Bicyclic pyrrole derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

 

The technical field to which the invention relates.

The present invention relates to bicyclic derivatives of pyrrole, suitable as drugs. More specifically, it relates to new bicyclic derivative of pyrrole, effective as inhibitors dipeptidylpeptidase IV (DPP-IV). It also relates to pharmaceutical compositions for the treatment of diabetes containing bicyclic derivative of pyrrole, effective as inhibitor dipeptidylpeptidase IV (DPP-IV), as the active ingredient.

The level of technology

DPP-IV is a serine protease that is widespread in the body, one of dipeptidylpeptidase able to hydrolyze and release the N-terminal dipeptide significant impact, in particular, peptides containing Proline as the second amino acid from the N-end. Therefore, DPP-IV is also known as end polypeptides. It is known that DPP-IV uses as substrates of various biological peptides in the endocrine system, the neuroendocrine system, immunological system, and the like. It is known that many physiologically active peptides, such as the family of polypeptides of the pancreas, presents the polypeptides of the pancreas (PP), neuropeptide Y (NPY) and the like; family glucal the h/VIP presented by vasoactive intestinal polypeptide (VIP), glucagon-like peptide-1 (GLP-1), dependent on glucose insulinotropic the polypeptide (GIP), releasing the growth hormone factor (GRF) and the like; and the collection chemokine are substrates for DPP-IV and influenced by DPP-IV, such as the activation/inactivation, accelerate metabolism, and the like (non-patent document 1).

DPP-IV it two amino acids (His-Ala) with the N-Terminus of GLP-1. It is known that despite the fact that cleaved peptide in a weak degree binds to the receptor GLP-1, it does not exert an activating effect on the receptor and functions as an antagonist (non-patent document 2). It is known that GLP-1 is very rapidly metabolized in the blood under the action of DPP-IV, and the concentration of active GLP-1 in the blood increases when the inhibition of DPP-IV (non-patent document 3). GLP-1 is a peptide secreted into the intestine during the digestion of sugars, and it is the main stimulant of insulin secretion by the pancreas in response to the presence of glucose. In addition, it is known that GLP-1 stimulates the synthesis of insulin in β-cells of the pancreas and stimulating effect on the proliferation of β-cells. In addition, it is known that receptors GLP-1 are present in the digestive tract, liver, muscles, adipose tissue and that of podobn is m, and we also know that in these tissues GLP-1 affects the functioning of the digestive tract, secretion of acid in the stomach, the synthesis and degradation of glycogen-dependent insulin glucose uptake and the like. Therefore, it is planned to develop an inhibitor of DPP-IV, effective against type 2 diabetes (non-insulin-dependent diabetes), which has the effect, resulting in increased production of insulin-dependent glucose levels in the blood, improving pancreatic function, reduce high concentrations of glucose in the blood after a meal, treat abnormalities of glucose tolerance, increased insulin resistance, and the like, by increasing the concentration of GLP-1 in blood (non-patent document 4).

It was reported on various inhibitors of DPP-IV. For example, in patent documents 1 and 2 reported that derivatives containing imidazole cycle, are effective as inhibitors of DPP-IV.

Patent document 1: international patent application WO02/068420, description.

Patent document 2: international application WO03/104229, description.

Non-patent document 1: J. Langner and S. Ansorge, "Cellular Peptidases in Immune Functions and Disease 2", Advances in Experimental Medicine and Biology, vol.477.

Non-patent document 2: L.B. Knudsen et al., European Journal of Pharmacology, vol.318, pp.429-435, 1996.

Non-patent document 3: T.J. Kieffer et al., Endocrinology, vol.136, p.3585-3596, 1995.

Neat ntny document 4: R. A. Pederson et al., Diabetes, vol.47, p.1253-1258, 1998.

Disclosure of inventions

The objective of the invention

The present invention is the provision of new compounds with high inhibitory activity against DPP-IV.

Means of solving the problem

The authors of the present invention conducted an extensive study to solve the above problem, and as a result have found that the following compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug (if necessary, in abbreviated form, in some cases, below they are referred to as compounds according to the present invention has a high inhibitory activity against DPP-IV, and thus made the present invention.

That is, the present invention provides the following:

[1] the Compound of formula (I):

[Formula 1]

in which R1represents a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

solid line and dotted line between And1and2designate a double bond (A1=And2or a simple link (A1-And2);

And1is a group of formula C(R4), and2represents a nitrogen atom when splosna the line and dotted line between And 1and2represent a double bond (A1=And2);

And1is a group of the formula C=O and2is a group of formula N(R5in the case where the solid line and dotted line between And1and2present simple relationship (A1-And2);

R2represents a hydrogen atom, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaromatic, optionally substituted of alkenyl or optionally substituted quinil;

R3represents a hydrogen atom, halogen atom, cyano, formyl, carboxyl, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaromatic, optionally substituted alkylaryl, optionally substituted cycloalkylcarbonyl, optionally substituted aroyl, optionally substituted heteroarylboronic, optionally substituted alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted carbarnoyl, hydroxyl, optionally substituted alkoxy, or a group of the formula: -Rd-C(O)O-Re, in what toroi Rd represents a simple bond, alkylen or albaniles, and Re is tetrahydrofuranyl, cinnamom, 5-methyl-2-oxo-1,3-dioxolan-4-elmetron, 5-(tert-butyl)-2-oxo-1,3-dioxolan-4-elmetron, or a group of the formula: -CH(R4a)OC(O)R4bin which R4arepresents a hydrogen atom, alkyl, alkenyl, cycloalkyl or alkoxy, and R4brepresents optionally substituted alkyl, optionally substituted of alkenyl, cycloalkyl, cycloalkane, optionally substituted alkoxy, optionally substituted, alkenylacyl, 2-inanimate, 5-inanimate or optionally substituted, aryloxy;

R4represents a hydrogen atom, hydroxyl, halogen atom, cyano, formyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted, cycloalkane, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted by an amino group, optionally substituted carbarnoyl, carboxyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted, aryloxy, optionally substituted aralkyl, optionally substituted, aralkylated, optionally substituted aroyl, optionally substituted, aaltio, optionally substituted arylsulfonyl, optionally substituted arylsulfonyl, optionally substituted, alkylthio, optionally substituted alkylsulfonyl, long is correctly substituted alkylsulfonyl, optionally substituted heteroaryl, optionally substituted heteroaromatic, optionally substituted heteroarylboronic, optionally substituted, heteroaromatic, optionally substituted alkylaryl, optionally substituted nitrogen-containing saturated heterocyclic group, optionally substituted alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted Uralelectromed, optionally substituted cycloalkylcarbonyl or a group of the formula: -Rd-C(O)O-Re in which Rd and Re have the meanings defined above;

R5represents a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted vinyl, optionally substituted nitrogen-containing saturated heterocyclic group or optionally substituted heteroaryl;

-Y represents a group of any of formula (A), formula (V), formula (C) and formula (D)below:

[Formula 2]

in which m1 is 0, 1, 2 or 3, and R6missing, or there are one or two R6and they independently represent a halogen atom, hydroxyl, oxo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, not necessarily Thames is nnow the amino group, carboxyl, optionally substituted alkoxycarbonyl or optionally substituted carbarnoyl, or two R6taken together, represent methylene or ethylene and may be associated with the two carbon atoms included in the cycle, with the formation of a new cycle;

[Formula 3]

in which m2 is 0, 1, 2 or 3, and R7missing, or there are one or two R7and they independently represent a halogen atom, hydroxyl, oxo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted by an amino group, carboxyl, optionally substituted alkoxycarbonyl or optionally substituted carbarnoyl, or two R7taken together, represent methylene or ethylene and may be associated with the two carbon atoms included in the cycle, with the formation of a new cycle;

[Formula 4]

where m3 and m4 are independently equal to 0 or 1, and R8missing, or there are one or two R8and they independently represent a halogen atom, hydroxyl, oxo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted by an amino group, carboxyl, optionally substituted, alkoxycarbonyl is or optionally substituted carbarnoyl, or two R8taken together, represent methylene or ethylene and may be associated with the two carbon atoms included in the cycle, with the formation of a new cycle; and

[Formula 5]

in which m5 is 1, 2 or 3, R9missing, or there are one or two R9and they independently represent a halogen atom, hydroxyl, oxo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted by an amino group, carboxyl, optionally substituted alkoxycarbonyl or optionally substituted carbarnoyl, or two R9taken together, represent methylene or ethylene and may be associated with the two carbon atoms included in the cycle, with the formation of a new cycle, and R10and R11independently represent a hydrogen atom, methyl, ethyl, propyl or isopropyl, or R10and R11taken together, represent cyclopropyl, cyclobutyl or cyclopentyl,

the prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[2] the Connection on p.[1] of the formula (II):

[Formula 6]

in which R1, R2, R3and Y have the meanings given in paragraph[1], and R12represents a hydrogen atom, optional samewe the hydrated alkyl or optionally substituted aryl, the prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[3] a Connection on p.[1] of the formula (III):

[Formula 7]

in which R1, R2, R3and Y have the meanings given in paragraph[1], and R13represents a hydrogen atom, hydroxyl, cyano, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted, cycloalkane, optionally substituted aryl, optionally substituted, aryloxy, optionally substituted aralkyl, optionally substituted, aralkylated, optionally substituted aroyl, optionally substituted heteroaryl, optionally substituted heteroaromatic, optionally substituted heteroarylboronic, optionally substituted, heteroaromatic, optionally substituted alkylaryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted Uralelectromed, optionally substituted cycloalkylcarbonyl, optionally substituted alkylsulfonyl or a group of the formula: -Rd-C(O)O-Re, in which Rd and Re have the meanings given in paragraph[1], a prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[4] Obedinenie, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to p.[3], where R13represents a hydrogen atom, hydroxyl, cyano, carboxyl, trifluoromethyl, optionally substituted aryl, optionally substituted, aryloxy, optionally substituted aroyl, optionally substituted alkylaryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted Uralelectromed, optionally substituted cycloalkylcarbonyl, optionally substituted alkylsulfonyl or a group of the formula: -Rd-C(O)O-Re in which Rd and Re have the meanings given in paragraph[1].

[5] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[4], where R2represents a group of any of the subsequent formula (E), formula (F), formula (G), formula (H), formulae (I) and formula (J):

[Formula 8]

in which each of the Z1and Z2represents an oxygen atom, a group of formula S(O)p, or a group of formula N(R22);

each of R14and R20missing, or there are one or two R14and/or one or two R20and they independently represent a halogen atom, hydroxyl, formyl, carboxyl, cyano, alkylthio, alkylsulfonyl, alkylsulfonyl, alkyl, halogen is Kil, cycloalkyl, alkoxy, halogenoalkane, optionally substituted by an amino group, optionally substituted carbarnoyl, alkoxycarbonyl, optionally substituted alkylsulphonyl, cycloalkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted nitrogen containing heteroaryl, or two R14or two R20taken together, represent1-3alkylenedioxy;

each of R15and R21missing, or there are one or two R15and/or one or two R21and they independently represent a halogen atom, cyano, alkyl, halogenated, cycloalkyl, alkoxy or halogenoalkane;

R16represents methyl, ethyl, chlorine atom or bromine atom;

R17represents a hydrogen atom, methyl, ethyl, chlorine atom or bromine atom;

R18represents a hydrogen atom, methyl or ethyl;

R19represents a hydrogen atom, methyl, ethyl, cyclopropyl or cyclobutyl;

p is 0, 1 or 2; and

R22represents a hydrogen atom or alkyl.

[6] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[5], where Y represents a group of formula (A), in which m1 is 1 or 2, or Y is a group of formula (B), in which m2 is 1 or 2, or Y represents a group of formula (C), in which each of m3 and m4 is 1.

[7] Connect the tion, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[6], where R2represents a group of formula (E), formula (H) and formula (I).

[8] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[7], where R1represents a hydrogen atom, optionally substituted C1-C3alkyl or optionally substituted aryl and the substituent(s) optionally substituted alkyl selected(s) from a fluorine atom, optionally substituted rolnych groups, carboxyl, optionally substituted alkoxycarbonyl groups, optionally substituted aryl groups and optionally substituted aryloxy.

[9] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[7], where R1represents a group of the formula: -Ra-Rb-Rc, in which

Ra is alkylene;

Rb is a simple bond or carbonyl; and

Rc is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted, aryloxy or optionally substituted heteroanalogues.

[10] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[7], where R1predstavlyaetes hydrogen, methyl or ethyl.

[11] the Connection on p.[1] of the formula (IV):

[Formula 9]

in which R1and R3have the meanings given in paragraph[1]; and R23represents a hydrogen atom or optionally substituted alkyl; R24represents a halogen atom, cyano, carbarnoyl, methyl, trifluoromethyl, deformity, MonitorMaster, methoxy, triptoreline, deformedarse or monitorless; and R25represents a hydrogen atom, a fluorine atom or a chlorine atom, a prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[12] a Connection on p.[1] of the formula (V):

[Formula 10]

in which R26represents a hydrogen atom, cyano, optionally substituted alkyl, optionally substituted carbarnoyl, hydroxyl or optionally substituted alkoxy; R27represents a chlorine atom, a bromine atom, cyano, carbarnoyl, methyl, trifluoromethyl, deformity, MonitorMaster, methoxy, triptoreline, deformedarse or monitorless; and R28represents a hydrogen atom or a fluorine atom, a prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[13] the Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to p.[12], where R27predstavljaet a chlorine atom or cyano.

[14] a Compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to PP.[12] or [13], where R26represents a hydrogen atom or optionally substituted carbarnoyl.

[15] the Compound of formula (VI):

[Formula 11]

in which R2and Y have the meanings given in paragraph[1], and R29is a hydrogen atom, optionally substituted alkyl, optionally substituted by alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroallyl, the prodrug of the compounds, or pharmaceutically acceptable salt of the compounds or prodrugs.

[16] a Pharmaceutical composition comprising a compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of PP[1]-[15], as an active ingredient.

[17] the Inhibitor dipeptidylpeptidase IV containing the compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[15], as an active ingredient.

[18] the Pharmaceutical composition for treating diabetes containing compound, its prodrug or farmaci is almost acceptable salt of the compounds or prodrugs according to any one of paragraphs.[1]-[15], as the active ingredient.

[19] Use of the compound, its prodrug or pharmaceutically acceptable salts of the compounds or prodrugs according to any one of paragraphs.[1]-[15] to obtain inhibitor dipeptidylpeptidase IV.

[20] Use of the compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[15] to obtain a pharmaceutical composition for the treatment of diabetes.

[21] a Method of treating diabetes, comprising introducing an effective amount of a compound, its prodrug or pharmaceutically acceptable salt of the compound or prodrug according to any one of paragraphs.[1]-[15] to a patient in need of treatment.

The compound of formula (I), its prodrug or pharmaceutically acceptable salt of the compound or prodrug below, in General, is called a "compound of the present invention, if it is necessary.

Advantages of the invention

The compound of the present invention has a high inhibitory activity against DDP-IV and suitable as pharmaceuticals for the treatment of diabetes.

Detailed Scripture preferred option

for carrying out the invention

The present invention is explained below.

In the present description, the number of substituents in each radical, defined by the term "optionally substituted" or "alseny", not specifically limited, provided that the substitution is possible, and it is 1 or more. Unless otherwise specified, the explanation of each radical refers also to the case where the radical is a fragment or Deputy in the other group.

"Halogen atom" includes, for example, fluorine atom, chlorine atom, bromine atom or iodine atom.

"Alkyl" includes, for example, a normal or branched alkyl group of 1-6 carbon atoms. Its specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl etc. Its preferred examples include linear or branched alkyl groups of 1-4 carbon atoms. Concrete examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.

"Alkenyl" includes, for example, alkeline group of 2-6 carbon atoms. Its specific examples are vinyl, propenyl, methylpropenyl, butenyl, methylbutanol etc.

"Quinil" includes, for example, alkyline group of 2-6 carbon atoms. Its specific examples are ethinyl, 1-PROPYNYL, 2-PROPYNYL, 2-butynyl, pentenyl, hexenyl etc.

"Cycloalkyl" includes, for example, cycloalkyl group of 3-10 atoms uglerode specific examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, substituted, norbornyl etc. Its preferred examples are cycloalkyl group of 3-6 carbon atoms. Specific examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

"Alkylene" includes, for example, alkylene group of 1-3 carbon atoms. Its specific examples include methylene, ethylene, trimethylene etc.

"Albaniles" includes, for example, alkenylamine group of 2-4 carbon atoms. Its specific examples are vinile, propylen, butylen etc.

"Aryl" includes, for example, aryl groups of 6-10 carbon atoms. Its specific examples are phenyl, 1-naphthyl, 2-naphthyl, etc.

"Aralkyl" includes, for example, a group formed by binding of the aryl group with alkalinous group. Its specific examples are benzyl, 2-phenylethyl, 1-naphthylmethyl etc.

"Heteroaryl" includes, for example, 5-10-membered monocyclic or polycyclic group containing one or more (e.g., 1-4) heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom. Its specific examples are pyrrolyl, thienyl, benzothiazyl, benzofuranyl, benzoxazolyl, benzothiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, Persil, pyrimidyl, pyridil, chinolin, and kinali, triazolyl, triazinyl, tetrazolyl, indolyl, imidazo[1,2-a]pyridyl, dibenzofurans, benzimidazolyl, Minoxidil, cannoli, chinadoll, indazoles, naphthyridin, hyalinosis, izohinolinove etc. Its preferred examples include 5 - or 6-membered ring group containing a heteroatom selected from nitrogen atom, sulfur atom and oxygen atom. Specific examples of such groups are pyridyl, thienyl, furyl, etc.

Heteroaryl fragment "heteroaromatic" includes the groups listed as examples of heteroaryl.

"Alkylaryl" includes, for example, alkylcarboxylic group of 2-4 carbon atoms. Its specific examples include acetyl, propionyl, butyryl etc.

"Cycloalkylcarbonyl includes cycloalkylcarbonyl group of 4-11 carbon atoms and the like. Its specific examples are cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, adamantylidene, norbornylene etc. Its preferred examples are cycloalkylcarbonyl group of 4-7 carbon atoms. Specific examples of such groups are cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl etc.

"Aroyl" includes, for example, aroline group of 7-11 carbon atoms. Its specific examples include benzoyl, 1-naphtol, 2-nattai and so on

Heteroaryl fragment "heteroarylboronic" includes the groups listed as examples of heteroaryl.

"Alkoxycarbonyl" includes, for example, alkoxycarbonyl group of 2-5 carbon atoms. Its specific examples are methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl etc.

"Aryloxyalkyl" includes, for example, aryloxyalkyl group of 7-11 carbon atoms, and the like. Its specific examples are vinyloxycarbonyl, 2-naphthaleneboronic, 1-naphthaleneboronic etc.

"Alkoxy" includes, for example, alkoxygroup from 1-4 carbon atoms. Its specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-butoxy etc.

"Cycloalkane" includes, for example, cycloalkylcarbonyl from 3-10 carbon atoms. Its specific examples are cyclopropylamine, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, adamantios, norbornylene etc. Its preferred examples are cycloalkylation of 3-6 carbon atoms. Its specific examples are cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy etc.

Cycloalkylcarbonyl fragment "cycloalkylcarbonyl" includes the groups listed as examples is cycloalkane.

"Aryloxy" includes, for example, alloctype of 6-10 carbon atoms. Its specific examples are phenoxy, 1 naphthyloxy, 2-naphthyloxy etc.

Uralkaliy fragment "aralkylated" includes the groups listed as examples of aralkyl. Its specific examples include benzyloxy, 2-phenylethylene etc.

Uralkaliy fragment "orelkinoservisa" includes the groups listed as examples of aralkyl.

Heteroaryl fragment "heteroaromatic" includes the groups listed as examples of heteroaryl.

"Alkylthio" includes, for example, ancilliary from 1-6 carbon atoms. Its specific examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, secondary butylthio, tert-butylthio, pentylthio, hexylthio, etc. Its preferred examples are ancilliary from 1-4 carbon atoms. Specific examples of such groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, secondary butylthio, tert-butylthio etc.

"Alkylsulfonyl" includes, for example, alkylsulfonyl group of 1-6 carbon atoms. Its specific examples are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, pentasulfide, exisulind etc. Its preferred examples are alkylsulfanyl group of 1-4 atoms in the of Lerida. Specific examples of such groups are methylsulfinyl, ethylsulfinyl, propylsulfonyl, isopropylphenyl, butylsulfonyl etc.

"Alkylsulfonyl" includes, for example, alkylsulfonyl group of 1-6 carbon atoms. Its specific examples are methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, peterculter, hexylsilane etc. Its preferred examples are alkylsulfonyl group of 1-4 carbon atoms. Specific examples of such groups are methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl etc.

"Aristeo" includes, for example, aristocraty of 6-10 carbon atoms. Its specific examples are phenylthio, 1 naphthylthio, 2-naphthylthio etc.

"Arylsulfonyl" includes, for example, arylsulfenyl group of 6-10 carbon atoms. Its specific examples are phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl etc.

"Arylsulfonyl" includes, for example, arylsulfonyl group of 6-10 carbon atoms. Its specific examples are phenylsulfonyl, tosyl, 1-naphthylmethyl, 2-naphthylmethyl etc.

"Nitrogen-containing saturated heterocyclic group" includes, for example, 5 - or 6-membered saturated heterocyclic group, which may contain one or two ATO is and nitrogen and may optionally contain an oxygen atom or a sulfur atom. Its specific examples are pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholine, diocletianopolis, hexamethylenimine, oxazolidinyl, diazolidinyl, imidazolidinyl, Oxymetazoline, dioxoimidazolidin, oxoacridine, dioxoimidazolidin, dioxothiazolidine, tetrahydrofuranyl, tetrahydropyranyl etc.

Deputy(s) in the "optionally substituted alkyl" includes, for example, (1) halogen atoms, (2) hydroxyl, (3) cyano, (4) carboxyl group, (5) optionally substituted cycloalkyl group, (6) optionally substituted aryl group, (7) optionally substituted heteroaryl group, (8) optionally substituted aroline group, (9) optionally substituted heteroarylboronic group, (10) optionally substituted arylaminomethylene group, (11) optionally substituted heteroarylboronic group, (12) optionally substituted alloctype, (13) optionally substituted arylsulfonyl group, (14) optionally substituted Arakishvili group, (15) optionally substituted alkoxygroup, (16) optionally substituted cycloalkylcarbonyl, (17) optionally substituted alkoxycarbonyl group, (18) optionally substituted aryloxyalkyl group, (19) optionally substituted amino group, (20) optional C is displaced carbamoyl group, (21) alkylsulfonyl group, (22) optionally substituted alkylcarboxylic group, (23) cycloalkylcarbonyl group, (24) tetrahydroprotoberberine group and (25) tetrahydropyranyloxy group.

The above paragraphs.(1)to(25) below.

The substituents in "optionally substituted cycloalkyl groups" under item(5) above include, for example, alkyl groups, kalkilya group, alkoxygroup, alkoxycarbonyl group and a fluorine atom.

The substituents in "optionally substituted aryl group" under item(6) above include the substituent(s)below as an example, for the "optionally substituted aryl".

The substituents in "optionally substituted heteroaryl group" under item(7) above include, for example,

(a) hydroxyl,

(b) the atoms of halogen,

(C) alkyl groups,

(d) alkyl groups, substituted atom and the halogen or alkoxygroup (for example, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-dottorati, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropan),

(e) alkoxygroup,

(f) alkoxygroup, substituted atom and the halogen or alkoxygroup (for example, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(fluorine is ethyl)ethoxy, 1-(deformity)-2,2-diflorasone, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

(g) cyano,

(h) a carboxyl group,

(i) alkoxycarbonyl group,

(j) carbamoyl group which may be substituted by alkyl group(s) (for example, carbarnoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol and diethylcarbamoyl),

(k) aryl group, and

(l) the amino group.

The substituents in "optionally substituted rolnych groups" under item(8) above include the substituents described as an example for "optionally substituted aryl group" under item(6) above.

The substituents in "optionally substituted heteroarylboronic groups" under item(9) above include the substituents described as an example for the "optionally substituted heteroaryl group" under item(7) above.

The substituents in "optionally substituted arylaminomethylene groups" under item(10) above include the substituents described as an example for "optionally substituted aryl group" under item(6) above.

The substituents in "optionally substituted heteroarylboronic groups" under item(11) above include the substituents described as an example for the "optionally substituted heteroaryl group" under item(7) above.

The substituents in "optionally substituted alloctype is" under item(12), and "optionally substituted arylsulfonyl groups" under item(13) above include substituents, see the example for "optionally substituted aryl group" under item(6) above.

Uralkaliy fragment "optionally substituted Arakishvili" under item(14) above, includes the groups listed as examples of aralkyl.

The substituents in "optionally substituted Arakishvili group include the substituents described as an example for "optionally substituted aryl group" under item(6) above.

The substituents in "optionally substituted alkoxygroup" under item(15) above include, for example,

(a) hydroxyl,

(b) carboxyl,

(C) alkoxygroup,

(d) alkoxycarbonyl group,

(e) an amino group which may be substituted by alkyl(s) (e.g., amino, dimethylamino, diethylamino),

(f) carbamoyl group substituted by alkyl(s)

(g) sulfamoyl group substituted by alkyl(s)

(h) raidgroup substituted by alkyl(s)

(i) a phenyl group which may be substituted by a halogen atom or alkoxy (for example, phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-isopropoxyphenyl and 3-isopropoxyphenyl),

j) 5-oxo-2-tetrahydrofuranyl,

(K) 1,3-dihydro-3-oxo-1-isobenzofuranyl,

(l) tetrahydrofuranyl,

(m) nitrogen-containing saturated heterocy the symbolic group,

(n) alkoxygroup, substituted atom and the halogen or alkoxygroup (for example, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy, 1-(deformity)-2,2-diflorasone, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

(o) cycloalkyl group,

(R) cycloalkyl group substituted by a halogen atom or alkoxygroup (for example, 2-forciblepoppy, 2-methoxycyclohexyl, 2-forceclosure, 3-forceclosure and 3-methoxyisobutyl), and

(q) the halogen atoms.

