.9 Hz).

Example362

Trihydrochloride 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-[4-(dimethylamino)phenyl]ndimethylacetamide

1) tert-Butyl{[5-(2-{[4-(dimethylamino)phenyl]amino}-2-OK is oethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (450 mg, yield 71%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and 4-(dimethylamino)aniline (500 mg, to 3.67 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16-of 2.27 (1H, m), is 2.40 (3H, s), 2.63 in (3H, s), 2,77 (2H, d, J=7,4 Hz), 2,90 (6H, s), 3,42 (2H, s)4,06 (2H, d, J=5,1 Hz), 4,20 (1H, OSS), to 6.58 (1H, USS), 6,66 (2H,, d, J=8.1 Hz), 7,02 (2H, d, J=7,7 Hz), 7,18 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=7,7 Hz).

2) Trihydrochloride 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-[4-(dimethylamino)phenyl]ndimethylacetamide (62 mg, yield 42%) was obtained as a purple powder from tert-butyl{[5-(2-{[4-(dimethylamino)phenyl]amino}-2-oxoethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (100 mg, 0,268 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,13-of 2.28 (1H, m), of 2.38 (3H, s), was 2.76 (3H, s), a 3.01 (6H, s), 3,13 (2H, s), of 3.77-3,86 (5H, m), 7,20 (2H, d, J=8.1 Hz), 7,35 (2H, d, J=8.1 Hz), 7,51 (2H, d, J=8.1 Hz), 8,30 (2H,, d, J=8.1 Hz), 8,56 (3H, USS).

Example363

Ethyl-5-(aminomethyl)-4-(4-were)-2,6-dineopentyl

1) a Mixture of 3-ethoxy-3-oxopropionate potassium (7.6 g, 45 mmol), magnesium chloride (2.8 g, 30 mmol) and tetrahydrofuran (75 ml) was stirred at 50°C for 4 h the resulting suspension was allowed to cool to room temperature, then added dropwise to the reaction mixture, the obtained permisiveness tert-butylalcohol acid (3.5 g, 30 mmol), N,N'-carbonyldiimidazole (5.8 g, 36 mmol) and tetrahydrofuran (50 ml)at room temperature for 1 h the mixture was stirred at room temperature for 3 days. The reaction mixture was distributed between ethyl acetate and 0,5h. hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain ethyl-5,5-dimethyl-3-oxohexanoate in the form of the crude product (5.9 g). A mixture of the crude product (5.9 g), ammonium acetate (9.8 g, 127 mmol), acetic acid (1,45 ml, 25 mmol) and toluene (200 ml) was heated at boiling under reflux, using a trap Dean-stark for 17 hours the Reaction mixture was allowed to cool to room temperature, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain ethyl 3-amino-5,5-dimethylhex-2-enoate (2.5 g, yield 52%) as a white powder.

1H-NMR (CDCl3) δ: 1.00 and (9H, s)of 1.27 (3H, t, J=7.2 Hz), to 1.98 (2H, s), 4,11 (2H, q, J=7.2 Hz), of 4.45 (2H, USS), with 8.05 (1H, s).

2) Ethyl-5-cyano-4-(4-were)-2,6-dineopentyl-1,4-dihydropyridines-3-carboxylate (3.5 g, yield 65%) was obtained in the ideal of a white powder of 5,5-dimethyl-3-oxopentanenitrile (2.4 g, 13 mmol), p-tolualdehyde (1.6 g, 13 mol) and ethyl-3-amino-5,5-dimethylhex-2-enoate (2.5 g, 13 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 1,01 (9H, s)of 1.03 (9H, s)of 1.17 (3H, t, J=7.2 Hz), to 2.06 (1H, d, J=13,7 Hz), and 2.27 (1H, d, J=13,7 Hz), 2,31 (3H, s), 2,52 (1H, d, J=13,7 Hz)to 3.34 (1H, d, J=13,7 Hz), 3.95 to-4,10 (2H, m), 4,63 (1H, s), 5,44 (1H, OSS), to 7.09 (2H, d, J=8.0 Hz), 7,17 (2H, d, J=8.0 Hz).

3) Ethyl-5-cyano-4-(4-were)-2,6-dineopentyl (3.2 g, yield 96%) was obtained as white powder from ethyl 5-cyano-4-(4-were)-2,6-dineopentyl-1,4-dihydropyridines-3-carboxylate (3.4 g, 8.2 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: of 0.91 (3H, t, J=7.2 Hz), a 1.01 (9H, s)a 1.08 (9H, s), is 2.40 (3H, s), 2,87 (2H, s), to 3.02 (2H, s)to 3.99 (2H, q, J=7.2 Hz), 7,20-7,30 (4H, m).

4) Ethyl-5-(aminomethyl)-4-(4-were)-2,6-dineopentyl (0,91 g, yield 90%) was obtained as colorless oil from ethyl 5-cyano-4-(4-were)-2,6-dineopentyl (1.0 g, 2.5 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,89 (3H, t, J=7.2 Hz), 0,99 (9H, s), was 1.04 (9H, s)of 1.33 (2H, USS), of 2.38 (3H, s), 2,78 (2H, s), is 2.88 (2H, s), and 3.72 (2H, s)to 3.89 (2H, q, J=7.2 Hz), 7,12 (2H, d, J=8.0 Hz), 7,20 (2H, d, J=8.0 Hz).

Example364

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}propan-1-ol

1) a Mixture of [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methylmethanesulfonate (1,91 g, 4,01 mmol), 1,3-propane diol (3,05 g, 40,1 mmol), Hydra is Yes sodium (60% in oil, 1,60 g, 40,1 mmol) and tetrahydrofuran (5 ml) was stirred at 55°C for 16 hours the Reaction mixture was allowed to cool to room temperature and was added 1N. hydrochloric acid to stop the reaction. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was purified column chromatography on silica gel to obtain tert-butyl{[5-[(3-hydroxypropoxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (840 mg, yield 46%) as a white powder.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 1,70-1,80 (2H, m), 2,16-of 2.27 (1H, m), 2,42 (3H, s), 2.63 in (3H, s)of 2.75 (2H, d, J=7,4 Hz), 3,40 (2H, t, J=5.8 Hz), 3,70 (2H, t, J=5.8 Hz), 4,06 (2H, d, J=4,7 Hz), 4,10 (2H, s), 4,20 (1H, USS), 7,03 (2H, d, J=7.9 Hz), 7,24 (2H, d, J=7.9 Hz).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}propan-1-ol (15 mg, yield 100%) was obtained as a white powder from tert-butyl{[5-[(3-hydroxypropoxy)methyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (18 mg, 0,0394 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 1.70 to-2,3 (2H, m), of 2.38 (3H, s)of 2.75 (2H, s), 3,35-4,20 (6H, m)4,06 (2H, d, J=4.5 Hz), 4,11 (2H, d, J=4.5 Hz), 7,00 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,51 (2H, d, J=8.1 Hz), 8,56 (3H, USS).

Example365

The dihydrochloride of 4-[({[5-(linomat the l)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalic acid

1) Dimethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalate (1.68 g, yield 95%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.18 g, of 2.86 mmol) and dimethyl-4-(methyl bromide)phthalate (820 mg, of 2.86 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,17-of 2.26 (1H, m), of 2.33 (3H, s)to 2.54 (3H, s), 2,78 (2H, d, J=7,4 Hz)to 3.92 (3H, s), 3,93 (3H, s), 4,11-to 4.15 (2H, m), is 4.21 (1H, USS), of 4.95 (2H, s)to 7.00 (2H, d, J=8.1 Hz), to 7.09 (2H, d, J=7.9 Hz), 7,16 (1H, DD, J=7,9) and 1.7 Hz), 7,47 (1H, d, J=1.5 Hz), a 7.62 (1H, d, J=7,7 Hz).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalic acid (1.60 g, yield 99%) was obtained as colorless oil from dimethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalate (1.68 g, of 2.72 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16-of 2.27 (1H, m), 2,39 (3H, s)to 2.67 (3H, USS), 3,10 (2H, d, J=7,0 Hz)to 4.23 (2H, d, J=4.9 Hz), 4,51 (1H, USS), free 5.01 (2H, s), 7,07 (2H, s), 7,21-7,24 (3H, m), 8,03 (1H, s), 8,13 (1H, d, J=7.9 Hz).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalic acid (396 mg, yield 84%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl who yl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phthalic acid (0,49 g, 0,830 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,17-of 2.26 (1H, m), of 2.33 (3H, s), of 2.56 (3H, ass), only 2.91 (2H, USS), 3,81 (2H, d, J=4.9 Hz), of 5.05 (2H, s), 7,13 (2H, d, J=7.9 Hz), 7,17-7,21 (3H, m), 7,39 (1H, d, J=1.5 Hz), to 7.59 (1H, d, J=7.9 Hz), 8,32 (3H, USS).

Example366

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-fermenting acid

1) 4-Bromo-3-terbisil-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,36 g, yield 78%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1.20 g, only 2.91 mmol) and (4-bromo-3-forfinal)methanol (597 mg, only 2.91 mmol) in a manner similar to the method of example 247-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,16 was 2.25 (1H, m), a 2.36 (3H, s)to 2.55 (3H, s), 2,78 (2H, d, J=7,2 Hz), 4,11-4,16 (2H, m), is 4.21 (1H, USS), a 4.86 (2H, s), 6,61-of 6.65 (1H, m), 7,00-7,06 (3H, m), 7,12-7,19 (3H, m).

2) 3-Fluoro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (520 mg, yield 39%) was obtained as a yellow oil of 4-bromo-3-terbisil-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,36 g 2,27 mmol) in a manner similar to the method of example 231-2).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15 was 2.25 (1H, m), of 2.33 (3H, s)to 2.55 (3H, s), 2,78 (2H, d, J=7,4 Hz), of 3.94 (3H, s), 4.09 to to 4.15 (2H, m), is 4.21 (1H, USS), ,94 (2H, C)for 6.81-6,85 (1H, m), 7,00 (2H, d, J=8.1 Hz), 7,10 (2H, d, J=7.9 Hz), 7,63-to 7.67 (2H, m).

3) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-fermenting acid (480 mg, yield 94%) was obtained as colorless oil from 3-fluoro-4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (520 mg, 0,899 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,16-of 2.26 (1H, m), of 2.33 (3H, s), of 2.56 (3H, s), of 2.81 (2H, d, J=7,4 Hz), 4.09 to to 4.16 (2H, m), 4,24 (1H, USS), 4,96 (2H, s), 6,88-6,92 (1H, m), 7,02 (2H, d, J=7.9 Hz), 7,11 (2H, d, J=7.9 Hz), 7,69-7,73 (2H, m).

4) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-fermenting acid (192 mg, yield 42%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-2-fermenting acid (480 mg, 0,850 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.8 Hz), 2,12-of 2.26 (1H, m), is 2.30 (3H, s), of 2.53 (3H, s), of 2.86 (2H, d, J=7,0 Hz), with 3.79 (2H, d, J=5.7 Hz), of 5.05 (2H, s), 7,05-7,16 (5H, m), to 7.59-to 7.64 (2H, m), 8,24 (3H, USS).

Example367

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)PI is one-3-yl]-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamide (172 mg, yield 66%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carbonylchloride (150 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,10 (6H, d, J=6.6 Hz), 2,00-2,09 (2H, m), 2,11-2,31 (1H, m), 2,31 (3H, s), is 2.44 (2H, t, J=6.3 Hz), at 2.59 (3H, s), with 2.93 (2H, t, J=6.3 Hz), 3,06 (2H, s), 3,85 (2H, s), 7,24 (4H, s), 8,35 (1H, s), at 8.36 (3H, USS), 11,42 (1H, USS).

Example368

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-phenyl-1,3-thiazole-4-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2-phenyl-1,3-thiazole-4-carboxamide (155 mg, yield 57%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 2-phenyl-1,3-thiazole-4-carbonylchloride (167 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,20-to 2.29 (1H, m), of 2.28 (3H, s), 2,61 (3H, s), 3.04 from (2H, s), 3,85 (2H, s), 7,26 (4H, s), 7,53-of 7.55 (3H, m), 7,95-7,98 (2H, m), 8,35 (1H, s), at 8.36 (3H, USS), 9,85 (1H, USS).

Example369

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyrazin-2-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyrazin-2-carboxamide (157 mg, yield 63%) was obtained as a white powder from tert-BU is Il{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and pyrazin-2-carbonylchloride (107 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.6 Hz), 2,18-of 2.28 (1H, m), and 2.27 (3H, s), 2.63 in (3H, s), of 3.12 (2H, s), 3,85 (2H, s), 7,21 (2H, d, J=8.1 Hz), 7,26 (2H, d, J=8.1 Hz), 8,46 (3H, OSS), to 8.70 (1H, s), 8,88 (1H, s), the remaining 9.08 (1H with), 10,48 (1H, USS).

Example370

The dihydrochloride of 4-[({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoic acid

1) 6N. Hydrochloric acid (200 ml) was added to tert-butyl{[5-(cyanomethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (16 g, 37 mmol) and the mixture was stirred at 90°C for 24 h, the Reaction mixture was washed with a mixed solvent of tetrahydrofuran-toluene (1:2) and concentrated under reduced pressure. The residue was dissolved in water and podslushivaet addition of 4n. an aqueous solution of sodium hydroxide. Received podslushannyy the solution was washed with ethyl acetate and concentrated under reduced pressure. To the residue was added tetrahydrofuran (100 ml) and water (50 ml) and the mixture vigorously stirred. Was added dropwise di-tert-BUTYLCARBAMATE (8.5 ml, 37 mmol) and the mixture was stirred at room temperature for 17 hours was Added to the reaction mixture 1H. hydrochloric acid for acidification of the aqueous layer and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated salt solution and is sewed over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was led from a mixture of hexane-ethyl acetate to obtain [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid (13 g, yield 80%) as a white powder.

1H-NMR (CDCl3) δ: 1,09 (9H, s)of 1.39 (9H, s), 2,43 (3H, s), 2,82 (3H, d, J=20 Hz)to 3.34 (2H, USS), of 3.43 (2H, USS), 4,05-of 4.25 (2H, m), 4,35-4,50 (1H, m), 6,97 (2H, DD, J=7,5, 24 Hz), 7,26 (2H, DD, J=7,5, 29 Hz).

2) a Mixture of [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid (0.50 g, 1.1 mmol), triethylamine (0.17 ml, 1.3 mmol) and tetrahydrofuran (20 ml) cooled in ice was added dropwise a solution of 2,4,6-trichlorobenzoyl (0.31 g, 1.3 mmol) in tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 14 hours, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml) and to the solution was added 2-oxo-2-phenylethyl-4-(hydroxymethyl)benzoate (from 0.37 g, 1.4 mmol) and 4-dimethylaminopyridine (0.17 g, 1.4 mmol). The resulting solution was stirred at room temperature for 30 minutes the Reaction mixture was distributed between ethyl acetate and water. The organic layer was washed sequentially with 0,1M aqueous citric acid solution, saturated aqueous sodium bicarbonate and saturated salt solution and dried the over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain 2-oxo-2-phenylethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoate (to 0.63 g, yield 80%) as a white powder.

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), 2,39 (3H, s), 2.49 USD (3H, s)2,84 (2H, s), of 3.43 (2H, s)4,08 (2H, d, J=4.0 Hz), 4,15-of 4.25 (1H, m), 5,11 (2H, s)5,59 (2H, s)6,94 (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7.9 Hz), 7,31 (2H, d, J=8,3 Hz), 7,45-of 7.55 (2H, m), 7,60-of 7.70 (1H, m), 7,95-of 8.00 (2H, m), 8,11 (2H, d, J=8,3 Hz).

3) 2-Oxo-2-phenylethyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoate (0,61 g, 0.88 mmol) was dissolved in ethyl acetate (2 ml) and water (2 ml), the resulting solution was sequentially added acetic acid (5 ml) and powdered zinc (0,42 g, 6.4 mmol). The resulting mixture was stirred at 55°C for 24 h, the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was distributed between ethyl acetate and water. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel and optionally recrystallized from a mixture of hexane-ethyl acetate to obtain 4-[({[5-{[(tert-butoxycarbonyl)and the Ino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoic acid (0.29 grams, yield 48%) as a white powder.

1H-NMR (CDCl3) δ: 1,02 (9H, s)of 1.36 (9H, s), of 2.38 (3H, s), 2,47 (3H, s), is 2.88 (2H, s), of 3.43 (2H, s), 4,10 (2H, d, J=5,1 Hz), 4,15-of 4.25 (1H, m), 5,11 (2H, s)6,94 (2H, d, J=7,7 Hz), 7,17 (2H, d, J=7,7 Hz), 7,30 (2H,, d, J=8.1 Hz), 8,07 (2H, d, J=8,1 Hz).