The substituents in "optionally substituted cycloalkylcarbonyl" under item(16) above and optionally substituted alkoxycarbonyl groups" under item(17) above include the substituents described as an example for the "optionally substituted alkoxygroup" under item(15) above.

The substituents in "optionally substituted aryloxyalkyl groups" under item(18) above include the substituents described as an example for "optionally substituted aryl group" under item(6) above.

The substituents in "optionally substituted amino group" under item(19) above include, for example,

(a) alkyl groups,

(b) alkylcarboxylic group,

(C) aroline group,

(d) alkylsulfonyl group,

(e) arylsulfonyl group,

(f) the optional Thames is by aryl groups (their substituents include, for example, halogen atoms, alkali and alkoxy),

(g) alkoxycarbonylmethyl group (the carbon atom of methyl fragment can be substituted by one or two alkilani, and two of the alkyl carbon atom of the methyl fragment can be connected to each other to form cyclopropyl, cyclobutyl or cyclopentyl together with the carbon atom of the methyl fragment), and

(h) kalkilya group.

As the optionally substituted amino groups can also be present as example (i) imides.

The substituents in "optionally substituted carbamoyl groups" by p.(20) above include, for example, alkyl groups and cycloalkyl group. Two Deputy in carbamoyl can be connected to each other to form an aliphatic heterocyclic ring, which may contain atoms of carbon atom(s) of nitrogen and/or atom(s) of oxygen, such as pyrrolidin (which may be substituted by hydroxyl), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, piperazine (the nitrogen atom of this piperazine may be substituted by stands or ethyl) or the like.

Specific examples of the "optionally substituted carbamoyl are carbarnoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol, diethylcarbamoyl, ethylmethylamino, methylpropylketone, cyclopropanecarbonyl, cyclopropa methylcarbamoyl, pyrrolidinecarbonyl, piperidinylcarbonyl, morpholinoethyl etc.

The substituents in "optionally substituted alkylcarboxylic groups" under item(22) above include, for example,

(a) halogen atoms,

(b) alkoxygroup,

(C) cycloalkyl group,

(d) alkoxycarbonyl group,

(f) optionally substituted aryl groups (their substituents include, for example, halogen atoms, alkali, alkoxy and alkoxycarbonyl), and

(f) hydroxyl.

Deputy(s) in each of the "optionally substituted, alkylthio", "optionally substituted alkylsulfonyl" and "optionally substituted alkylsulfonyl" includes a substituent(s), is given as an example for the "optionally substituted alkyl".

Deputy(s) in each of the "optionally substituted alkenyl" and "optionally substituted quinil" includes, for example,

(1) hydroxyl,

(2) the atoms of halogen,

(3) alkyl groups,

(4) alkyl groups, substituted atom and the halogen or alkoxygroup (for example, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-dottorati, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropan),

(5) alkoxygroup,

(6) alkoxygroup, substituted atom and the halogen or alkoxygroup (for example, format the XI, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy, 1-(deformity)-2,2-diflorasone, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

7) phenyl group or aroline group which may be substituted by the following (AA), (bb) or (CC):

(AA) alkoxygroup(and), which can be substituted by an atom of halogen or alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-butoxy, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy, 1-(deformity)-2,2-diflorasone, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

(bb) alkyl group(s), which may be substituted atom and halogen (for example, methyl, ethyl, propyl, isopropyl, butyl, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-dottorati),

(SS) atom(s) halogen,

(8) cyano,

(9) carboxyl group,

(10) alkoxycarbonyl group,

(11) carbamoyl group which may be substituted by alkyl(s) (for example, carbarnoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol and diethylcarbamoyl),

p> (12) alkylsulfonyl group, and

(13) fenoxaprop.

The substituent(s) "optionally substituted vinyl group" includes, for example, halogen atoms and alkyl groups.

Specific examples of substituted vinyl groups are 1-propylene, 2-methyl-1-propene, 2-chloro-1-propylene, etc.

The substituent(s) "optionally substituted cycloalkyl group includes the substituents according to claim 5, shown as example for the "optionally substituted cycloalkyl group" as a substituent(s) for the above-mentioned "optionally substituted alkyl group".

The substituent(s) "optionally substituted aryl group" includes, for example,

(1) hydroxyl,

(2) the atoms of halogen,

(3) alkyl groups,

(4) alkyl groups, substituted atom and halogen, alkoxygroup or cycloalkyl group (for example, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-dottorati, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropan),

(5) a phenyl group which may be substituted by the following (AA), (bb) or (CC):

(AA) alkoxygroup(and), which can be substituted by an atom of halogen or alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-b is toxi, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy, 1-(deformity)-2,2-diflorasone, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

(bb) alkyl group(s), which may be substituted atom and halogen (for example, methyl, ethyl, propyl, isopropyl, butyl, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl, 1-(deformity)-2,2-dottorati),

(SS) atom(s) halogen,

(6) a cyano,

(7) a carboxyl group,

(8) alkoxycarbonyl group which may be substituted atom(I) halogen (e.g., methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, secondary butoxycarbonyl, tert-butoxycarbonyl, formicoxenini, deformational, 2,2-differentoccasions, 2,2,2-cryptgetuserkey, methoxycarbonyl and etoxycarbonyl),

(9) carbamoyl group which may be substituted by alkyl group(s) (for example, carbarnoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol and diethylcarbamoyl),

(10) alkylsulfonyl group,

(11)1-3alkylenedioxy,

(12) formyl group,

(13) optionally substituted fenoxaprop (their substituents include the indicate, for example, halogen atoms, alkyl groups and alkoxygroup),

(14) nitrogen-containing saturated heterocyclic group (for example, pyrrolidinyl, piperidinyl, morpholinyl and piperazinil (the nitrogen atom of the piperazine may be substituted, for example, stands, ethyl or propylene)),

(15) cycloalkylcarbonyl, which can be substituted by hydroxyl, oxo, carboxyla, carboxymethyl, alkoxycarbonyl, alkoxycarbonylmethyl (for example, methoxycarbonylmethyl, ethoxycarbonylmethyl or isopropoxycarbonyloxymethyl), alkyl, perakyla (for example, formation, deformation, trifluoromethyl, 2,2-defloration, 2,2,2-triptorelin or perforation), alkoxyalkyl (for example, methoxymethyl, ethoxymethyl or isopropoxyethanol), cycloalkylation (for example, cyclopropylacetylene, cyclopropylacetylene or cyclobutylamine), alkoxy, cycloalkane or atom(I) halogen (e.g., 3-carboxycellulose, 3 ethoxycarbonylmethoxy, 3 ethoxycarbonylmethoxy, 2-methylcyclopropyl, 2-ferricopiapite, 3 methoxycyclohexyl, 3 fertilisations, 3,3-divorcelawyers and 3-(2-foradil)cyclobutylamine),

(16) alkoxygroup, which can be substituted by hydroxyl, oxo, carboxyla, alkoxycarbonyl, cycloalkyl, alkoxy, cycloalkane, optionally substituted oxygen-containing heterotsiklicheskikh group (for example, 5 - or 6-membered saturated heterocyclic group containing the atom(s) of oxygen, specific examples of which are tetrahydrofuranyl, tetrahydropyranyl etc.; the substituent(s) includes, for example, halogen atoms, oxo, and alkoxy) or atom(s) halogen (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-butoxy, 2-hydroxyethoxy, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethyl, cyclopropylmethoxy, cyclobutylmethyl, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, isopropoxyphenoxy, cyclopropylmethoxy, cyclobutenedione, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy and 1-(deformity)-2,2-diflorasone),

(17) diversitronics,

(18) alkeneamine group which may be substituted by halogen atom (for example, vinyl, propenyl, methylpropenyl, butenyl and methylbutanal),

(19) an amino group which may be substituted by alkyl(s) (for example, amino, methylamino, ethylamino, propylamino, dimethylamino, methylethylamine, diethylamine),

(20) optionally substituted alkylcarboxylic groups (their substituents include, for example, halogen atoms, alkoxy and cycloalkyl),

(21) alkylcarboxylic (for example, metalcarbon is lexi, ethylcarbonate, isopropylcarbonate),

(22) cycloalkyl group which may be substituted by fluorine atom (for example, cyclopropyl, cyclobutyl, cyclopentyl, 2-forciblepoppy, 2-forceclosure, 3-forcecommittimeout, substituted and norbornyl),

(23) cycloalkylcarbonyl group which may be substituted by fluorine atom (for example, cyclopropanecarbonyl, 2-forcecoercion, cyclobutanecarbonyl and cyclopentanecarbonyl),

(24) ancilliary,

(25) alkylsulfonyl group,

(26) optionally substituted heteroaryl groups (their substituents include, for example, halogen atoms, alkali, alkoxy, halogenated, halogenoalkane),

(27) subsequent group of formula (T1)-(T16):

[Formula 12]

in which RTmissing, or there is one or more RTand they independently represent a halogen atom, hydroxyl, oxo, carboxyl, optionally substituted alkyl (the substituent(s) includes, for example, halogen atoms and alkoxy), optionally substituted alkoxycarbonyl (his Deputy(and) includes, for example, halogen atoms and alkoxy), optionally substituted alkoxy (the substituent(s) includes, for example, halogen atoms and alkoxy), optionally substituted carbarnoyl (his Deputy(and) includes, for example, alkali) or saturated heterocyclic g is the SCP oxycarbonyl (saturated heterocyclic group includes, for example, 5 - or 6-membered saturated heterocyclic group containing the atom(s), oxygen atom(s) of nitrogen and/or atom(s) of sulfur, each in an amount of 1 or 2, specific examples of which are tetrahydrofuranyl, tetrahydropyranyl, dihydrofurane, tetrahydrothiopyran, tetrahydrothiopyran, pyrrolidinyl, piperidinyl, piperazinil, imidazolidinyl, oxazolidinyl and diazolidinyl), or two RTtaken together, can represent methylene, ethylene, trimethylene, tetramethylene or butylen and may contact one or more carbon atoms that are part of the cycle, with the formation of a new cycle; and RXrepresents a hydrogen atom or alkyl,

(28) aroline group, and

(29) groups of the formula: -Rd-CO(O)-Re in which Rd and Re have the meanings given above.

The substituent(s) each optionally substituted heteroaryl", "optionally substituted aralkyl", "optionally substituted heteroaromatic", "optionally substituted arole", "optionally substituted heteroarylboronic", "optionally substituted aryloxyalkyl", "optionally substituted, aryloxy", "optionally substituted, aralkylated", "optionally substituted uraltrackservice", "optionally substituted, heteroaromatic", "optionally substituted, aristeo", "optionally substituted arylsulfonyl" and "not battelino substituted arylsulfonyl" includes a substituent(s), given as examples for the above "optionally substituted aryl".

The substituent(s) "optionally substituted alkylcarboxylic group includes the substituents described as an example of "optionally substituted alkylcarboxylic groups" by p.(22) as substituent(s) for the above "optionally substituted alkyl".

The substituent(s) "optionally substituted cycloalkylcarbonyl group" includes, for example, halogen atoms and alkoxygroup.

Deputy(s) in each "optional substituted alkoxygroup" and "optionally substituted alkoxycarbonyl group includes the substituents described as an example of "optionally substituted alkoxygroup" under item(15) as substituent(s) for the above "optionally substituted alkyl".

Deputy(s) in each "optional substituted cycloalkylation" and "optionally substituted cycloalkylcarbonyl group includes the substituents described as an example of "optionally substituted cycloalkanones" p.(16) as substituent(s) for the above "optionally substituted alkyl".

Deputy(s) in the "optionally substituted amino group" includes the substituents described as an example of "optional samisen the x amino group" under item(19) as substituent(s) for the above "optionally substituted alkyl".

The substituent(s) "optionally substituted carbamoyl group" includes, for example,

(1) optionally substituted alkyl groups (their substituents include, for example, hydroxyl, halogen atoms, alkoxy, optionally substituted atom and halogen, cycloalkane, optionally substituted atom and halogen, and tetrahydrofuranyl),

(2) cycloalkyl group which may be substituted by an atom of halogen,

(3) aryl group which may be substituted by the following (AA), (bb), (CC) or (dd):

(AA) atom(s) halogen,

(bb) alkoxygroup, which can be substituted atom and halogen (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-butoxy, formatosi, deformedarse, triptoreline, 2,2-diflorasone, 2,2,2-triptoreline, perforators, 2-fluoro-1-(permitil)ethoxy and 1-(deformity)-2,2-diflorasone),

(SS) alkyl group(s), which may be substituted atom and halogen (for example, methyl, ethyl, propyl, isopropyl, butyl, methyl, ethyl, propyl, isopropyl, butyl, vermeil, deformity, trifluoromethyl, 2,2-dottorati, 2,2,2-triptorelin, perforated, 2-fluoro-1-(permitil)ethyl and 1-(deformity)-2,2-dottorati),

(dd)1-3alkylenedioxy(and),

(4) alkylsulfonyl group,

(5) cycloalkylcarbonyl group,

(6) optionally substituted by arylsulfonic the performance communications groups (their substituents include, for example, halogen atoms, alkali, halogenated, alkoxy, halogenoalkane),

(7) alkylcarboxylic group,

(8) alkoxycarbonyl group,

(9) optionally substituted aroline groups (their substituents include, for example, halogen atoms, alkali, halogenated, alkoxy, halogenoalkane, alkoxycarbonyl and C1-3alkylenedioxy),

(10) cycloalkenyl group,

(11) isoxazolyl group, and

(12) optionally substituted adamantylidene groups (their substituents include, for example, hydroxyl).

Specific examples of the "optionally substituted of carbamoyl are carbarnoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol, diethylcarbamoyl, ethylmethylamino, phenylcarbamoyl, formethylcarbamoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopropylmethanol, cyclohexyloxycarbonyl, 2,3-dihydroxypropane, tetrahydrofurfurylaminocarbonyl, methoxyethanol, triptoreline, adamantanol, hydroxyadamantane etc.

Two Deputy in carbamoyl can be connected to each other to form a 4-6-membered aliphatic heterocyclic ring, which may contain atoms of carbon, nitrogen, oxygen or sulfur, such as pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine oxide, piperazine (the nitrogen atom of this piperaz which may be substituted stands, the ethyl or propylene) or the like, and carbarnoyl may be optionally substituted by hydroxyl. Specific examples of such substituted carbamoyl are pyrrolidinecarbonyl, piperidinylcarbonyl, morpholinomethyl, 4-hydroxypiperidine etc.

Deputy(s) in the "optionally substituted nitrogen-containing saturated heterocyclic group" includes, for example,

(1) halogen atoms,

(2) alkyl groups,

(3) alkyl groups, substituted atom and the halogen or alkoxy (for example, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2-dottorati, perforated and methoxyethyl),

(4) alkoxygroup,

(5) alkoxygroup, substituted atom and the halogen or alkoxy (for example, formatosi, deformedarse, triptoreline, methoxyethoxy, ethoxyethoxy, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxypropane),

(6) cyano, and

(7) oxoprop.

In the case when there are two R6, R7, R8or R9they can be at one and the same carbon atom or may be located at different carbon atoms, respectively.

The expression "two R6, R7, R8or R9taken together, represent methylene or ethylene and associated with one or more carbon atoms that are part of the cycle, with the formation of a new cycle" means that he is able to form spirocerca or bicyclic ring, respectively, on the same carbon atom or different carbon atoms.

The expression "two RTtaken together, represent methylene, ethylene, trimethylene, tetramethylene or butylen and contact one or two carbon atoms that are part of the cycle, with the formation of a new cycle" means that they can form spirocerca or bicyclic ring, respectively, on the same carbon atom or different carbon atoms.

"Halogenoalkane" includes, for example, alkoxygroup of 1-4 carbon atoms, substituted atom and halogen. Its specific examples are formatosi, deformedarse, triptoreline etc.

"Halogenated" includes, for example, alkyl groups of 1-4 carbon atoms, substituted atom and halogen. Its specific examples are vermeil, deformity, trifluoromethyl, 2-foretel, perforated etc.

"C1-3alkylenedioxy" includes, for example, methylenedioxy, Ethylenedioxy, trimethylenediamine.

"Substituted alkyl" for R4bincludes, for example, alkyl groups of 1-3 carbon atoms, substituted cycloalkyl of 3-7 carbon atoms (for example, cyclopentyl, cyclohexyl or cycloheptyl) or optionally substituted aryl (e.g. phenyl). Its specific examples include benzyl, p-Chlorobenzyl, p-methoxybenzyl, p-tormentil, cyclopentylmethyl, cyclohexylmethyl etc.

"Replaced alkenyl for R4bon the em for example, alkeline group of 2-3 carbon atoms, substituted cycloalkyl from 5-7 carbon atoms (for example, cyclopentyl, cyclohexyl or cycloheptyl) or aryl (e.g. phenyl). Its specific examples are vinyl, propenyl, allyl, Isopropenyl etc. which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

"Alkenylacyl for R4bincludes, for example, linear or branched alkenylacyl from 2-8 carbon atoms. Its specific examples are allyloxy, isobutyryloxy etc.

"Substituted alkoxy" for R4bincludes, for example, alkoxygroup from 1-3 carbon atoms, substituted cycloalkyl of 3-7 carbon atoms (for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or optionally substituted aryl (e.g. phenyl). Its specific examples include benzyloxy, penetrate, cyclopropylmethoxy, cyclopropylmethoxy, cyclopentylmethyl etc.

"Replaced alkenylacyl for R4bincludes, for example, alkenylacyl of 2 or 3 carbon atoms, substituted cycloalkyl of 3-7 carbon atoms (for example, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl) or optionally substituted aryl (e.g. phenyl). Its specific examples are vinyloxy, propanolol and, allyloxy, isopropanolate etc. which are substituted by phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

Specific examples of the "optionally substituted, aryloxy for R4bare phenoxy, p-nitrophenoxy, p-methoxyphenoxy, p-fervency, naphthoxy etc.

Specific examples of each "substituted alkoxycarbonyl" and a group of the formula: -Rd-CO(O)-Re in which Rd and Re have the meanings given above, are pivaloyloxymethyl, 1-(pivaloyloxy)etoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)etoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolan-4-ylmethoxycarbonyl, 5-(tert-butyl)-2-oxo-1,3-dioxolan-4-ylmethoxycarbonyl, ecotoxicologically, prophylaxisloreducelhe, n-butoxyethoxyethanol, isobutoxyethanol, 1-(ethoxycarbonyl)etoxycarbonyl, 1-(tert-butoxycarbonylamino)etoxycarbonyl, 1-(atomic charges)etoxycarbonyl, 1-(isobutoxy)etoxycarbonyl, cyclohexyloxycarbonyl, 1-(cyclohexyloxycarbonyloxy)etoxycarbonyl, cyclopentanecarbonyl, 1-(cyclopentanecarbonyl)etoxycarbonyl etc.

Deputy(s) in each of the "optionally substituted alkyl" and "optionally substituted alkoxy" for Rc includes, for example, halogen atoms, alkoxygroup and cycloalkyl group.

The substituent(s) "is not necessary for adenom heteroarenes" for Rc includes deputies, given as examples of the "optionally substituted heteroaryl" under item(7) as substituent(s) represented by the above "optionally substituted alkyl".

As alkylene" for Rd the examples above, preferably is methylene.

As Alcanena" for Rd the examples above, it is preferable that vinile.

As an example, "prodrugs" are those that can easily be either hydrolyzed in vivo to form compounds (I) of the present invention. Its specific examples include compounds obtained by conversion of the amino groups of the compounds of formula (I) in-NHQX. As examples QXthere is the following:

(1)

[Formula 13]

(2) -COR33

(3) -COO-CR34(R35)-OCOR36

(4) -COOR37

where R33represents a hydrogen atom, alkyl or optionally substituted aryl; R34and R35independently are a hydrogen atom or alkyl; R36represents a hydrogen atom, alkyl, aryl or benzyl; and R37is alkyl or benzyl.

Preferred examples of QXare the group (1) and group (3). Preferred examples of the groups (3) are groups in which R34represents a hydrogen atom, R35represents a hydrogen atom, methyl or ethyl, and R36is the tsya stands or ethyl. These compounds can be obtained in the usual way (for example, J. Med. Chem., 35, 4727 (1992) and WO 01/40180). In addition, the prodrug may present itself, which becomes a source compound under physiological conditions, as described in "Development of Medicines Vol.7, Molecular Design", pp.163-198, Hirokawa Shoten, 1990.

Examples of "pharmaceutically acceptable salts are salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, etc. and organic acid salts such as salt, acetic acid salt, propionic acid salt, oxalic acid salt, succinic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, maleic acid salt, fumaric acid salt methanesulfonic acid, salt benzosulfimide acid, salt of p-toluensulfonate acid, salt, ascorbic acid, etc.

In addition, the present invention includes compounds of formula (I), their prodrugs and pharmaceutically acceptable salts of the compounds and prodrugs. The present invention also includes a hydrate and a solvate (e.g., ethanol solvate). In addition, the present invention includes all tautomers, all existing stereoisomers and all crystalline forms of the compounds of formula (I) according to the present invention.

Preferred examples of the compounds of the present invention is Vlada following compounds. In the compounds represented in the following tables, in some cases, the following abbreviations are used to simplify the description.

2-Py: 2-pyridyl, 3-Py: 3-pyridyl, 4-Py: 4-pyridyl, Ph: phenyl, Et is ethyl, Me: methyl, n-Pr: n-propyl, i-Pr: isopropyl, n-butyl: n-butyl, t-Bu: tert-butyl, Bn: benzyl, AC: acetyl, cycpro: cyclopropyl, cycbu: cyclobutyl, cychex: cyclohexyl, etoet: ethoxyethyl, meoet: methoxyethyl, f2etoet: 2.2-dipteridaceae, f2meoet: deformatsiei, cycprooet: cyclopropylacetic, isoproet: isopropoxide, ms: methanesulfonyl, etomet: ethoxymethyl, meomet: methoxymethyl, f2meomet: deformational and f2etomet: 2.2-diplomatically.

In some cases, further reductions are used for incomplete structures.

[Formula 15]

[Formula 17]

[Formula 18]

[Formula 20]

When the fragment corresponding to Y, described in paragraph[1], represents an unsubstituted or substituted 3-aminopyrrolidine-1-yl, unsubstituted or substituted 3-aminopiperidin-1-yl, or unsubstituted or substituted (3-amino)hexahydroazepin-1-yl in the above compounds with non 1-366, bol is e are preferred bicyclic derivatives of pyrrole, in which the amino group in position 3 is an absolute configuration represented by the following formula (F1):

[Formula 28]

in which m1 and R6have the meanings given in paragraph[1].

When the fragment corresponding to Y, described in paragraph[1], represents unsubstituted or substituted (2-aminotetralin)the amino group in the above compounds, numbered compounds 1-366, more preferred are compounds in which the amino group in position 1 and position 2 are absolute configuration represented by the following formula (F2) or (F3):

[Formula 29]

in which m2 and R7have the meanings given in paragraph[1].

In addition, even more preferred are compounds in which the amino group in position 1 and position 2 are absolute configuration represented by the following formula (F4):

[Formula 30]

in which m2 and R7have the meanings given in paragraph[1].

In the following description, the link shows a wedge-shaped solid line or broken line, as in the formula (J1) and the formula (J2indicates the absolute configuration in relation to the amino group, and the bond shown with a bold line, as in the formula (J3), shows the absolute configuration in relation to the amino group (for example, formula (J3) is (±)CIS-form).

[Formula 31]

in which m2 and R7have the meanings given in paragraph[1].

Of compounds having non 1-366, as the compounds of formula (I)described in paragraph[1], compounds having the formula "alkoxycarbonyl", "optionally substituted alkoxycarbonyl", "optionally substituted cycloalkylcarbonyl", "optionally substituted aryloxyalkyl", "optionally substituted Uralelectromed or a group of the formula: -Rd-C(O)O-Re in which Rd and Re have the meanings given above, are such that this Deputy in some cases turns into "carboxyl" under physiological conditions in a living organism through oxidation, recovery, hydrolysis or the like, with the participation of the enzyme or by hydrolysis under the action of acid in the stomach or the like.

Below is illustrated the method of obtaining the compounds of formula (I) according to the present invention referring to examples, which should not be construed as limiting the scope of invention. In the present description, in some cases, we use the following abbreviations to simplify the description.

Boc: tert-butoxycarbonyl

Cbz: benzyloxycarbonyl

TMS: trimethylsilyl

TBS: tert-butyldimethylsilyl

SEM: 2-[(trimethylsilyl)this is XI]methyl

Ac: acetyl

Me: methyl

Et: ethyl

Pr: propyl

i-Pr: isopropyl

Bu: butyl

i-Bu: isobutyl

t-Bu: tert-butyl

Ph: phenyl

Bn: benzyl

Ms: methanesulfonyl

TFA: triperoxonane acid

Alloc: allyloxycarbonyl.

The compound of formula (I) can be synthesized from well-known compounds by a combination of well-known methods of synthesis. For example, it is possible to synthesize any of the following ways.

The method of obtaining 1

The compound of formula (1-17) or its salt can be obtained, for example, in the following way:

[Formula 32]

where R1, R2, R6, R7, R8, R9, R10, R11, R29m1m2m3m4and m5have the meanings defined above; X1represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonate, tripterocalyx or p-toluensulfonate); R51is Alloc, N=C(Ph)2, NHBoc, NHCbz, or a group of the following formula (G1):

[Formula 33]

R52is Alloc, Boc or Cbz; and Y1is a secured form of primary or secondary amino group in Y, described in p.[1].

1) stage 1

The compound (1-8) can be obtained by the interaction of the compound (1-1) with a compound selected from the compounds (1-2), the compound (1-3), the connection is in (1-4), compounds (1-5), compounds (1-6) (1-7) in an inert solvent in the presence or absence of a base. The base includes, for example, organic bases (for example, 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]Nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline) and inorganic bases (e.g. sodium ethylate, sodium methylate, tert-butyl potassium and sodium hydride). A number of reasons, usually choose within 1-5 EQ. in EQ. the compounds (1-1). The amount used of the compound (1-2), the compound (1-3), compounds (1-4), compounds (1-5), compounds (1-6) or the compound (1-7), usually chosen in the range of 1-2 EQ. in EQ. the compounds (1-1). The inert solvent includes, for example, alcohols (e.g. methanol, ethanol or 2-propanol), ethers (tetrahydrofuran, and 1,4-dioxane) and the mixture of these solvents. The reaction temperature may be selected within the range from about 50°to about 120°C.

The compound (1-2) can be obtained by the method described in method get 19 below, the compound (1-3) - method described in the method of obtaining 20 below, and the compound (1-5) - method, described in method get 21 below. In respect of the compound (16), you can use a commercially available reagent or compound (1-6) can be obtained by a method described in the literature (for example, Synthesis 391 (1994), Org. Lett. 5, 1591 (2003), Synthesis 1065 (1992), Synlett 755 (2002), J. Org. Chem. 56, 3063 (1991), J. Org. Chem. 60, 4177 (1995) and J. Org. Chem. 57, 6653 (1992)). The compound (1-7) can be obtained in the same manner as described in the literature (for example, J. Org. Chem. 61, 6700 (1996)) or the like.

2) stage 2

The compound (1-10) produced by interaction of the compound (1-8) with the compound (1-9) in an inert solvent. The amount used of the compound (1-9), usually chosen in the range of 1 EQ. to an excess of EQ. in EQ. compounds (1-8). The inert solvent includes, for example, organic bases (for example, 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]Nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine and picoline), alcohols (e.g. methanol, ethanol or 2-propanol), acetic acid and mixtures of these solvents. The reaction temperature is selected in the range from about 50°to about 150°C., and usually the reaction is carried out at the boil under reflux.

3) stage 3

The compound (1-12) can be obtained by the interaction of the compounds (1-10) with the compound (1-11) in an inert solvent in the presence or absence of a base (see, for example, J. Heterocycl. Chem. 37, 1033 (000), J. Chem. Soc., Perkin Trans. 1, 13, 1833 (1999) and J. Med. Chem. 38, 3838 (1995)). The amount used of the compound (1-11), usually chosen in the range of 1-5 EQ. in EQ. compounds (1-10). The base includes, for example, carbonates of alkali metals (e.g. potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate), hydrides of alkali metals (e.g. sodium hydride and potassium hydride) and hydroxides of alkali metals (e.g. potassium hydroxide and sodium hydroxide). It suitable example is potassium carbonate. A number of reasons, usually choose within 1-3 EQ. in EQ. compounds (1-10). The inert solvent includes, for example, aprotic solvents (for example, N,N-dimethylformamide and dimethylsulfoxide), ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone) and mixtures of these solvents. Its suitable examples are N,N-dimethylformamide and dimethylsulfoxide. The reaction temperature may be selected within the range from about 10°to about 180°C.

4) stage 4

The compound (1-13) can be obtained by the interaction of the compound (1-12) with a base in an inert solvent (see, for example, WO 02/068420). The base includes, for example, hydrides of alkali metals (e.g. sodium hydride and potassium hydride) and the like. Its a good example is sodium hydride. The number used is emaho Foundation, usually choose within 1-3 EQ. in EQ. compounds (1-12). The inert solvent includes N,N-dimethylformamide, ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane) and the mixture of these solvents. Its a good example is tetrahydrofuran. The reaction temperature may be selected within the range from about 10°to about 100°C.

5) stage 5

The compound (1-15) can be obtained from compound (1-13) for the following reactions(1)-(3).

(1) the Compound (1-13) is subjected to interaction with the compound (1-14) in pyridine in the presence of a base. The reaction temperature may be selected within the range from about 50°to about 160°C. the Amount used of the compound (1-14), usually chosen in the range of 1-5 equivalents.

(2) Base added to the reaction mixture obtained in paragraph(1) above, and conducting the reaction. The base includes cesium carbonate, potassium carbonate, sodium carbonate, etc. a Number of reasons, usually choose within 1-5 EQ. The reaction temperature is selected in the range from about 50°to about 160°C.

(3) Methyliodide added to the reaction mixture obtained in paragraph(2) above, and conducting the reaction. The number of methyliodide, usually chosen in the range of 1-5 EQ. The reaction temperature is selected in the range from about 10°to about 40°C.

6) stage 6

At this stage 6 is you can carry out the following method of obtaining (A) or method get ().

The method of obtaining (A): compound (1-16) can be obtained by the interaction of the compound (1-15) with a mixture of sodium tungstate and an aqueous solution of hydrogen peroxide in an inert solvent. The inert solvent includes alcohols (e.g. ethanol, methanol or 2-propanol), organic acids (e.g. acetic acid and propionic acid), etc. usually in an inert solvent use solvent mixture of alcohol and organic acids. The amount of sodium tungstate, usually chosen in the range of 1-5 EQ. in EQ. the compound (1-15). The amount of aqueous hydrogen peroxide solution (normally 30% aqueous solution), usually chosen in the range 10-100 EQ. in EQ. the compound (1-15). The reaction temperature may be selected within the range from about -10°to about 70°C.

Method get (): connection (1-16) can be obtained by the interaction of the compound (1-15) with axonom (registered trade name; Aldrich) in an inert solvent. The inert solvent includes, for example, alcohols (e.g. ethanol, methanol and 2-propanol), etc. the Number of used Oksana, usually chosen in the range 1-20 EQ. in EQ. the compound (1-15). The reaction temperature may be selected within the range from about -10°to about 70°C.

7) stage 7

The compound (1-17) can be obtained from compound (1-16) in the e way, as in stage 2, described in the production method of 2.

The method of obtaining 2

Each of the compounds of formula (2-2) and formula (2-5) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, R4X1, Y1and Y have the meanings given above.

1) stage 1

The compound (2-1) can be obtained by the interaction of the compound (1-16) with a base in an inert solvent. The base includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, etc. It suitable example is sodium hydroxide. The amount used of the base, usually chosen in the range of 1 EQ. to a large excess of EQ. in EQ. compound (1-16). The inert solvent includes, for example, water, alcohols (e.g. methanol, ethanol and 2-propanol, tetrahydrofuran, and mixtures of these solvents. The reaction temperature may be selected within the range from about 50°to about 100°C.

At this stage, in some cases, get a connection, in which the protective group for a primary amino group or secondary amino group in Y is removed. It is possible to obtain the compound (2-1)in which the primary amino group or secondary amino group in Y is again protected by a protective group (such as Boc or Cbz) in the same way the floor of the treatment, as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)).

2) stage 2

The compound (2-2) can be obtained from compound (2-1) in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)) or something.

3) stage 3

The compound (2-4) can be obtained by the interaction of the compounds (2-1) with compound (2-3) in an inert solvent in the presence of a base. The amount used of the compound (2-3), usually chosen in the range of 1-5 EQ. in EQ. the compounds (2-1). The base includes, for example, carbonates of alkali metals (e.g. potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate), hydrides of alkali metals (e.g. sodium hydride and potassium hydride) and hydroxides of alkali metals (e.g. potassium hydroxide and sodium hydroxide). It suitable example is potassium carbonate. A number of reasons, usually choose within 1-5 EQ. in EQ. the compounds (2-1). The inert solvent includes, for example, aprotic solvents (for example, N,N-dimethylformamide and dimethylsulfoxide), ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone) and mixtures of these solvents. Its a good example is N,N-dimethylformamide. The reaction temperature may be selected within the range of the approximately 0°to approximately 180°C.

4) stage 4

The compound (2-5) can be obtained from compound (2-4) in the same manner as described in stage 2 above.

The method of obtaining 3

The compound of the formula (3-3) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above, and R54O represents the "optionally substituted alkoxy", "optionally substituted, aryloxy", "optionally substituted, aralkylated", "optionally substituted, heteroaromatic", "optionally substituted, cycloalkane".

1) stage 1

The compound (3-2) can be obtained by the interaction of the compound (1-16) with the compound (3-1) in an inert solvent in the presence of a base. The base includes tert-butyl potassium, tert-butyl sodium, cesium carbonate, potassium carbonate, sodium carbonate, sodium phenolate, potassium phenolate, sodium hydride, etc. It suitable example is sodium hydride. A number of reasons, usually choose within 1-5 EQ. in EQ. the compounds (3-1). The inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and mixtures of these solvents. The reaction temperature may be selected within the range from about -10°to about 50°C.

2) stage 2

The compound (3-3) can be obtained from compound (3-2) in the same way is, as in stage 2, described in the production method of 2.

The method of obtaining 4

The compound of formula (4-3) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above, and R55S represents optionally substituted, alkylthio" or "optionally substituted, aristeo".

1) stage 1

The compound (4-2) can be obtained from compound (1-16) in the same way as in stage 1, as described in the method of obtaining 3.

2) stage 2

The compound (4-3) can be obtained from compound (4-2) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 5

Each of the compounds of formula (5-2) and formula (5-4) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings given above.

1) stage 1

The compound (5-1) can be obtained by the interaction of the compound (1-16) with sodium cyanide or potassium cyanide in an inert solvent. The amount of sodium cyanide or potassium cyanide, usually chosen in the range from 0.8 to 5 equivalents. in EQ. compound (1-16). The inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixtures of these solvents, etc. of Temperaturregler can be selected in the range from about 10°to about 100°C.

2) stage 2

The compound (5-2) can be obtained from the compounds (5-1) in the same way as in stage 2, described in the production method of 2.

3) stage 3

The compound (5-3) can be obtained by the interaction of the compounds (5-1) with an aqueous solution of hydrogen peroxide in an inert solvent in the presence of a base. The base includes, for example, inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc. a Number of reasons, usually chosen in the range of 0.5-10 equivalents. in EQ. the compounds (5-1). The amount of aqueous solution of hydrogen peroxide, usually chosen in the range 1-20 EQ. in EQ. the compounds (5-1). The inert solvent includes dimethyl sulfoxide, acetone, etc. It suitable example is dimethyl sulfoxide. The reaction temperature may be selected within the range from about 10°to about 100°C.

4) stage 4

The compound (5-4) can be obtained from compound (5-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 6

The compound of formula (6-3) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above, and R56R57N represents optionally substituted attester asuu saturated heterocyclic group" or "optionally substituted by an amino group".

1) stage 1

The compound (6-2) can be obtained by the interaction of the compound (1-16) with the compound (6-1) in the presence or absence of a base in an inert solvent. The amount used of the compound (6-1), usually chosen in the range 1-100 EQ. in EQ. compound (1-16). When the compound (1-16) is liquid, it can also be used as solvent. The inert solvent includes alcohols (e.g. ethanol, methanol and 2-propanol) and so on, the reaction Temperature can be selected within the range from about 50°to about 150°C.

2) stage 2

The compound (6-3) can be obtained from compound (6-2) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 7

The compound of formula (7-3) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above; R58is "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted of alkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heteroaromatic" or "optionally substituted aralkyl"; and M1is lithium, magnesium chloride or magnesium bromide.

1) stage 1

The compound (7-2) can receive the th interaction of the compound (1-16) with the compound (7-1) in an inert solvent. The amount used of the compound (7-1), usually chosen in the range 1-10 EQ. in EQ. compound (1-16). The inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixtures of these solvents, etc. the reaction Temperature can be selected within the range of about -10°to about 50°C.

2) stage 2

The compound (7-3) can be obtained from compound (7-2) in the same way as in stage 2, described in the production method of 2.

The way to obtain 8

The compound of formula (8-3) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above, and R59C(O) represents the "optionally substituted aroyl", "optionally substituted heteroarylboronic" or "optionally substituted alkylaryl".

1) stage 1

The compound (8-2) can be obtained by the interaction of the compound (1-16) with the compound (8-1) in an inert solvent in the presence of a base. The amount used of the compound (8-1), usually chosen in the range 1-10 EQ. in EQ. compound (1-16). The base includes sodium hydride, etc. of the Inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, mixtures of these solvents, etc. the reaction Temperature can be selected within the range of about 50°C to primer is 150°C.

2) stage 2

The compound (8-3) can be obtained from compound (8-2) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 9

The compound of formula (9-4) as the compounds of formula (I) or its salt get, for example, in the following way:

[Formula 41]

where R1, R2, R4, Y1and Y have the meanings defined above, and X3represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonate, tripterocalyx or p-toluensulfonate).

1) stage 1

In those cases where R2in p.[4] represents a group of any of formula (E), formula (F), formula (G), and formula (H), the compound (9-1) can be obtained from compound (2-4) in the following way 1.

Method 1

The compound (9-1) can be obtained by the interaction of the compound (2-4) with an acid in an inert solvent. The acid includes inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc. with a suitable example is sulfuric acid. The amount of acid, usually chosen in the range of 1 EQ. to a large excess of EQ. in EQ. compounds (2-4). The inert solvent includes water and the like. The reaction temperature is selected in the range from about 50°C to PR is approximately 200°C.

At this stage, in some cases, get a connection, in which the protective group for a primary amino group or secondary amino group in Y is removed. It is possible to obtain the compound (9-1)in which the primary amino group or secondary amino group in Y is again protected by a protective group (such as Boc or Cbz), in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)).

In those cases where R2in p.[4] represents a group of any of formulae (I) or formula (J), the compound (9-1) can be obtained from compound (2-4) in the following way 2 [(1)-(2)].

Method 2

(1) R2in the compound (2-4) remove method similar to that described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.), Tetrahedron 27, 5523 (1971) and Aus. J. Chem. 22, 1321 (1969)) or the like.

(2) carry out the same reaction as in method 1 in stage 1, described in the production method of 9.

2) stage 2

The compound (9-3) can be obtained from compound (9-1) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic Transformation, VCH publisher Inc., 1989, Bioorg. Med. Chem. Lett. 11, 1993 (2001), Organic Letters 4, 4033 (2002), Organic Letters 5, 4987 (2003), Synlett 128 (2004) and J. Am. Chem. Soc. 124, 116847 (2002)) or the like.

In those cases where R2in p.[4] represents a group of any of formula (E), formula (F), formula (G), or formula (H), the compound (9-3) can be obtained from soy is inane (9-1) in the same way, as in stage 3, described in the method of obtaining 1.

3) stage 3

Connection (9-4) can be obtained from compound (9-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 10

Each of the compounds of formula (10-6), formula (10-8) and formula (10-10 as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2X3, Y1and Y have the meanings defined above, and R60is the above group, R54O, R55S or R56R57N.

1) stage 1

The compound (10-1) can be obtained from compound (2-1) in the same way as in stage 1, described in the production method of 9.

2) stage 2

The compound (10-2) can be obtained from compound (10-1) in the same way as described in the literature (for example, WO 03/104229 and Chem. Pharm. Bull. 50, 1163 (2002)).

3) stage 3

The compound (10-3) can be obtained from compound (10-2) in the same way as in stage 2, described in the production method of 9.

4) stage 4

Connection (10-5) can be obtained from compound (10-3) in the same way as in stage 1, as described in the method of obtaining 3, in stage 1, described in method 4, or stage 1, described in the method of obtaining 6.

5) stage 5

Connection (10-6) can be obtained from compound (10-5) in the same way as in stage 2, described is a method of producing 2.

6) stage 6

Connection (10-7) can be obtained from compound (10-3) in the same way as in stage 1, described in the production method of 5.

7) stage 7

Connection (10-8) can be obtained from compound (10-7) in the same way as in stage 2, described in the production method of 2.

8) stage 8

Connection (10-9) can be obtained from compound (10-7) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989, WO 03/104229 and WO 03/104229).

At this stage, in some cases, get a connection, in which the protective group for a primary amino group or secondary amino group in Y is removed. You can get a connection (10-9), in which the primary amino group or secondary amino group in Y is again protected by a protective group (such as Boc or Cbz), in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)).

9) stage 9

Connection (10-10) can be obtained from compound (10-9) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 11

The compound of formula (11-4) as the compounds of formula (I) or its salt get, for example, in the following way:

where R1, R2, Y1and Y have the meanings defined above, and R61is "optionally substituted alkoxy", "optional is substituted on aryloxy", "optionally substituted, aralkylated", "optionally substituted, heteroaromatic", "optionally substituted, cycloalkane", "optionally substituted, alkylthio", "optionally substituted, aristeo", cyano, an "optionally substituted nitrogen-containing saturated heterocyclic group", "optionally substituted for the amino group", "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted of alkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heteroaromatic", "optionally substituted aralkyl", "optionally substituted aroyl", "optionally substituted heteroarylboronic" or optionally substituted alkylaryl".

1) stage 1

The compound (11-1) can be obtained by the interaction of the compound (10-3) with methanethiol sodium in an inert solvent in the presence or absence of a base. The base includes, for example, inorganic bases such as sodium hydride, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.; and organic bases, such as 1-hydroxybenzotriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]Nona-5-ene, 1,4-diazabicyclo[5,4,0]undec-7-ene, pyridine, dimethylaminopyridine, Pico is in etc The amount of base is usually selected in the range of 1 EQ. to a large excess of EQ. in EQ. compound (10-3). The number of methanethiol sodium, usually chosen in the range of 1 EQ. to a large excess of EQ. in EQ. compound (10-3). The inert solvent includes, for example, aprotic solvents (for example, N,N-dimethylformamide and dimethylsulfoxide), ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone) and mixtures of these solvents. The reaction temperature may be selected within the range from about 10°to about 120°C.

2) stage 2

The compound (11-2) can be obtained from compound (11-1) in the same way as in stage 6, as described in the method of obtaining 1.

3) stage 3

The compound (11-3) can be obtained from compound (11-2) in the same way as in stage 1, as described in the method of obtaining 3, in stage 1, described in method 4, in stage 1, described in the production method of 5, in stage 1, described in the production method of 6, in stage 1, described in the production method of 7, or stage 1, described in the production method of 8.

4) stage 4

The compound (11-4) can be obtained from compound (11-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 12

Each of the compounds of formula (12-3) and formula (12-5) as the connection form is s (I) or its salt get for example, in the following way:

[Formula 44]

where a1And2, R1, R2, Y1and Y have the meanings defined above; a compound of formula (12-1) includes the compound (9-3)described in the production method of 9, the compound (11-3), described in the method of obtaining 11; L1 represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and R62is "optionally substituted alkyl", "optionally substituted of alkenyl", "optionally substituted quinil", "optionally substituted cycloalkyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted aralkyl" or "optionally substituted heteroaromatic".

1) stage 1

The compound (12-2) can be obtained from compound (12-1) in the same way as described in the literature (for example, Synth. Commun. 33, 2671 (2003), Tetrahedron Letters 42, 863 (2001), Synthesis, 926 (1995), Tetrahedron Letters 37, 1095 (1996), J. Org. Chem. 64, 5366 (1999), Indian J. Chem., Sect B 35, 141 (1996) and J. Heterocycl. Chem. 24, 1313 (1987)).

2) stage 2

The compound (12-3) can be obtained from compound (12-2) in the same way as in stage 2, described in the production method of 2.

3) stage 3

The compound (12-4) can be obtained from compound (12-2) in the same way as described in the literature (for example, Chem. Rev. 95, 2457 (1995), Chem. Rev. 103, 1979 (2003), Chem. Rev. 100, 3009 (2000), Organic Process Research & Development 5, 254 (2001), J. Med. Chem. 4, 999 (2002), Synthesis 563 (1997), J. Org. Chem. 65, 9001 (2000), J. Org. Chem. 64, 4196 (1999), J. Org. Chem. 67, 3904 (2002), Adv. Synth. Catal. 345, 620 (2003) and J. Med. Chem. 43, 675 (2000)).

4) stage 4

Connection (12-5) can be obtained from compound (12-4) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 13

The compound of formula (13-4) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R2M1, Y1and Y have the meanings defined above; a compound of formula (12-1) is such as described above; and R63is "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted aryl" or "optionally substituted heteroaryl".

1) stage 1

The compound (13-1) can be obtained from compound (12-1) in the same way as described in the literature (for example, J. Heterocycl. Chem. 30, 957 (1993), Chem. Pharm. Bull. 42, 237 (1994), Aust. J. Chem. 47, 1009 (1994) and J. Heterocycl. Chem. 12, 517 (1975)).

2) stage 2

The compound (13-3) can be obtained from compound (13-1) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

In respect of the compound (13-2), you can use the available industrial or compound (13-2) can be obtained by a method described, for example, in Japanese Chemical Association, Jikken Called Koza (Experimentl Chemistry) Vol.25, Maruzen Co., Ltd.

3) stage 3

Connection (13-4) can be obtained from compound (13-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 14

The compound of formula (14-2) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R2, R63, Y1and Y have the meanings given above.

1) stage 1

The compound (14-1) can be obtained from compound (13-3) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

2) stage 2

The compound (14-2) can be obtained from compound (14-1) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 15

The compound of formula (15-4) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R2, Y1and Y have the meanings defined above; R64O represents the "optionally substituted alkoxy", "optionally substituted, aryloxy", "optionally substituted, aralkylated", "optionally substituted, heteroaromatic" or "optionally substituted, cycloalkane"; and X2represents a hydroxyl or a leaving group (for example, iodine atom, bromine atom, chlorine atom is and, methansulfonate, tripterocalyx or p-toluensulfonate).

1) the Stage 1-2

Connection (15-3) can be obtained from compound (13-1) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), Organic Reactions (New York) 42, 335-656 (1992), Tetrahedron Lett. 44, 4873 (2003) and J. Am. Chem. Soc. 125, 4978 (2003)).

2) stage 3

Connection (15-4) can be obtained from compound (15-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 16

The compound of formula (16-2) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R2, R63, Y1and Y have the meanings given above.

1) stage 1

The compound (16-1) can be obtained from compound (13-3) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989), J. Org. Chem. 65, 6179 (2000), J. Org. Chem. 58, 6913 (1993), Bull. Chem. Soc. Jpn. 67, 1107 (1994) and J. Org. Chem. 60, 2430 (1995).

2) stage 2

The compound (16-2) can be obtained from compound (16-1) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 17

The compound of formula (17-2) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R 2, Y1and Y have the meanings defined above; and R65C(O) represents carboxyl, "optionally substituted carbarnoyl", "optionally substituted alkoxycarbonyl", "optionally substituted aryloxyalkyl", "optionally substituted Uralelectromed", "optionally substituted cycloalkylcarbonyl", "optionally substituted alkylaryl", "optionally substituted heteroarylboronic", "optionally substituted aroyl" or "optionally substituted cycloalkylcarbonyl".

1) stage 1

The compound (17-1) can be obtained from compound (13-1) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., (1989) and A. Hassner et al., Organic Synthesis Based on Name Reactions and Unnamed Reactions, Elsevier Science Ltd., (1994)).

In the case of compound (17-1), in which R65(C)About is "optional substituted alkoxycarbonyl", "optionally substituted aryloxyalkyl", "optionally substituted Uralelectromed" or "optionally substituted cycloalkylcarbonyl", this compound can be converted into another compound (17-1), in which R65(C)About is carboxyla, in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)) and the like.

2) stage 2

Connection (17-2) can be obtained from compound (17-1) takinge way as in stage 2, described in the production method of 2.

The method of obtaining 18

The compound of formula (18-4) as the compounds of formula (I) or its salt get, for example, in the following way:

where a1And2, R1, R2, R3X1, Y1and Y have the meanings defined above; CO2N presented in connection (18-1), indicates that R3or R4in the formula (I) are carboxyl or that carboxyl has incomplete structure R3, R4or R5; and CO2R66presented in conjunction (18-3) and the compound (18-4), refers to the form in which the CO2N in the compound (18-1) becomes CO2R66and, more specifically, CO2R66means, for example, the formula: C(O)O-Re, where Re is the values defined above.

1) stage 1

Connection (18-3) can be obtained by the interaction of the compounds (18-1) with compound (18-2) in an inert solvent in the presence of a base. The number of used connections (18-2), usually chosen in the range of 1-3 EQ. in EQ. connection (18-1). The base includes, for example, carbonates of alkali metals (e.g. potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate), hydroxides of alkali metals (e.g. potassium hydroxide and the hydroxide of the Seminary), hydrides of alkali metals (for example, Ki is reed sodium and potassium hydride) and alkoxyalkyl alkali metals (for example, tert-butyl potassium). Its suitable examples are potassium carbonate and sodium hydride. A number of reasons, usually choose within 1-5 EQ. in EQ. connection (18-1). The inert solvent includes, for example, aprotic solvents (for example, N,N-dimethylformamide and dimethylsulfoxide), ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone) and mixtures of these solvents. Its a good example is N,N-dimethylformamide. The reaction temperature may be selected within the range from about 10°to about 100°C.

In relation to compounds (18-2), you can use industrially available reagent or compound (18-2) can be obtained by a method described in the literature (for example, WO03/027098, WO00/06581 and R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

2) stage 2

Connection (18-4) can be obtained from compound (18-3) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 19

The compound (1-2)described in the production method of 1, can be obtained, for example, in the following way:

where m1, R6and R51have the meanings given above.

1) stage 1

Connection (19-2) can be obtained from compound (19-1) in the same way as described in the literature (for example, J. Org. Chem. 58, 879 (1993)).

2) stage 2

The compound (1-2)can be obtained from compound (19-2) in the same way, as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)) or something.

The method of obtaining 20

The compound (1-3)described in the production method of 1, can be obtained, for example, in the following way:

where m1, R6and R51have the meanings defined above, and R80is alkyl.

1) stage 1

The compound (20-2) can be obtained by the interaction of the compounds (20-1) with thionyl chloride in alcohol. The alcohol includes methanol, ethanol, etc. the Amount of thionyl chloride, as a rule, choose within 2-10 EQ. in EQ. connection (20-1). The reaction temperature can be selected within the range of about -90°to about 30°C.