4) of the Dihydrochloride of 4-[({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoic acid (0,22 g, yield 92,4%) was obtained as pale yellow powder from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetyl}oxy)methyl]benzoic acid (0.25 g, 0.44 mmol) in a manner similar to the method of example 276-3).

1H-NMR (DMSO-d6) δ: 1,01 (9H, s), is 2.37 (3H, s), 2,73 (3H, USS), 3,00-3,30 (2H, m), of 3.57 (2H, USS), 3,82 (2H, USS), 5,11 (2H, s), to 7.09 (2H, d, J=7.9 Hz), 7,28 (2H, d, J=7.9 Hz), 7,34 (2H, d, J=8,2 Hz), 7,94 (2H, d, J=8,2 Hz), 8,19 (3H, USS).

Example371

The dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-3-carboxylic acid

1) [3-(Methoxycarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (320 mg, yield 47%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (0.50 g, 1,22 mmol) and methyl-2-(methyl bromide)furan-3-carboxylate (266 mg, 1,22 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6,8 Hz)to 1.38 (9H, s), 2,15-of 2.26 (1H, m), is 2.37 (3H, what), to 2.55 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,82 (3H, s), 4.09 to-4,13 (2H, m), 4,19 (1H, OSS), at 5.27 (2H, s), of 6.68 (1H, d, J=1.9 Hz), 7,00 (2H, d, J=8.1 Hz), 7,11 (2H, d, J=7.9 Hz), 7,31 (1H, d, J=1.9 Hz).

2) 2-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-3-carboxylic acid (310 mg, yield 99%) was obtained as colorless oil from [3-(methoxycarbonyl)-2-furyl]methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (320 mg, 0,581 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-2,22 (1H, m), is 2.37 (3H, s)to 2.55 (3H, s), 2,80 (2H, d, J=7,4 Hz), 4.09 to to 4.16 (2H, m)to 4.23 (1H, OSS), at 5.27 (2H, s), 6,72 (1H, d, J=1.9 Hz), 7,02 (2H, d, J=7.9 Hz), 7,13 (2H, d, J=7,4 Hz), 7,34 (1H, d, J=1.9 Hz).

3) of the Dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-3-carboxylic acid (241 mg, yield 81%) was obtained as a pale-yellow solid from 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]furan-3-carboxylic acid (310 mg, 0,577 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16 was 2.25 (1H, m)to 2.35 (3H, s), 2,53 (3H, USS), 2,90 (2H, USS), 3,80 (2H, d, J=5,1 Hz), of 5.26 (2H, s)of 6.71 (1H, d, J=1.9 Hz), 7,12 (2H, d, J=7.9 Hz), 7,19 (2H, d, J=7.9 Hz), 7,72 (1H, d, J=1.9 Hz), 8,32 (3H, USS).

Example372

The dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)PI is one-3-yl]carbonyl}oxy)methyl]-3-nitrobenzoic acid

1) 4-(Methoxycarbonyl)-2-nitrobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (1,91 g, yield 63%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,91 g, 4,63 mmol) and methyl-4-(hydroxymethyl)-3-nitrobenzoate (978 mg, 4,63 mmol) in a manner similar to the method of example 247-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.28 (1H, m), of 2.34 (3H, s), to 2.57 (3H, s), and 2.79 (2H, d, J=7,4 Hz)to 3.99 (3H, s), 4,10-4,17 (2H, m)to 4.23 (1H, USS), 5,41 (2H, s), 7.03 is-to 7.09 (3H, m), 7,13 (2H, d, J=7.9 Hz), 8,08 (1H, DD, J=8,1, 1.5 Hz), 8,68 (1H, d, J=1.5 Hz).

2) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-nitrobenzoic acid (300 mg, yield 93%) was obtained as colorless oil from 4-(methoxycarbonyl)-2-nitrobenzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (0.33 g, 0,545 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-of 2.34 (4H, m), 2,59 (3H, s), and 2.83 (2H, d, J=6.8 Hz), 4,10-4,18 (2H, m), 4.26 deaths (1H, USS), 5,42 (2H, s), 7,02-7,20 (5H, m), 8,12-8,16 (1H, m), 8,73 (1H, s).

3) of the Dihydrochloride of 4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]-3-nitrobenzoic acid (247 mg, yield 86%) was obtained as a white solid from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-Mei is phenyl)pyridine-3-yl]carbonyl}oxy)methyl]-3-nitrobenzoic acid (300 mg, 0,507 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.8 Hz), 2,16 was 2.25 (1H, m)to 2.29 (3H, s), 2,60 (3H, USS), 2,94-of 3.00 (2H, m), 3,81 (2H, d. J=5.5 Hz), 5,42 (2H, s), 7,17 (4H, s), 7,24 (1H, d, J=8.1 Hz), 8,13 (1H, DD, J=8,1) and 1.7 Hz), 8,39 (3H, USS), 8,48 (1H, d, J=1.7 Hz).

Example373

The dihydrochloride methyl-3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate

1) Ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (2,34 g, yield 81%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (2,09 g 5,07 mmol) and ethyl-3-hydroxy-1-methyl-1H-pyrazole-4-carboxylate (863 mg, 5,07 mmol) in a manner similar to the method of example 183-1).

1H-NMR (CDCl3) δ: of 1.03 (9H, s), 1.26-1.28 (in 3H, m)to 1.37 (9H, s), a 2.36 (3H, s)to 2.66 (3H, s), of 2.86 (2H, s), 3,68 (3H, s), 4,13 (1H, OSS), to 4.23 (2H, q, J=7,1 Hz), the 4.90 (2H, s), 7,11 (2H, d, J=8,3 Hz), 7,16 (2H, d, J=8.1 Hz), a 7.62 (1H, s).

2) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (2,22 g, yield 99%) was obtained as colorless oil from ethyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (2,34 g, 4.14 mmol) in a manner similar to the method of example 9-1).

1H-YAM who (CDCl 3) δ: 1,04 (9H, s)to 1.37 (9H, s)to 2.35 (3H, s)to 2.66 (3H, s), is 2.88 (2H, s), 3,70 (3H, s), 4.09 to 4,18 (2H, m), 4,24 (1H, USS), of 4.95 (2H, s), was 7.08 (2H, d, J=7.5 Hz), 7,18 (2H, d, J=7,7 Hz), 7,68 (1H, s).

3) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (480 mg, yield 91%) was obtained as colorless oil from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.51 g, 0,950 mmol) in a manner similar to the method of example 305-3).

1H-NMR (CDCl3) δ: of 1.03 (9H, s)to 1.37 (9H, s), a 2.36 (3H, s)to 2.66 (3H, s), of 2.86 (2H, s), 3,68 (3H, s), 3,76 (3H, s), 4.09 to to 4.17 (2H, m), 4,19 (1H, USS), the 4.90 (2H, s), 7,10 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=8.1 Hz), 7,62 (1H, s).

4) Dihydrochloride methyl-3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (349 mg, yield 76%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate (480 mg, 0,872 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.05 (9H, s), of 2.38 (3H, s), 2.91 in (3H, USS), or 3.28 (2H, USS), the 3.65 (3H, s), 3,66 (3H, s)to 3.89 (2H, USS), the 4.90 (2H, s), 7,27 (2H, d, J=7.9 Hz), 7,33 (2H, d, J=8.1 Hz), of 8.09 (1H, s), 8,32 (3H, USS).

Example374

The dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carbon is Oh acid

The dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (210 mg, yield 76%) was obtained as a white solid from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0.29 grams, 0,540 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,04 (9H, s), of 2.38 (3H, s), 2,87 (3H, USS), 3,23 (2H, OSS), to 3.64 (3H, s)to 3.89 (2H, USS), a 4.86 (2H, s), 7,27 (2H, d, J=7.9 Hz), 7,33 (2H, d, J=7.9 Hz), 8,00 (1H, s), compared to 8.26 (3H, USS).

Example375

The dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxamide

1) tert-Butyl{[5-({[4-(aminocarbonyl)-1-methyl-1H-pyrazole-3-yl]oxy}methyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (110 mg, yield 18%) was obtained as colorless oil from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylic acid (0,60 g, 1.12 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 1,04 (9H, s)to 1.37 (9H, s), is 2.37 (3H, s)of 2.64 (3H, s), 2,87 (2H, s), of 3.69 (3H, s), 4,11-4,16 (2H, m), equal to 4.97 (2H, s), of 5.24 (1H, OSS), to 6.43 (1H, USS), 7,01 (2H, d, J=7,7 Hz), 7,20 (2H, d, J=8,3 Hz), 7,69 (1H, s).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxamide (70,3 mg, yield 67) was obtained as a white solid from tert-butyl{[5-({[4-(aminocarbonyl)-1-methyl-1H-pyrazole-3-yl]oxy}methyl)-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (110 mg, 0,205 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,04 (9H, s), of 2.38 (3H, s), 2.91 in (3H, USS)at 3.25 (2H, USS), 3,63 (3H, s), 3,88 (2H, OSS), to 4.92 (2H, s), 6.35mm (1H, OSS), to 7.09 (1H, USS), 7,27 (2H, d, J=7,0 Hz), 7,34 (2H, d, J=7.5 Hz), to $ 7.91 (1H, s), 8,29 (3H, USS).

Example376

The dihydrochloride {2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid

1) 2-(2-Ethoxy-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (980 mg, yield 70%) was obtained as colorless oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (1,00 g, 2,42 mmol) and ethyl[2-(methyl bromide)phenyl]acetate (624 mg, 2,42 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6,8 Hz)of 1.20 (3H, t, J=7.2 Hz), to 1.38 (9H, s), 2,15-of 2.26 (1H, m)to 2.35 (3H, s), of 2.51 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,51 (2H, s), as 4.02-4.09 to (2H, m), 4.09 to-4,13 (2H, m), 4,19 (1H, USS), 5,02 (2H, s), of 6.99 (2H, d, J=8,3 Hz), 7,06-was 7.08 (3H, m), 7,16-7,21 (2H, m), 7,26-7,31 (1H, m).

2) {2-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (600 mg, yield 62%) was obtained as colorless oil from 2-(2-ethoxy-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (980 mg, 1,71 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.93 (6H, d, J=6.8 G is), of 1.37 (9H, s), 2,10-of 2.21 (1H, m), of 2.34 (3H, s), 2.49 USD (3H, s), was 2.76 (2H, d, J=7,2 Hz), 3,53 (2H, s), 4,05 is 4.13 (2H, m), the 4.29 (1H, USS), free 5.01 (2H, s), 6,98 (2H, d, J=8,3 Hz), 7,02-7,11 (3H, m), 7.18 in-to 7.32 (3H, m).

3) Dihydrochloride {2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (125 mg, yield 62%) was obtained as a white solid from {2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (210 mg, 0,374 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,16-of 2.28 (1H, m), a 2.36 (3H, s), is 2.88 (2H, USS), 3,47 (2H, s), 3,81 (2H, d, J=5,1 Hz), 4,99 (2H, s), 6,98 (1H, d, J=7.5 Hz), 7,13-to 7.32 (7H, m), 8,27 (3H, USS).

Example377

The dihydrochloride of 2-(2-amino-2-oxoethyl)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate

1) 2-(2-Amino-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (323 mg, yield 83%) was obtained as colorless oil from {2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbonyl}oxy)methyl]phenyl}acetic acid (0.39 g, 0,695 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,13-of 2.26 (1H, m)to 2.35 (3H, s)of 2.50 (3H, s), was 2.76 (2H, d, J=7,4 Hz), 3,47 (2H, s), 4,06 is 4.13 (2H, m), 4,24 (1H, USS), free 5.01 (2H, s), of 6.99 (2H, d, J=8.1 Hz), 7,06-7,10 (3H, m), 7,19-to 7.35 (3H, m).

2) of the Dihydrochloride of 2-(2-amino-2-octoate is)benzyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinate (209 mg, yield 68%) was obtained as a white solid from 2-(2-amino-2-oxoethyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinate (323 mg, 0,577 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 0.96 (6H, d, J=6.6 Hz), 2,14 was 2.25 (1H, m), a 2.36 (3H, s)to 2.55 (3H, s), with 2.93 (2H, USS), of 3.32 (2H, s), 3,82 (2H, d, J=5,1 Hz), to 5.08 (2H, s)6,94 (2H, d, J=7,4 Hz), 7,14-7,30 (7H, m), 7,51 (1H, USS), 8,35 (3H, USS).

Example378

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}thiophene-2-carboxylate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}thiophene-2-carboxylate (460 mg, yield 68%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.50 g, 1.25 mmol) and methyl-3-hydroxythiophene-2-carboxylate (0.20 g, 1.25 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6,8 Hz)of 1.39 (9H, s), 2,18-of 2.27 (1H, m), of 2.38 (3H, s), of 2.72 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,80 (3H, s), 4,06-4,11 (2H, m), 4,20 (1H, USS), 4,79 (2H, s), of 6.50 (1H, d, J=5.5 Hz), 7,06 (2H, d, J=8.1 Hz), 7,18 (2H, d, J=7.9 Hz), 7,29 (1H, d, J=5,5 Hz).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}thiophene-2-carboxylate (126 mg, yield 84%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-meth is l-4-(4-were)pyridine-3-yl]methoxy}thiophene-2-carboxylate (158 mg, 0,293 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.4 Hz), 2,15-of 2.28 (1H, m), is 2.37 (3H, s), is 2.88 (3H, s), 3,11 (2H, USS), 3,71 (3H, s), 3,82 (2H, s), to 4.87 (2H, s)6,86 (1H, d, J=5.7 Hz), 7,21-7,34 (4H, m), to 7.77 (1H, d, J=5.5 Hz), at 8.36 (3H, USS).

Example379

The dihydrochloride methyl-4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate

1) Ethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate (910 mg, yield 96%) was obtained as colorless oil from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (0.66 g, of 1.66 mmol) and ethyl-4-hydroxy-2-methyl-1,3-thiazole-5-carboxylate (0.31 g, of 1.66 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.28 (3H, t, J=7.2 Hz), of 1.39 (9H, s), 2,17-of 2.26 (1H, m), is 2.37 (3H, s), of 2.53 (3H, s), 2,77 (2H, d, J=7,2 Hz), 4,08 (2H, d, J=4.5 Hz), 4,25 (2H, q, J=7,0 Hz)to 5.13 (2H, s), to 7.09 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=7.9 Hz).

2) 4-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid (750 mg, yield 87%) was obtained as colorless oil from ethyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate (910 mg, 1,60 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3/sub> ) δ: 1,01 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,18-of 2.30 (1H, m), of 2.38 (3H, s), to 2.57 (3H, s), of 2.81 (3H, USS), 2,95 (2H, d, J=7.0 Hz), 4.09 to to 4.15 (2H, m), or 4.31 (1H, USS), with 5.22 (2H, s), 7,05 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz).

3) Methyl-4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate (420 mg, yield 77%) was obtained as a pale yellow solid from 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid (530 mg, 0,982 mmol) in a manner similar to the method of example 305-3).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15-of 2.27 (1H, m), is 2.37 (3H, s)to 2.54 (3H, s), 2,68 (3H, s), 2,77 (2H, d, J=7,4 Hz), with 3.79 (3H, s)4,08 (2H, d, J=4.9 Hz), is 4.21 (1H, USS), 5,14 (2H, s), to 7.09 (2H,, d, J=8.1 Hz), 7,16 (2H, d, J=7.9 Hz).

4) Dihydrochloride methyl-4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate (342 mg, yield 85%) was obtained as a pale-yellow solid from methyl 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylate (420 mg, 0,759 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,13-of 2.28 (1H, m), of 2.38 (3H, s)to 2.55 (3H, s), with 2.93 (3H, USS), of 3.13 (2H, USS), 3,70 (3H, s), 3,80 (2H, OSS), to 5.17 (2H, s), 7,20-7,26 (2H, m), 7,31 (2H, d, J=7,4 Hz), scored 8.38 (3H, USS).

Example380

The dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-IU is ylphenyl)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid

The dihydrochloride of 4-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid (145 mg, yield 69%) was obtained as a white solid from 4-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-2-methyl-1,3-thiazole-5-carboxylic acid (220 mg, 0,408 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,15-of 2.28 (1H, m), of 2.38 (3H, s), of 2.53 (3H, s), 2,90 (3H, USS), 3,10 (2H, USS), 3,75-of 3.85 (2H, m), 5,11 (2H, s), 7,25 (2H, d, J=6.4 Hz), 7,32 (2H, d, J=7,7 Hz), 8,15-8,42 (3H, m).