2) stage 2

The compound (20-3) can be obtained by the interaction of the compound (20-2) with a base in an aqueous solvent. The base includes sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and so on, the reaction Temperature can be selected within the range from about 30°to about 100°C.

3) stage 3

Connection (20-4) can be obtained from compound (20-3) in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)) or something.

4) stage 4

The compound (1-3) can be obtained by the interaction of the compounds (20-4) with a reducing agent in an inert solvent. The reducing agent which engages alumoweld lithium complexes of borane (e.g., a complex of borane-dimethyl sulfide complex and borane-tetrahydrofuran) and the like. The inert solvent include tetrahydrofuran, 1,4-dioxane, mixtures of these solvents and the like. The reaction temperature may be selected within the range from about -20°to about 60°C.

Examples of synthesis of compounds (1-2A)-(1-2j) as specific examples of the compound (1-2) is presented below. Compounds (1-2A)-(1-2j) include their pharmaceutically acceptable salts.

where R51has the values defined above.

In respect of the hydrochloride of compound (1-2E), you can also use industrial available connection. It is also possible to synthesize the compound (1-2) of the substituted DL-ornithine well known manner. A concrete example of this method is the one described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

Examples of synthesis of compounds (1-3A)-(1-3i) as specific examples of the compounds (1-3) below. Compounds (1-3A)-(1-3i) include their pharmaceutically acceptable salts.

[Formula 55]

where R51has the values defined above.

[Formula 56]

where R51has the values defined above, and Y10represents NH2, Alloc, NHBoc or NHCbz.

where R51has the values defined above.

[Formula 58]

where R51has the values defined above.

Examples of synthesis of compounds (1-3w)-(1-3dd) as specific examples of the compounds (1-3) below. Compounds (1-3w)-(1-3dd) include their pharmaceutically acceptable salts.

where R51has the values defined above.

The compound (1-3) can be synthesized from substituted D-ornithine well known manner. A concrete example of this method is the one described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

The method of obtaining 21

The compound (1-5)described in the production method of 1, can be obtained, for example, in the following way:

where m2, R7and R51have the meanings given above.

1) stage 1

Connection (21-2) can be obtained from compound (21-1) in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)) or something.

2) Stage 2-4

The compound (1-5) can be obtained from compound (21-2) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic Transformation, VCH publisher Inc., 1989).

Examples of when NASA compounds (1-5A)-(1-a) as specific examples of the compound (1-5) is presented below. Compounds (1-5A)-(1-a) include their pharmaceutically acceptable salts.

Compounds (1-5A)-(1-a) can be obtained by methods described in the literature (for example, WO 01/74774 and R.C. Larock, Comprehensive Organic Transformation, VCH publisher Inc., 1989).

where R51has the values defined above.

Examples of synthesis of compounds (1-5bb)-(1-5tt) as specific examples of the compound (1-5) is presented below. Compounds (1-5bb)-(1-5tt) include their pharmaceutically acceptable salts.

Compounds (1-5bb)-(1-5tt) can be obtained by methods described in the literature (for example, WO 01/74774, R.C. Larock, Comprehensive Organic Transformation, VCH publisher Inc., 1989 and Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)).

where R51has the values defined above.

The method of obtaining 22

Connection (22-10) as a concrete example of the compound (1-6)described in the production method of 1, can be obtained, for example, in the following way:

[Formula 63]

where R100, R101and R102independently represent a hydrogen atom, "optionally substituted alkyl", "optionally substituted aryl" or "optionally substituted aralkyl", and R99represents a hydrogen atom or methoxy.

1) stage 1

Connection (22-3) can be obtained by carrying out reductive amination of compound (22-1) with ISOE what Itanium connection (22-2) in the same way, as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989).

2) Stage 2-4

Connection (22-7) can be obtained from compound (22-3) in the same way as described in the literature (for example, WO01/07436).

3) stage 5

Connection (22-8) can be obtained from compound (22-7) in the same way as described in the literature (for example, Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.)).

4) stage 6

Connection (22-9) can be obtained from compound (22-8) in the same way as described in the literature (for example, J. Chem. Soc. Perkin Trans. I 3281 (2001), Heterocycles 38, 17 (1994), Tetrahedron Lett. 34, 6673 (1993), J. Org. Chem. 60, 4602 (1995) and J. Med. Chem. 38, 2866 (1995)).

5) stage 7

Connection (22-10) can be obtained from compound (22-9) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.

Examples of synthesis of compounds (22-10A)-(22-10l) as specific examples of the compound (22-10) is presented below. Connection (22-10A)-(22-10l) include their pharmaceutically acceptable salts.

[Formula 64]

The method of obtaining 23

Each of the compounds of formula (23-2), formula (23-3), formula (23-5), formula (23-6), formula (23-7), formula (23-8) and formulas (12-1) to receive, for example, in the following way:

[Formula 65]

where a1And2, R1, R2and Y1have the meanings given to you is e; R67O represents the "optionally substituted alkoxy; and each of M2and M3represents lithium, sodium or potassium.

1) stage 1

Connection (23-2) can be obtained from compound (23-1) in the same way as described in the literature (e.g., Can. J. Chem. 78, 697 (2000)).

2) stage 2

Connection (23-3) can be obtained by the interaction of the compounds (23-2) with 2.5-dimethoxytetrahydrofuran in the presence of thionyl chloride and in the presence or absence of an inert solvent. The amount of thionyl chloride, usually chosen in the range of 0.1-3 EQ. in EQ. connection (23-2). The amount of 2,5-dimethoxytetrahydrofuran, usually chosen in the range 10-100 EQ. in EQ. connection (23-2), and 2,5-dimethoxytetrahydrofuran can also be used as solvent. The inert solvent includes, for example, aprotic solvents (for example, N,N-dimethylformamide and dimethylsulfoxide), ethers (e.g. diethyl ether, tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), aprotic solvents (e.g. acetonitrile, N,N-dimethylformamide and dimethylsulfoxide and mixtures of these solvents. Its suitable examples are N,N-dimethylformamide and dimethylsulfoxide. The reaction temperature may be selected within the range from about 10°to about 80°C.

3) stage 3

Connection (23-5) the floor shall be arranged by the interaction of the compounds (23-3) with compound (23-4) in an inert solvent. The number of used connections (23-4), usually chosen in the range of 1-5 EQ. in EQ. connection (23-3). The inert solvent includes alcohols (e.g. methanol, ethanol and 2-propanol) and the like. The reaction temperature may be selected within the range from about 30°to about 100°C.

4) stage 4

Connection (23-6) can be obtained by the interaction of the compounds (23-5) with a base in an inert solvent. As examples of the base can lead hydroxides of alkali metals (e.g. potassium hydroxide and sodium hydroxide), and can be used an aqueous solution of the base. A number of reasons, usually choose within 1-30 EQ. in EQ. connection (23-5). The inert solvent includes alcohols (e.g. methanol, ethanol and 2-propanol), water, mixtures of these solvents and the like. The reaction temperature may be selected within the range from about 30°to about 130°C.

5) stage 5

Connection (23-7) can be obtained from compound (23-5) in the same way as in stage 2, described in the production method of 2.

6) stage 6

Connection (23-8) can be obtained from compound (23-7) in the same way as in stage 4 above.

7) stage 7

The compound (12-1) can be obtained by the interaction of the compounds (23-6) in an inert solvent in the presence or absence of organic acids. The organic acid includes, but is, for example, acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonate acid, p-toluensulfonate acid and ascorbic acid. The inert solvent includes alcohols (e.g. methanol, ethanol and 2-propanol), ethers (e.g. tetrahydrofuran and 1,4-dioxane), ketones (e.g. acetone), aprotic solvents (e.g. acetonitrile, N,N-dimethylformamide and dimethylsulfoxide and mixtures of these solvents. The reaction temperature may be selected within the range from about 0°to about 100°C.

The method of obtaining 24

Each of the compounds of formula (24-3), formula (24-6) and formula (24-8) as the compounds of formula (I)or their salts and a compound of the formula (13-1) receive, for example, in the following way:

where a1And2, R1, R2, Y1and Y have the meanings defined above; C(O)NR68R69represents optionally substituted carbarnoyl"; and R70is "optionally substituted alkyl", "optionally substituted of alkenyl", "optionally substituted quinil", "optionally substituted cycloalkyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted aralkyl" or "optional is entrusted substituted heteroaromatic".

1) stage 1

Connection (24-2) can be obtained from compound (23-6) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 972-976, 1989)).

2) stage 2, stage 6 and stage 8

In the same way as in stage 2, described in the production method of 2, you can get a connection (24-3) from compound (24-2), the connection (24-6) from compound (24-5) and connection (24-8) from compound (24-7).

3) stage 3

Connection (24-4) can be obtained from compound (23-6) in the same way as described in the literature (e.g., Bioorg. Med. Chem. Lett. 11, 2951 (2001), Tetrahedron Letters 42, 8955 (2001), Organic Letters 2, 4091 (2000), Synlett 5, 715 (2002), Bioorg. Med. Chem. Lett. 11, 287 (2001), Tetrahedron Letters 45, 7107 (2004) and Tetrahedron Letters 42, 3763 (2001)).

4) stage 4

The compound (13-1) can be obtained from compound (24-4) in the same way as described in the literature (for example Tetrahedron Letters 45, 7107 (2004)).

5) stage 5

Connection (24-5) can be obtained from compound (13-1) in the same way as described in the literature (e.g., Indian J. Chem. 33B, 1103 (1994)).

6) stage 6 and stage 8

Connection (24-6) can be obtained from compound (24-5) in the same way as in stage 2, described in the production method of 2.

7) stage 7

Connection (24-7) can be obtained from compound (24-5) in the same way as described in the literature (for example, R.C. Larock, Comprehensive Organic transformation, VCH publisher Inc., 1989) or the like.

The method of obtaining 25

The compound of formula (25-1) as the compound of formula (I), or its salt to obtain, for example, in the following way:

[Formula 67]

where R2, R29, Y and Y1have the meanings given above.

1) stage 1

The compound (25-1) can be obtained from compound (1-13) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 26

Each of the compounds of formula (26-2), formula (26-4), formula (26-6) and formula (26-8) as the compounds of formula (I)or their salts get, for example, in the following way:

[Formula 68]

where a1And2, R1, R2, Y1and Y have the meanings defined above; and R71is alkyl.

1) stage 1 and stage 3

Connection (26-3) can be obtained from compound (12-1) in the same way as described in the literature (for example, J. Amer. Chem. Soc. 74, 3916 (1952)).

2) stage 2

Connection (26-2) can be obtained from compound (26-1) in the same way as in stage 2, described in the production method of 2.

3) stage 4

Connection (26-4) can be obtained from compound (26-3) in the same way as in stage 2, described in the production method of 2.

4) stage 5 and stage 7

Connection (26-7) can be obtained from compound (26-1) in the same way as described in the literature (for example, J. Org. Chem. 22, 355 (1957)).

6) stage 6

Connection (26-6) can be obtained from compound (26-5) W the way as in stage 2, described in the production method of 2.

7) stage 8

Connection (26-8) can be obtained from compound (26-7) in the same way as in stage 2, described in the production method of 2.

The method of obtaining 27

The compound of formula (27-2) as the compounds of formula (23-1)described in the production method of 23, can be obtained, for example, in the following way:

[Formula 69]

where R1, R2, R29and Y1have the meanings given above.

1) stage 1

Connection (27-1) can be obtained from compound (1-13) in the same way as described in the literature (for example Tetrahedron 50, 3259 (1994)).

2) stage 2

Connection (27-2) can be obtained from compound (27-1) in the same way as described in the literature (for example Tetrahedron 50, 3259 (1994)).

Unless otherwise noted, the source compounds, reagents and the like can be industrially available compounds or can be obtained from well-known compounds using well known methods.

In each of the methods of preparation, described above, when the original connection in each reaction contains a reactive group such as hydroxyl group, amino group or carboxyl group, a reactive group in another place than the place at which the desired reaction, it is pre-protect with suitable protective g is uppoi, if necessary, the protective group is removed after carrying out each reaction or after performing multiple reactions, whereby it is possible to obtain the desired compound. As a protective group for protecting the hydroxyl group, amino group, carboxyl group or the like can be used conventional protective group used in the field of chemical synthesis. The introduction and removal of such a protective group can be performed using conventional method (for example, the method described by T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 2ndEdition, John Wiley & Sons, Inc. (1991)).

For example, a protective group for hydroxyl include tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl and the like. The protective group for the amino group include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Such a protective group for hydroxyl can be removed by reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran, in the presence of acid, such as hydrochloric acid, sulfuric acid or acetic acid. In the case of tert-butyldimethylsilyloxy group it is also possible to perform the removal in a solvent such as tetrahydrofuran, in the presence of, for example, tetrabutylammonium fluoride. In that case, if the protective group for amino group is tert-butoxycarbonyl, it can remove the, for example, by reaction in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform or aqueous methanol, in the presence of acid, such as hydrochloric acid or triperoxonane acid. In the case of benzyloxycarbonyl, the deletion may, for example, by reaction in a solvent such as acetic acid in the presence of acid, such as Hydrobromic acid.

As an example of the form in which the protected carboxyl, you can give tert-butyl esters, orthoepy or amides of the acids. The protective group used for the protection, remove as follows. In the case of tert-butyl esters destruction carried out, for example, by reaction in an aqueous solvent in the presence of hydrochloric acid. In the case of orthoepical destruction carried out, for example, by treatment with an acid and then alkali such as sodium hydroxide, in a solvent such as aqueous methanol, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane. In the case of the amides of the acids, the removal can be carried out, for example, by reaction in a solvent such as water, aqueous methanol or aqueous tetrahydrofuran, in the presence of acid, such as hydrochloric acid or sulfuric acid.

The compound of formula (I) include those containing the center of the optical activity. Such a compound containing the center of the optical activity, can be obtained in the form of racemic modificat is and or can be obtained in the form of optically active compounds, when using optically active parent compound. If necessary, the resulting racemic modification can be physically or chemically divided into optical antipodes well known manner. Preferably the diastereomers obtained from racemic modification by interaction with the reagent for optical separation. The diastereomers, differing in form, can be divided well-known method, such as fractionated crystallization.

The compound or prodrug according to the present invention can be converted into a salt, for example, by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol or acetone. Pharmaceutically acceptable acid includes, for example, inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and so on; and organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonate acid, p-toluensulfonate acid, ascorbic acid, etc.

It is expected that the compounds of the present invention are suitable for treatment of various diseases as a result of their inhibit the subsequent steps on DPP-IV. Compounds described in this application, are suitable for suppression of hyperglycemia that occurs after a meal in subjects with the condition of prediabetes, the treatment of non-insulin-dependent diabetes, treatment of autoimmune diseases, such as arthritis or rheumatic arthritis, treating diseases of the mucous membranes of the intestines, accelerate growth, suppression of rejection of organs in transplantation, for the treatment of obesity, treatment of eating disorders, treatment of HIV infection, suppression of metastasis of malignant tumors, treatment prostatomegaly, treatment of periodontitis and osteoporosis treatment.

When used for the treatment of compounds of the present invention can be introduced in the form of pharmaceutical compositions for oral or parenteral (e.g. intravenous, subcutaneous or intramuscular injection, topically, rectally, percutaneously or inhalation). Compositions for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions and suspensions. Compositions for parenteral administration include, for example, water or oil based injectable preparations, ointments, creams, lotions, aerosols, suppositories and patches. Data pharmaceutical compositions are prepared by conventional methods, and they may contain non-toxic and inactive carriers or fillers commonly used in the field of formats is I.

Although the dose varies depending on the specific compounds of the disease, age, weight and sex of the patient, symptom, route of administration and the like, bicyclic derivative of pyrrole according to the present invention, its prodrug or pharmaceutically acceptable salt, derivative or prodrug usually impose an adult (body weight: 50 kg) at a dose in the range of 0.1-1000 mg/day, preferably 1-300 mg/day one-, two -, or three times a day. It is also possible to introduce derivative, prodrug, or salt with intervals of several days to several weeks.

Compounds of the present invention can be used in combination with drugs such as drugs for diabetes, drugs for the treatment of complications of diabetes, lipid-lowering drugs, antihypertensives, anti-obesity drugs, diuretics, etc. (the medicines below are called concomitant medications) to enhance the effect of the compounds. The introduction of the compounds of the present invention and the concomitant drug(s) is not limited. You can enter them with the object of introducing at the same time or at different times. It is also possible to prepare a mixture of the compounds of the present invention and the concomitant drug(s). Dose soputstvuyuschie the drug(s) it is possible to choose carefully based on the dose used in the clinic. You can carefully choose the ratio of the compounds of the present invention and the concomitant drug(s), depending on the subject of administration, route of administration, the condition being treated, symptoms, combination of compounds and concomitant drug(s) and the like. For example, when the object of this introduction is man, concomitant drug(s) administered in an amount of 0.01-100 parts by weight per one part by weight of compounds of the present invention.

Medicines to treat diabetes include products based on insulin (for example, products based on the insulin of animal origin, obtained from the pancreas of bovine or swine; and products on the basis of human insulin synthesized by genetic engineering techniques using Escherichia coli or yeast), a means of improving insulin resistance (e.g., pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011), inhibitors of α-glucosidase (for example, voglibose, acarbose, miglitol and emiglitate), drugs biguanide (e.g., Metformin), tools that enhance insulin secretion (for example, preparations based sulfonylureas, such as tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolasa the ID, acetohexamide, glyclopyramide, glimepiride, etc.; Repaglinide, sinapinic, nateglinide and mitiglinide), GLP-1 analogs, GLP-1 (e.g., exenatide, liraglutide, SUN-E7001, AVE010, BIM-51077 and CJC1131), inhibitors of protein-tyrosinosis (for example, Vanadate) and β3 agonists (e.g., GW-427353B and N-5984).

Medicines for the treatment of complications of diabetes include inhibitors illegitimates (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minareted, fidarestat, SK-860, CT-112), neurotrophic factors (e.g., NGF, NT-3 and BDNF), inhibitors of the RCC (e.g., LY-333531), AGE inhibitors (e.g., ALT946, pimagedine, paroxetin and N-phenacylthiazolium bromide (ALT766)), eliminators of free oxygen (for example, titanova acid) and cerebrovasculature (for example, tiaprid and meksiletin). Lipid-lowering drugs include inhibitors of HMG-CoA reductase inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin and their sodium salts), inhibitors stvalentines, ACAT inhibitors, and the like. Antihypertensive drugs include inhibitors of the angiotensin converting enzyme (for example, captopril, enalapril, alacepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril and trandolapril), antagonists of angiotensin II (e.g., olmesartan, medoxomil, candesartan, cilexetil, losartan, eprosartan, in losartan, telmisartan, irbesartan and tasosartan), calcium antagonists (e.g., nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipin, nilvadipine and amlodipine) and the like.

Drugs for the treatment of obesity include, for example, anti-obesity drugs Central action (e.g., phentermine, sibutramine, amfepramone, dexamfetamine, mazindol and SR-141716A), inhibitors of pancreatic lipase (e.g., orlistat), peptidergic drugs that cause anorexia (e.g., leptin and CNTF (ciliary trophic factor nerves)and cholecystokinin agonists (e.g., lintitript and FPL-15849). Diuretics include xanthine derivatives (theobromine sodium salicylate and theobromine, calcium salicylate), preparations based thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, bestellinformationen, panflutes, polythiazide and methyclothiazide), drugs with activity against aldosterone (e.g., spironolactone, and triamterene), inhibitors carbonatehydroxide (e.g., acetazolamide), preparations based chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside and indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide and furosemide.

Concomitant drugs preferably are GLP-1 analogs, GLP-1, inhibitors of α-glucosidase, the drug is of biguanide, substances that increase the secretion of insulin, a substance that increases insulin resistance, and the like. The above examples of concomitant drugs can be used in combination of two or more drugs in the right proportions.

In those cases, when the connection of the present invention is used in combination with a concomitant drug(s), the number of used drug(s) can be reduced so that it was within safe limits from the point of view of the side effects of the drug(s). In particular, the dose of drugs biguanide can be reduced compared with the conventional dose. Therefore, the side effects caused by these drugs are preventable. In addition, it is possible to reduce the dose of drugs for the treatment of complications of diabetes, hypoglycemic agents, antihypertensive agents, and the like. In the side effects caused by these drugs effectively warned.

Examples

The present invention is more specifically described below with reference to reference examples, working examples and experimental examples, which should not be construed as limiting the scope of invention. The nomenclature of the compounds represented in the reference examples and working examples below, not always is based on the IUPAC system. Abbreviations used in these examples, in some cases, to simplify the description and they are the same values that were defined above.

Example 1

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

A solution of 4 N. hydrochloric acid/1,4-dioxane (5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (185 mg) in 1,4-dioxane (3 ml) and the resulting mixture was stirred at 25°C. for 2 h and then concentrated under reduced pressure to obtain specified in the title compound (170 mg).

1H NMR (400 MHz, CD3OD) δ of 7.48-7,41 (m, 1H), was 7.36-7,16 (m, 3H), 6,91-of 6.78 (m, 3H), 6,57-of 6.49 (m, 1H), 5,69 (s, 2H), 4,06 (kV, J=7,0 Hz, 2H), of 3.73-of 3.60 (m, 2H), 3,50 (s, 3H), 3,49-of 3.42 (m, 1H), 3,10-of 2.92 (m, 2H), 2,10-to 1.98 (m, 1H), 1,80 is 1.70 (m, 1H), 1,65-of 1.45 (m, 2H), 1,40 (t, J=7.0 Hz, 3H).

MC (ESI+) 533 (M++1, 100%).

Example 2

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in example 1.

1H NMR (400 MHz, CD3OD) δ 7,47-7,44 (m, 2H),7,30-7,16 (m, 2H), 6,65 return of 6.58 (m, 1H), 5,72 with 5.2 (m, 2H), of 3.73 (s, 3H), 3,70-3,61 (m, 1H), 3,51-to 3.41 (m, 1H), 3.27 to (s, 3H), 3,23-3,10 (m, 1H), 3,05-of 2.97 (m, 2H), 2,13-2,03 (m, 1H), 1,82-1,72 (m, 1H), 1,63-of 1.41 (m, 2H).

MC (ESI+) 427 (M++1, 88%).

Example 3

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in example 1.

1H NMR (400 MHz, CD3OD) δ 7,47-7,44 (m, 1H), 7,32-7,20 (m, 2H), 6,65-6,60 (m, 1H), 5,67-to 5.57 (m, 2H), 3,52 is-3.45 (m, 1H), 3.27 to 3.15 in (m, 2H), 3,26 (s, 3H), 3,09-to 2.94 (m, 2H), 2,12-2,04 (m, 1H), 1,83 is 1.75 (m, 1H), 1,66 was 1.43 (m, 2H).

MC (ESI+) 413 (M++1, 93%).

Example 4

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in example 1.

1H NMR (400 MHz, CD3OD) δ 7,49-7,44 (m, 1H), 7,31-7,17 (m, 2H), 6,63-to 6.57 (m, 1H), 5,78-5,63 (m, 2H), 3,81 (s, 3H), 3,79-3,68 (m, 1H), to 3.58 (s, 3H), 3,37-3,17 (m, 2H), 3.15 and was 3.05 (m, 1H), 3,03 of 2.92 (m, 1H), 2,15-2,03 (m, 1H), 1,84-to 1.76 (m, 1H), 1,67 was 1.43 (m, 2H).

MC (ESI+) 475 (M++1, 100%).

Example 5

6-(3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)dione hydrochloride

Specified in the header connection sintezirovany the corresponding connection in the same way, as described in example 1.

1H NMR (400 MHz, CD3OD) δ 7,43-7,40 (m, 1H), 7,25-7,11 (m, 2H), 6,47-6.42 per (m, 1H), 6,04 (s, 1H), 5,66-of 5.53 (m, 2H), 3,48 (s, 3H), 3,38 of 3.28 (m, 2H), 3,25 (s, 3H), 2.95 and-to 2.85 (m, 2H), 2,81-a 2.71 (m, 1H), 2,07-to 1.98 (m, 1H) 1,84-1,73 (m, 1H), 1,67-1,49 (m, 2H).

MC (ESI+) 402 (M++1, 100%).

Example 6

6-(3-Aminopiperidin-1-yl]-5-(2-chloro-5-terbisil)-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)dione hydrochloride

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in example 1.

1H NMR (400 MHz, CD3OD) δ 7,47-the 7.43 (m, 1H),? 7.04 baby mortality-6,98 (m, 1H), 6,17-6,14 (m, 1H), equal to 6.05 (s, 1H), 5.56mm (s, 2H), 3,49 (s, 3H), 3,40-is 3.21 (m, 2H), 3.27 to (s, 3H), 2,97-2,70 (m, 3H), 2,08-to 1.98 (m, 1H), 1,86-of 1.73 (m, 1H), 1,68 of 1.46 (m, 2H).

MC (ESI+) 420 (M++1, 100%).

Example 7

2-{[6-(3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-yl]oxy}benzamide hydrochloride

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in example 1.

1H NMR (400 MHz, CD3OD) δ 8,04-of 7.97 (m, 1H), 7,50-7,41 (m, 2H), 7,32-7,17 (m, 2H), 7,00-6,91 (m, 2H), 6,67-6,59 (m, 1H), 5,71 (s, 2H), only 3.57 (s, 3H), 3.72 points-3,20 (m, 3H), 3,15-of 2.97 (m, 2H), 2,15-2,03 (m, 1H), 1,87 is 1.75 (m, 1H), 1.70 to of 1.42 (m, 2H).

MC (ESI+) 532 (M++1, 100%).

Each of the compounds of examples 8-70 synthesized by the methods described in the corresponding reference example and example 1.