Example381

The dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(carboxymethyl)-1H-pyrazole-4-carboxylic acid

1) Ethyl-1-acetyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (1.12 g, yield 77%) was obtained as a white solid from tert-butyl{[5-(hydroxymethyl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (1,00 g, 2.51 mmol) and ethyl-1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (597 mg, a 3.01 mmol) in a manner similar to the method of example 214-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.8 Hz), is 1.31 (3H, t, J=7.2 Hz), of 1.39 (9H, s), 2,14-of 2.27 (1H, m), a 2.36 (3H, s), of 2.51 (3H, s)to 2.67 (3H, s), 2,78 (2H, d, J=7,4 Hz), 4.09 to (2H, d, J=5,1 Hz), 4,20 (1H, USS), 4,28 (2H, kV, J=7,1 Hz), free 5.01 (2H, s), to 7.09 (2H, d, J=8.1 Hz), 7,17 (2H, d, J=7.9 Hz), 8,49 (1H, s).

2) To a solution of ethyl-1-acetyl-3-[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (0,86 g, for 1.49 mmol) in a mixture of tetrahydrofuran (10 ml)-methanol (5 ml) was added a saturated aqueous solution of sodium bicarbonate (10 ml) and the mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (798 mg, yield 99%) as a colourless oil.

1H-NMR (CDCl3) δ: of 0.91 (3H, d, J=6.6 Hz), of 0.97 (3H, d, J=6.6 Hz), 1,24-of 1.29 (3H, m), 1,40-of 1.46 (9H, m), 2,19-of 2.28 (1H, m), a 2.36 (3H, USS), 2,65-2,78 (5H, m), a 3.87-Android 4.04 (2H, m), 4,08 is 4.35 (5H, m), to 4.87 (1H, USS), 6,91-7,01 (2H,, m), 7,07-to 7.15 (2H, m), to 7.84 (1H, s).

3) To a solution of ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (1,09 g, 2.03 mmol) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 98 mg of 2.44 mmol) and the mixture was stirred at room temperature for 30 minutes was Added to the reaction a mixture of tert-butylbromide (0,36 ml of 2.44 mmol) and the mixture was stirred under heating at 60°C for 30 minutes, the Reaction mixture was diluted with ethyl acetate, washed with saturated salt solution and dried over anhydrous sulfate is m magnesium. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel to obtain ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-tert-butoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (960 mg, yield 72%) as a colourless oil.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.28 (3H, t, J=7,1 Hz)of 1.39 (9H, s)of 1.44 (9H, s), 2,14 was 2.25 (1H, m), a 2.36 (3H, s)to 2.66 (3H, s), was 2.76 (2H, d, J=7,4 Hz), 4,08 (2H, d, J=4.9 Hz), 4,17-4,27 (3H, m)to 4.52 (2H,with), 4,91 (2H, s), to 7.09 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=8.1 Hz), 7,73 (1H, s).

4) To a mixed solution of ethyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-tert-butoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (960 mg, 1.48 mmol) in a mixture of tetrahydrofuran (15 ml)-methanol (10 ml) was added 1N. an aqueous solution of sodium hydroxide (10 ml) and the mixture was heated at the boil under reflux for 1 h the Reaction mixture was allowed to cool to room temperature and acidified 0,5h. hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(carboxymethyl)-1H-pyrazole-4-carboxylic acid(838 mg, yield 99%) as oil. From the obtained oil (107 mg, 0,189 mmol) was obtained as a white solid substance of the dihydrochloride of 3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(carboxymethyl)-1H-pyrazole-4-carboxylic acid with (58.2 mg, yield 59%) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,14-of 2.28 (1H, m), of 2.38 (3H, s), 2,82 (3H, USS), totaling 3.04 (2H, USS), 3,76-3,86 (2H, m), of 4.77 (2H, s), a 4.86 (2H, s), 7,26 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=7.9 Hz), of 8.04 (1H, s), 8,27 (3H, USS).

Example382

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-methoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-methoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (560 mg, 0,636 mmol) was obtained as colorless oil from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(carboxymethyl)-1H-pyrazole-4-carboxylic acid (870 mg, 1.48 mmol) in a manner similar to the method of example 305-3).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,15 was 2.25 (1H, m), a 2.36 (3H, s)to 2.66 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 3,76 (3H, s), of 3.77 (3H, s)4,08 (2H, d, J=4,7 Hz), 4,22 (1H, USS)and 4.65 (2H, s), 4,91 (2H,with), was 7.08 (2H, d, J=8.1 Hz), 7,16 (2H, d, J=7.9 Hz), 7,74 (1H, s).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-methoxy-2-oxoethyl)-H-pyrazole-4-carboxylate (to 59.8 mg, yield 63%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-methoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (98,7 mg, 0,166 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,15-of 2.28 (1H, m), is 2.37 (3H, s), is 2.74 (3H, OSS), to 2.94 (2H, OSS), to 3.67 (3H, s), 3,68 (3H, s), a 4.86 (2H, s), 4,91 (2H, s), 7.23 percent (2H, d, J=8.1 Hz), 7,29 (2H, d, J=8.1 Hz), 8,09-8,19 (4H, m).

Example383

The dihydrochloride [3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-(methoxycarbonyl)-1H-pyrazole-1-yl]acetic acid

1) To a solution of methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-methoxy-2-oxoethyl)-1H-pyrazole-4-carboxylate (0,46 g, 0,775 mmol) in tetrahydrofuran was added 1N. an aqueous solution of sodium hydroxide (1 ml) and the mixture was stirred at room temperature for 30 minutes the Reaction mixture was acidified 0,5h. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain [3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-(methoxycarbonyl)-1H-pyrazole-1-yl]acetic acid (450 mg, yield 99%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.03 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2.21 are of 2.34 (1H, m), 2,43 (3H, s), 3,02-3,26 (5H, m), 3,76 (3H, s), 4,13-4,19 (2H, m), to 4.62 (2H, s), 4,99-5,11 (2H, m), 7,12 (2H, d, J=7,0 Hz), 7,30 (2H, d, J=7,5 Hz), 7.68 per to 7.75 (1H, m).

2) Dihydrochloride [3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-(methoxycarbonyl)-1H-pyrazole-1-yl]acetic acid (42,4 mg, yield 44%) was obtained as a white solid from [3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-(methoxycarbonyl)-1H-pyrazole-1-yl]acetic acid (100 mg, 0,172 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,14-of 2.28 (1H, m), of 2.38 (3H, s), 2,85 (3H, USS), of 3.07 (2H, USS), 3,68 (3H, s), 3.75 to of 3.85 (2H, m), 4,78 (2H, s), the 4.90 (2H, s), 7,25 (2H, d, J=7.9 Hz), 7,31 (2H, d, J=7.9 Hz), 8,12 (1H, s), 8,31 (3H, USS).

Example384

The dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-amino-2-oxoethyl)-1H-pyrazole-4-carboxylate

1) Methyl-1-(2-amino-2-oxoethyl)-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (150 mg, yield 37%) was obtained as a white solid from [3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-4-(methoxycarbonyl)-1H-pyrazole-1-yl]acetic acid (400 mg, 0,689 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3 ) δ: 0,99 (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-to 2.29 (1H, m), a 2.36 (3H, s), 2,68 (3H, s), 2,77 (2H, d, J=7,4 Hz), of 3.78 (3H, s)4,08 (2H, d, J=5,1 Hz), 4,22 (1H, USS), of 4.54 (2H, s), 4,94 (2H, s), to 7.09 (2H,, d, J=8.1 Hz), 7,16 (2H, d, J=7.9 Hz), 7,74 (1H, s).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-(2-amino-2-oxoethyl)-1H-pyrazole-4-carboxylate (141 mg, yield 98%) was obtained as a white solid from methyl-1-(2-amino-2-oxoethyl)-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1H-pyrazole-4-carboxylate (150 mg, 0,259 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,14-of 2.27 (1H, m), 2,39 (3H, s), of 2.86 (3H, OSS), to 3.09 (2H, OSS), to 3.67 (3H, s), 3,81 (2H, d, J=4,7 Hz), 4,58 (2H, s), 4,89 (2H, s), 7,26 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8,1 Hz), 7,58 (1H, s), with 8.33 (3H, USS).

Example385

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]terephthalamide

1) tert-Butyl{[5-{[4-(aminocarbonyl)benzoyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (248 mg, yield 98%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (260 mg, 0.48 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-to 2.29 (1H, m), of 2.34 (3H, s)of 2.50 (3H, s), and 2.79 (2H, USS), of 4.13 (2H, USS), 4,37 (1H, USS), of 5.84 (1H, USS), 6,33 (1H, USS), 7,05 (2H, d, J=,1 Hz), 7,19 (2H, d, J=8.1 Hz), 7,37 (1H, USS), 7,47 (2H, d, J=8.1 Hz), 7,73 (2H, d, J=8,1 Hz).

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]terephthalamide (233 mg, yield 99%) was obtained as a white powder from tert-butyl{[5-{[4-(aminocarbonyl)benzoyl]amino}-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (248 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.3 Hz), 2,19-2,31 (1H, m), 2,31 (3H, s), 2,61 (3H, s), 3,05 (2H, USS), 3,85 (2H, USS), 7,25 (4H, s), 7,51 (1H, OSS), to 7.68 (2H, d, J=8.1 Hz), 7,89 (2H, d, J=8.1 Hz), of 8.09 (1H, USS), of 8.37 (3H, USS), 10,16 (1H, USS).

Example386

The dihydrochloride ethyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-4-carboxylate

1) Ethyl-1-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-4-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and utilisedictated (314 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):567

2) Dihydrochloride ethyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-4-carboxylate (324 mg, yield 69%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d ) δ: 0,98 (6H, d, J=6.3 Hz), of 1.20 (3H, t, J=6.9 Hz), 1,54-to 1.59 (2H, m), 2,10-of 2.28 (1H, m), of 2.34 (3H, s), 2,36 is 2.46 (1H, m), 2,62 was 2.76 (4H, m)to 3.09 (2H, USS), 3,74-3,82 (4H, m), 4,07 (2H, q, J=6.9 Hz), 7,19 (2H, d, J=7.5 Hz), 7,26 (2H, d, J=7.5 Hz), 8,17 (1H, OSS), to 8.45 (3H, USS).

Example387

The dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-oxazol-4-carboxylate

1) Ethyl-2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-oxazol-4-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl-2-amino-1,3-oxazol-4-carboxylate (312 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):566

2) Dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-oxazol-4-carboxylate (224 mg, yield 48%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6,6 Hz)of 1.29 (3H, t, J=7.2 Hz), 2,13-of 2.26 (1H, m)to 2.29 (3H, s), 2.63 in (3H, s), 3,06 (2H, USS), 3,82 (2H, s), 4,27 (2H, q, J=7.2 Hz), 7,15-7,29 (4H, m), 8,44 (3H, OSS), to 8.45 (1H, s), to 9.32 (1H, USS), 11,14 (1H, USS).

Example388

The dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylate

1) Ethyl-2-[({[5-{[(tertbutoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl-2-amino-1,3-thiazole-4-carboxylate (344 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):582

2) Dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)amino]-1,3-thiazole-4-carboxylate (282 mg, yield 51%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.27 (3H, t, J=7.2 Hz), 2,11-of 2.30 (1H, m)to 2.35 (3H, s), 2,62 (3H, s), 3,06 (2H, USS), 3,81 (2H, s), are 4.24 (2H, q, J=7.2 Hz), 7,21 (2H, d, J=7.8 Hz), 7,30 (2H, d, J=7.8 Hz), to $ 7.91 (1H, s), 8,42 (3H, s), 8,76 (1H, USS), 11,21 (1H, USS).

Example389

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-phenylpiperidine-1-carboxamide

1) tert-Butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{[(4-phenylpiperazin-1-yl)carbonyl]amino}pyridine-3-yl)methyl]carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and 4-phenylpiperidine (322 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):571

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-4-phenylpiperidine-1-carboxamide (240 mg, yield 44%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6 ) δ: 0,99 (6H, d, J=6.6 Hz), 1,54 is 1.58 (2H, m), 2,14-of 2.26 (1H, m), and 2.26 (3H, s)of 2.50 (3H, s), 2,58 is 2.75 (5H, m), of 3.12 (2H, USS), 3,82 (2H, USS), 3.95 to 3,99 (2H, m), 7,11-7,37 (9H, m), 8,19 (1H, USS), 8,44 (1H, USS).

Example390

The dihydrochloride methyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyrrolidin-2-carboxylate

1) Methyl-1-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyrrolidin-2-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and compound methyl ester DL-Proline (286 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):539

2) Dihydrochloride methyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyrrolidin-2-carboxylate (400 mg, yield 78%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), of 1.80 (3H, USS), 2,04-of 2.09 (1H, m), 2,11-of 2.23 (1H, m), 2,39 (3H, s), 2.63 in (2H, s), of 3.07 (4H, USS)and 3.59 (3H, s), 3,86 (2H, USS), 4,11-4,17 (1H, m), 4,11-4,17 (1H, m), 7,21 (2H, d, J=7,8 Hz), 7,32 (2H, d, J=7.8 Hz), to 7.93 (1H, USS), 8,39 (3H, USS).

Example391

The dihydrochloride ethyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-3-carboxylate

1) Ethyl-1-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-3-carboxylate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl-3-piperidinecarboxylate (314 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):567

2) Dihydrochloride ethyl-1-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)piperidine-3-carboxylate (256 mg, yield 48%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 1,19 (3H, t, J=6.9 Hz), 1,39 of 1.46 (2H, m), of 1.78 (2H, USS), 2,16-of 2.23 (1H, m), is 2.37 (3H, s), 2.57 m (2H, s), 3,03 (2H, s), 3,66-and 3.72 (1H, m), 3,82 (2H, USS), of 4.05 (2H, q, J=6,9 Hz), 7,17 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 8,11 (1H, USS), 8,29 (3H, USS).

Example392

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione

1) tert-Butyl{[5-(1,3-dioxotetrahydrofuran[1,5-a]pyridine-2(3H)-yl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl-2-piperidinecarboxylate (314 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):553

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione (282 mg, yield 57%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method Primera-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 1,20-of 1.35 (1H, m), 1,36 of 1.50 (1H, m), 1,59-of 1.65 (1H, m)to 1.79 (1H, USS), 1,99 (1H, USS), 2,22-2,31 (1H, m), 2,32 (6H, s)to 2.35 (3H, s), 2,70-to 2.74 (1H, m), 2,82 (2H, d, J=6.9 Hz), 3,72-of 3.78 (4H, m), 7,05-to 7.09 (2H, m), 7,10-7,27 (2H, m), 8,13 (3H, USS).

Example393

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione

1) tert-Butyl{[5-(1,3-dioxo-1,5,10,10a-tetrahydroimidazo[1,5-b]isoquinoline-2(3H)-yl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and ethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (410 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):569

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-10,10a-dihydroimidazo[1,5-b]isoquinoline-1,3(2H,5H)-dione (368 mg, yield 68%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,18-of 2.34 (1H, m), is 2.30 (3H, s), of 2.34 (3H, s), 2,34 (2H, d, J=7,2 Hz), 2,95 (1H, DD, J=9,9, and 17.1 Hz), and 3.16 (1H, DD, J=4,8, 15.6 Hz), of 3.78 (2H, m)4,06 (1H, DD, J=9,9, 4,8 Hz), 4,08 (1H, d, J=17,1 Hz), 4,79 (1H, d, J=15.6 Hz), 7,07-7,31 (8H, m), 8,18 (3H, USS).

Example394

The dihydrochloride methyl-2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate is

The dihydrochloride methyl-2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate (230 mg, yield 89%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and methyl-2-(chlorocarbonyl)benzoate (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-of 2.27 (1H, m), is 2.40 (3H, s)to 2.66 (3H, s), 2,95 (2H, USS), of 3.77 (3H, s), with 3.79 (2H, OSS), to 6.58 (1H, d, J=7.5 Hz), 7.23 percent (2H, d, J=7.8 Hz), 7,34 (2H, d, J=7.8 Hz), 7,49 (1H, t, J=7.5 Hz), 7,53 (1H, t, J=7.5 Hz), of 7.70 (1H, d, J=7.5 Hz), of 8.25 (3H, USS), there is a 10.03 (1H, USS).

Example395

The dihydrochloride of 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid

1) 2-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (247 mg, yield 98%) was obtained as a white powder from methyl-2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoate (260 mg, 0.48 mmol) in a manner similar to the method of example 36-1).

1H-NMR (CDCl3) δ: to 0.92 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,04-to 2.18 (1H, m), is 2.41 (3H, s)to 2.55 (3H, s), 2,82 (2H, USS), 4.09 to (3H, USS), 6,17 (1H, USS), 6,91 (1H, OSS), to 7.09 (2H, USS), 7,25-7,27 (3H, m), 7,37 (1H, USS), 7,88 (1H, OSS).

2) of the Dihydrochloride of 2-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (220 mg, Ihad 94%) was obtained as a white powder from 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (247 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,18-of 2.26 (1H, m), 2,43 (3H, s), is 2.74 (3H, s), 3,05 (2H, USS), 3,86 (2H, USS), 6,38 (1H, d, J=6.9 Hz), 7,25 (2H, d, J=8.1 Hz), 7,37 (2H, d, J=8.1 Hz), 7,41 (1H, t, J=6.9 Hz), 7,49 (1H, t, J=6.9 Hz), 7,76 (1H, d, J=6.9 Hz), 8,35 (3H, USS), 10,02 (1H, USS).

Example396

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1H-isoindole-1,3(2H)-dione

1) tert-Butyl{[5-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (221 mg, yield 94%) was obtained as a white powder from 2-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)benzoic acid (260 mg, 0.48 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: of 1.03 (6H, d, J=6.6 Hz), of 1.39 (9H, s)2,02 (3H, s), 2.21 are 2,31 (1H, m), is 2.40 (3H, s), and 2.83 (2H, d, J=7.5 Hz), 4,20 (2H, d, J=5.4 Hz), 4,30 (1H, USS), 6,98 (2H, d, J=8.1 Hz), 7,03 (2H, d, J=8.1 Hz), to 7.67-7,72 (2H, m), 7,75-7,79 (2H, m).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1H-isoindole-1,3(2H)-dione (213 mg, yield 99%) was obtained as a white powder from tert-butyl{[5-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (221 mg, 0.45 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (6H, d, J=6.3 Hz), 2,19 (3H, s), 2,19 of-2.32 (1H, m)to 2.35 (3H, s), and 2.83 (2H, d, J=6.3 Hz), of 3.69 (2H, USS), 7,05 (2H, d, J=7.8 Hz), 7,13 (2H, the, J=7.8 Hz), the 7.85 (4H, USS), 8,03 (3H, USS).

Example397

The dihydrochloride methyl-3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate

1) Methyl-3-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and methyl-3-hydroxybenzoate (304 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):562

2) Dihydrochloride methyl-3-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate (172 mg, yield 32%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,14-of 2.28 (1H, m), is 2.44 (3H, s)to 2.67 (3H, s), to 3.02 (2H, s), 3,85 (2H, s)to 3.89 (3H, s), 7,26 (2H, d, J=8.1 Hz), was 7.36 (1H, s), 7,39 (2H, d, J=8.1 Hz), 7,53 (1H, t, J=7,8 Hz), 7,80 (1H, d, J=7.8 Hz), of 8.37 (3H, USS), of 9.75 (1H, USS).

Example398

The dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate

1) Methyl-4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotine is islote (412 mg, 1.0 mmol) and methyl-4-hydroxybenzoate (304 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):562

2) Dihydrochloride methyl-4-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)oxy]benzoate (182 mg, yield 34%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,14-to 2.29 (1H, m), 2,43 (3H, s), 2,62 (3H, s), with 2.93 (2H, USS), a-3.84 (2H, s), 3,85 (3H, s)to 7.00 (2H, d, J=8.7 Hz), 7,24 (2H, d, J=8.1 Hz), 7,39 (2H, d, J=8.1 Hz), of 7.96 (2H, t, J=8.7 Hz), 8,29 (3H, USS), 9,71 (1H, USS).

Example399

The dihydrochloride methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate

1) Methyl-5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate was obtained as an oil from 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and methanol (62 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

EIMC(M+1):443

2) Dihydrochloride methyl-5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]carbamate (330 mg, yield 80%) was obtained as a white powder from the oil obtained in the above stage 1), a method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-to 2.18 (1H, m), 2,39 (3H, s), 2.63 in (3H, s), 3,11 (2H, s), of 3.48 (3H, s), 3,82 (2H, s), 7,18 (2H, d, J=7.8 Hz), 7,33 (2H, d, J=7.8 Hz), 8,44 (3, OSS), 9,03 (1H, USS).

Example400

The dihydrochloride of ethyl{3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,4-dioxoimidazolidin-1-yl}acetate

1) Diethyl-2,2'-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)imino]diacetate was obtained as white crystals (260 mg, yield 43%) of 5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)nicotinic acid (412 mg, 1.0 mmol) and diethyl-2,2'-iminodiacetate (380 mg, 2.0 mmol) in a manner similar to the method of example 95-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), 1,24 (6H, t, J=6.9 Hz), to 1.38 (9H, s), 2,09-of 2.24 (1H, m), is 2.40 (3H, s), 2.49 USD (3H, s)of 2.75 (2H, d, J=6.9 Hz), a 3.87 (4H, s), of 4.12 (4H, q, J=6.9 Hz), 4,23 (1H, USS), 6,33 (1H, USS),? 7.04 baby mortality (2H, d, J=7.8 Hz), 7,25 (2H, d, J=7,8 Hz).

2) Dihydrochloride ethyl{3-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-2,4-dioxoimidazolidin-1-yl}acetate (240 mg, yield 98%) was obtained as a white powder from diethyl-2,2'-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)imino]diacetate (260 mg, 0.43 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 1,19 (6H, t, J=7.2 Hz), 2,22 to 2.35 (1H, m)to 2.35 (3H, s)of 2.50 (3H, s), of 2.86 (2H, d, J=7,2 Hz), 3,74-of 3.80 (3H, m), as 4.02-4,17 (5H, m),? 7.04 baby mortality-7,11 (2H, m), 7,21-7,27 (2H, m), 8,25 (3H, USS).

Example401

The dihydrochloride ethyl-6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]the Mino}carbonyl)pyridine-2-carboxylate

The dihydrochloride ethyl-6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylate (230 mg, yield 89%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and ethyl-6-(chlorocarbonyl)pyridine-2-carboxylate (149 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.35 (3H, t, J=7.2 Hz), 2,11-of 2.28 (1H, m), and 2.27 (3H, s), 2,60 (3H, s), 3,05 (2H, USS), a-3.84 (2H, USS), 4,37 (2H, q, J=7.2 Hz), 7,22 (1H, d, J=7.8 Hz), 7,26 (2H, d, J=7.8 Hz), 8,21-8,31 (3H, m), scored 8.38 (3H, USS), for 9.90 (1H, USS).

Example402

The dihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylic acid

1) 6-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylic acid (247 mg, yield 98%) was obtained as white powder from ethyl-6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylate (260 mg, 0.48 mmol) in a manner similar to the method of example 36-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,14-of 2.26 (1H, m), of 2.28 (3H, s), 2,52 (3H, s)2,84 (2H, USS), is 4.15 (2H, s), 4,42 (1H, USS), 7,01 (2H, d, J=7.8 Hz), 7,10 (2H, d, J=7.8 Hz), to 7.99 (1H, USS), 8,21-8,31 (2H, m), 9,36 (1H, USS).

2) Dihydrochloride 6-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]am is but}carbonyl)pyridine-2-carboxylic acid (221 mg, yield 94%) was obtained as a white powder of 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylic acid (247 mg, 0.47 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,11-to 2.29 (1H, m), of 2.25 (3H, s), 2,60 (3H, s), 3.04 from (2H, USS), 3,85 (2H, USS), 7,19 (1H, d, J=7.8 Hz), 7,26 (2H, d, J=7.8 Hz), 8.17 and compared to 8.26 (3H, m), of 8.37 (3H, USS), 10,67 (1H, USS).

Example403

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyridine-2,6-dicarboxamide

1) tert-Butyl{[5-({[6-(aminocarbonyl)pyridine-2-yl]carbonyl}amino)-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (221 mg, yield 94%) was obtained as a white powder of 6-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]amino}carbonyl)pyridine-2-carboxylic acid (260 mg, 0.48 mmol) in a manner similar to the method of example 3-1).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 1.39 (9H, s), 2,18-to 2.29 (1H, m)to 2.35 (3H, s), to 2.57 (3H, s), and 2.79 (2H, d, J=7.5 Hz), is 4.15 (2H, USS), the 4.29 (1H, USS), of 5.53 (1H, OSS), to 6.75 (1H, USS), 7,07 (2H, d, J=7.8 Hz), 7,19 (2H,, d, J=7.8 Hz), 8,02 (1H, t, J=7.8 Hz), 8,29 (1H, DD, J=1,2, 7,8 Hz), 8,31 (1H, DD, J=1,2, 7,8 Hz), a total of 8.74 (1H, s).

2) of the Dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]pyridine-2,6-dicarboxamide (206 mg, yield 94%) was obtained as a white powder from tert-butyl{[5-({[6-(aminocarbonyl)pyridine-2-yl]carbonyl}amino)-2-isobutyl--methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (221 mg, 0.45 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.3 Hz), 2,12-of 2.28 (1H, m), of 2.25 (3H, s), 2.63 in (3H, s), of 3.07 (2H, USS), 3,86 (2H, USS), 7,19 (2H, d, J=7.8 Hz), 7,28 (2H, d, J=7.8 Hz), 7,76 (1H, s), 8,08-to 8.20 (3H, m), 8,43 (3H, USS), 8,80 (1H, s), 10,77 (1H, USS).

Example404

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1-benzyl-4-methoxy-1H-pyrazole-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1-benzyl-4-methoxy-1H-pyrazole-3-carboxamide (230 mg, yield 81%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 1-benzyl-4-methoxy-1H-pyrazole-3-carbonylchloride (188 mg, 0.75 mmol) in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,18-of 2.26 (1H, m)to 2.35 (3H, s), of 2.51 (3H, s), 2.91 in (2H, OSS), to 3.67 (3H, s), 3,81 (2H, USS), of 5.15 (2H, s), 7,16-7,39 (9H, m), 8,11 (1H, s), 8,21 (3H, USS).

Example405

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,5-dimethyl-1H-pyrazole-3-carboxamide

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-1,5-dimethyl-1H-pyrazole-3-carboxamide (235 mg, yield 97%) was obtained as a white powder from tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (192 mg, 0.5 mmol) and 1,5-dimethyl-1H-pyrazole-3-carbonylchloride (118 mg, 0.75 mmol)in a manner similar to the method of example 223.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,18 was 2.25 (1H, m), 2,32 (3H, s), of 2.33 (3H, s), 2,53 (2H, OSS), to 3.73 (3H, s), 3,82 (2H, USS), 6,38 (1H, s), 7,20 (2H, d, J=7.8 Hz), 7,24 (2H, d, J=7.8 Hz), 8,31 (3H, s), 9,58 (1H, USS).

Example406

The dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid

The dihydrochloride [5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid (0.56 g, yield 94%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid (0,63 g of 1.43 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s)to 2.41 (3H, s), 2,73 (3H, USS), 3,19 (2H, USS), 3,35 is-3.45 (2H, m), 3.75 to 3,90 (2H, m), 7,16 (2H, d, J=7,4 Hz), 7,38 (2H, d, J=7,4 Hz), 8,16 (3H, USS).

Example407

The dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate

1) (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate (0,091 g, yield 28%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetic acid (0,63 g of 1.43 mmol) in a manner similar to the method of example 176-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), and 2.14 (3H, s), is 2.40 (3H, s), 2,48 (3H, s), and 2.83 (2H, s), 3,39 (2H, s), 4.09 to (2H, d, J=4.9 Hz), 4,10-of 4.25 (1H, m), was 4.76 (2H, s)6,94 (2H, d, J=7.9 Hz), 721 (2H, d, J=7.9 Hz).

2) Dihydrochloride (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate (of 0.085 g, yield 99%) was obtained as pale yellow powder (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]acetate (0,090 g, 0.16 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (9H, s), and 2.14 (3H, s), of 2.38 (3H, s), 2,71 (3H, USS), of 3.13 (2H, USS), 3,52 (2H, OSS), to 3.73 (2H, OSS), to 4.92 (2H, s), 7,10 (2H, d, J=7.5 Hz), 7,31 (2H, d, J=7.5 Hz), 8,15 (3H, USS).

Example408

Methyl-5-(aminomethyl)-6-isobutyl-2-(methoxymethyl)-4-(4-were)nicotinate

1) a Mixture of methyl-4-methoxyacetate (5,85 g, 40 mmol), ammonium acetate (15,4 g, 200 mmol), acetic acid (2.3 ml, 40 mmol) and toluene (100 ml) was heated at boiling under reflux, using a trap Dean-stark for 10 hours the Reaction mixture was allowed to cool to room temperature, washed her saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain methyl 3-amino-4-methoxybutyl-2-enoate in the form of the crude product (5.8 g). Methyl-5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-were)-1,4-dihydropyridines-3-carboxylate (7.8 g, yield 55%) was obtained as pale yellow powder of the crude product (5.8 g), 5-methyl-3-oxopentanenitrile (5.7 g, pure is and 87,5%, 40 mmol) and p-tolualdehyde (4.8 g, 40 mmol) in a manner similar to the method of example 1-2).

1H-NMR (CDCl3) δ: 0,97 (6H, DD, J=6,6, to 12.8 Hz), 1,80-2,00 (1H, m), 2,20-2,40 (2H, m), 2,31 (3H, s), of 3.48 (3H, s), of 3.57 (3H, s), 4,56 (1H, s), with 4.64 (1H, d, J=16.4 Hz), to 4.73 (1H, d, J=16.4 Hz), 7,05-to 7.15 (5H, m).

2) Methyl-5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-were)nicotinate (7.5 g, yield 99%) was obtained as a white powder from methyl 5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-were)-1,4-dihydropyridines-3-carboxylate (7.7 g, 22 mmol) in a manner similar to the method of example 23-3).

1H-NMR (CDCl3) δ: 1.00 m (6H, d, J=6.6 Hz), of 2.20 to 2.35 (1H, m), is 2.41 (3H, s), 2,97 (2H, d, J=7,2 Hz), 3,37 (3H, s)and 3.59 (3H, s), 4,71 (2H, s), 7,15-to 7.35 (4H, m).

3) Methyl-5-(aminomethyl)-6-isobutyl-2-(methoxymethyl)-4-(4-were)nicotinate (7,1 g, yield 93%) was obtained as a pale-yellow oil from methyl 5-cyano-6-isobutyl-2-(methoxymethyl)-4-(4-were)nicotinate (7,4 g, 21 mmol) in a manner similar to the method of example 1-4).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.8 Hz), 1,22 (2H, USS), 2,15-of 2.30 (1H, m), 2,39 (3H, s), 2,82 (2H, d, J=7,4 Hz)to 3.36 (3H, s), 3,49 (3H, s)to 3.67 (2H, s)and 4.65 (2H, s), 7,11 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

Example409

Trihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(pyridine-2-ylthio)methyl]pyridine-3-yl}methylamine

1) tert-Butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(pyridine-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (480 mg, yield 78%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were-6-neopentylene-3-yl]methylmethanesulfonate (600 mg, 1.2 mmol) and 2-mercaptopyridine (145 mg, 1.3 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s)to 2.35 (3H, s), 2,62 (3H, s), and 2.83 (2H, s)4,08 (2H, d, J=4.9 Hz), 4,14 (2H, s), 4,19 (1H, s), 6,91-to 6.95 (1H, m), 7.03 is-7,06 (3H, m), 7,17 (2H, d, J=to $ 7.91 Hz), 7,39 was 7.45 (1H, m), 8,31 (1H, d, J=4,1 Hz).

2) Trihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(pyridine-2-ylthio)methyl]pyridine-3-yl}methylamine (167 mg, yield 82%) was obtained as a powder from tert-butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(pyridine-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (200 mg, mmol 0,395) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s), a 2.36 (3H, s), 2,90 (3H, s), or 3.28 (2H, s), 3,83 (2H, d, J=4,7 Hz), 4,19 (2H, s), 7,11-7,16 (1H, m), 7.23 percent-7,33 (5H, m), 7,62-to 7.67 (1H, m), 8,31 (3H, USS), 8,33-to 8.34 (1H, m).

Example410

The dihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(1H-1,2,4-triazole-3-ylthio)methyl]pyridine-3-yl}methylamine

1) tert-Butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(4H-1,2,4-triazole-3-ylthio)methyl]pyridine-3-yl}methyl)carbamate (455 mg, yield 2%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (600 mg, 1.2 mmol) and 3-mercapto-1,2,4-triazole (131 mg, 1.3 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s), is 2.37 (3H, s)of 2.64 (3H, s), and 2.83 (2H, s)4,08 (2H, d, J=4.9 Hz), of 4.12 (2H, s), 4,22 (1H, s),? 7.04 baby mortality (2H, d, J=7,7 Hz), 7,20 (2H, d, J=7,7 Hz), 8,02 (1H, s).

2) Dihydroiso the ID {6-methyl-4-(4-were)-2-neopentyl-5-[(1H-1,2,4-triazole-3-ylthio)methyl]pyridine-3-yl}methylamine (160 mg, yield 85%) was obtained as a powder from tert-butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(4H-1,2,4-triazole-3-ylthio)methyl]pyridine-3-yl}methyl)carbamate (200 mg, 0,403 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s), 2,39 (3H, s), of 2.86 (3H, s), 3,21 (2H, s), 3,81 (2H, d, J=4,1 Hz), 4,08 (2H, s), from 7.24 (2H, d, J=8.0 Hz), 7,35 (2H, m, J=8.0 Hz), 8,23 (3H, OSS), to 8.45 (1H, s).