Example 8

1H NMR (300 MHz, DMSO-d6) δ 8,18 (users, 3H), 7,86 (d, J=6,6 Hz, 1H), EUR 7.57 (m, 1H), 7,43 (t, J=7,6 Hz, 1H), 6,62 (d, J=7.9 Hz, 1H), 6,12 (s, 1H), 5,64 (d, J=16.2 Hz, 1H), 5.56mm (d, J=16.2 Hz, 1H), 3,39 (s, 3H), 3,36 is 3.23 (m, 2H), 3,11 (s, 3H), 2,92 is 2.75 (m, 3H), 1.91 a and 1.80 (m, 2H), 1,55-is 1.51 (m, 2H).

MC (ESI+) 393 (M++1, 100%).

Example 9

1H NMR (400 MHz, CD3OD) δ 7,10-7,03 (m, 1H), 6,28 and 6.25 (m, 1H), 6,02 (s, 1H), to 5.58 (s, 2H), 3,47 (s, 3H), 3,41-and 2.79 (m, 5H), of 3.27 (s, 3H), 2,10-of 1.52 (m, 4H).

MC (ESI+) 422 (M++1, 100%).

Example 10

1H NMR (300 MHz, DMSO-d6) δ 8,14 (users, 3H), 7.23 percent-to 7.18 (m, 1H), 6,95-of 6.90 (m, 1H), equal to 6.05 (s, 1H), 5,98-5,94 (m, 1H), of 5.40 (d, J=16.5 Hz, 1H), 5,32 (d, J=16.5 Hz, 1H), 3,38 (s, 3H), 3,35 is 3.23 (m, 2H), 3,11 (s, 3H), 2,86-of 2.81 (m, 2H), 2,68-of 2.64 (m, 1H), 2,32 (s, 3H), 1,88-of 1.74 (m, 2H), 1,49-of 1.44 (m, 2H).

MC (ESI+) 400 (M++1, 100%).

Example 11

1H NMR (300 MHz, CD3OD) δ 7,09-to 6.88 (m, 3H), to 6.19 (d, J=7.5 Hz, 1H), to 5.93 (s, 1H), 5,43 (d, J=16,3 Hz, 1H), are 5.36 (d, J=16,3 Hz, 1H), 3,38 (s, 3H), 3.27 to is 3.21 (m, 2H), 3,14 (s, 3H), 2,89-by 2.73 (m, 3H), 2,31 (s, 3H), 1,94 is 1.91 (m, 1H), 1.70 to 1,49 (m, 3H).

MC (ESI+) 382 (M++1, 100%).

Example 12

1H NMR (300 MHz, CDCl3) δ of 7.64-to 7.59 (m, 1H), 6,83-6,79 (m, 1H), 6,32 (d, J=2.4 Hz, 1H), 5,67 (s, 1H), to 5.66 (s, 1H), ceiling of 5.60 (s, 1H), 3,74 (s, 3H), 3,47 (s, 3H), on 3.36 (s, 3H), 3,03-of 2.93 (m, 2H), 2,86-2,82 (m, 1H), 2,69-2,61 (m, 1H), 2,52 is 2.46 (m, 1H), 1,88-to 1.61 (m, 4H).

MC (ESI+) 423 (M++1, 100%).

Example 13

1H NMR (300 MHz, CDCl3) δ 8,50 (users, 3H), 7,71-the 7.65 (m, 1H), 7,07-7,00 (m, 1H), 6,57-6,53 (m, 1H), of 5.84 (d, J=16,7 Hz, 1H), 5,73 (s, 1H), 5,64 (d, J=16,7 Hz, 1H), 3,59 is 3.57 (m, 1H), 3.45 points (s, 3H), 3,39-3,37 (m, 1H), 3.33 and (s, 3H), 3,16-to 3.09 (m, 1H), 2,70 of 2.68 (m, 2H), 2,08-to 2.06 (m, 1H), 1,80-of 1.78 (m, 2H), 1.60-to was 1.58 (m, 1H).

MC (ESI+) 411 (M ++1, 100%).

Example 14

1H NMR (300 MHz, DMSO-d6) δ 8,28 (users, 3H), 5,91 (s, 1H), 5.08 to 4,89 (m, 2H), 3,35 (s, 3H), 3,35 of 3.28 (m, 2H), 3,21 (s, 3H), 2,99-2,89 (m, 3H), 1,95 is 1.91 (m, 2H), 1,76 (s, 3H), 1,67-to 1.63 (m, 2H).

MC (ESI+) 330 (M++1, 100%).

Example 15

1H NMR (300 MHz, DMSO-d6) δ 8,07 (users, 3H), 7,53-7,49 (m, 1H), 7,32-7,24 (m, 2H), 6,41-6,38 (m, 1H), equal to 6.05 (s, 1H), 5,63 (s, 2H), 3,37 (s, 3H), 3,30-3,19 (m, 2H), 3,14 (s, 3H), 2,82-2,78 (m, 2H), 2,62-2,60 (m, 1H), 1,91-to 1.87 (m, 1H), 1,71 was 1.69 (m, 1H), 1,47-of 1.45 (m, 2H).

MC (ESI+) 411 (M++1, 100%).

[Formula 78]

Example 16

1H NMR (400 MHz, CD3OD) δ 7,47-the 7.43 (m, 1H), 7,22-7,19 (m, 2H),? 7.04 baby mortality-7,01 (m, 1H), 6,79 to 6.75 (m, 2H), 6,18-x 6.15 (m, 1H), 6,03 (s, 1H), 5.56mm (s, 2H), free 5.01 (s, 2H), of 3.73 (s, 3H), 3,47 (s, 3H), 3,40-by 2.73 (m, 5H), 2,12-of 1.52 (m, 4H).

MC (ESI+) 526 (M++1, 100%).

Example 17

1H NMR (400 MHz, CD3OD) δ 7,49-the 7.43 (m, 1H), 7,32-7,27 (m, 1H), 7.18 in-to 7.15 (m, 1H), 7,08-7,03 (m, 1H), 5,91 (s, 1H), 3,50 (s, 3H), 3,40-3,30 (m, 1H), 3,12 (s, 3H), 3,11-3,00 (m, 2H), 2,80-of 2.66 (m, 2H), 2,01-of 1.92 (m, 1H), 1,68-1,59 (m, 1H), 1,50-of 1.30 (m, 2H).

MC (ESI+) 384 (M++1, 100%).

Example 18

1H NMR (400 MHz, CD3OD) δ 8,58-8,56 (m, 1H), at 8.36-of 8.33 (m, 1H), 8,25-8,17 (m, 2H), 8,12-8,07 (m, 1H), of 7.90-to 7.84 (m, 1H), 7,46-7,42 (m, 1H), 7,05-6,99 (m, 1H), 6,27-6,23 (m, 1H), 6,13 (s, 1H), to 5.93 (s, 2H), to 5.56 (s, 2H), 3,50 (s, 3H), 3,40-3,30 (m, 2H), 3,01 of 2.92 (m, 2H), 2,89-2,77 (m, 1H), 2,10-2,03 (m, 1H), 1,92-of 1.81 (m, 1H), 1,75-of 1.53 (m, 2H).

MC (ESI+) 547 (M++1, 100%).

Example 19

1H NMR (400 MHz, CD3OD) δ 8,04 shed 8.01 (m, 2H), to 7.67-7,63 (m, 1H), 7,54 is 7.50 (m, 2H), 7,44-7,40 (m, 1H), 7.03 is-6,98 (m, 1H), 6,24-of 6.20 (m, 1H), 6,11 (s, 1H), 5.56mm (s, 2H), of 5.39 (s, 2H), 3,51 (s, 3H), 3,40-3,30 (m, 2H), 3.00, it is only 2.91 (m, 2H), 2,85-2,79 (who, 1H), 2,10-2,02 (m, 1H), 1,90 and 1.80 (m, 1H), 1,72-of 1.53 (m, 2H).

MC (ESI+) 524 (M++1, 100%).

Example 20

1H NMR (400 MHz, CD3OD) δ of 7.48-7,44 (m, 1H), 7,06-7,01 (m, 1H), 6.22 per to 6.19 (m, 1H), 6,07 (s, 1H), of 5.55 (s, 2H), 3.45 points (s, 3H), 3,40 of 3.28 (m, 2H), 3.00 and of 2.92 (m, 2H), 2,85-2,77 (m, 1H), 2,11-a 2.01 (m, 1H), 1,90-of 1.81 (m, 1H), 1,82-1,53 (m, 2H).

MC (ESI+) 406 (M++1, 100%).

[Formula 79]

Example 21

1H NMR (400 MHz, CD3OD) δ 7,47-the 7.43 (m, 1H), 7,30-7,17 (m, 2H), of 6.49-6,44 (m, 1H), 5,69 (s, 2H), only 3.57 (s, 3H), 3,30 (s, 3H), 3,18-2,90 (m, 5H), 2,08 of 1.99 (m, 1H), 1.77 in by 1.68 (m, 1H), 1.55V is 1.35 (m, 2H).

MC (ESI+) 445 (M++1, 59%).

Example 22

1H NMR (400 MHz, CD3OD) δ 7,49-7,42 (m, 1H), 7,30-7,21 (m, 2H), 6,58-is 6.54 (m, 1H), USD 5.76 (s, 2H), 3,29 (s, 3H), 3,10-of 2.75 (m, 3H), 3,05 (s, 3H), 2,53 of-2.32 (m, 2H), 1,98-of 1.85 (m, 1H), 1,62-1,49 (m, 1H), 1,40-of 1.16 (m, 2H).

MC (ESI+) 470 (M++1, 100%).

Example 23

1H NMR (400 MHz, CD3OD) δ 7,47-the 7.43 (m, 1H), 7,29-7,21 (m, 2H), 6,47-to 6.43 (m, 1H), of 5.75 (s, 2H), of 3.94 (s, 3H), of 3.54 (s, 3H), of 3.32 (s, 3H), 3,10-of 2.81 (m, 4H), 2,72-2,62 (m, 1H), 1,96-1,89 (m, 1H), 1,61-and 1.54 (m, 1H), 1,40-1,25 (m, 2H).

MC (ESI+) 460 (M++1, 100%).

Example 24

1H NMR (400 MHz, CD3OD) δ 7,47-7,44 (m, 1H), 7,29-7,17 (m, 2H), 6,47-to 6.43 (m, 1H), 5,79-5,69 (m, 2H), 4,43-4,34 (m, 2H), of 3.56 (s, 3H), at 3.35 (s, 3H), 3,17-of 2.72 (m, 5H), 2,07-of 1.97 (m, 1H), 1,72-to 1.63 (m, 1H), 1,48-of 1.30 (m, 2H), 1,43-to 1.38 (m, 3H).

MC (ESI+) 474 (M++1, 100%).

Example 25

1H NMR (400 MHz, CD3OD) δ 7,47-7,44 (m, 1H), 7,30-7,20 (m, 2H), 6,56-of 6.52 (m, 1H), 5,72-of 5.68 (m, 2H), 3,42 (s, 3H), of 3.27 (s, 3H), 3.27 to 3,20 (m, 1H), 3,16-3,11 (m, 6H), 2.95 and-to 2.85 (m, 3H), 2,08 of 1.99 (m, 1H), 1,76 by 1.68 (m, 1H), 1,50-of 1.30 (m, 3H).

MC (ESI+) 473 (M++1, 10%).

Example 26

1H NMR (400 MHz, CD3OD) δ 7,46-the 7.43 (m, 1H), 7,30-7,20 (m, 2H), 6,55-6,50 (m, 1H), 5,79-the ceiling of 5.60 (m, 2H), 3,91-3,62 (m, 8H), 3,40 (s, 3H), of 3.27 (s, 3H), 3.27 to 3,10 (m, 1H), 2,97 is 2.75 (m, 3H), 2.05 is-of 1.95 (m, 1H), 1,78-to 1.63 (m, 1H), 1,54-1,25 (m, 3H).

MC (ESI+) 515 (M++1, 100%).

Example 27

1H NMR (400 MHz, CD3OD) δ 7,46-the 7.43 (m, 1H), 7,29-7,20 (m, 2H), 6,53-6.48 in (m, 1H), 5,69 (s, 2H), 3,71-3,59 (m, 4H), 3,50-2,78 (m, 5H), 3,44 (s, 3H), 3,34-3,26 (m, 3H), 2,09-of 1.93 (m, 5H), 1,78 by 1.68 (m, 1H), 1,65-to 1.38 (m, 2H).

MC (ESI+) 499 (M++1, 100%).

Example 28

1H NMR (400 MHz, CD3OD) δ 7,39-7,34 (m, 1H), 7,22-7,11 (m, 2H), 6,50-to 6.43 (m, 1H), 5,67-5,52 (m, 2H), 4,48-of 3.80 (m, 4H), 3,55-3,47 (m, 3H), at 3.35 (s, 3H), 3,30-3,10 (m, 2H), 2,85-2,11 (m, 5H), 1,69-of 1.41 (m, 4H).

MC (ESI+) 485 (M++1, 100%).

Example 29

1H NMR (400 MHz, CDCl3) δ 7,39 was 7.36 (m, 1H), 7,21-7,10 (m, 2H), 6,46-6.42 per (m, 1H), 5,69 (d, J=17 Hz, 1H), 5,61 (d, J=17 Hz, 1H), to 3.58 (s, 3H), at 3.35 (s, 3H), 3,32-of 3.27 (m, 2H), is 3.08-3,03 (m, 1H), 2.91 in-and 2.83 (m, 2H), 2,78-2,60 (m, 2H), 1.85 to to 1.16 (m, 4H), 1,10-1,02 (m, 1H), and 0.61-of 0.56 (m, 2H), 0,31 is 0.27 (m, 2H).

MC (ESI+) 499 (M++1, 100%).

Example 30

1H NMR (400 MHz, CDCl3) δ 8,46 (users, 3H), 7,37-7,33 (m, 1H), 7,25-7,10 (m, 2H), 6,60 (users, 1H), 6,52-6.42 per (m, 1H), 5,72-of 5.50 (m, 2H), 3,56-of 3.42 (m, 1H), 3,49 (s, 3H), 3,40-3,13 (m, 4H), of 3.32 (s, 3H), 2,88-of 2.72 (m, 2H), 2,12-to 1.98 (m, 1H), 1,96 is 0.99 (m, 15H).

MC (ESI+) 541 (M++1, 100%).

Example 31

1H NMR (400 MHz, CDCl3) δ 8,70-8,33 (users, 3H), 7,38-7,34 (m, 1H), 7,22-7,10 (m, 2H), 6,91-6,77 (users, 1H), to 6.43-6,36 (m, 1H), 5,74 (d, J=16 Hz, 1H), 5,50 (d, J=16 Hz, 1H), 4,51 (m, 1H), 3,49 (s, 3H), of 3.32 (s, 3H), 3,28-3,18 (m, 2H), 2,83-to 2.74 (m, 2H), 2,53-of 2.30 (m, 2H), 2,09-1,90 (m, 3H), 1,81-to 1.60 (m, 6H).

MC (ESI+) 499 (M++1, 100%).

Example 32

MC (ESI+) 519 M ++1, 100%).

Example 33

1H NMR (400 MHz, CDCl3) δ 8,43 (users, 3H), 7,39-7,33 (m, 1H), 7.23 percent-7,13 (m, 2H), 6,60-6,53 (m, 1H), 5,74-5,52 (m, 2H), 4,47 of $ 2.53 (m, 11H), 3,50-of 3.31 (m, 6H), 2,20-1,22 (m, 8H).

MC (ESI+) 529 (M++1, 100%).

Example 34

1H NMR (400 MHz, CDCl3) δ 7,40-7,35 (m, 1H), 7,21-7,13 (m, 2H), 6,50-of 6.45 (m, 1H), 5,78-5,52 (m, 2H), 4,27-to 4.15 (m, 1H), 3,98-3,14 (m, 7H), 3,53-to 3.49 (m, 3H), 3,35-to 3.33 (m, 3H), 2,94-2,82 (m, 1H), 2,75-to 2.65 (m, 1H), 2,13-to 1.38 (m, 8H).

MC (ESI+) 529 (M++1, 100%).

Example 35

1H NMR (400 MHz, CD3OD) δ 7,51 was 7.45 (m, 1H), 7,31-to 7.18 (m, 2H), 7,03 (kV, J=5.4 Hz, 1H), 6,53-of 6.45 (m, 1H), 5,81-the 5.65 (m, 2H), 4,69-4,56 (m, 1H), only 3.57 (s, 3H), of 3.32 (s, 3H), 3,21-to 2.67 (m, 5H), 2,13-to 1.82 (m, 3H), 1,80 was 1.69 (m, 1H), 1,67 (d, J=5.4 Hz, 3H), 1,66-1,22 (m, 10H).

MC (ESI+) 616 (M++1, 100%).

[Formula 80]

Example 36

1H NMR (400 MHz, CDCl3) δ 7,37-7,31 (m, 1H), 7,00-of 6.90 (m, 1H), 6,32 and 6.25 (m, 1H), 5,63-of 5.50 (m, 2H), 3,53 of 3.28 (m, 3H), 3.45 points-of 3.33 (m, 6H), 3,28-3,03 (m, 6H), 2,82-to 2.65 (m, 2H), 2.21 are of 2.10 (m, 1H), 1,81-of 1.40 (m, 3H)

MC (ESI+) 491 (M++1, 100%).

Example 37

1H NMR (400 MHz, CDCl3) δ 8,50 (users, 3H), 7,37-7,31 (m, 1H), 6,95-6,85 (m, 2H), 6,25-6,18 (m, 1H), 5,62 (d, J=17 Hz, 1H), 5,46 (d, J=17 Hz, 1H), to 3.58 is 3.40 (m, 1H), 3,47 (s, 3H), 3,38-3,20 (m, 2H), 3,32 (s, 3H), 3,01 (s, 3H), 2,82-2,72 (m, 2H), 2,20-of 1.41 (m, 4H).

MC (ESI+) 477 (M++1, 100%).

Example 38

1H NMR (400 MHz, CDCl3) δ 8,59 (users, 3H), 7,38-7,31 (m, 1H), 7,02 (users, 1H), 6,93-6,87 (m, 1H), 6,25-6,13 (m, 1H), 5,63 (d, J=17 Hz, 1H), 5,44 (d, J=17 Hz, 1H), 3,61-of 3.53 (m, 1H), 3.45 points (s, 3H), and 3.31 (s, 3H), 3,38-3,20 (m, 2H), 3,03-2,95 (m, 1H), 2,83-by 2.73 (m, 2H), 2,23-of 1.62 (m, 4H), 0,93-0,83 (m, 2H), 0.74 and is 0.58 (m, 2H).

MC (ESI+) 503 (M++1, 100%)

Example 39

1H NMR (400 MHz, CDCl3) δ charged 8.52 (users, 3H), 7,41-7,35 (m, 1H), 7,00-6,89 (m, 1H), 6,78 (users, 1H), 6.30-in-6,16 (m, 1H), 5,78-5,62 (m, 1H), 5,49 is 5.38 (m, 1H), 3,59-is 3.21 (m, 5H), 3,52 (s, 3H), of 3.33 (s, 3H), 2,88-a 2.71 (m, 2H), 2.21 are of 1.45 (m, 4H), 1,16 was 1.04 (m, 1H), 0,65-0,49 (m, 2H), range 0.38-0.25 in (m, 2H).

MC (ESI+) 517 (M++1, 100%).

Example 40

1H NMR (400 MHz, CDCl3) δ 8,60 (users, 3H), 7,41-7,30 (m, 1H), of 6.96-6,83 (m, 1H), 6,77 (users, 1H), 6,28-6,10 (m, 1H), 5,75-5,33 (m, 2H), 4,59 was 4.42 (m, 1H), 3,49 (s, 3H), 3,40-3,19 (m, 2H), 3.33 and (s, 3H), 2,84-of 2.66 (m, 2H), 2,54 is 2.33 (m, 2H,), 2,22 is 1.91 (m, 3H), 1,87 of 1.50 (m, 6H).

MC (ESI+) 517 (M++1, 100%).

Example 41

1H NMR (400 MHz, CDCl3) δ 8,50 (users, 3H), 7,37-7,33 (m, 1H), 6,93-6,89 (m, 2H), 6.30-in-6,23 (m, 1H), 5,64 (d, J=17 Hz, 1H), the 5.45 (d, J=17 Hz, 1H), 3,79-to 3.58 (m, 4H), 3,55-up 3.22 (m, 3H), 3,51 (s, 3H), on 3.36 (s, 3H), 3,34 (s, 3H), 2,89-2,69 (m, 2H), 2,18 was 1.43 (m, 4H).

MC (ESI+) 521 (M++1, 100%).

Example 42

1H NMR (400 MHz, CDCl3) δ 8,57 (users, 3H), 7,51 (users, 1H), 7,41-7,29 (m, 1H), 6,95-6,83 (m, 1H), 6,21-6,11 (m, 1H), 5,67 (d, J=17 Hz, 1H), 5,44 (d, J=17 Hz, 1H), or 4.31-of 3.97 (m, 2H), 3,51-of 3.12 (m, 3H), of 3.45 (s, 3H), 3,29 (s, 3H), 2,82-2,69 (m, 2H), 2,11-of 1.35 (m, 4H).

MC (ESI+) 545 (M++1, 100%).

Example 43

1H NMR (400 MHz, CD3OD) δ 7,49-7,44 (m, 1H), 7,08-7,00 (m, 1H), 6,29-6,24 (m, 1H), 5,64 (d, J=17 Hz, 1H), 5,58 (d, J=17 Hz, 1H), only 3.57 (s, 3H), 3,30 (s, 3H), 2,30-1,25 (m, 23H).

MC (ESI+) 613 (M++1, 100%).

Example 44

1H NMR (400 MHz, CDCl3) δ 7,38-7,33 (m, 1H), 6,97-6,89 (m, 1H), 6,33-6,24 (m, 1H), 5,72-5,49 (m, 2H), 4,00-3,62 (m, 8H), 3,50-to 3.34 (m, 6H), 3,45-2,62 (m, 5H), 2,19-1,49 (m, 4H).

MC (ESI+) 533 (M++1, 100%).

[Formula 81]

Example 45

1 H NMR (300 MHz, DMSO-d6) δ 8,79 (d, J=4.0 Hz, 1H), 8,04 (users, 3H), 7,88 (d, J=7.5 Hz, 1H), 7,60 (t, J=7.7 Hz, 1H), 7,46 (t, J=7.5 Hz, 1H), 6,62 (d, J=7.5 Hz, 1H), 5,69 (d, J=16,3 Hz, 1H), 5,59 (d, J=16,3 Hz, 1H), on 3.36 (s, 3H), 3,24-3,19 (m, 1H), 3.15 in (s, 3H), 2,94-by 2.73 (m, 4H), 1,92-1,90 (m, 1H), 1.70 to to 1.67 (m, 1H), 1,46 is 1.23 (m, 3H), of 0.74 and 0.68 (m, 2H), 0,58-of 0.53 (m, 2H).

MC (ESI+) 476 (M++1, 100%).

Example 46

1H NMR (300 MHz, DMSO-d6) δ 8,96 (d, J=7.5 Hz, 1H), 7,99 (users, 3H), of 7.90-7,87 (m, 1H), to 7.61 (m, 1H), 7,45 (t, J=7,4 Hz, 1H), 6,62 (d, J=7.7 Hz, 1H), 5,70 (d, J=16.5 Hz, 1H), 5,59 (d, J=16.5 Hz, 1H), 4,39-or 4.31 (m, 1H), 3,37 (s, 3H), 3,26-3,19 (m, 1H), 3.15 in (s, 3H), 2,92-and 2.83 (m, 3H), 2.26 and-of 2.23 (m, 2H), 2,03-to 1.87 (m, 3H), 1,74-of 1.62 (m, 3H), 1,42 is 1.23 (m, 3H).

MC (ESI+) 490 (M++1, 100%).

Example 47

1H NMR (400 MHz, CD3OD) δ 7,76-7,73 (m, 1H), EUR 7.57-7,52 (m, 1H), 7,44-7,38 (m, 1H), 6,76-6,72 (m, 1H), of 5.81 (d, J=17 Hz, 1H), 5,73 (d, J=17 Hz, 1H), 3,60-of 3.53 (m, 4H), 3,53 (s, 3H), 3,38 (s, 3H), of 3.28 (s, 3H), 3,14-3,11 (m, 1H), 2,92-to 2.85 (m, 2H), was 2.76 of 2.68 (m, 2H), 1,99-of 1.84 (m, 1H), 1,78-to 1.59 (m, 1H), 1,51 is 1.13 (m, 2H).

MC (ESI+) 494 (M++1, 100%).

Example 48

1H NMR (400 MHz, CD3OD) δ 5,16-free 5.01 (m, 2H), 3,47-to 3.41 (m, 2H), 3,44 (s, 3H), 3,34 (s, 3H), 3,29-up 3.22 (m, 1H), 3,12-3,03 (m, 2H), 2,94-2,87 (m, 1H), 2,17-to 1.77 (m, 3H), 1.77 in-of 1.73 (m, 3H), 1,64 of 1.50 (m, 1H), 0,87-of 0.79 (m, 2H), 0,64-of 0.58 (m, 2H).

MC (ESI+) 413 (M++1, 100%).

Example 49

1H NMR (400 MHz, CD3OD) δ 5,15-5,02 (m, 2H), 3,60-to 3.52 (m, 4H), 3,48-of 3.06 (m, 5H), 3,47 (s, 3H), 3,37 (s, 3H), 3,34 (s, 3H), 2,14-2,05 (m, 1H), 1,96-of 1.78 (m, 3H), 1,76-of 1.73 (m, 3H), 1,66-of 1.55 (m, 1H).

MC (ESI+) 431 (M++1, 100%).

Example 50

1H NMR (400 MHz, CD3OD) δ 7,80 to 7.75 (m, 1H), 7,60-7,53 (m, 1H), 7,47-7,41 (m, 1H), 6,83-of 6.78 (m, 1H), by 5.87 (d, J=17 Hz, 1H), 5,73 (d, J=17 Hz, 1H), 4,21-4,07 (m, 2H), and 47 (C, 3H), 3,30 (s, 3H), 3,25 was 2.76 (m, 5H), 2,11-to 1.98 (m, 1H), 1,78-of 1.35 (m, 3H).