Example411

Trihydrochloride [5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4-(4-were)-2-neopentylene-3-yl]methylamine

1) tert-Butyl{[5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (373 mg, yield 75%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (500 mg, 1.0 mmol) and 2-mercaptoimidazole (110 mg, 1.1 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s)to 2.41 (3H, s)to 2.55 (3H, s), 2,82 (2H, s), of 3.94 (2H, s)4,06 (2H, d, J=4.9 Hz), 4,20 (1H, s)6,94 (1H, USS), 7,01 (2H, d, J=7.9 Hz), 7,06 (1H, USS), of 7.23 (2H, d, J=7.9 Hz).

2) Trihydrochloride [5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4-(4-were)-2-neopentylene-3-yl]methylamine (160 mg, yield 79%) was obtained as a powder from tert-butyl{[5-[(1H-imidazol-2-ylthio)methyl]-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (200 mg, 0,404 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,01 (9H, s), is 2.40 (3H, s)to 2.67 (3H, s), of 3.07 (2H, USS, 3,74 (2H, USS), 4,17 (2H, s), 7,18 (2H, d, J=7.9 Hz), 7,33 (2H, d, J=7.9 Hz), of 7.70 (2H, s), compared to 8.26 (3H, USS).

Example412

Trihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(pyrimidine-2-ylthio)methyl]pyridine-3-yl}methylamine

1) tert-Butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(pyrimidine-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (380 mg, yield 77%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (500 mg, 1.0 mmol) and 2-mercaptopyrimidine (123 mg, 1.1 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s)to 2.35 (3H, s)to 2.65 (3H, s), and 2.83 (2H, s)4,08 (2H, d, J=4.9 Hz), 4,14 (2H, s), 4,19 (1H, USS), 6,92 (1H, t, J=4.9 Hz), 7,06 (2H, d, J=7.8 Hz), 7,18 (2H, d, J=7.8 Hz), 8,43 (2H, d, J=4,9 Hz).

2) Trihydrochloride {6-methyl-4-(4-were)-2-neopentyl-5-[(pyrimidine-2-ylthio)methyl]pyridine-3-yl}methylamine (180 mg, yield 88%) was obtained as a powder from tert-butyl({6-methyl-4-(4-were)-2-neopentyl-5-[(pyrimidine-2-ylthio)methyl]pyridine-3-yl}methyl)carbamate (200 mg, mmol 0,395) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s)to 2.35 (3H, s), 2,85 (3H, s), 3,17 (2H, USS), of 3.80 (2H, s), 4,18 (2H, s), 7,21-7,13 (5H, m), by 8.22 (3H, OSS), to 8.57 (2H, d, J=4,9 Hz).

Example413

Trihydrochloride [5-{[(5-methoxy-1H-benzimidazole-2-yl)thio]methyl}-6-methyl-4-(4-were)-2-neopentylene-3-yl]methylamine

1) tert-Butyl{[5-{[(5-methoxy-1H-benzimidazole-2-yl)thio]methyl}--methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (530 mg, yield 92%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (500 mg, 1.0 mmol) and 5-methoxy-2-benzimidazolethiol (198 mg, 1.1 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), of 2.33 (3H, s)of 2.64 (3H, s), and 2.83 (2H, s), 3,82 (3H, s)4,07 (2H, d, J=5,1 Hz), 4,22 (2H, s), 4,25 (1H, s), 6,77-6,84 (2H, m), 7,01 (2H, d, J=7.9 Hz), 7,14-7,16 (3H, m), 7,49 (1H, d, J=8,9 Hz).

2) Trihydrochloride [5-{[(5-methoxy-1H-benzimidazole-2-yl)thio]methyl}-6-methyl-4-(4-were)-2-neopentylene-3-yl]methylamine (194 mg, yield 91%) was obtained as a powder from tert-butyl{[5-{[(5-methoxy-1H-benzimidazole-2-yl)thio]methyl}-6-methyl-4-(4-were)-2-neopentylene-3-yl]methyl}carbamate (200 mg, 0,365 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1,02 (9H, s), is 2.30 (3H, s), and 2.83 (3H, s), of 3.12 (2H, USS), of 3.77 (2H, s), 3,81 (3H, s), 4,37 (2H, s), 6,94-7,02 (2H, m), 7,20-7,27 (4H, m), 7,46 (1H, d, J=8,9 Hz), 8,23 (3H, USS).

Example414

The dihydrochloride methyl-3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylate

1) Methyl-3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylate (800 mg, yield 52%) was obtained as a powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methylmethanesulfonate (1.4 g, 2,85 mmol) and methyl-3-HYDR the XI-1H-pyrazole-5-carboxylate (426 mg, 3.0 mmol) in a manner similar to the method of example 33-1).

1H-NMR (CDCl3) δ: 1,02 (9H, s)to 1.37 (9H, s), a 2.36 (3H, s), 2,62 (3H, s), of 2.86 (2H, s)to 3.89 (3H, s), 4,13 (2H, d, J=4.5 Hz), 4,20 (1H, USS), 4,84 (2H, s), 6,13 (1H, s),? 7.04 baby mortality (2H, d, J=7.8 Hz), 7,16 (2H, d, J=7,8 Hz), of 9.89 (1H, USS).

2) Dihydrochloride methyl-3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylate (142 mg, 75%yield) was obtained as a powder from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylate (200 mg, 0,373 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s), is 2.37 (3H, s)2,84 (3H, s), 3,23 (2H, USS), 3,81 (3H, s), a 3.87 (2H, USS), a 4.83 (2H, s), 6,17 (1H, s), 7,25 (2H, d, J=7.9 Hz), 7,33 (1H, d, J=7.9 Hz), 8,29 (3H, USS).

Example415

The dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylic acid

1) 3-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylic acid (914 mg, yield 81%) was obtained as a white solid from methyl 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylate (1,16 g of 2.16 mmol) in a manner similar to the method of example 9-1).

1H-NMR (DMSO-d6) δ: 1.00 and (9H, s)of 1.34 (9H, s), 2,32 (3H, s), of 2.53 (3H, s), 2,69 (2H, s), a 3.87 (2H, d, J=3.2 Hz), to 4.73 (2H, s), the 6.06 (1H, s), 6,83 (1H, t, J=4,1 is C), 7,13-7,21 (4H, m), 12,91 (1H, s).

2) of the Dihydrochloride of 3-{[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylic acid (180 mg, yield 95%) was obtained as a white powder from 3-{[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]methoxy}-1H-pyrazole-5-carboxylic acid (200 mg, 0,383 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: of 1.03 (9H, s), is 2.37 (3H, s), of 2.51 (3H, s), 2,78 (2H, s), 3,85 (2H, s), 4,80 (2H, s)6,09 (1H, s), 7.23 percent (2H, d, J=7.9 Hz), 7,32 (2H, d, J=7.9 Hz), 8,16 (3H, USS).

Example416

The dihydrochloride 4-(methoxycarbonyl)benzyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate

1) 4-(Methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene (of 7.36 g, yield 70%) was obtained as a white solid from 5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylglycol acid (7.8 g, and 18.3 mmol) in a manner similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)of 1.36 (9H, s)to 2.35 (3H, s), of 2.53 (3H, s), 2,87 (2H, s), 3,93 (3H, s), 4,17 (2H, s), to 4.98 (2H, s), 7,02 (2H, d, J=7.9 Hz), to 7.09 (2H, d, J=8,2 Hz), 7,11 (2H, d, J=7.9 Hz), to 7.93 (2H, d, J=8,2 Hz).

2) Dihydrochloride 4-(methoxycarbonyl)benzyl-5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentanoate (181 mg, yield 95%) was obtained as a white powder from 4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-4-were)-6-neopentanoate (200 mg, 0,348 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 and (9H, s), of 2.33 (3H, s), of 2.51 (3H, s), 2,90 (2H, s), 3,83 (2H, s), 3,86 (3H, s), 5,07 (2H, s), 7,12-7,21 (6H, m), 7,87 (2H, d, J=8,3 Hz), 8,13 (3H, USS).

Example417

The dihydrochloride of 4-[({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]carbonyl}oxy)methyl]benzoic acid

1) 4-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]carbonyl}oxy)methyl]benzoic acid (1.68 g, yield 86%) was obtained as a white solid from 4-(methoxycarbonyl)benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentanoate (2.0 g, of 3.48 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 1,01 (9H, s)to 1.37 (9H, s)to 2.35 (3H, s)to 2.55 (3H, s), 2,89 (2H, s), 4,16-4,20 (3H, m), free 5.01 (2H, s), 7,02-7,13 (6H, m), to 7.99 (2H, d, J=8,3 Hz).

2) of the Dihydrochloride of 4-[({[5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylene-3-yl]carbonyl}oxy)methyl]benzoic acid (150 mg, yield 79%) was obtained as a white powder from 4-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-2-methyl-4-(4-were)-6-neopentylene-3-yl]carbonyl}oxy)methyl]benzoic acid (200 mg, 0,357 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 and (9H, s), of 2.34 (3H, s), of 2.51 (3H, s), 2,90 (2H, s), a-3.84 (2H, d, J=5.7 Hz), is 5.06 (2H, s), 7,10-to 7.18 (6H, m), a 7.85 (2H, d, J=8,3 Hz), 8,11 (3H, USS).

Example418

The dihydrochloride of 4-(trifluoromethyl)benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate

1) 4-(Trifluoromethyl)benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (350 mg, yield 85%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and 1-(methyl bromide)-4-(trifluoromethyl)benzene (250 mg, 1.05 mmol) by the method similar to the method of example 169-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6,8 Hz)to 1.37 (9H, s), 2,11-to 2.29 (1H, m), is 2.37 (3H, s), 2,48 (3H, s)of 2.75 (2H, d, J=6.6 Hz), 3,42 (2H, s), a 4.03 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 5,09 (2H, s)6,91 (2H, d, J=7,7 Hz), 7,14 (2H, d, J=7,7 Hz), 7,33 (2H, d, J=8.1 Hz), 7,60 (2H, d, J=8,1 Hz).

2) Dihydrochloride 4-(trifluoromethyl)benzyl[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (283 mg, yield 66%) was obtained as a white powder from 4-(trifluoromethyl)benzyl[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (330 mg, 0,564 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6)δ: 0,97 (6H, d, J=6.6 Hz), 2,09 was 2.25 (1H, m), a 2.36 (3H, s), 2,77 (3H, s), of 3.12 (2H,s), of 3.77 (2H, d, J=5,1 Hz), 5,14 (2H, s), to 7.09 (2H, d, J=8.1 Hz), 7,24 (2H, d, J=8,1 Hz), 7,47 (2H, d, J=8,1 Hz), 7,76 (2H, d, J=8.1 Hz), 8,35 (3H, USS).

Example419

The dihydrochloride of 4-terbisil[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate

1) 4-Terbisil[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (325 mg, yield 86%) was obtained in the ideal of white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and 1-(methyl bromide)-4-fervently (198 mg, 1.05 mmol) by the method similar to the method of example 169-1).

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,11-of 2.26 (1H, m), of 2.38 (3H, s)to 2.46 (3H, s), is 2.74 (2H, d, J=7,4 Hz)to 3.38 (2H, s), was 4.02 (2H, d, J=4.9 Hz), 4,20 (1H, OSS), to 5.00 (2H, s), make 6.90 (2H, d, J=7.9 Hz), 6,88-7,07 (2H, m),7,14 (2H, d, J=7.9 Hz), 7,15-of 7.25 (2H, m).

2) Dihydrochloride 4-terbisil[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (234 mg, yield 82%) was obtained as a white powder from 4-terbisil[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetate (300 mg, 0,561 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,12-of 2.26 (1H, m), of 2.38 (3H, s)2,84 (3H, s), 3,26 (2H, d, J=6.8 Hz), with 3.79 (2H, d, J=4.5 Hz), to 5.03 (2H, s), 7,12 (2H, d, J=7.9 Hz), 7,17-7,39 (6H, m), to 8.57 (3H, USS).

Example420

The dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(2-oxo-2-pyrrolidin-1-retil)pyridine-3-yl]methyl}amine

1) tert-Butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(2-oxo-2-pyrrolidin-1-retil)pyridine-3-yl]methyl}carbamate (120 mg, yield 36%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and pyrrolidine (440 mg, 2,11 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,12 was 2.25 (1H, m), 2,39 (3H, s)to 2.55 (3H, s), is 2.74 (2H, d, J=7,4 Hz), 2,86-of 2.97 (4H, m), or 3.28 (2H, s)to 3.36 (2H, t, J=6.5 Hz), a 4.03 (2H, d, J=4,7 Hz), 4,20 (1H, USS), 7,01 (2H, d, J=7.9 Hz), 7,21 (2H, d, J=7.9 Hz).

2) Dihydrochloride {[2-isobutyl-6-methyl-4-(4-were)-5-(2-oxo-2-pyrrolidin-1-retil)pyridine-3-yl]methyl}amine (62,4 mg, yield 66%) was obtained as a white powder from tert-butyl{[2-isobutyl-6-methyl-4-(4-were)-5-(2-oxo-2-pyrrolidin-1-retil)pyridine-3-yl]methyl}carbamate (100 mg, 0,208 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.26 (1H, m), is 2.40 (3H, s), 2,80 (3H, s), is 2.88 (2H, t, J=6,1 Hz), 3,12-3,29 (4H, m), 3,42 (2H, s), 3,81 (2H, s), 7,17 (2H, d, J=7.9 Hz), 7,38 (2H, d, J=7.9 Hz), 8,43 (3H, USS).

Example421

The dihydrochloride ethyl-1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylate

1) Ethyl-1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylate (330 mg, yield 50%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and ethylpiperidine-4-carboxylate (553 mg, to 3.52 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.27 (3H, t, J=7.2 Hz), of 1.37 (9H, s), and 1.54 (1H, DD, J=13,2, 9.8 Hz), 1,64 is 1.75 (1H, m)to 1.87 (1H, DD, J=13,2, and 2.6 Hz), 2,12-of 2.27 (1H, m), of 2.38 (3H, s), 2.49 USD (3H, s), is 2.74 (2H, d, J=7,2 Hz), 2,81-a 3.01 (3H, m), 3,30 (2H, s), 3,49-of 3.60 (1H, m), is 4.15 (2H, q, J=7.2 Hz), 4,20 (1H, USS), 6,98 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=8,1 Hz).

2) Dihydrochloride ethyl-1-{[5(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylate (8.2 mg, yield 43%) was obtained as white powder from ethyl-1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylate (20 mg, 0,0354 mmol) in a manner similar to the method of example 2-3).

EIMC(M+1):466.

Example422

The dihydrochloride of 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylic acid

1) 1-{[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylic acid (240 mg, yield 87%) was obtained as white powder from ethyl-1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylate (290 mg, 0,513 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 1,01 (6H, d, J=6,4 Hz)to 1.37 (9H, s), 1,48-of 1.62 (1H, m)of 1.73 (1H, d, J=11,1 Hz), 1,89 (1H, d, J=a 10.6 Hz), 2,14-to 2.29 (1H, m), is 2.40 (3H, s), is 2.74 (3H, s), 2.77-to of 3.00 (2H, m), 3,06 (2H, d, J=6.0 Hz), 3,42 (2H, s), 3,53 (1H, d, J=12,8 Hz), 4,10 (2H, d, J=5,09 Hz), 4,20 (1H, USS), 4.26 deaths (1H, d, J=12,6 Hz)and 4.65 (1H, s), 7,01 (2H, d, J=7.5 Hz), 7,27 (2H, d, J=7.5 Hz).

2) of the Dihydrochloride of 1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylic acid (220 mg, yield 100%) was obtained as a white powder from 1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}piperidine-4-carboxylic acid (230 mg, 0,428 mmol) in a manner similar to the method of example 2-3).

EIC(M+1):438

Example423

The dihydrochloride of N-2-substituted-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ndimethylacetamide

1) tert-Butyl{[5-[2-(2-adamantylamine)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (50 mg, yield 13%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (300 mg, 0,703 mmol) and 2-adamantanamina (396 mg, 2,11 mmol) in a manner similar to the method of example 311-1).

1H-NMR (CDCl3) δ: of 0.95 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 1,53-to 1.63 (2H, m), 1,67-1,84 (9H, m), 2,12-of 2.26 (1H, m), 2,39 (3H, s), to 2.57 (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,30 (2H, s), of 3.97 (2H, d, J=8.1 Hz), 4,06 (2H, d, J=5,09 Hz), 4,20 (1H, USS), 4,22 (1H, s), the 5.45 (1H, d, J=8,3 Hz), of 6.96 (2H, d, J=7.9 Hz), 7,22 (2H, d, J=7.9 Hz).

2) of the Dihydrochloride of N-2-substituted-2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]ndimethylacetamide (45.1 mg, yield 100%) was obtained as a white powder from tert-butyl{[5-[2-(2-adamantylamine)-2-oxoethyl]-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (48 mg, 0,0857 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.4 Hz), 1,47 (2H, d, J=12.1 Hz), 1,63-1,94 (12H, m), 2,08-of 2.26 (1H, m), is 2.40 (3H, s), 2,80 (3H, s), up 3.22 (2H, d, J=of 5.84 Hz), 3,44 (2H, s), 3,81 (2H, s), 7,19 (2H, d, J=7.9 Hz), 7,34 (2H,, d, J=7.9 Hz), 7,87 (1H, d, J=7,7 Hz), 8,49 (3H, USS).

Example424

The dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-(2-thienylmethyl)ndimethylacetamide

1) [5-{[(is pet-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, at 1.17 mmol) and thiophene-2-methylamine (133 mg, at 1.17 mmol) was dissolved in tetrahydrofuran (5 ml) was added under ice cooling diethylthiophosphate (286 mg, about 1.75 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, the Reaction mixture was poured into a saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{2-oxo-2-[(2-thienylmethyl)amino]ethyl}pyridine-3-yl)methyl]carbamate (493 mg, yield 81 %) as a white powder.

1H-NMR (CDCl3) δ: of 0.96 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,11-of 2.27 (1H, m), is 2.37 (3H, s), of 2.56 (3H, s), was 2.76 (2H, d, J=7,2 Hz), 3,30 (2H, s), a 4.03 (2H, d, J=4.9 Hz), 4,20 (1H, USS), 4,51 (2H, d, J=5.7 Hz), 6,85-to 7.00 (4H, m), 7,16 (2H, d, J=7.9 Hz), 7.23 percent (1H, DD, J=5,1, 1,1 Hz).

2) of the Dihydrochloride of 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-(2-thienylmethyl)ndimethylacetamide (300 mg, yield 66%) was obtained as a white powder from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{2-oxo-2-[(2-thienylmethyl)amino]ethyl}pyridine-3-yl)methyl]carbamate (480 mg, of 0.92 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.6 Hz), 2,12 is 2.33 (1H, m), is 2.37 (3H, s), 2,47 (3H, s), 2,59 (2H, s), or 3.28 (2H, s), 3,76 (2H, s), 4,37 (H, d, J=5.8 Hz), 6.89 in-6,94 (1H, m), 6,97 (1H, DD, J=5.0 and 3.5 Hz), the 7.43 (1H, DD, J=5.0 and 1.2 Hz), 8,04 (3H, USS).

Example425

Trihydrochloride 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-(pyridine-3-ylmethyl)ndimethylacetamide

1) tert-Butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{2-oxo-2-[(pyridine-3-ylmethyl)amino]ethyl}pyridine-3-yl)methyl]carbamate (394 mg, yield 65%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and 3-(aminomethyl)pyridine (133 mg, 1,17 mmol) in a manner similar to the method of example 424-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 2,14-to 2.29 (1H, m), of 2.38 (3H, s)to 2.55 (3H, s)of 2.75 (2H, d, J=7,2 Hz), was 4.02 (2H, d, J=4.9 Hz), 4,20 (1H, USS), 4,35 (2H, d, J=5.8 Hz), vs. 5.47 (1H, s), to 6.88 (2H, d, J=7.9 Hz), to 7.15 (2H, d, J=7,7 Hz), 7,54 (1H, d, J=7,7 Hz), to 8.45 (1H, d, J=1.5 Hz), 8,55 (1H, DD, J=4,7, 1.3 Hz).

2) Trihydrochloride 2-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-N-(pyridine-3-ylmethyl)ndimethylacetamide (380 mg, yield 98%) was obtained as a white powder from tert-butyl[(2-isobutyl-6-methyl-4-(4-were)-5-{2-oxo-2-[(pyridine-3-ylmethyl)amino]ethyl}pyridine-3-yl)methyl]carbamate (380 mg, of 0.74 mmol) by the method similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-of 2.24 (1H, m), is 2.40 (3H, s), 2,78 (3H, s), 3,20 (2H, d, J=7,4 Hz), of 3.43 (2H, s), 4,37 (2H, d, J=5.7 Hz), 7,16 (2H, d, J=8.1 Hz), 7,33 (2H, d, J=8.1 Hz), 8,00 (1H, DD, J=8,0, 5.6 Hz), of 8.28 (1H, d, J=8.1 Hz), 8,48 (3H, USS), 8,70-8,77 (1H, m), 8,80 cent to 8.85 (1H, m).

Example 426

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylate

1) [5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol), methyl-4-aminothiophene-3-carboxylate (184 mg, 1,17 mmol) and hexaphosphate 0-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU, 1.0 g, 1,75 mmol) was dissolved in N,N-dimethylformamide (10 ml) and the mixture was stirred at room temperature for 24 h the Reaction mixture was poured into a saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified column chromatography on silica gel to obtain methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylate (440 mg, yield 66%) as a white powder.

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.4 Hz), of 1.40 (9H, s), 2,24 is 2.33 (1H, m)to 2.35 (3H, s), of 2.53 (3H, s), 2,77 (2H, d, J=7,2 Hz), 3,52 (2H, s), with 3.79 (3H, s)4,06 (2H, d, J=4,1 Hz), 4,20 (1H, USS), 7,02 (2H, d, J=7.9 Hz), 7,17 (2H, d, J=7.9 Hz), 7.95 is-7,98 (1H, m), 7,98-8,02 (1H, m).

2) Dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylate (161 mg, yield 65%) was obtained as white is orosco of methyl-4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylate (262 mg, 0.46 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,98 (6H, d, J=6.6 Hz), 2,11-of 2.27 (1H, m)to 2.35 (3H, s), 2,48 (3H, s), 2,80 (2H, s), 3,14 (2H, s), 3,76-3,86 (5H, m), 7,17 (2H, d, J=7.9 Hz), 7,32 (2H, d, J=7.9 Hz), 7,80 (1H, d, J=3.2 Hz), compared to 8.26-8,45 (3H OSS), RS 9.69 (s, 1H).

Example427

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylic acid (183 mg, yield 67%) was obtained as a white powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylate (280 mg, 0,495 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.40 (9H, s), 2,11-of 2.24 (1H, m), a 2.36 (3H, s), 2,52 (3H, s), 2,78 (2H, s)to 3.49 (2H, s), a 4.03 (2H, s), 4,20 (1H, USS), 6,98-of 7.25 (4H, m), a 7.85-with 8.05 (2H, m).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylic acid (143 mg, yield 64%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)thiophene-3-carboxylic acid (170 mg, 0,428 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,11-of 2.27 (1H, m)to 2.35 (3H, s)of 2.50 (3H, s), and 2.79 (2H, s), 3,14 (2H, s), 3,81 (2H, s), 7,17 (2H, d, J=8.1 Hz),7,30 (2H, d, J=8.1 Hz), 7,79 (1H, d, J=3.6 Hz), 8,29 (1H, d, J=3.6 Hz), 8,33-8,44 (3H, s)of 9.89 (1H, s).

Example428

The dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate

1) Methyl-4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (442 mg, yield 67%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and methyl-4-aminobenzoate (177 mg, 1,17 mmol) in a manner similar to the method of example 426-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), to 1.38 (9H, s), 2,15-of 2.28 (1H, m), 2.63 in (3H, s), 2,77 (2H, d, J=7,4 Hz), 3,47 (2H, s)to 3.89 (3H, s)4,06 (2H, d, J=5,1 Hz), 4,20 (1H, USS), 7,01 (2H, d, J=7.9 Hz), 7.23 percent (2H, d, J=7.9 Hz), 7,42 (2H, d, J=8.7 Hz), of 7.97 (2H, d, J=8.7 Hz).

2) Dihydrochloride methyl-4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (142 mg, yield 97%) was obtained as a white powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (154 mg, 0,275 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2,10-of 2.30 (1H, m), a 2.36 (3H, s), 2.49 USD (3H, s), 2,71 (2H, s), 3,01 (2H, s), of 3.77 (2H, s), 3,82 (3H, s), 7,17 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), a 7.62 (2H, d, J=8,9 Hz), of 7.90 (2H, d, J=8,9 Hz), 8,15 (3H, USS).

Example429

The dihydrochloride of 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methyl who enyl)pyridine-3-yl]acetyl}amino)benzoic acid

1) 4-({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid (275 mg, yield 100%) was obtained as a white powder from methyl 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate (280 mg, 0,500 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: 0,99 (6H, d, J=6.2 Hz), of 1.37 (9H, s), 2,12-of 2.27 (1H, m)to 2.35 (3H, s), 2,87 (3H, s), 3,19 (2H, s), a 3.87 (2H, s), is 4.15 (2H, d, J=6.2 Hz), 4,20 (1H, USS), 7,10 (2H, d, J=8.1 Hz), 7,25 (2H, d, J=8,1 Hz), to 7.68 (2H, d, J=8.5 Hz), 8,68 (2H, d, J=8,5 Hz).

2) Dihydrochloride 4-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid (235 mg, yield 92%) was obtained as a white powder from 4-({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoic acid acid (270 mg, 0,495 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,12-of 2.28 (1H, m), is 2.37 (3H, s)of 2.50 (3H, s), 2,80 (2H, s)and 3.15 (2H, s), 3,82 (2H, s), 7,20 (2H, d, J=8.1 Hz), 7,34 (2H, d, J=8.1 Hz), 7,60 (2H, d, J=8,9 Hz), 7,87 (2H, d, J=8,9 Hz), 8,35 (3H, USS).

Example430

The dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylate

1) Ethyl-2-({[(benzyloxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylate (3.5 g, 10.9 mmol) was dissolved in 30% solution (50 ml) of hydrogen bromide in acetic Ki the lot and the solution was stirred at room temperature for 2 hours A white precipitate was collected by filtration and was dissolved in a saturated aqueous solution of sodium bicarbonate. The resulting solution was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. Insoluble substances were filtered off and the filtrate was concentrated under reduced pressure to obtain ethyl-2-(aminomethyl)-1,3-thiazole-4-carboxylate (793 mg, yield 40%) as oil. Of oil (793 mg) and [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (454 mg, 1.07 mmol) was obtained as a white powder (ethyl-2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylate (649 mg, yield 100%) in a manner similar to the method of example 424-1).

1H-NMR (CDCl3) δ: 0,97 (6H, d, J=6.6 Hz), of 1.35 to 1.47 (12H, m), 2,13-of 2.28 (1H, m), a 2.36 (3H, s), of 2.53 (3H, s)of 2.75 (2H, d, J=7,2 Hz), to 3.34 (2H, s), a 4.03 (2H, d, J=5.3 Hz), 4,20 (1H, USS), 4,43 (2H, q, J=7.2 Hz), of 4.66 (2H,, d, J=6.0 Hz), 6,93 (2H, d, J=7.9 Hz), 7,14 (2H, d, J=7.9 Hz), 8,14 (1H, s).

2) Dihydrochloride ethyl-2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylate (138 mg, yield 81%) was obtained as white powder from ethyl-2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylate (178 mg, 0,299 mmol) in a manner similar to the method of example 2-3).

1H-NMR (VHI is-d 6) δ: 0,98 (6H, d, J=6.4 Hz), is 1.31 (3H, t, J=7.2 Hz), 2,10-of 2.23 (1H, m), of 2.38 (3H, s), 2.49 USD (3H, s), 2,77 (2H, s), 3,14 (2H, s)to 3.41 (2H, s), 3,80 (2H, s), or 4.31 (2H, q, J=7.2 Hz), 4,51 (2H, d, J=5.8 Hz), 7,17 (2H, d, J=8.1 Hz), 7,32 (2H, d, J=8.1 Hz), at 8.36 (3H, USS), 8,91 (1H, s).

Example431

The dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylic acid

1) 2-[({[5-{[(tert-Butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylic acid (438 mg, yield 100%) was obtained as white powder from ethyl-2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylate (460 mg, 0,773 mmol) in a manner similar to the method of example 9-1).

1H-NMR (CDCl3) δ: of 0.93 (6H, d, J=6.6 Hz), of 1.34 (9H, s), 2,09-of 2.26 (1H, m), of 2.34 (3H, s), 2.40 a (2H, s), 2,48 (3H, s), 3,24 (2H, s), 3,80 (2H, s), 4,20 (1H, USS), 4,48 (2H, d, J=5.8 Hz), to 7.09 (2H, d, J=7,0 Hz), 7,19 (2H,, d, J=7,0 Hz), 8,39 (1H, s).

2) of the Dihydrochloride of 2-[({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylic acid (235 mg, yield 91%) was obtained as a white powder from 2-[({[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)methyl]-1,3-thiazole-4-carboxylic acid (270 mg, 0,495 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 1.00 m (6H, d, J=6.6 Hz), 2,12-of 2.28 (1H, m), is 2.37 (3H, s)of 2.50 (3H, s), 280 (2H, (C)and 3.15 (2H, s), 3,82 (2H, s), 7,20 (2H, d, J=8.1 Hz), 7,34 (2H, d, J=8.1 Hz), 7,60 (2H, d, J=8,9 Hz), 7,87 (2H, d, J=8,9 Hz), 8,35 (3H, USS).

Example432

The dihydrochloride methyl-1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}prolinate have been obtained

1) Methyl-1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}prolinate have been obtained (456 mg, yield 72%) was obtained as a white powder from [5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetic acid (500 mg, 1,17 mmol) and monohydrochloride of methylpropene (194 mg, 1,17 mmol) in a manner similar to the method of example 426-1).

1H-NMR (CDCl3) δ: 0,98 (6H, d, J=6.6 Hz), of 1.37 (9H, s), 1,84 is 2.00 (3H, m), is 2.05 (3H, s), 2,08-of 2.24 (2H, m)of 2.75 (3H, s), 3,15-3,26 (2H, m), of 3.48 (2H, s), 3,71 (3H, s), 4,11-is 4.21 (3H, m), or 4.31-4,55 (2H, m), 7,02-to 7.15 (2H,, m), 7,28-7,41 (2H, m).

2) Dihydrochloride methyl-1-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}prolinate have been obtained (277,5 mg, yield 64%) was obtained as a white powder from methyl-1-{[5-{[(tert-butoxycarbonyl)amino]methyl}-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}prolinate have been obtained (456 mg, 0,848 mmol) in a manner similar to the method of example 2-3).

1H-NMR (DMSO-d6) δ: 0,97 (6H, d, J=6.4 Hz), 1,76 is 1.91 (3H, m), 2,04-of 2.24 (2H, m), is 2.40 (3H, s)to 2.65 (3H, s), 2,96 (2H, s), 3,17 (2H, t, J=6,7 Hz), 3,42 (2H, s), 3,61 (3H, s), of 3.77 (2H, s), 4,19-4,32 (2H, m), to 7.15 (2H, d, J=7,4 Hz), 7,37 (2H, d, J=7,4 Hz), 8,10 (3H, s).

Example433

The dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-methylphe who yl)pyridine-3-yl]-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide

To a solution of tert-butyl{[5-amino-2-isobutyl-6-methyl-4-(4-were)pyridine-3-yl]methyl}carbamate (383 mg, 1.0 mmol) in tetrahydrofuran (5 ml) was added 3-cyanobenzoate (245 mg, 1.5 mmol) and then triethylamine (280 μl, 2.0 mmol). The mixture was stirred for 18 hours was Added to the reaction mixture, a saturated aqueous solution of sodium bicarbonate (5 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in ethanol (5 ml) was added hydroxylamine hydrochloride (192 mg, 3.0 mmol) and sodium carbonate (420 mg, 4.0 mmol) and the mixture was stirred at 80°C for 15 hours was Added to the reaction mixture distilled water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain oil. To a solution of the obtained oil in tetrahydrofuran (3 ml) was added N,N'-carbonyldiimidazole (324 mg, 2.0 mmol) and the mixture was stirred at 65°C for 2 hours was Added to the reaction mixture, a saturated aqueous solution of sodium carbonate (5 ml) and the mixture was extracted with ethyl acetate. The organization is a mini layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was purified column chromatography on silica gel with obtaining oil. To a solution of the obtained oil in ethyl acetate (2 ml) was added 4n. an ethyl acetate solution of hydrogen chloride (2 ml) and the mixture was stirred at room temperature for 3 hours the Solvent is evaporated under reduced pressure and the obtained residue was led from hexane to obtain the dihydrochloride of N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide (115 mg, yield 21%) as a white powder.