MC (ESI+) 518 (M++1, 100%).

Example 51

1H NMR (400 MHz, CD3OD) δ of 7.90-7,86 (m, 1H), 7,26-7,19 (m, 1H), 6,59-6,55 (m, 1H), of 5.84 (d, J=17 Hz, 1H), 5,73 (d, J=17 Hz, 1H), 3,65-3,55 (m, 4H), 3,53 (s, 3H), 3,41 (s, 3H), 3,37 (s, 3H), 3,14 was 2.76 (m, 5H), 2,11-a 2.01 (m, 1H), 1,81-1,71 (m, 1H), 1,61-to 1.38 (m, 2H).

MC (ESI+) 512 (M++1, 100%).

Example 52

1H NMR (400 MHz, CD3OD) δ 7,92-a 7.85 (m, 1H), 7,27-7,20 (m, 1H), 6,60-6,53 (m, 1H), by 5.87 (d, J=17 Hz, 1H), 5,74 (d, J=17 Hz, 1H), 4,23-4,10 (m, 2H), 3,49 (s, 3H), 3,40-2,82 (m, 5H), 3,30 (s, 3H), 2,12-2,02 (m, 1H), 1,71 to 1.37 (m, 3H).

MC (ESI+) 536 (M++1, 100%).

[Formula 82]

Example 53

1H NMR (300 MHz, DMSO-d6) δ 8,15 (users, 3H), 7,51-of 7.48 (m, 1H), 7,32-7,21 (m, 2H), to 6.43 (d, J=6,8 Hz, 1H), 5,63 (d, J=16.6 Hz, 1H), 5,55 (d, J=16.6 Hz, 1H), 3,66 (s, 3H), 3,36-and 3.16 (m, 2H), and 3.16 (s, 3H), 2,96-of 2.72 (m, 3H), 1,92-1,90 m, 1H), 1,62 is 1.60 (m, 1H), 1,25-1,22 (m, 2H).

MC (ESI+) 436 (M++1, 100%).

Example 54

1H NMR (300 MHz, DMSO-d6) δ 8,18 (users, 3H), 7,87 (d, J=6,8 Hz, 1H), 7,60 (t, J=7.5 Hz, 1H), 7,44 (d, J=7.5 Hz, 1H), 6,78-6,76 (m, 1H), 5,74 (d, J=16.4 Hz, 1H), 5,63 (d, J=16.4 Hz, 1H), to 3.64 (s, 3H), 3,22-3,18 (m, 2H), 3.15 in (s, 3H), 3,01-2,95 (m, 2H), 2,68-of 2.66 (m, 1H), 1,96-of 1.92 (m, 1H), 1,63-to 1.61 (m, 1H), 1.41 to to 1.32 (m, 2H).

MC (ESI+) 427 (M++1, 100%).

[Formula 83]

Example 55

1H NMR (300 MHz, DMSO-d6) δ 10,01-9,87 (m, 1H), 8,35-8,17 (m, 3H), 7,51 (d, J=7.7 Hz, 1H), 7,32-to 7.18 (m, 2H), 6,34-6,21 (m, 1H), 5,65-5.56mm (m, 2H), 4,42-4.26 deaths (m, 2H), to 3.67 (s, 3H), 3,55-to 3.36 (m, 2H), 3.15 in (s, 3H), 2.91 in-2,60 (m, 3H), and 2.79 (s, 6H), 2,01-1,49 (m, 4H).

MC (ESI+) 458 (M++1, 56%).

Example 56

1H NMR (300 MHz, DMSO-d6) δ 8,12 (users, 3H), 7,49 (d, J=7.5 Hz, 1H), 7,31-7,22 (m, 2H), of 6.31-6,28 (m, 1H), 5,63-of 5.53 (m, 2H), 4,55-4,51 (m, 2H), 3,70 (s, 3H), of 3.65 (s, 3H), 3,50-3,47 (m, 1H), 3,17 (s, 3H), is 3.08 was 3.05 (m, 1H), 2,79-2,75 (m, 3H), 1,94 is 1.91 (m, 1H), 1.56 to about 1.35 (m, 3H).

MC (ESI+) 446 (M++1, 10%).

Example 57

1H NMR (300 MHz, CDCl3) δ 9,25 (users, 3H), 7,44 and 7.36 (m, 1H), 7.18 in? 7.04 baby mortality (m, 2H), 6,44-to 6.39 (m, 1H), of 5.68 (s, 2H) a 3.83 (s, 3H), 3.46 in-of 3.60 (m, 1H), 3,37 (s, 3H), 3,22 totaling 3.04 (m, 3H), 2,70-of 2.64 (m, 1H), 2,12-of 1.94 (m, 1H), 1,68-of 1.42 (m, 3H).

MC (ESI+) 482 (M++1, 48%).

Example 58

1H NMR (300 MHz, CDCl3) δ 7,40-7,37 (m, 1H), 7,20-7,16 (m, 2H), 6,51-6.48 in (m, 1H), 5,79 (d, J=16.5 Hz, 1H), to 5.57 (d, J=16.5 Hz, 1H), 3,62 (s, 3H), 3.46 in-3,44 (m, 1H), 3,37 (s, 3H), 3,34-of 3.32 (m, 1H), 3,14-to 3.09 (m, 1H), 2,87-to 2.85 (m, 2H), 1,86-of 1.62 (m, 4H).

MC (ESI+) 420 (M++1, 61%).

Example 59

1H NMR (300 MHz, DMSO-d6) δ 8,07 (users, 3H), 7,50-7,47 (m, 1H), 7,29-7,19 (m, 2H), 6.30-in-6,28 (m, 1H), 5,58 (d, J=16.1 Hz, 1H), 5,49 (d, J=16.1 Hz, 1H), 3,61 (s, 3H), and 3.16 (s, 3H), 3,07 totaling 3.04 (m, 2H), 2.91 in-to 2.65 (m, 3H), 2,31 (s, 3H), 1.93 and-1,90 (m, 1H), 1,57-and 1.54 (m, 1H), 1,25-of 1.15 (m, 2H).

MC (ESI+) 416 (M++1, 100%).

Example 60

1H NMR (300 MHz, CDCl3) δ 10,12 (s, 1H), 7,51 (users, 3H), 7,38-7,35 (m, 1H), 7.24 to 7,11 (m, 2H), 6,44 (d, J=6.2 Hz, 1H), 5,73-5,69 (m, 2H), 3,79 (s, 3H), 3,49-3,44 (m, 1H), 3,39 (s, 3H), 3,23-3,20 (m, 1H), 3,03-2,78 (m, 3H), 1,90-1.55V (m, 4H).

MC (ESI+) 430 (M++1, 85%).

Example 61

1H NMR (300 MHz, CDCl3) to $ 7.91 δ (users, 3H), 7,39 was 7.36 (m, 1H), 7,21-7,13 (m, 2H), 6,38 (d, J=7.5 Hz, 1H), 5,70 (s, 2H), 3,44 (s, 3H), 3,37 (s, 3H), 3,31-of 3.27 (m, 1H), 3,20-3,17 (m, 2H), 3,06-to 2.94 (m, 2H), 2,53 (s, 3H), 2,15-of 1.85 (m, 2H), 1,65-and 1.54 (m, 2H).

MC (ESI+) 444 (M++1, 100%).

Example 62

1H I Is R (300 MHz, CDCl3) δ 7,38 and 7.36 (m, 1H), 7,26-7,19 (m, 4H), of 6.96-6.89 in (m, 2H), 6,52-of 6.49 (m, 1H), 6,66-5,52 (m, 2H), of 3.84 (s, 3H), 3,39 (s, 3H), 3,19 is 3.15 (m, 1H), to 3.09 (s, 3H), 3.04 from is 2.46 (m, 4H), 1,80-of 1.40 (m, 4H).

MC (ESI+) 508 (M++1, 100%).

[Formula 84]

Example 63

1H NMR (300 MHz, DMSO-d6) δ with 8.33 (s, 1H), 8,31 (users, 3H), 7,50 (d, J=6,6 Hz, 1H), 7,33-7,21 (m, 2H), of 6.49 (d, J=6,6 Hz, 1H), 5,64 (d, J=17,0 Hz, 1H), 5.56mm (d, J=17,0 Hz, 1H), 3,56-of 3.54 (m, 1H), 3,42 (s, 3H), 3,26-3,19 (m, 1H), is 3.08-2,87 (m, 3H), 1,96-of 1.93 (m, 1H), 1,75-1,72 (m, 1H), 1,52 was 1.43 (t, 2H).

MC (ESI+) 397 (M++1, 100%).

Example 64

1H NMR (300 MHz, DMSO-d6) δ of 8.40 (s, 1H), 8,21 (users, 3H), 7,58-7,53 (t, 1H), 7,20-7,13 (t, 1H), to 6.19 (s, 1H), 6,05-6,01 (t, 1H), ceiling of 5.60 (d, J=16,8 Hz, 1H), 5,52 (d, J=16,8 Hz, 1H), 3,42 (s, 3H), 3,31-and 3.16 (m, 2H), 2.91 in-2,84 (m, 2H), 2,73-to 2.67 (m, 1H), 1,92-to 1.79 (m, 2H), 1.55V to 1.47 (m, 2H).

MC (ESI+) 390 (M++1, 100%).

Example 65

1H NMR (300 MHz, DMSO-d6) δ 8,28 (users, 4H), EUR 7.57-7,52 (m, 1H), 7,19 for 7.12 (m, 1H), 6,14-6,09 (m, 1H), ceiling of 5.60 (d, J=17,0 Hz, 1H), of 5.53 (d, J=17,0 Hz, 1H), 3,42 (s, 3H), 3,23-is 3.21 (m, 1H), 3,01 (s, 3H), of 3.00 (s, 3H), 2,96-to 2.94 (m, 2H), 2,79 was 2.76 (m, 2H), 1,90-of 1.88 (m, 1H), 1.70 to to 1.67 (m, 1H), 1,35-of 1.30 (m, 2H).

MC (ESI+) 461 (M++1, 100%).

Example 66

1H NMR (300 MHz, DMSO-d6) δ 8,23 (s, 1H), 8,19 (users, 3H), 7,58-7,53 (m, 1H), 7,20-7,13 (m, 1H), to 6.19-x 6.15 (m, 1H), 5.56mm (s, 2H), 3,69-3,55 (m, 6H), 3,48-to 3.41 (m, 2H), 3,41 (s, 3H), 3,22-3,17 (m, 1H), 3.00 and-2,96 (m, 2H), 2,81-and 2.79 (m, 2H,), 1,90-of 1.88 (m, 1H), 1,69-to 1.67 (m, 1H), of 1.35 and 1.33 (m, 2H).

MC (ESI+) 503 (M++1, 100%).

[Formula 85]

Example 67

1H NMR (300 MHz, DMSO-d6) δ 8,02 (users, 3H), to 7.61-7,56 (m, 1H), 7.24 to to 7.18 (m, 1H), 6,65-661 (m, 1H), of 5.55 (s, 2H), 3,69 (s, 3H), of 3.64 (s, 3H), 3,53-to 3.50 (m, 1H), 3.27 to-3,17 (m, 2H), is 3.08-3,03 (m, 1H), 2,96-of 2.93 (m, 1H), 1,97-of 1.95 (m, 1H), 1,78 is 1.75 (m, 1H), 1,49-of 1.45 (m, 2H).

MC (ESI+) 493 (M++1, 100%).

Example 68

1H NMR (300 MHz, DMSO-d6) δ a 8.34 (s, 1H), 8,21 (s, 1H), 7,99 (users, 3H), to 7.61-7,56 (m, 1H), 7,25-7,17 (m, 1H), 6.48 in-6,44 (m, 1H), 5,54 (s, 2H), 3,54-3,51 (m, 1H), 3,42 (s, 3H), 3.27 to is 3.21 (m, 2H), 3,11-of 3.07 (m, 1H), 2,97-to 2.94 (m, 1H), 1,97-of 1.95 (m, 1H), 1,79-to 1.77 (m, 1H), 1,51 to 1.47 (m, 2H).

MC (ESI+) 458 (M++1, 100%).

Example 69

1H NMR (300 MHz, DMSO-d6) δ 8,03 (users, 3H), to 7.61-of 7.55 (m,

1H), 7.24 to 7,17 (m, 1H), 6,54-6,50 (m, 1H), 5,54 (s, 2H)and 3.59 (s, 3H), 3,55-of 3.53 (m, 1H), 3,29-up 3.22 (m, 2H), 3,12-is 3.08 (m, 1H), 2.95 and-of 2.93 (m, 1H), 1,96-of 1.94 (m, 1H), 1,79-to 1.77 (m, 1H), 1,49 to 1.47 (m, 2H).

MC (ESI+) 440 (M++1, 100%).

Example 70

6-[(3S)-3-Aminopiperidin-1-yl]-5-(2-chloro-5-terbisil)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile hydrochloride

MS (ESI+) 445 (M++1, 100%).

Example 71

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-1,3-dimethy-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate sodium

[Formula 87]

1 N. aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) was added to methyl 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate hydrochloride (53 mg) and the resulting mixture was stirred at 80°C for 3 hours After cooling the reaction of races the thief to 25°C, thereto was added water followed by washing with ethyl acetate, the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain specified in the title compound (41 mg) as a solid white color.

1H NMR (400 MHz, CDCl3) δ ppm 7,41-7,38 (m, 1H), 7,22-7,13 (m, 2H), 6.42 per-6,38 (m, 1H), 5,67 (d, J=17 Hz, 1H), 5,58 (d, J=17 Hz, 1H), the 3.65 (s, 3H), of 3.27 (s, 3H), 3,20-3,13 (m, 1H), 3,05-2,95 (m, 1H), 2,93-to 2.85 (m, 1H), 2,83-2,75 m, 1H), 2,64-of 2.54 (m, 1H), 1,83-of 1.73 (m, 1H), 1,64-of 1.52 (m, 1H), 1,40-1,25 (m, 2H).

MC (ESI+) 445 (M++1, 100%).

The compound of example 72 was synthesized from the corresponding compound by the method described in example 1.

Example 72

Ethyl 3-amino-5-[(3R)-3-aminopiperidin-1-yl]-1-(2-Chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate hydrochloride

MS (ESI+) 402 (M++1, 100%).

Example 73

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-7-hydroxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)dione triptorelin

Triperoxonane acid (1.5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (54 g) in chloroform (1 ml) and the resulting mixture was stirred at room temperature for 2 hours the Reaction solution, concentri is ovali under reduced pressure to obtain specified in the connection header (45 mg).

1H NMR (300 MHz, DMSO-d6) δ ppm of 8.27 (s, 1H), of 7.90 (users, 3H), 7,49 was 7.45 (m, 1H), 7,28-to 7.18 (m, 2H), 6,29-of 6.26 (m, 1H), 5,48 (s, 2H), 3,60 (s, 3H), 3,18-is 3.08 (m, 2H), 3,14 (s, 3H), 2,98-of 2.72 (m, 3H), 1,87-of 1.85 (m, 1H), 1,66-of 1.64 (m, 1H), 1,33 to 1.31 (m, 2H).

MC (ESI+) 418 (M++1, 100%).

Example 74

Methyl 6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chloro-5-terbisil)-7-cyano-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-2-carboxylate

Medicinepharmacy (170 μl) was added to a solution of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-1-(2-chloro-5-terbisil)-4-cyano-1H-pyrrole-2-carboxylate (104 mg) in reagent 10 hydrochloric acid-methanol (4 ml) and the resulting mixture was stirred under heating at 90°C in a sealed tube for 15 hours, the Reaction solution was concentrated under reduced pressure and to to the residue was added chloroform. Precipitated precipitated solid was removed by filtration and the filtrate was concentrated under reduced pressure. To the obtained residue was added diethyl ether and precipitated precipitated solid substance was collected by filtration to obtain crude product indicated in the title compound (107 mg).

MS (ESI+) 459 (M++1, 13%).

Each of the compounds of examples 75 and 76 was synthesized from the corresponding compound by the method described in example 1.

Example 75

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-Chlorobenzyl)-7-methoxy-1,3-dimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(NN)Dion triptorelin

1H NMR (300 MHz, DMSO-d6) δ ppm 7,40-7,37 (m, 1H), 7,22 for 7.12 (m, 2H), 6,39-6,36 (m, 1H), of 5.84 (d, J=17,4 Hz, 1H), 5,49 (d, J=17,4 Hz, 1H), of 3.77 (s, 3H), 3,70 (s, 3H), 3,42-to 3.33 (m, 2H), 3,37 (s, 3H), 3,13-3,10 (m, 1H), 2,96-is 2.88 (m, 2H,), 1,87-of 1.64 (m, 4H).

MS (ESI+) 432 (M++1, 100%).

Example 76

6-[(3R)-3-Aminopiperidin-1-yl]-5-(2-chloro-5-terbisil)-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile

1H NMR (300 MHz, DMSO-d6) δ 8,27 (users, 3H), EUR 7.57-7,53 (m, 1H), 7,21-7,14 (m, 1H), 6,39-6,34 (m, 1H), 5,54 (d, J=17,4 Hz, 1H), 5,48 (d, J=17,4 Hz, 1H), 3,47-3,44 (m, 1H), 3,40 (s, 3H), 3.25 to 3.15 in (m, 2H), 3,05-a 3.01 (m, 1H), 2,94-2,87 (m, 1H), 2,53 (s, 3H), 1,94-of 1.92 (m, 1H), 1,79-to 1.77 (m, 1H), 1,52 is 1.48 (m, 2H).

MC (ESI+) 429 (M++1, 100%).

Reference example 1

tert-Butyl {(3R)-1-[2,2-dicyano-1-(methylthio)vinyl]piperidine-3-yl}carbamate

A solution of [bis(methylthio)methylene]propanedinitrile (10 g) and (R)-tert-3-butylpiperazine-3-ylcarbamate (11.8 g) in ethanol (350 ml) was stirred at 80°C for 3 h and the reaction solution was cooled to 25°C. and then concentrated under reduced pressure to obtain specified in the title compound (19 g) in the form of amorphous material, light yellow color.

1H NMR (400 MHz, CDCl3) δ ppm 4,60-4,48 (m, 1H), 4,18-a 4.03 (m, 1H), 3,94-of 3.80 (m, 1H), of 3.77-3,61 (m, 1H), 3,59-to 3.35 (m, 2H), 2,61 (s, 3H), 2,12-2,00 (m, 1H), 1,98 is 1.86 (m, 1H), 1,82 by 1.68 (m, 1H), 1,68 of 1.50 (m, 1H), of 1.46 (s, 9H).

MC (ESI+) 323 (M++1, 40%).

Reference example 2

This is l 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-1-(2-Chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate

2-Chlorobenzylamino (1.7 ml) was added to a solution of tert-butyl {(3R)-1-[2,2-dicyano-1-(methylthio)vinyl]piperidine-3-yl}carbamate (15 g) in isopropanol (28 ml) and the resulting mixture was boiled under reflux. After 5 h was added 2-chlorobenzylamino (2.8 ml), followed by boiling under reflux for 10 hours, the Reaction solution was cooled to 25°C. and then concentrated under reduced pressure and the resulting residue was roughly purified column chromatography on silica gel (hexane/ethyl acetate = 5/1 to 1/1). Thus obtained reaction mixture (9,82 g) was dissolved in acetone (90 ml) followed by addition of potassium carbonate (6.2 g) and ethylbromoacetate (1.5 ml) and the resulting mixture was stirred at 60°C for 3 hours the Reaction solution was cooled to 25°C. and thereto was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue (7,53 g) was dissolved in tetrahydrofuran (150 ml) and the resulting solution was cooled to 0°C. Then was added sodium hydride (60% dispersion, 780 mg) and the resulting mixture was stirred for 1 h with slow warming to 25°C. To the reaction solution was added saturated aqueous restorelite ammonium, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and concentrated under reduced pressure, and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1 to 1/1) to obtain the specified title compound (2.7 g) as an amorphous substance of white color.

MS (ESI+) 502 (M++1, 100%).

Reference example 3

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

In nitrogen atmosphere methylisothiocyanate (71 μl) and potassium carbonate (143 mg) was added to solution (2.5 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-1-(2-Chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (260 mg) in pyridine and the resulting mixture was stirred under heating at 130°C for 3 hours After cooling the reaction solution to 25°C and then concentration under reduced pressure were added toluene (5 ml) and the resulting mixture was concentrated under reduced pressure. This operation was repeated three times. To the obtained residue were added acetone (2.5 ml) and the resulting mixture was cooled to 0°C. To this was added dropwise methyliodide (65 μl) and the resulting mixture was heated to 25°C and was stirred for 4 h To the reaction solution was added saturated aqueous solution of chloride of ammo the Oia, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 5/1 to 1/1) to obtain the specified title compound (250 mg).

1H NMR (400 MHz, CDCl3) δ 7,41 and 7.36 (m, 1H), 7.23 percent-was 7.08 (m, 2H), of 6.49-6,40 (m, 1H), 5,71 (d, J=17,0 Hz, 1H), 5,61 (d, J=17,0 Hz, 1H), 3,80 at 3.69 (m, 1H), 3,52 (s, 3H), 3,50-of 3.42 (m, 1H), 3.04 from-2.91 in (m, 3H), 2,68 (s, 3H), 1,88 to 1.76 (m, 1H), 1,74 of 1.50 (m, 3H), of 1.42 (s, 9H).

MC (ESI+) 543 (M++1, 40%).

Reference example 4

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

The sodium tungstate dihydrate (139 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-3-methyl-2-(methylthio)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (230 mg) in a mixture of methanol (2 ml), acetic acid (0.7 ml) and water (0.25 ml) and the resulting mixture was heated to 50°C. thereto was added dropwise a 30% aqueous hydrogen peroxide solution (0,29 ml) followed by stirring at 60°C for 4 h After cooling the reaction mixture, the precipitate was collected by filtration, washed with water and then dried under reduced pressure to obtain specified in the title compound (230 mg) in the form of solid substances is white.

MS (ESI+) 575 (M++1, 46%).

Reference example 5

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (100 mg) in ethanol (1 ml) was added 1 n sodium hydroxide solution (1 ml) and the resulting mixture was stirred at 80°C for 5 hours After cooling the reaction solution thereto was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (81 mg) as a solid white color.

MS (ESI+) 513 (M++1, 40%).

Reference example 6

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Potassium carbonate (700 mg) and methyliodide (0,34 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-2-hydroc and-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1.3 g) in N,N-dimethylformamide and the resulting mixture was stirred at 25°C for 4 h After the reaction to the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (1.1 g) as a solid white color.

1H NMR (400 MHz, CDCl3) δ 7,42-7,38 (m, 1H), 7,25-7,13 (m, 2H), 6,56-6.48 in (m, 1H), 5,69 (d, J=16.5 Hz, 1H), 5,59 (d, J=16.5 Hz, 1H), 3,76 (s, 3H), 3.75 to the 3.65 (m, 1H), 3,50-to 3.41 (m, 1H), 3,35 (s, 3H), 3,01-2,84 (m, 3H) 1,89-of 1.78 (m, 1H), 1,69-of 1.45 (m, 3H), of 1.42 (s, 9H).

MC (ESI+) 527 (M++1, 100%).

Reference example 7

Ethyl ester of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-2,2-dicyanovinyl)glycine

Methyl ester of glycine hydrochloride (3.3 g) and triethylamine (3,7 ml) was added to a solution of tert-butyl {(3R)-1-[2,2-dicyano-1-(methylthio)vinyl]piperidine-3-yl}carbamate (1.3 g) in ethanol (30 ml) and the resulting mixture was boiled under reflux. After 4 h to this solution was added triethylamine (1.5 ml), followed by boiling under reflux for 7 hours After cooling the reaction solution to 25°C. thereto was added a saturated aqueous solution of sodium bicarbonate with the consequences of the soup by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1 to 1/1) to obtain the specified title compound (360 mg) as an amorphous substance of white color.

1H NMR (400 MHz, CDCl3) δ 5,76 (users, 1H), 4,58 (userd, 1H), 4,27 (kV, J=7,1 Hz, 2H), 4,15 (DD, J=1,0, 5,2 Hz, 2H), 3,84-with 3.79 (m, 1H), 3,69-to 3.58 (m, 2H), 3,40-3,30 (m, 1H), 3,28-3,18 (t, 1H), 2,05-1,95 (t, 1H), 1,89-1,79 (t, 1H), 1,74-1,63 (t, 1H), 1.60-to 1,49 (t, 1H), 1,45 (s, 9H), 1,32 (t, J=7,1 Hz, 3H).

MC (ESI+) 378 (M++1, 10%).

Reference example 8

Ethyl ester of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-2,2-dicyanovinyl)-N-(2-Chlorobenzyl)glycine

A solution of ethyl ester of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-2,2-dicyanovinyl)glycine (300 mg), 2-chlorobenzylamino (0.15 ml) and potassium carbonate (330 mg) in acetone (4 ml) was stirred at 25°C for 24 h To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silicagel is e (hexane/ethyl acetate = 5/1 to 1/1) to obtain the specified title compound (340 mg) as an amorphous substance of white color.

MS (ESI+) 502 (M++1, 25%).

Reference example 9

Ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-1-(2-Chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate

A solution of ethyl ester of N-(1-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-2,2-dicyanovinyl)-N-(2-Chlorobenzyl)glycine (320 mg) in tetrahydrofuran (5 ml) was cooled to 0°C, followed by addition of sodium hydride (33 mg) and the resulting mixture was stirred for 1 h while warming to 25°C. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1 to 1/1) to obtain the specified title compound (300 mg).