1H-NMR (DMSO-d6) δ: 0,99 (6H, d, J=6.6 Hz), 2.21 are to 2.29 (1H, m)to 2.29 (3H, s)of 2.50 (3H, s), 2,96 (2H, s), 3,82 (2H, s), 7,21 (4H, s), a 7.62 (1H, t, J=7.5 Hz), 7,79 (1H, d, J=7.5 Hz), to 7.93 (1H, d, J=7.5 Hz), of 8.25 (3H, USS), 10,13 (1H, USS), 13,12 (1H, USS).

Experimental example 1

The definition of inhibiting dipeptidyl peptidase IV activity in plasma of rats

The reaction was carried out according to the method of Raymond et al. (Diabetes, vol. 47, pp. 1253-1258, 1998), using 96-well flat-bottomed plate at 30°C. To a mixture of water (69 μl), 1M Tris-HCl buffer (10 μl, pH 7.5) and 1 mm aqueous solution of Gly-Pro-p-NA (100 ml) was added N,N-dimethylformamide solution (1 μl)containing the test compound, resulting in the mixed solution. To the obtained mixed solution was added to the plasma (20 μl), prepared from the blood of rats SD common is the procedure, and started enzymatic reaction at 30°C. was Measured by optical density after 0 h and 1 h using a microplate reader at a wavelength of 405 nm and determined the increment (∆ODs). At the same time defined the increment (∆ODc), the optical density of the reaction mixture without the test compound and the increment (∆ODb) optical density of the reaction mixture without the test compound and the enzyme was calculated percent inhibition of enzyme activity of dipeptidylpeptidase IV according to the following formula:

{1-[(ΔODs-ΔODb)/(ΔODc-ΔODb)]}×100

Inhibiting dipeptidyl peptidase IV activity of the test compounds, expressed in the value of the IC50(nm), shown in table 5.

Table 5
The test compound (example no.) The IC value50(nm)
1520

As shown above, the compound of the present invention has a high inhibiting dipeptidyl peptidase IV activity and useful as a tool for prevention or treatment of diabetes and the like.

Experimental example 2

The definition of inhibiting dipeptidyl peptidase IV activity in plasma of rats

Inhibit the expansion of dipeptidyl peptidase IV activity of the test compounds was determined by the method of experimental example 1. The results are shown in table 6.

Table 6
The test compound (example no.) The IC value50(nm)
1325
2212
265,1
4056
170100
21012
2677,4
3053,5
31220
33619
35015
42116
4227,3

As shown above, the compound of the present invention has a high inhibiting dipeptidyl peptidase IV activity and therefore is useful as a means for prevention or treatment of diabetes and the like.

Example 1 obtaining a composition(manufacture of capsules)

1) connection example 130 mg
2) fine powder of cellulose10 mg
3) lactose19 mg
4) magnesium stearate1 mg
Total60 mg

Components 1), 2), 3) and 4) are mixed and filled with a mixture of gelatin capsules.

Example 2 obtaining a composition(manufacture of tablets)

1) connection example 130 mg
2) lactose50 mg
3) corn starch15 mg
4) calcixerollic44 mg
5) magnesium stearate1 mg
Total for 1000 tablets140 g

All number of components 1), 2) and 3) and 30 g of component 4) mix with water, dried in vacuum and granularit. The granules are mixed is 14 g component 4) and 1 g of the component 5), and the mixture is pressed in a tablet machine, deliver 1000 tablets containing 30 mg of compound of example 1 on the pill.

Industrial applicability

The compound of the present invention has a high inhibitory peptidase activity and useful as a tool for prevention or treatment of diabetes and the like.

This application is based on filed in Japan patent application No. 373776/2003, 30491/2004 and 165977/2004, the contents of which are included in this description by reference.

1. The compound represented by the formula

where R1and R2are the same or different and each represents:
(1) C1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group1-6alkoxycarbonyl group and1-6alkoxygroup;
(2)6-14aryl group, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group; or
(3) (C7-13aracelio group;
R3represents a C6-14aryl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, halogen atom, With1-6alkoxycarbonyl group, carboxyl group, hydro is a system of groups, With1-6alkoxygroup, optionally substituted by 1 to 3 halogen atoms;
R4represents an amino group;
L represents a C1-10alkylenes group;
Q is a bond, C1-10alkylenes group or2-10alkenylamine group; and
X represents:
(1) a hydrogen atom;
(2) cyano;
(3) (3A) a carboxyl group;
(3b) karbamoilnuyu group;
(3C)1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group1-6alkoxycarbonyl group and1-6alkylcarboxylic;
(3d) aromatic heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and1-6alkoxycarbonyl group;
(3E) nah heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;
(3f)7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group1-6alkoxycarbonyl group, halogen atom, ceanography, nitro, C1-6alkoxygroup,1-6alkyls Honiley group and 1-6alkyl group, (C1-6alkyl group optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group);
(3g) karbamoilnuyu group, mono - or disubstituted With1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;
(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted With1-6alkyl group optionally substituted by 1 to 3 halogen atoms;
(3i)1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;
(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group;
(3k)7-13aralkylamines group, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy-group, carboxyl group, With1-6alkoxycarbonyl group and1-6alkyl group;
(3l) aromatic heterocyclyl-C1-6alkylcarboxylic group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and1-6alkoxycarbonyl group;
(3m)1-6alkylsulfonyl group, optionally substituted by 1-3 mixing is italiani, selected from a carboxyl group, carbamoyl group and1-6alkoxycarbonyl group;
(3n)6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group1-6alkoxycarbonyl group and1-6alkylsulfonyl group;
(3O) nitrogen-containing heterocyclyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, carboxyl group and1-6alkoxycarbonyl group;
(3P)6-14arylacetamides heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3q)7-13erolkilutera heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3r) nah heterocyclyl-oxycarbonyl group;
(3s) phosphonopropyl, optionally mono - or disubstituted With1-6alkyl group;
(3t) aromatic heterocyclyl-C7-13aracelikarsaalyna group;
(3u)3-10cycloalkyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(3v)6-14arylcarbamoyl group, optionally substituted -3 substituents, selected from amino, optionally mono - or disubstituted by C1-6alkyl group, carboxyl group, With1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group;
(3w) aromatic heterocyclyl-karbamoilnuyu group, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(4) (4A)1-6alkylcarboxylic;
(4b)1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(4C)6-14alloctype, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group1-6allylthiourea, carbamoyl group1-6alkoxygroup,1-6alkylsulfonyl group1-6alkylsulfonyl group and1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);
(4d) a 5 - or 6-membered aromatic geterotsiklicheskikh, optionally substituted 1-3 will replace the guides and selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(4E) condensed aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4f) aromatic heterocyclyl-C1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group; or
(4g) aromatic heterocyclyl-C6-14alloctype;
(5) (5A) C1-6allylthiourea, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(5b)6-14killigrew, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group, C1-6ancilliary and carbamoyl group, or
(5s) 5 - or 6-membered aromatic heterocyclisation, optionally substituted by 1-3 substituents selected from C1-6alkyl groups, amoxilina group, With1-6alkoxycarbonyl group and carbamoyl group;
(6) (6A) amino group;
(6b) C1-6alkoxycarbonyl1-10alkylamino;
(6C) carboxin1-10alkylamino;
(6d)7-13arachidonoylethanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6E) carbamoylating;
(6f) a mono - or dis1-6alkylcarboxylic;
(6g)1-6alkylsulfonamides;
(6h)6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group;
(6i) aromatic heterocyclyl-sulfonylamino, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino;
(6j) mono - or di(C1-6alkylsulphonyl)amino group;
(6k)3-10cycloalkylcarbonyl;
(6l)6-14arylcarboxamide, optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl group, a C1-6alkoxygroup, carboxyl group, With1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group;
(6m)7-13aralkylamines;
(6n)8-13arylalkylamine;
(6o) aromatic heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group7-13aranceles group1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6) nitrogen-containing heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6q)6-14arylacetamides heterocyclyl-carbonylation;
(6r) tetrahydroprotoberberine;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-bestfurnitureonline.com;
(6t)1-6alkoxycarbonylmethyl, optionally substituted C1-6alkoxycarbonyl group;
(6u)6-14aryloxypropanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6v)7-13aralkylamines or
(6w) aromatic hetero is iklil-carbamoylating, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) Oxymetazoline;
(7C) dioxoimidazolidin, optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7d) oxopiperidin;
(7E) dioxopiperazinyl;
(7f) oxodegradable;
(7g) dikshithar;
(7h) oxazolyl, optionally substituted C1-6alkoxycarbonyl group;
(7i) dioxoimidazolidin or dioxothiazolidine, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7k) 1,3(2H,5H)-dioxotetrahydrofuran[1,5-a]pyridinyl;
(7l) 1,3(2H,5H)-dioxo-10,10A-dihydroimidazo[1,5-b]ethenolysis or
(7m)6-14aryl group, optionally substituted C1-6alkoxycarbonyl group;
when the condition is and, that when X represents ethoxycarbonyl group, Q represents a C1-10alkylenes group or2-10alkynylamino group, and that the compound is not 2,6-aminobutiramida 3-aminomethyl-4-(4-forfinal)-5-pentylpyridine, or its salt.

2. The compound according to claim 1, where X is a
(2) cyano;
(3) (3A) a carboxyl group;
(3b) karbamoilnuyu group;
(3C) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and1-6alkylcarboxylic;
(3d) aromatic heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group;
(3E) nah heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;
(3f)7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group, halogen atom, ceanography, nitro, C1-6alkoxygroup,1-6alkylsulfonyl group the s and C 1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);
(3g) karbamoilnuyu group, mono - or disubstituted With1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;
(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms;
(3i)1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;
(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group;
(3K)7-13aralkylamines group, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy-group, carboxyl group, C1-6alkoxycarbonyl group and1-6alkyl group;
(3l) aromatic heterocyclyl-C1-6alkylcarboxylic group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(3m)1-6alkylsulfonyl group, optionally substituted by 1-3 will replace the guides and selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(3n)6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylsulfonyl group;
(3O) nitrogen-containing heterocyclyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, carboxyl group and C1-6alkoxycarbonyl group;
(3P)6-14arylacetamides heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3q)7-13erolkilutera heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3r) nah heterocyclyl-oxycarbonyl group;
(3s) phosphonopropyl, optionally mono - or disubstituted by C1-6alkyl group;
(3t) aromatic heterocyclyl-C7-13aracelikarsaalyna group;
(3u)3-10cycloalkyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(3v)6-14arylcarbamoyl group, optionally substituted by 1-3 what zamestitelyami, selected from amino, optionally mono - or disubstituted by C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group; or
(3w) aromatic heterocyclyl-karbamoilnuyu group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4) (4A)1-6alkylcarboxylic;
(4b)1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(4C)6-14alloctype, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group1-6allylthiourea, carbamoyl group, C1-6alkoxygroup, C1-6alkylsulfonyl group1-6alkylsulfonyl group and1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group);
(4d) a 5 - or 6-membered aromatic geterotsiklicheskikh, optionally substituted 1-3 mandated what teli, selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group), carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(4E) condensed aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4f) aromatic heterocyclyl-C1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or
(4g) aromatic heterocyclyl-C6-14alloctype;
(5) (5A)1-6allylthiourea, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(5b)6-14killigrew, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group1-6ancilliary and carbamoyl group, or
(5s) 5 - or 6-membered aromatic heterocyclisation, optionally substituted by 1-3 substituents selected from C1-6alkyl groups, amoxilina group, With1-6alkoxycarbonyl group and carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) Oxymetazoline;
(7C) dioxoimidazolidin, optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7d) oxopiperidin;
(7E) dioxopiperazinyl;
(7f) oxodegradable;
(7g) dikshithar;
(7h) oxazolyl, optionally substituted C1-6alkoxycarbonyl group;
(7i) dioxoimidazolidin or dioxothiazolidine, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and1-6alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and1-6alkoxycarbonyl group;
(7k) 1,3(2H,5H)-dioxotetrahydrofuran[1,5-a]pyridinyl;
(7l) 1,3(2H,5H)-dioxo-10,10A-dihydroimidazo[1,5-b]ethenolysis or
(7m)6-14aryl group, optionally substituted C1-6alkoxycarbonyl group.

3. The compound according to claim 1, where R1and R2are the same or different and each represent a 1-10alkyl group, optionally substituted by 1-3 substituents selected from C3-10cycloalkyl group1-6alkoxycarbonyl group and1-6alkoxygroup.

4. The compound according to claim 1, where R represents a C6-14aryl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group optionally substituted by 1 to 3 halogen atoms, and halogen atom.

5. The compound according to claim 1, where Q is a bond.

6. The compound according to claim 1, where X is a
(3) (3A) a carboxyl group;
(3b) karbamoilnuyu group;
(3C) C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and1-6alkylcarboxylic;
(3d) aromatic heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group and1-6alkoxycarbonyl group;
(3E) nah heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;
(3f)7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from carboxyl GRU is dust, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group, halogen atom, ceanography, nitro, C1-6alkoxygroup,1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);
(3g) karbamoilnuyu group, mono - or disubstituted by C1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;
(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted With1-6alkyl group optionally substituted by 1 to 3 halogen atoms;
(3i)1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;
(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C1-6alkyl group;
(3k)7-13aralkylamines group, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy-group, carboxyl group, C1-6alkoxycarbonyl group and1-6alkyl group;
(3l) aromatic heterocyclyl-C1-6alkylcarboxylic group, optionally substituted 13 deputies, selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(3m)1-6alkylsulfonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and1-6alkoxycarbonyl group;
(3n)6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and1-6alkylsulfonyl group;
(3O) nitrogen-containing heterocyclyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, carboxyl group and1-6alkoxycarbonyl group;
(3P)6-14arylacetamides heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3q)7-13erolkilutera heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3r) nah heterocyclyl-oxycarbonyl group;
(3s) phosphonopropyl, optionally mono - or disubstituted by C1-6alkyl group;
(3t) aromatic heterocyclyl-C7-13aracelikarsaalyna group;
(3u)3-10cycloalkyl-C1-6alkoxycarbonyl group, optionally substituted 1 - substituents, selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(3v)6-14arylcarbamoyl group, optionally substituted by 1-3 substituents selected from amino, optionally mono - or disubstituted With1-6alkyl group, carboxyl group, With1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group; or
(3w) aromatic heterocyclyl-karbamoilnuyu group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4) (4A) C1-6alkylcarboxylic;
(4b)1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(4C)6-14alloctype, optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group1-6allylthiourea, carbamoyl group, C1-6alkoxygroup,1-6alkylsulfonyl group, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected is from a carboxyl group, C1-6alkoxycarbonyl group and carbamoyl group);
(4d) a 5 - or 6-membered aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from C1-6alkyl groups With1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4E) condensed aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4f) aromatic heterocyclyl-C1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or
(4g) aromatic heterocyclyl-C6-14alloctype;
(5) (5A) C1-6allylthiourea, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(5b)6-14killigrew, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group, C1-6ancilliary and carbama the school group, or
(5s) 5 - or 6-membered aromatic heterocyclisation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group; or
(6) (6A) amino group;
(6b)1-6alkoxycarbonyl1-10alkylamino;
(6C) carboxin1-10alkylamino;
(6d)7-13arachidonoylethanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6E) carbamoylating;
(6f) a mono - or dis1-6alkylcarboxylic;
(6g) C1-6alkylsulfonamides;
(6h)6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group;
(6i) aromatic heterocyclyl-sulfonylamino, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6alkylsulphonyl)amino;
(6j) mono - or di(C1-6alkylsulphonyl)amino group;
(6k)3-10cycloalkylcarbonyl;
(6l)6-14arylcarboxamide, optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated1-6alkyl group, a C1-6alkoxygroup, carboxy who enoy group, With1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group;
(6m)7-13aralkylamines;
(6n)8-13arylalkylamine;
(6o) aromatic heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group7-13aranceles group1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6) nitrogen-containing heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6q)6-14arylacetamides heterocyclyl-carbonylation;
(6r) tetrahydroprotoberberine;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-bestfurnitureonline.com;
(6t)1-6alkoxycarbonylmethyl, optionally substituted C1-6alkoxycarbonyl group;
(6u)6-14aryloxypropanolamine, optionally substituted 13 deputies, selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6v)7-13aralkylamines; or
(6w) aromatic heterocyclyl-carbamoylating, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group.

7. The compound according to claim 1, where X represents a carboxyl group.

8. The compound according to claim 1, which is a
5-(aminomethyl)-2-methyl-4-(4-were)-6-neopentylglycol acid;
5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)nicotinic acid;
methyl-3-{[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]methoxy}-1-methyl-1H-pyrazole-4-carboxylate;
{[2-isobutyl-6-methyl-4-(4-were)-5-(2-morpholine-4-yl-2-oxoethyl)pyridine-3-yl]methyl}amine;
methyl-3-({[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]acetyl}amino)benzoate;
N-[5-(aminomethyl)-6-isobutyl-2-methyl-4-(4-were)pyridine-3-yl]isoxazol-4-carboxamid
or its salt.

9. Agent for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity, containing a compound according to claim 1 or its salt.

10. Inhibitor of peptidases containing compound according to claim 1 or its salt.

11. The inhibitor of claim 10, where peptidase represents dipeptide is tadasu-IV.

12. The use of compounds according to claim 1 or its salt to obtain funds for the prevention or treatment of diabetes, diabetic complications, impaired glucose tolerance or obesity.

13. The use of compounds according to claim 1 or its salt to obtain an inhibitor of peptidases.

14. A method of preventing or treating diabetes, diabetic complications, impaired glucose tolerance or obesity in a mammal, comprising administration to the mammal of a compound according to claim 1 or its salt.

15. Method of inhibiting the peptidases in a mammal, comprising administration to the mammal of a compound according to claim 1 or its salt.

16. The method of obtaining the compound represented by the formula

where R1, R2, R3and Q are as defined in claim 1;
La is a bond or C1-9alkylenes group; and
Ha is a
(1) a hydrogen atom;
(3) (3A) a carboxyl group;
(3b) karbamoilnuyu group;
(3C)1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and1-6alkylcarboxylic;
(3d) aromatic heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents, vibrancies carboxyl group, carbamoyl group, thiocarbamoyl group and C1-6alkoxycarbonyl group;
(3E) nah heterocyclyl-C1-6alkoxycarbonyl group, optionally substituted C1-6alkyl group;
(3f)7-13aracelikarsaalyna group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group, halogen atom, ceanography, nitro, C1-6alkoxygroup,1-6alkylsulfonyl group and1-6alkyl group, (C1-6alkyl group optionally substituted by 1-3 substituents selected from halogen atom, carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group);
(3g) karbamoilnuyu group, mono - or disubstituted With1-6alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and C1-6alkoxygroup;
(3h) carbamoyl1-6alkylcarboxylic group, optionally mono - or disubstituted by C1-6alkyl group optionally substituted by 1 to 3 halogen atoms;
(3i)1-6alkoxycarbonyl1-6alkylcarboxylic group, optionally substituted C1-6alkyl group;
(3j) a mono - or dis3-10cycloalkylcarbonyl group, optionally substituted C-6 alkyl group;
(3k)7-13aralkylamines group, optionally substituted by 1-3 substituents selected from halogen atom, hydroxy-group, carboxyl group, C1-6alkoxycarbonyl group and1-6alkyl group;
(3l) aromatic heterocyclyl-C1-6alkylcarboxylic group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(3m) C1-6alkylsulfonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(3n)6-14arylsulfonyl group, optionally substituted by 1-3 substituents selected from C1-6alkyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, C1-6alkoxycarbonyl group and C1-6alkylsulfonyl group;
(3O) nitrogen-containing heterocyclyl-carbonyl group optionally substituted by 1 to 3 substituents selected from a hydroxy-group, carboxyl group and C1-6alkoxycarbonyl group;
(3P)6-14arylacetamides heterocyclyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;
(3q)7-13erolkilutera heterocyclyl-carbonyl group, optional the part substituted by 1 to 3 halogen atoms;
(3r) nah heterocyclyl-oxycarbonyl group;
(3s) phosphonopropyl, optionally mono - or disubstituted With1-6alkyl group;
(3t) aromatic heterocyclyl-C7-13aracelikarsaalyna group;
(3u)3-10cycloalkyl-C1-6alkoxycarbonyl group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(3v)6-14arylcarbamoyl group, optionally substituted by 1-3 substituents selected from amino, optionally mono - or disubstituted by C1-6alkyl group, a carboxyl group, a C1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group; or
(3w) aromatic heterocyclyl-karbamoilnuyu group, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4) (4A) C1-6alkylcarboxylic;
(4b)1-10alkoxygroup, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(4C)6-14alloctype, optionally substituted by 1-3 substituents selected from the volume of halogen, carboxyl group, With1-6alkoxycarbonyl group, C1-6allylthiourea, carbamoyl group, C1-6alkoxygroup, C1-6alkylsulfonyl group, C1-6alkylsulfonyl group and C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group);
(4d) a 5 - or 6-membered aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 or 2 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4E) condensed aromatic geterotsiklicheskikh, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(4f) aromatic heterocyclyl-C1-6alkoxygroup, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group; or
(4g) aromatic heterocyclyl-C1-6-alloctype;
(5) (5A)1-6alkylthio the PPU, optionally substituted by 1-3 substituents selected from a hydroxy-group, carboxyl group, carbamoyl group and C1-6alkoxycarbonyl group;
(5b)6-14killigrew, optionally substituted by 1-3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group, C1-6ancilliary and carbamoyl group, or
(5s) 5 - or 6-membered aromatic heterocyclisation, optionally substituted by 1-3 substituents selected from C1-6alkyl groups, carboxyl groups, With1-6alkoxycarbonyl group and carbamoyl group;
(6) (6A) amino group;
(6b)1-6alkoxycarbonyl1-10alkylamino;
(6C) carboxin1-10alkylamino;
(6d)7-13arachidonoylethanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6E) carbamoylating;
(6f) a mono - or dis1-6alkylcarboxylic;
(6g) C1-6alkylsulfonamides;
(6h)6-14arylsulfonamides, optionally substituted C1-6alkylsulfonyl group;
(6i) aromatic heterocyclyl-sulfonylamino, optionally substituted by 1-3 substituents selected from C1-6alkyl group and mono - or di(C1-6al is ylcarbonyl)amino;
(6j) mono - or di(C1-6alkylsulphonyl)amino group;
(6k)3-10cycloalkylcarbonyl;
(6l)6-14arylcarboxamide, optionally substituted by 1-3 substituents selected from a halogen atom, ceanography, optionally halogenated C1-6alkyl group, a C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group, aromatic heterocyclic group, non-aromatic heterocyclic group and carbamoyl group;
(6m)7-13aralkylamines;
(6n)8-13arylalkylamine;
(6o) aromatic heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, a C6-14aryl group7-13aranceles group, C1-6alkoxygroup, a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6) nitrogen-containing heterocyclyl-carbonylation, optionally substituted by 1-3 substituents selected from C1-6alkyl group, (C1-6alkyl group optionally substituted by 1 to 3 substituents selected from a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group), a carboxyl group, a C1-6alkoxycarbonyl group and carbamoyl group;
(6q)6-14arylazo terasul heterocyclyl-carbonyl of the amino group;
(6r) tetrahydroprotoberberine;
(6s) 4-oxo-4,5,6,7-tetrahydro-1-bestfurnitureonline.com;
(6t)1-6alkoxycarbonylmethyl, optionally substituted C1-6alkoxycarbonyl group;
(6u)6-14aryloxypropanolamine, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group;
(6v)7-13aralkylamines; or
(6w) aromatic heterocyclyl-carbamoylating, optionally substituted by 1-3 substituents selected from a carboxyl group, With1-6alkoxycarbonyl group and carbamoyl group; or
(7) (7a) tetrazolyl;
(7b) Oxymetazoline;
(7C) dioxoimidazolidin, optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7d) oxopiperidin;
(7E) dioxopiperazinyl;
(7f) oxodegradable;
(7g) dikshithar;
(7h) oxazolyl, optionally substituted C1-6alkoxycarbonyl group;
(7i) dioxoimidazolidin or dioxothiazolidine, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and C1-6alkoxycarbonyl group;
(7j) 4-oxo-2-thioxo-1,3-thiazolidin-5-yl or 4-oxo-2-thioxo-1,3-oxazolidin-5-yl, each of which is optionally substituted C1-6alkyl group, optionally substituted by 1-3 substituents selected from a carboxyl group and1-6alkoxycarbonyl group;
(7k) 1,3(2H,5H)-dioxotetrahydrofuran[1,5-a]pyridinyl;
(7l) 1,3(2H,5H)-dioxo-10,10A-dihydroimidazo[1,5-b]ethenolysis or
(7m)6-14aryl group, optionally substituted C1-6alkoxycarbonyl group;
or its salt, comprising the exposure of the compounds represented by the formula

wherein each symbol is as defined above, or its salt of reduction reaction.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: phosphorus-organic compound of formula can be used for selective isolation of thorium (IV) from solutions containing mixtures of thorium (IV), uranium (VI) and lanthanium (III) compounds.

EFFECT: elaboration of novel highly efficient means for selective isolation of thorium from mixtures with uranium and lanthanium compounds.

1 cl, 2 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to fire retardant based on mixed hydroxyethylated tetramethylphosphonylpentaerithrite and methylphosphonic acid ethers and applied in aircraft industry as additive to polymer honeycombs and composite materials thus decreasing combustibility thereof. Offered fire retardant is characterised by production method and physical and chemical properties. Method of offered fire retardant production interaction of dimethylphosphonate and methylphosphonic acid dichloranhydride with pentaerithrite. Prepared mixture is trated with ethylene oxide. Stages of production method can include application of water or hydrochloric acid solution. All components of reaction mixture are taken in specified molar ratio at certain temperature conditions. Produced fire retardant is liquid of dynamic viscosity 270.0-280.0 centipoise at 75°C. Phosphorus mass fraction is 15.8-16.2%. Volatile mass fraction is 1.2-2.0%. Alcohol hydroxyl OH-group content is 10.8-11.4 %. Acid value is 1.0-2.0 mg KOH per for 1 g.

EFFECT: production of new effective additive to polymer honeycombs and composite materials thus decreasing combustibility thereof.

1 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to fire retardant based on hydroxyethylated diethyleneglycol and methylphosphonic acid ethers and applied as additive to polymer honeycombs and composite materials thus decreasing combustibility thereof. Offered fire retardant is characterised by production method and physical and chemical properties. Method of fire retardant production includes interaction of methylphosphonic acid dichloranhydride with diethyleneglycol. Besides water, hydrochloric acid and dimethylphosphonate can be appliedfor process. Then produced mixture is treated with ethylene oxide. Reagents are used in specified molar ratio at certain temperature conditions. Produced fire retardant is moderately viscous liquid of dynamic viscosity 600.0-630 centipoise at 25°C, phosphorus mass fraction 16.8-17.5 %, volatile mass fraction 1.2-1.3 %.

EFFECT: production of new effective additive to polymer honeycombs and composite materials thus decreasing combustibility thereof.

1 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to fire retardants based on pentaerythrite and methylphosphoric acid esters including that oxypropylated which can be used as the additive in composite polymeric materials for combustibility decrease. Offered fire retardants are characterised by production methods and physical and chemical properties. Fire retardants production methods include interaction of methylphosphoric acid dichloranhydride and pentaerythrite in certain molar ratio and certain temperature conditions. And for fire retardant production dimethylmethylphosphonate can be used. Resulted from interaction of methylphosphoric acid dichloranhydride and pentaerythrite, fire retardant is viscous water- and alcohol-soluble liquid at 20÷25°C being semicrystalline substance with phosphorus content 14.1÷14.36%, alcohol OH-group content 13.6-14.0 %, acid OH-group content 2.5-3.5 % and pentaerythrite 1.15-1.3 %. Once produced fire retardant is processed with propylene oxide at certain temperature conditions, it is possible to produce fire retardant representing viscous substance with phosphorus content 10.0÷10.3%, alcohol OH-group content 10÷12%, volatile content 1.5-2.0 % and KOH acid value 0.1-0.4 mg per 1 g of product.

EFFECT: production of new effective polymer-honeycomb additives and combustibility decreasing composite materials.

2 cl, 4 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

FIELD: chemistry.

SUBSTANCE: invention refers to C-phosphorylated acetamidines containing reactionable CH-acid methylene group which can be used as parent compound for bromine derivative C-phosphorylated acetamidines for medicine and agriculture concerns as biologically active substances. C-phosphorylated acetamidines in this invention are characterised by general formula: where R1 is selected from group i-C3H7, i-C4H9, C4H9; R2 is selected from groups C(O)CH3, C(O)C3H7, C(O)C6H5, P(O)(OC4H9-i)2; R3 represents C1-C4-alkyl; R4 is selected from groupC1-C4-alkyl or phenyl provided that R4 represents phenyl if R2 represents group P(O)(OC4H9-i)2.

EFFECT: expansion of chemical compounds range, suitable for production of biologically active substances.

1 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to method of production of C-phosphorylated alkylamidines serving as parent compounds of biologically active compounds for medicine and agriculture, of formula: where R1=C3-C4alkyl or isoalkyl; R2=CH3, C6H5; R3=C2-C4-alkyl or isoalkyl; R4=H, CH3, C3H7, C6H5, COOC2H5. Method includes in production of sodium derivatives of C-phosphorylated alkylamidines resulted from reaction of C-phosphorylated acetamidine with sodium. Produced sodium derivative is alkylated with alkylhalogenide in dioxane medium at mole ratio sodium:C-phosphorylated acetamidine:alkylhalogenide (1:1:1÷1.1), respectvely at temperature 20÷50°C.

EFFECT: production of new C-phosphorylated alkylamidines with high yield exceeding 78%.

1 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to protection of metals from corrosion using lacquer coating. This engineering problem can be solved by using calcium hydroxyethylidenediphosphonate with formula CH3(OH)C(PO3)2Ca2 as an anti-corrosion pigment, with higher anti-corrosion activity as compared to the prototype - protonated zinc hydroxyethylidenediphosphonate and a control specimen - zinc tetraoxychromate.

EFFECT: low-toxic high performance anti-corrosion pigment.

1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention concerns process of production of diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate represented by the formula , which is the key intermediate compound in synthesis of antiviral nucleoside analogue. The invention also concerns new intermediate compounds of formulae and , and their production of compound (2) obtained under this invention, which is an antiviral nucleoside analogue (especially against hepatitis B virus) represented by the formula .

EFFECT: high purity grade and high output.

4 ex

FIELD: organic chemistry, medicine, biochemistry.

SUBSTANCE: invention describes compound of the formula (I): wherein R1 means hydrogen atom (H); R2 means -SH, -S-C(O)-R8, -P(O)(OR5)2, -P(O)(OR5)R6, -P(O)(OR5)-R7-C(O)-R8, -P(O)(OR5)-R7-N(R5)-S(O)2-R9 or -P(O)(OR5)-R7-N(R5)-C(S)-N(R6)2; R3 means tetrazole, -C(O)OR6, -C(O)O-R7-OC(O)R5; R4 means optionally substituted aryl, or R4 means N-heterocyclyl. Also, invention describes compounds of the formula (II): and (III): wherein X means -CH2- or -O-, and pharmaceutical compositions comprising indicated compounds. Proposed compounds possess inhibitory effect on activity of plasma carboxypeptidase B and used as anti-thrombosis agents.

EFFECT: valuable medicinal and biochemical properties of compounds.

34 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new 2-pyridone derivatives of formula (I): where R1, R2, R4, R5, G1, G2, L, Y and n are as specified in the invention formula, and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy. These compounds have neutrophil elastase inhibition effect.

EFFECT: new compounds with useful biological properties.

7 cl, 1 tbl, 150 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I), their isomers and pharmaceutically acceptable salts. In the general formula (I) A is (II) ; X1 is methylene; X2 is CN, CHO, C(O)R6; X6 is a link; R1 is R13C(O)-; R2 is hydrogen; R3 is selected out of group including H, phenyl-(C0-6)alkyl, (C1-6)alkyl, optionally substituted by -X6OR9 group; R4 is H or (C1-6)alkyl; or R3 and R4 form (C3-8)cycloalkylene together with carbon atom to which R3, R4 are linked; R5 is (C1-9)alkyl, benzyl. Invention also concerns compounds of formulae (la), (lb), (Ic), and pharmaceutical composition based on the claimed compounds.

EFFECT: new compounds inhibiting cathepsin.

22 cl, 2 dwg, 89 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining heterocycles of formula I , where X, A, R10-R17 are as defined in point 1 of the claim, while a) isothiocyanate of formula II is transformed into thiourea of formula IV by interaction with primary amine of formula III, and b) thiourea of formula IV is transformed into compound of formula I by interaction with sulfochloride R6SO2Cl in the presence of a base, where A, X, n, m and R10 to R17 in compounds of formulae II, III and IV are as defined in formula I, and R6 is (C1-C4)-alkyl, trifluoromethyl or phenyl non-sustituted or substituted by methyl, trifluoromethyl, F, CI, Br or polymer carreir. The transportation is shown by combination formulae

EFFECT: new multipurpose synthesis technique for heterocyclic compounds of the general formula I.

8 cl, 31 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula (I) and their pharmaceutically acceptable salts. Compounds of claimed invention possess properties of agonists of mGlu 1 receptors and can find application in treatment of such diseases as psychosis, schizophrenia, Alzheimer's disease, etc. In general formula (I) one of R1 and R2 stands for trifluoromethyl, the other stands for hydrogen; R3, R3' independently on each other stand for hydrogen or halogen.

EFFECT: obtaining medication which possesses properties of agonists of mGlu 1 receptors.

7 cl, 2 tbl, 2 dwg, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

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