1H NMR (400 MHz, CDCl3) δ 7,40-7,35 (m, 1H), 7,21-to 7.09 (m, 2H), 6,57-of 6.49 (m, 1H), 5,47-and 5.30 (m, 2H), 4,07 (kV, J=7,0 Hz, 2H), 3,76-to 3.64 (m, 1H), 3,40-3,30 (m, 1H), 3.00 and-2,82 (m, 3H), 1,87-of 1.74 (m, 1H), 1,72 of 1.46 (m, 3H) of 1.41 (s, 9H), of 1.07 (t, J=7.0 Hz, 3H).

MC (ESI+) 502 (M++1, 29%).

Reference example 10

tert-Butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl]carbamate

Under cooling in ice water (2 ml) and to the centered sulfuric acid (4 ml) was added to tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (300 mg), and the resulting mixture was stirred at 140°C. After 3 h the reaction solution was cooled to 0°C and the pH was brought to 8 or higher by adding dropwise 5 N. of an aqueous solution of potassium carbonate. The reaction solution was extracted with chloroform and the organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. To the obtained residue was added di-tert-BUTYLCARBAMATE (372 mg), 1,4-dioxane (5 ml) and saturated aqueous sodium bicarbonate solution (5 ml) and the resulting mixture was stirred at room temperature for 8 hours To the reaction solution was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the obtained residue was added diethyl ether, followed by filtration and the precipitate was washed with hexane to obtain specified in the title compound (200 mg) in the form of a solid of light yellow color.

1H NMR (400 MHz, DMSO-d6) δ ppm 11,07 (s, 1H), make 6.90 (d, J=8.0 Hz, 1H), 5,44 (s, 1H), 3,71-of 3.53 (m, 2H), 3,47-to 3.35 (m, 1H), and 3.31 (s, 3H), 3,19 (s, 3H), was 2.76-to 2.65 (m, 1H), 2,62 of $ 2.53 (m, 1H), 1.85 to of 1.65 (m, 2H), 1,57 of 1.28 (m, 2H), 1,44 (, 9H).

MC (ESI+) 378 (M++1, 100%).

Reference example 11

tert-Butyl {(3R)--[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl]carbamate

A solution of tert-butyl [(3R)-1-(1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl]carbamate (60 mg), 2-chlorobenzylamino (32 μl) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure and was purified preparative thin-layer chromatography (hexane/ethyl acetate = 1/2) to obtain the specified title compound (10 mg) as an amorphous substance of white color.

1H NMR (400 MHz, CDCl3) δ 7,39 was 7.36 (m, 1H), 7.18 in-7,07 (m, 2H), 6,51-6.42 per (m, 1H), 5,67 (d, J=16,8 Hz, 1H), 5,59 (s, 1H), 5.56mm (d, J=16,8 Hz, 1H), 3,85-3,74 (m, 1H), 3,48 (s, 3H), on 3.36 (s, 3H), 3,12-3,03 (m, 1H), 2,82-2,62 (m, 3H), 1,80 to 1.47 (m, 4H), USD 1.43 (s, 9H).

MC (ESI+) 502 (M++1, 100%).

Reference example 12

tert-Butyl {1-[5-(2-chloro-5-terbisil)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl]carbamate

[Formula 104]

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 13.

1H NMR (400 MHz, CDCl3) δ 7,38-7,30 (m, 1H), 6,92-6,83 (m, 1H), 6.22 per 6,13 (m, 1H), 5,62 (d, J=17,0 Hz, 1H), 5,61 (s, 1H), 5,52 (d, J=17,0 Hz, 1H), 3,85-and 3.72 (m, 1H), 3,48 (s, 3H), at 3.35 (s, 3H), 3,14-3,03 (m, 1H), 2,83-of 2.64 (m, 3H), 1,79-of 1.45 (m, 4H), 1,42 (s, 9H).

MC (ESI+) 520 (M++1, 100%).

Reference example 13

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

A solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (110 mg), 3-ethoxyphenol (31 μl) and potassium carbonate (39 mg) in N,N-dimethylformamide (2 ml) was stirred at 50°C for 1 H. After cooling the reaction solution were added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 3/1 to 1/1) to obtain the specified title compound (86 mg) as a solid white color.

MS (ESI+) 633 (M++1, 100%).

Reference example 14

tert-Butyl {(3R)-1-[2-[2-(aminocarbonyl)phenoxy]-5-(2-Chlorobenzyl)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-the l}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in referential example 1.

MS (ESI+) 632 (M++1, 100%).

Reference example 15

tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

To a mixed solution of dimethyl sulfoxide (250 ml) and water (25 ml) was added tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (17.9 g) and potassium carbonate (4.7 g). A water bath was added dropwise an aqueous solution of hydrogen peroxide (30-35% aqueous solution, 17 ml) and the resulting mixture was stirred at 25°C. for 15 hours To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was three times washed with water and then once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure to obtain specified in the title compound (15.6 g) as an amorphous substance of light-yellow color.

MS (ESI+) 545 (M++1, 100%).

Reference example 16

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1 is-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Sodium azide (154 mg) and ammonium chloride (125 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (250 mg) in N,N-dimethylformamide (4 ml) and the resulting mixture was stirred at 150°C for 8 hours To it addition was added sodium azide (154 mg) and ammonium chloride (125 mg) and was stirred for another 6 hours After cooling the reaction solution to 25°C was added a 10% aqueous solution of potassium bisulfate followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified HPLC with obtaining specified in the title compound (23 mg) as a solid white color.

MS (ESI+) 570 (M++1, 100%).

Reference example 17

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-pyrrolo-1-ylcarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

After stirring tert-butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (12,6 g) and 2,5-dimethoxytetrahydrofuran (150 ml) at 25°C. was added dropwise thionyl chloride (1.7 ml) and the scientists and the mixture was stirred at 40°C for 6 hours After cooling the reaction solution to 25°C was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain the specified title compound (15.9 g) as an amorphous yellow substance.

MS (ESI+) 595 (M++1, 100%).

Reference example 18

Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

The sodium methylate (28% solution in methanol, 0.2 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-7-(1H-pyrrolo-1-ylcarbonyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (410 mg) in methanol (5 ml) and the resulting mixture was stirred at 60°C for 2 hours After cooling the reaction solution to 25°C. thereto was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sulfate Natrii then filtered, the filtrate was concentrated under reduced pressure to obtain specified in the title compound (380 mg) as an amorphous substance of white color.

MS (ESI+) 560 (M++1, 100%).

Reference example 19

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-7-(morpholine-4-ylcarbonyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

1-Hydroxybenzotriazole (117 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (147 mg), triethylamine (of 0.21 ml) and morpholine (63 μl) was added to a solution of 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (140 mg) in N,N-dimethylformamide (3 ml) and the resulting mixture was stirred at 25°C for 20 hours To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain the specified title compound (106 mg) as a solid white color.

MS (ESI+) 615 (M++1, 100%)./p>

Reference example 20

6-{(3R)-3-[(tert-Butoxycarbonyl)amino]piperidine-1-yl}-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid

1M aqueous sodium hydroxide solution (10 ml) was added to a solution of methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (2,08 g) in 1,4-dioxane (10 ml) and the resulting mixture was stirred at 80°C for 5 hours After cooling the reaction solution to 25°With added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,95 g) as an amorphous substance of light-yellow color.

MS (ESI+) 546 (M++1, 100%).

Reference example 21

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

In acetonitrile (5 ml) was dissolved 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylic KIS the GTC (350 mg) and the solution was stirred at 80°C for 1 h The reaction solution was cooled to 25°C. and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (270 mg) as an amorphous substance of white color.

MS (ESI+) 402 (M++1, 100%).

Reference example 22

tert-Butyl {(3R)-1-[7-chloro-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1,00 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (294 mg) and the resulting mixture was stirred over night at room temperature. The pH value of the reaction solution was brought to 2 with 10% aqueous solution of potassium bisulfate and extracted with ethyl acetate (200 ml). The organic layer was washed with 10% aqueous solution of potassium bisulfate and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain specified in the connection header (917 mg).

1H NMR (300 MHz, CDCl3) δ 7,41-7,38 (m, 1H), 7,20-7,10 (m, 2H) 6.42 per (d, J=6,6 Hz, 1H), 5,78-5,70 (m, 2H), 3,79 (s, 3H), 3,59-3,55 (m, 1H), on 3.36 (s, 3H), 3,12 is 2.80 (m, 4H), 1,64 was 1.43 (m, 4H), of 1.42 (s, 9H).

MC (ESI+) 536 (M++1, 100%).

Reference example 23

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Paraformaldehyde (600 mg) and 50% aqueous solution of dimethylamine (1.80 g) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1,00 g) in ethanol (10 ml) and acetic acid (5 ml) and the resulting mixture was stirred under heating at 80°C. After cooling the reaction the solution to 25°C. thereto was added toluene (30 ml) and the resulting mixture was concentrated under reduced pressure. This operation was repeated three times. The obtained residue was acidified with 10% aqueous solution of potassium bisulfate and was twice extracted with chloroform (100 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/2) to obtain specified in the connection header (913 mg).

1H NMR (300 MHz, CDCl3) δ 7,37 (d, J=7,3 Hz, 1H), 7.18 in-7,07 (m, 2H), of 6.31 (d, J=7.5 Hz, 1H), 5,71-to 5.58 (m, 2H), of 3.84 (s, 3H), 3.46 in-3,12 (m, 4H), to 3.36 (s, 3H), 2,89-of 2.64 (m, 3H), 2,22 (s, 6H), ,79-1,45 (m, 4H), of 1.42 (s, 9H).

MC (ESI+) 559 (M++1, 43%).

Reference example 24

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-(methoxymethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

[Formula 116]

Methyliodide (25 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (112 mg) in acetone (5 ml) and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to the solution of the obtained residue in methanol (2 ml) was added a 28% solution of sodium methylate in methanol (2 ml) followed by stirring under heating at 60°C for 4 h, the Methanol evaporated under reduced pressure and the pH of the residue was brought to 2 with an aqueous solution of potassium bisulfate and extracted with ethyl acetate (100 ml). The organic layer was washed with 10% aqueous solution of potassium bisulfate and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography on silica gel (hexane/ethyl acetate = 1/5) to obtain the specified title compound (26 mg).

1H NMR (30 MHz, CDCl3) δ 7,37 (d, J=7.7 Hz, 1H), 7.18 in-7,07 (m, 2H), 6,37 (d, J=7,0 Hz, 1H), 5,71-the ceiling of 5.60 (m, 2H), 4,67 with 4.64 (m, 1H), and 4.40 (s, 3H), and 3.72 (s, 3H), 3,71 at 3.69 (m, 1H), 3.43 points (s, 3H), on 3.36 (s, 3H), 3,35-3,30 (m, 1H), 2,82-2,78 (m, 3H), 1,80-of 1.45 (m, 4H), of 1.42 (s, 9H).

MC (ESI+) 546 (M++1, 36%).

Reference example 25

tert-Butyl {(3R)-1-[7-bromo-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

To a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1,00 g) in N,N-dimethylformamide (20 ml) was added N-bromosuccinimide (392 mg) and the resulting mixture was stirred over night at room temperature. The pH value of the reaction solution was brought to 2 with 10% aqueous solution of potassium bisulfate and extracted with ethyl acetate (200 ml). The organic layer was washed with 10% aqueous solution of potassium bisulfate and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain specified in the connection header (to 1.143 g).

1H NMR (300 MHz, CDCl3) δ 7,39 (d, J=7,3 Hz, 1H), 7,20-7,10 (m, 2H), 6,40 (d, J=7,1 Hz, 1H), USD 5.76 (s, 2H), equal to 4.97-of 4.95 (m, 1H), 3,83 (s, 3H), 3,67-3,59 (m, 1H), on 3.36 (s, 3H), 3,23-2,82 (m, 3H), 2,54-2,52 (m, 1H), 1.91 a-1,89 (m, 1H), 1,71-is 1.51 (m, 3H), 1,43 (cm 9H).

MC (ESI+) 582 (M++1, 52%).

Reference example 26

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-fluoro-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

[Formula 118]

The xenon fluoride (56 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1,00 g) in acetonitrile (10 ml) and the resulting mixture was stirred over night at room temperature. After adding to the reaction solution, saturated aqueous sodium bicarbonate solution, the acetonitrile evaporated under reduced pressure and the residue was twice extracted with chloroform (50 ml). The organic layer was dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (8 mg).

1H NMR (300 MHz, CDCl3) δ 7,41-7,37 (m, 1H), 7,20-7,11 (m, 2H), 6,46 (d, J=6,8 Hz, 1H), 5,69 (d, J=16,3 Hz, 1H), 5,59 (d, J=16,3 Hz, 1H), 4,73-4,69 (m, 1H), 3,76-3,74 (m, 1H), 3,61 (s, 3H), on 3.36 (s, 3H), 3,29-of 3.25 (m, 1H), 2,78 was 2.76 (m, 3H), 1,69-of 1.45 (m, 4H), of 1.42 (s, 9H).

MC (ESI+) 520 (M++1, 17%).

Reference example 27

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3,7-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}ka is bamat

[Formula 119]

Methyliodide (38 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (168 mg) in acetone (4 ml) and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure and a solution of the obtained residue in tetrahydrofuran (5 ml) was added 1 N. aqueous sodium hydroxide solution (3 ml), followed by stirring under heating at 60°C for 3 hours, the Tetrahydrofuran is evaporated under reduced pressure and to the residue was added water, followed by extraction twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. Then a solution of the obtained residue in dichloromethane (6 ml) was added dropwise to a cooled on ice to a solution of triethylsilane (144 μl) and methanesulfonic acid (60 ml) in dichloromethane (10 ml) and the resulting mixture was stirred at 0°C for 1 h To this was added 10% potassium carbonate solution followed by extraction twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The remainder of cleansing and column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (101 mg).

1H NMR (300 MHz, CDCl3) δ 7,37 (d, J=7,3 Hz, 1H), 7,17-7,07 (m, 2H), 6.35mm (d, J=6,7 Hz, 1H), 5,70 (s, 1H), 4,93-4,91 (m, 1H), 4,93-4,91 (m, 1H), 3.75 to to 3.73 (m, 1H), 3,70 (s, 3H), on 3.36 (s, 3H), 3,31-3,29 (m, 1H), 2,90 2.63 in (m, 3H), of 2.33 (s, 3H), 1,92-1,90 (m, 1H), 1,63 of 1.46 (m, 3H), of 1.42 (s, 9H).

MC (ESI+) 516 (M++1, 61%).

Reference example 28

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Phosphorus oxychloride (551 ml) was added to dimethylformamide (10 ml) at room temperature and was stirred for 5 minutes a Solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (502 mg) in N,N-dimethylformamide (1 ml) was added to the reaction solution and the resulting mixture was stirred at room temperature for 3 hours To the reaction solution was added water, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with 10% aqueous solution of potassium bisulfate and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (290 mg).

1H NMR (300 MHz, CDCl3) δ 10,10 (s, 1H), 7,43-7,40 (m, 1H) 7.23 percent for 7.12 (m, 2H), 6,46 (d, J=7,1 Hz, 1H), 5,80 (d, J=16.0 Hz, 1H), 5,59 (d, J=16.0 Hz, 1H), br4.61-4,59 (m, 1H), 3,84 (s, 3H), 3,66-to 3.64 (m, 1H), 3,38 (s, 3H), 3,37-of 3.31 (m, 1H), 2,90-to 2.85 (m, 3H), 1,88-of 1.85 (m, 1H), 1,59-of 1.55 (m, 3H), of 1.42 (s, 9H).

MC (ESI+) 530 (M++1, 39%).

Reference example 29

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-(1-hydroxyethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

A solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (132 mg) in tetrahydrofuran (4 ml) was cooled to 0°C, followed by addition of bromide Metalmania (417 μl) and the resulting mixture was stirred at 0°C for 2 hours To the reaction solution was added saturated an aqueous solution of ammonium chloride followed by extraction twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure to get crude product indicated in the title compound (167 mg).

MS (ESI+) 546 (M++1, 46%).

Reference example 30

tert-Butyl {(3R)-1-[7-acetyl-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Manganese dioxide (0.66 g) was added to a solution of crude tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-(1-hydroxyethyl)-1,3-dimethyl-2,4-di the CSR-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (167 mg) in dichloromethane (5 ml) and the resulting mixture was stirred over night at room temperature. Then the reaction solution was heated to 45°C. and was stirred for 3 hours the Reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (33 mg).

MC (ESI+) 546 (M++1, 46%).

1H NMR (300 MHz, CDCl3) δ 7,42-7,38 (m, 1H), 7,22-7,11 (m, 2H), to 6.43-6,40 (m, 1H), 5,77-the ceiling of 5.60 (m, 2H), 5,54-the 5.51 (m, 1H), 3,62-of 3.60 (m, 1H), 3,42 (s, 3H), on 3.36 (s, 3H), 3,34-of 3.32 (m, 1H) 2,79-to 2.65 (m, 3H), at 2.59 (s, 3H), 1,88-to 1.82 (m, 1H), 1,65 is 1.48 (m, 2H), of 1.42 (s, 9H).

MC (ESI+) 544 (M++1, 34%).

Reference example 31

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Bis(dibenzylideneacetone)palladium (18 mg), tetrafluoroborate three-tert-butylphosphine (22 mg), potassium phosphate (329 mg) and 4-methoxyphenylalanine acid (236 mg) was added to a solution of tert-butyl {(3R)-1-[7-bromo-5-(2-Chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (90 mg) in dioxane (4 ml) and the resulting mixture was stirred under heating at 50°C for 15 hours, the Reaction solution was filtered through celite and washed with tetrahydrofuran, the filtrate was concentrated under reduced pressure. To the residue was added 10% aqueous solution carbonatebuy followed by extraction twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain the specified title compound (10 mg).

1H NMR (300 MHz, CDCl3) δ 7,41-7,37 (m, 1H), 7,26-7,10 (m, 4H), 6,92 (d, J=8,8 Hz, 1H), 6,52-6,50 (m, 1H), 5,80 (d, J=16,7 Hz, 1H), to 5.66 (d, J=16,7 Hz, 1H), a 3.87 (s, 3H), 3,52-to 3.50 (m, 1H), 3,37 (s, 3H), of 3.07 (s, 3H), 2,80-2,40 m, 4H), 1,62-of 1.39 (m, 4H), to 1.38 (s, 9H).

MC (ESI+) 608 (M++1, 76%).

Reference example 32

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

4-Methoxybenzylidene (0.5 ml) and potassium carbonate (486 mg) was added to a solution of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-1-(2-chloro-5-terbisil)-4-cyano-1H-pyrrole-2-carboxylate (920 mg) in pyridine (1 ml)and the resulting mixture was stirred at 130°C for 6 hours To it was added 4-methoxybenzylidene (2,0 ml) followed by stirring under heating for 24 hours the Reaction solution was cooled to 25°C., then concentrated under reduced pressure and to the residue was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride, dried over betwo the major sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (15 ml) followed by addition of potassium carbonate (486 mg) and methyliodide (0.33 ml) and the resulting mixture was stirred at 25°C for 3 hours To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with chloroform. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate) to obtain the specified title compound (750 mg) as an amorphous substance of light-yellow color.

MS (ESI+) 651 (M++1, 100%).

Reference example 33

tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chloro-5-terbisil)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 15.

MS (ESI+) 669 (M++1, 100%).

Reference example 34

Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]is eremein-7-carboxylate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference examples 17 and 18.

MS (ESI+) 684 (M++1, 100%).

Reference example 35

Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

Under nitrogen atmosphere a solution of aluminium chloride (395 mg) in anisole (1.5 ml) was added to methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (260 mg) and the resulting mixture was stirred at 65°C within 4 h After cooling the reaction solution to 25°C. to it was added 1 n hydrochloric acid and the aqueous layer washed with ethyl acetate. The aqueous layer was neutralized 1 N. aqueous sodium hydroxide solution and was extracted with chloroform. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. To the obtained residue was added di-tert-BUTYLCARBAMATE (415 mg), 1,4-dioxane (4 ml) and saturated aqueous sodium bicarbonate solution (4 ml) and the resulting mixture was stirred at 25°C during the 16 hours To the reaction solution was added water, followed by extraction with chloroform. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. To the obtained residue was added diethyl ether/hexane and the resulting mixture was filtered and then washed with hexane to obtain specified in the title compound (121 mg) as a solid light yellow color.

MS (ESI+) 564 (M++1, 100%).

Reference example 36

Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-1-methyl-2,4-dioxo-3-(2-oxo-2-phenylethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

A solution of methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (50 mg), α-bromoacetophenone (27 mg) and potassium carbonate (25 mg) in N,N-dimethylformamide was stirred at 25°C for 14 hours To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. Received estato which was purified preparative thin-layer chromatography (hexane/ethyl acetate = 2/1) to obtain the specified title compound (51 mg) as a solid white color.

MS (ESI+) 682 (M++1, 100%).

Reference example 37

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-3-methyl-2,4-dioxo-3-(2-oxo-2-phenylethyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference examples 20 and 21.

MS (ESI+) 624 (M++1, 100%).

Reference example 38

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Methylisothiocyanate (of 7.36 ml) and potassium carbonate (14,86 g) was added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}1-(2-chloro-5-terbisil)-4-cyano-1H-pyrrole-2-carboxylate (27,96 g) in pyridine and the resulting mixture was stirred under heating at 130°C for 13 hours After cooling the reaction solution to 25°C to it was added toluene (50 ml) and the resulting mixture was concentrated under reduced pressure. This operation was repeated three times. The pH value of the obtained residue was brought to 2 with an aqueous solution of potassium bisulfate and loose precipitated solid substance was collected by filtration and washed with water and then hexane. The thus obtained solid substance was dried at 45°C under reduced pressure p is the receiving specified in the connection header (28,56 g).

MS (ESI+) 547 (M++1, 86%).

Reference example 39

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

The sodium tungstate dihydrate (0,91 g) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-methyl-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (1.51 g) in a mixture of methanol (9 ml), acetic acid (3 ml) and water (1 ml), was added dropwise a 30% aqueous hydrogen peroxide solution (0,29 ml) at room temperature and was stirred for 2 hours, After cooling the reaction mixture, the methanol evaporated under reduced pressure and the pH of the residue was brought to 9 with an aqueous solution of potassium carbonate. Added a 10% aqueous solution of sodium bisulfate and was stirred for 30 min, followed by extraction with ethyl acetate (200 ml). The organic layer is washed with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,61 g).

1H NMR (300 MHz, CDCl3) δ to 7.99 (s, 1H), 7,41 and 7.36 (m, 1H), of 6.96-6.89 in (m, 1H), 6,20 (d, J=7.5 Hz, 1H), 5,70 (d, J=16,7 Hz, 1H), 5,59 (d, J=16,7 Hz, 1H), 4.53-in-4,51 (m, 1H), 3,74 at 3.69 (m, 1H), 3,55 (s, 3H), 3,52-of 3.46 (m, 1H), 3,05-2,94 (m, 3H), 1,88-of 1.85 (m, 1H), 1.70 to to 1.60 (m, 3H), of 1.41 (s, 9H).

M (ESI+) 515 (M ++1, 66%).

Reference example 40

tert-Butyl {(3R)-1-[7-(aminocarbonyl)-5-(2-chloro-5-terbisil)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 15.

MS (ESI+) 533 (M++1, 73%).

Reference example 41

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-3-methyl-4-oxo-7-(1H-pyrrolo-1-ylcarbonyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 17.

MS (ESI+) 583 (M++1, 100%).

Reference example 42

Methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 18.

1H NMR (300 MHz, CDCl3) δ of 8.04 (s, 1H), 7,40-7,35 (m, 1H), 6,93-6,86 (m, 1H), 6,03 (d, J=7,1 Hz, 1H), 5,85 (d, J=16,8 Hz, 1H), 5,74 (d, J=16,8 Hz, 1H), 4,68-of 4.66 (m, 1H), 3,98 (s, 3H), 3,68-3,66 (m, 1H), of 3.56 (s, 3H), 3.33 and-of 3.31 (m, 1H), 2,97-of 2.93 (m, 3H), 1,83-of 1.81 (m, 1H), 1,65-of 1.56 (m, 3H), of 1.41 (s, 9H).

MC (ESI+) 548 (M++1, 41%).

Reference primer

6-{(3R)-3-[(tert-Butoxycarbonyl)amino]piperidine-1-yl}-5-(2-chloro-5-terbisil)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 20.

MS (ESI+) 534 (M++1, 6%).

Reference example 44

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-3-methyl-7-(morpholine-4-ylcarbonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 19.

1H NMR (300 MHz, CDCl3) δ 7,89 (s, 1H), 7,39-7,34 (m, 1H), 6,92-6,87 (m, 1H), 6,21-to 6.19 (m, 1H), 5,74 (d, J=16.6 Hz, 1H), 5,59 (d, J=16.6 Hz, 1H), 4,60-4,58 (m, 1H), 3,92-3,71 (m, 7H), 3,57-3,51 (m, 2H), 3,54 (s, 3H), 3,30 of 3.28 (m, 1H), 2,87 was 2.76 (m, 3H), 1,78-of 1.57 (m, 4H), of 1.41 (s, 9H).

MC (ESI+) 603 (M++1, 19%).

Reference example 45

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Specified in the title compound was synthesized from the corresponding compounds in the same manner as described in reference example 21.

1H NMR (300 MHz, CDCl3) δ 7,88 (s, 1H), 7,37-7,32 (m, 1H), 6.90 to-6,83 (m, 1H), 6,09 (d, J=9,3 Hz, 1H), the 6.06 (s, 1H), 5,73 (d, J=16.9 and Hz, 1H), 5,62 (d, J=16,GC, 1H), 4,69 with 4.65 (m, 1H), 3,80-of 3.78 (m, 1H), 3,54 (s, 3H), 3,13-is 3.08 (m, 1H), 2.77-to is 2.74 (m, 3H), 1,72 is 1.60 (m, 4H), of 1.42 (s, 9H).

MC (ESI+) 490 (M++1, 71%).

Reference example 46

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Methansulfonate acid (21 μl) and 30% aqueous hydrogen peroxide solution (54 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (132 mg) in methanol (4 ml) and the resulting mixture was stirred at room temperature for 2 hours To the reaction solution added a 10% aqueous solution of sodium sulfite followed by extraction with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/2) to obtain the specified title compound (54 mg).

1H NMR (300 MHz, CDCl3) δ ppm to 7.35 (d, J=7.5 Hz, 1H), 7,17-7,07 (m, 2H), 6,37 (d, J=6,8 Hz, 1H), 5,86 (users, 1H), ceiling of 5.60-5.56mm (m, 2H), 4,82 (users, 1H), 3,71 (s, 3H), 3,65-3,63 (m, 1H), 3,37 (s, 3H), 3,35-to 3.33 (m, 1H), 2,84-2,70 (m, 3H), 1,95-of 1.93 (m, 1H), 1,62-of 1.41 (m, 3H), of 1.41 (m, 9H).

MC (ESI+) 518 (M++1, 82%).

Reference example 47

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-2,7-dicyano-3-methyl-4-oxo-4,-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

An aqueous solution (2 ml) of sodium cyanide (338 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (890 mg) in tetrahydrofuran (10 ml) and the resulting mixture was stirred at room temperature for 3 hours To the reaction solution was added water, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with 10% potassium carbonate solution and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 2/1) to obtain specified in the connection header (758 mg).

1H NMR (300 MHz, CDCl3) δ 7,42-7,37 (m, 1H), 6,99-6,91 (m, 1H), to 6.19 (d, J=7,3 Hz, 1H), of 5.68 (d, J=16,7 Hz, 1H), to 5.57 (d, J=16,7 Hz, 1H), to 4.52 figure-4.49 (m, 1H), of 3.78 (s, 3H), 3.72 points-3,70 (m, 1H), 3,55-to 3.50 (m, 1H), 3,10-of 3.06 (m, 2H), 3.00 and-at 2.93 (m, 1H), 1.91 a-1,89 (m, 1H), 1,74 is 1.58 (m, 3H), of 1.41 (s, 9H).

MC (ESI+) 540 (M++1, 11%).

Reference example 48

tert-Butyl {(3R)-1-[2-(aminocarbonyl)-5-(2-chloro-5-terbisil)-7-cyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Potassium carbonate (42 mg) and then an aqueous solution of hydrogen peroxide (30-35% aqueous solution of 170 ml) was added the dropwise to a solution of tert-butyl {(3R)-1-[5-(2-chloro-5-terbisil)-2,7-dicyano-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (162 mg) in a mixture of dimethyl sulfoxide (10 ml) and water (2 ml) and the resulting mixture was stirred over night at room temperature. To the reaction solution was added a 10% aqueous solution of sodium sulfite followed by extraction with ethyl acetate (200 ml). The organic layer is washed with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (77 mg).

1H NMR (300 MHz, CDCl3) δ a 7.62 (s, 1H), 7,42-7,37 (m, 1H), 6,97-6,91 (m, 1H), 6,21 (d, J=7,0 Hz, 1H), of 5.84 (s, 1H), 5,71 (d, J=16,7 Hz, 1H), ceiling of 5.60 (d, J=16,7 Hz, 1H), 4,58-4,55 (m, 1H), a 3.87 (s, 3H), 3.75 to to 3.73 (m, 1H), 3,54-3,49 (m, 1H), 3,05-2,95 (m, 3H), 1,87-of 1.85 (m, 1H), 1.70 to of 1.66 (m, 3H), of 1.42 (s, 9H).

MC (ESI+) 458 (M++1, 100%).

Reference example 49

tert-Butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-methoxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

Potassium carbonate (41 mg) and methyliodide (13 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-Chlorobenzyl)-7-hydroxy-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (50 mg) in N,N-dimethylformamide (2 ml) and the resulting mixture was stirred at room temperature for 5 hours To the reaction solution was added 10% aqueous solution bisulfate feces is I followed by extraction with ethyl acetate (100 ml). The organic layer was washed with 10% aqueous solution of potassium bisulfate and saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (17 mg).

MS (ESI+) 532 (M++1, 69%).

Reference example 50

tert-Butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-2,3-dimethyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate

A solution of tert-butyl {(3R)-1-[5-(2-chloro-5-terbisil)-7-cyano-3-methyl-2-(methylsulphonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-6-yl]piperidine-3-yl}carbamate (890 mg) in tetrahydrofuran (2 ml) was cooled to 0°C and added dropwise to 3 M solution of bromide Metalmania/diethyl ether (333 μl). After 30 min the reaction solution was heated to room temperature and was stirred for 1 h To the reaction solution was added saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate (100 ml). The organic layer was washed saturated aqueous sodium chloride, dried over sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified column is a chromatography on silica gel (hexane/ethyl acetate = 1/1) to obtain the specified title compound (64 mg).

1H NMR (300 MHz, CDCl3) δ 7,40-7,35 (m, 1H), 6,95-to 6.88 (m, 1H), 6,18 (d, J=6,9 Hz, 1H), of 5.68 (d, J=16,8 Hz, 1H), to 5.57 (d, J=16,8 Hz, 1H), 4,58-4,55 (m, 1H), 3,78-3,74 (m, 1H), 3,54 (s, 3H), 3,50 is-3.45 (m, 1H), 3.04 from-to 2.94 (m, 3H), 2.63 in (s, 3H), 1,88 of-1.83 (m, 1H), 1,68-of 1.62 (m, 2H), 1,43-of 1.41 (m, 1H), of 1.41 (s, 9H).

MC (ESI+) 529 (M++1, 100%).

Test determination of inhibitory activity against DPP-IV in vitro

Human serum containing the enzyme DPP-IV, bred in 9-20 times a buffer for setting a test and added into the microtiter plates. Made each solution of each test substance in various concentrations with subsequent submission of the substrate (4-methyl-coumaryl-7-amide glycyl-L-Proline, Peptide Laboratories Co., Ltd) to the final concentration in the range of 10-100 μm and the reaction was carried out at room temperature. To stop the reaction was added acetic acid to a final concentration of 0.5% and was determined by the fluorescence intensity at a wavelength of excitation of 360 nm and the wavelength determination of 460 nm using a fluorescent plate reader for tablets. Hoped the concentration providing 50% inhibition, the value IC50according to the inhibitory activity of the enzyme, obtained by the addition of each test compound to the set of concentration values.

Test connection Inhibitory activity against human DPP-IV IC50(nm)
Example 176
Example 221
Example 326
Example 428
Example 515
Example 61,9
Example 760
Example 87,4
Example 1455
Example 1812
Example 197,1
Example 204,3
Example 2444
Example 257,6
Example 263,2
Example 279,8
Example 286,4
Por the measures 29 the 5.7
Example 30the 4.7
Example 315,0
Example 327,5
Example 33to 12.0
Example 345,8
Example 3710
Example 385,3
Example 394,1
Example 406,8
Example 414,1
Example 42the 5.7
Example 436,9
Example 449,0
Example 454,8
Example 465,6
Example 5631
Example 6028
Example 61
Example 6256
Example 6327
Example 6413
Example 656,2
Example 665,5
Example 703800
Example 721200

Industrial applicability

The present invention makes it possible to obtain compounds that have inhibitory activity against DPP-IV and have increased security, absence of toxicity and the like.

Compounds of the present invention are suitable for suppression of hyperglycemia that occurs after a meal in subjects with prediabetes, the treatment of non-insulin-dependent diabetes, the treatment of autoimmune diseases such as arthritis and articular rheumatism, treatment of diseases of the intestinal mucosa, accelerate growth, suppression of rejection of organs in transplantation, for the treatment of obesity, treatment of eating disorders, treatment of HIV infection, suppression of metastasis of tumors, treatment of prostatomegaly, treatment of periodontitis and osteoporosis treatment.

1. With the Association of the formula (I):
[Formula 1]

in which R1represents a hydrogen atom or alkyl, optionally substituted (1) aralkylamines, (2) Arola, (3) izokhinolinom or (4) aryl, optionally substituted alkoxygroup;
solid line and dotted line between And1and2designate a double bond (A1=And2or a simple link (A1-And2);
And1is a group of formula C(R4), and2represents a nitrogen atom in the case where the solid line and dotted line between And1and2represent a double bond (A1=And2);
And1is a group of the formula C=O and2is a group of formula N(R5in the case where the solid line and dotted line between And1and2present simple relationship (A1-And2);
R2represents alkyl, optionally substituted by cyano, aryl, optionally substituted alkoxygroup, aralkyl, optionally substituted by halogen atom, cyano, alkoxygroup, alkyl or carbamoyl, or quinil;
R3represents a hydrogen atom, halogen atom, cyano, formyl, carboxyl, alkyl, optionally substituted (1) amino group, optionally substituted by alkyl, or (2) alkoxygroup, aryl, optionally substituted alkoxygroup, tetrazolyl, alkylsulphonyl, cyclol ylcarbonyl, heteroarylboronic where heteroaryl is a 4-6-membered monocyclic radical containing 1-2 heteroatoms selected from nitrogen atom and oxygen atom, alkoxycarbonyl, carbarnoyl, optionally substituted alkyl, cycloalkyl or cycloalkenyl, hydroxyl, alkoxygroup or a group of the formula: -Rd-C(O)O-Re in which Rd represents a simple bond, and Re is a group of the formula: -CH(R4a)OC(O)R4bin which R4ais alkyl and R4bis cycloalkane or aryloxy;
R4represents a hydrogen atom, hydroxyl, cyano, alkyl, carbarnoyl, carboxyl, aryloxy, optionally substituted alkoxygroup or carbamoyl, alkylsulfonyl, alkylsulphonyl or alkoxycarbonyl;
R5represents a hydrogen atom or alkyl;
-Y represents a group of formula (A)below:
[Formula 2]

in which m1 is 2, and R6no,
or pharmaceutically acceptable salt of the compounds.

2. The compound according to claim 1 of formula (II):
[Formula 6]

in which R1, R2, R3and Y have the meanings defined in claim 1, and R12represents a hydrogen atom or alkyl, or a pharmaceutically acceptable salt of the compounds.

3. The compound according to claim 1 of formula (III):
[Formula 7]
in which R1, R2, R3and Y have the meanings defined in claim 1, and R13represents a hydrogen atom, hydroxyl, cyano, carboxyl, alkyl, aryloxy, optionally substituted alkoxygroup or carbamoyl, alkylsulphonyl, alkoxycarbonyl, alkylsulfonyl,
or pharmaceutically acceptable salt of the compounds.

4. The compound or pharmaceutically acceptable salt of the compound according to claim 3, where R13represents a hydrogen atom, hydroxyl, cyano, carboxyl, aryloxy, optionally substituted alkoxygroup or carbamoyl, alkylsulphonyl, alkoxycarbonyl or alkylsulfonyl.

5. The compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 4, where R2represents a group represented by any of the subsequent formula (E), formula (H) and
formula (I):
[Formula 8]

in which each of R14and R20missing, or there are one or two R14and/or one or two R20and they independently represent a halogen atom, cyano, alkyl, alkoxygroup or carbarnoyl;
R19represents a hydrogen atom or methyl.

6. The compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 4, where R1represents a hydrogen atom or optionally substituted C1-C3

7. The compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 4, where R1represents a group of the formula: -Ra-Rb-Rc, in which
Ra is alkylene;
Rb is a simple bond or carbonyl; and
Rc is aryl, optionally substituted alkoxygroup.

8. The compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 4, where R1represents a hydrogen atom, methyl or ethyl.

9. The compound or pharmaceutically acceptable salt of the compound according to claim 5, where R1represents a hydrogen atom, methyl or ethyl.

10. The compound according to claim 1 of formula (IV):
[Formula 9]

in which R1and R3have the meanings given in claim 1; R23represents a hydrogen atom or alkyl; R24represents a halogen atom, cyano, carbarnoyl, methyl or methoxy; and
R25represents a hydrogen atom, a fluorine atom or a chlorine atom, or a pharmaceutically acceptable salt of the compounds.

11. The compound according to claim 1 of formula (V):
[Formula 10]

in which R26represents a hydrogen atom, cyano, alkyl, optionally substituted (1) amino group, optionally substituted by alkyl, or (2) alkoxygroup, carbarnoyl, optionally substituted alkyl, cycloalkyl or cycloalkylation, GI is roxil or alkoxy; R27represents a chlorine atom, a bromine atom, cyano, carbarnoyl, methyl or methoxy; and R28represents a hydrogen atom or a fluorine atom,
or pharmaceutically acceptable salt of the compounds.

12. The compound or pharmaceutically acceptable salt of the compound according to claim 11, where R27represents a chlorine atom or cyano.

13. The compound or pharmaceutically acceptable salt of the compound according to § § 11 or 12, where R26represents a hydrogen atom or carbarnoyl, optionally substituted alkyl, cycloalkyl or cycloalkylation.

14. The compound according to claim 1, selected from the group of compounds represented by the following formulas


,
or its pharmaceutically acceptable salt.

15. The compound of formula (VI):
[Formula 11]

in which R2and Y have the meanings defined in claim 1, and R29is alkyl,
or pharmaceutically acceptable salt of the compounds.

16. Pharmaceutical composition having the properties of the inhibitor dipeptidylpeptidase IV containing the compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 15 as an active ingredient.

17. The inhibitor dipeptidylpeptidase IV, containing with the unity or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 15, as the active ingredient.

18. Pharmaceutical composition for treating diabetes containing compound or pharmaceutically acceptable salt of the compound according to any one of claims 1 to 15 as an active ingredient.

19. The use of the compounds or pharmaceutically acceptable salts of the compounds according to any one of claims 1 to 15 for receiving the inhibitor dipeptidylpeptidase IV.

20. The use of the compounds or pharmaceutically acceptable salts of the compounds according to any one of claims 1 to 15 for obtaining a pharmaceutical composition for the treatment of diabetes.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of pyrazolo[1,5-a]pyrimidine with general formula 1 (values of radicals are given in the formula of invention), a pharmaceutical composition containing said derivatives and use of the novel compounds for preparing a medicinal agent for treating one or more diseases associated with cyclin-dependant kinalse CDK2.

EFFECT: novel compounds have useful biological properties.

36 cl, 87 tbl, 607 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: present invention relates to antagonists of serotonin 5-HT5 receptors with general formula 1 and their pharmaceutically acceptable salts and/or hydrates, particularly to substituted 3-sulphonyl-[1,2,3]triazolo[1,5-a]quinazolines and 3-sulphonyl-thieno[2,3-e][1,2,3]triazolo [1,5-a]pyrimidines, as active compounds for pharmaceutical compositions and medicinal agents, and methods of producing said compounds. In general formula 1 , Ar is a phenyl which is unsubstituted or substituted with halogen or at least one lower alkyl; R1 is a hydrogen atom or optionally substituted amine group, or optionally substituted 5-6 member azaheterocyclyl, bonded by a nitrogen atom to a carbon atom of a triazolopyrimidine ring with 1-2 heteroatoms selected from nitrogen, oxygen or sulphur, and optionally annulated with a benzene ring; where the substitutes are selected from hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C8cycloalkyl, alkoxy group, acyl, saturated or unsaturated optionally annulated 5-7 member heterocyclyl, where heteroatoms are selected from nitrogen, oxygen or sulphur, optionally substituted phenyl; R2 and R3 together with carbon atoms to which they are bonded form an optionally substituted benzene or thiophene ring, where substitutes are selected from C1-C5alkyl or halogen atom.

EFFECT: invention also relates to pharmaceutical compositions and medicinal agents, a method of treating or preventing development of CNS diseases mediated by action of serotonin 5-HT5 receptors, for example Alzheimer's disease.

20 cl, 6 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazolpyrimidine derivatives of formula (I) where p is 0 or 1; R1 and R2 can independently represent H, halogen, lower alkyl, lower alkoxy, possibly substituted with one or more halogens or CF3; R3 is lower alkyl, hydroxy-lower alkyl or NRaRb; Ra and Rb are independently selected from a group consisting of H; cycloalkyl containing 3-6 carbon atoms; phenyl; lower alkyl possibly substituted with one or more hydroxy, fluorine, C3-6cycloalkyl, phenyl, pyridyl or NRcRd, where Rc and Rd are independently selected from H or lower alkyl; or where Ra and Rb together with the nitrogen atoms to which they are bonded can form a 5- or 6-member hetero-ring, possibly additionally containing 1 or 2 heteroatoms selected from O or N, and possibly substituted with lower alkyl or hydroxy-lower alkyl; R4 is H, Cl, lower alkoxy, cycloalkyl, containing 3-6 carbon atoms, or straight lower alkyl which is possibly substituted with one or more F; R5 is H; halogen or lower alkyl; as well as to their pharmaceutically acceptable salts.

EFFECT: invention also relates to pharmaceutical compositions based on these compounds and their use in preparing medicine for treating or preventing acute and/or chronic neurological disorders in which activation of mGluR2 is involved.

19 cl, 179 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to new 2-alkylamino-3-arylsulphonylcycloalkano[e]pyrazolo[1,5-a]pyrimidines of general formula 1 and 2-alkylamino-3-arylsulphonylcycloalkano[d]pyrazolo[1,5-a]pyrimidines of general formula 2 with properties of serotonin 5-NT6 receptor antagonists, to pharmaceutical compositions containing specified compounds as a principle, medical products and method of treatment and the prevention of CNS diseases. In general formulae 1 and 2, R1 represents hydrogen atom or C1-C3 alkyl; R2 represent C1-C3 alkyl; R3 represent hydrogen atom, one or two optionally substituted identical halogen atoms, C1-C3 alkyl or hydroxyl optionally substituted with C1-C3alkyl; n represents an integer 1, 2 or 3. The invention also relates to the method for making the compounds of general formula 1 or 2 by interaction of 3-amino-4-arylsulphonyl-2H-pyrazoles of general formula 3 with relevant β-dicarbonyl compounds of general formula 4 or their derivatives of general formula 5. 3, 4, 5, where: R1, R2, R3 and n have said values.

EFFECT: new 2-alkylamino-3-arylsulphonyl-cycloalkano[e or c1]pyrazolo[1,5]pyrimidines - serotonin 5-NT6 receptor antagonists, methods of making and applying thereof.

12 cl, 1 dwg, 4 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention is related to 4-((2)-4'-hydroxybutene-2'-yl)-2-R-6-phenyl-1,2,4-triazolo[5,1-c][1,2,4]triazine-7-ons of common formula (1) ,

where R=H, CH3,SCH3 have antiviral action against herpesvirus of simple type 1 (HSV-1).

EFFECT: new derivatives have useful biological properties.

1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to antagonists of serotonin 5-HT6 receptors of common formula 1 and their pharmaceutically acceptable salts and/or hydrates, pharmaceutical compositions, dosage forms and methods of production. Invention also includes new compounds of formula 1.1. In formulae 1 and 1.1 , Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur and heteroatom; R1 represents atom of hydrogen, unnecessarily substituted C1-C5 alkyl; Ar represents aryl, selected from unnecessarily substituted phenyl or unnecessarily substituted 5-6-member heteroaryl, which contains atom of nitrogen or atom of sulfur as heteroatom; R1 represents atom of hydrogen, which is unnecessarily substituted C1-C5 alkyl; R21,R22, R31, R32 independently from each other represent atom of hydrogen or substituent of aminogroup, selected from unnecessarily substituted C1-C4 alkyl, unnecessarily substituted phenyl, or R31 and R32 together with atom of nitrogen, to which they are bound, create unnecessarily substituted saturated 6-member heterocycle, possibly containing atom of nitrogen in cycle; or R1 together with atom of nitrogen, to which it is bound, and R21 and R22 together with atom of nitrogen, to which they are bound, create substituted pyrimidine cycle. In formula 1.1 R4, R5 and R6 independently from each other represent atom of hydrogen, unnecessarily substituted C1-C3 alkyl or phenyl.

EFFECT: compounds of invention may find application for treatment and prevention of development of conditions and disorders of central nervous system.

13 cl, 11 dwg, 4 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a combined product containing compounds of formula (I): where: R1 and R2 represent CF3; R3 and R4 represent fluoro; R5 and R6 represent hydrogen; R7 presents Cl, X represents CR8, where R8 represents Cl; and R9 represents NH2; or its veterinary acceptable salt, and b) doramectin. The invention also relates to an antiparasitic veterinary composition based on the said combined product.

EFFECT: obtaining a combined product which can be used in veterinary for treating parasitic infections in mammals.

4 cl, 1 dwg, 1 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Novel insecticides // 2379301

FIELD: chemistry.

SUBSTANCE: compounds with formula I are described, where each of E and Z is oxygen; A is C1-C6alkylene or a 3-member monocyclic ring system, which can be monosubstituted; Y is C1-C6alkylene; p equals 0; q equals 0 or 1; B represents a 3- or 4-member ring system which is completely or partially saturated and can contain a heteroatom selected from oxygen, possibly substituted; each R1 independently represents halogen, nitro group, C1-C6alkyl; or each R1 independently represents an amino group; n equals 1, 2; each of R2 and R3 represents hydrogen; D represents a group and agronomically acceptable salts of said compounds. Also described is a method of producing formula I compounds, intermediate compounds, a pesticide composition containing a formula I compound, as well as an insect control method and a method of protecting plant propagation material.

EFFECT: novel anthranylamide derivatives have good insecticidal activity.

16 cl, 8 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: novel isoquinoline derivatives are described by general formula I, where q equals zero; p equals zero or one; Ra is -COOH or WR8; under the condition that, if Ra is -COOH, then p equals zero, and if Ra is -WR8, then p equals one; W is selected from an oxygen atom and -NR9-, where R9 is selected from a group consisting of a hydrogen atom, acyl and alkyl; and R8 is selected from a group consisting of a hydrogen atom and alkyl; R1 is selected from a group consisting of a hydrogen atom, alkyl, alkyl substituted with one group selected from alkoxy and dialkylamino, a halogen atom, heteroaryl containing up to six carbon atoms, one of which is nitrogen, aminoacyl, aryl, aryl substituted with alkyl, and -XR6, where X is an oxygen atom, -S(O)n- or -NR7, where n equals zero, one or two, R6 is selected from a group consisting of alkyl, aryl, aryl substituted with one group selected from a halogen atom, alkoxy, alkylcarbonylamino and alkylsulfonamide, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, and R7 is a hydrogen atom or aryl; R2 and R3 are independently selected from a group consisting of a hydrogen atom, amino, amino substituted with alkoxy-substituted phenylsulfonyl, alkyl, alkyl substituted with up to three times by a halogen atom, aryl, halogen atom -NR6C(O)NR6R6, and -XR6, where X is an oxygen atom or -S(O)n-, where n equals zero, one or two, each of the substitutes R6 is independently selected from a group consisting of hydrogen, alkyl, alkyl substituted with aryl, aryl , aryl substituted with one or two groups selected from a halogen atom, alkyl, alkyl substituted with up to three times by a halogen, alkoxy, alkoxy substituted with up to three times by a halogen, aryloxy substituted with a halogen, nitro, alkylsulfonamide, arylsulfonamide and alkyl-substituted arylsulfonamide, cycloalkyl, heteroaryl, containing up to six carbon atoms, one of which is nitrogen, under the condition that if X is -SO2-, R6 cannot be a hydrogen atom; or R2 and R3 together with carbon atoms to which they are bonded, are bonded with formation of an aryl group; R4 and R5 are independently selected from a hydrogen atom or aryl; R is selected from a group which includes a hydrogen atom, deuterium and methyl; R' is selected from a group consisting of a hydrogen atom, deuterium, alkyl or alkyl substituted with one group selected from hydroxyl, amino, carboxyl, aryl, aryl substituted with one hydroxyl and heteroaryl, containing up to five carbon atoms, two of which can be nitrogen; on the other hand, R and R' and the carbon atom to which they are bonded can be bonded with formation of cycloalkyl; R" is formed from a hydrogen atom and alkyl, or R" together with R' and the nitrogen atom to which they are bonded can be bonded with formation of a heterocyclic group containing up to six carbon atoms, one of which is nitrogen; R'" is selected from a group consisting of hydroxyl, alkoxy, alkoxy substituted with aryl, acyloxy, aryl, -S(O)n-R10, where R10 is hydrogen, and n is zero; or its pharmaceutically acceptable salts, esters or amides; under the condition that restrictive conditions given in paragraph 1 of the formula of invention are met. The invention also relates to specific produced and described compounds, a pharmaceutical composition based on compounds with general formula I, a method of treating, preventing and pretreatment using said pharmaceutical composition, a method of inhibiting activity of hydrolase enzyme, based on taking an effective amount of a formula I compound, a composition for preventing and pretreatment, based on formula I compound and erythropoietin.

EFFECT: new isoquinoline derivatives have useful biological properties.

53 cl, 4 tbl, 253 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted derivatives of N-(3-benzoylaminophenyl)-4-pyridyl-2-pyrimidine amine of general formula (I), with inhibitory activity towards protein kinase, method of producing said derivatives and pharmaceutical compositions based on the derivatives. In the compound of formula 1 R1 is hydrogen and R2 is NR5R6, or R1 is NR5R6 and R2 is hydrogen; R3 is trifluoromethyl; R4 is lower alkyl; and R5 and R6 are independently hydrogen, lower alkyl, di(lower alkyl)amino-lower alkyl, N-lower alkylpiperidinyl, N-lower alkylpyrrolidinyl, or lower alkyl, or NR5R6 together represent pyrrolidino, piperidino, morpholino, N-lower alkylpiperazino, 1N-imidazolyl, 1H-2-lower alkylimidazolyl, 1H-4-lower alkylimidazolyl or 1H-2,4-di-lower alkylimidazolyl, or a pharmaceutically acceptable salt of such a compound.

EFFECT: compounds can be used in treating diseases related to inhibition of protein kinase activity, such as neoplastic diseases or leukaemia.

13 cl, 21 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

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