Secondary amines as renin inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

 

This invention relates to new compounds of the formula (I). The invention also relates to related aspects, including methods of making the compounds, pharmaceutical compositions containing one or more compounds of the formula (I) and in particular their use as renin inhibitors in cardiovascular diseases and renal failure.

In the system the renin-angiotensin (RAS) biologically active angiotensin II (Ang II) is formed by two-step mechanism. Highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then converted to Ang II under the action of a less specific angiotensin-converting enzyme (ACE). It is known that Ang II operates on at least two subtypes of receptors, called AT1and AT2. If AT1seems transmits most of the known functions of Ang II, the role AT2still unknown.

The modulating RAS represents a major progress in the treatment of cardiovascular diseases. The ACE inhibitors and blockers AT1deemed suitable for treatment of hypertension (Waeber B. et al, "The renin-angiotensin system: role in experimental and human hypertension", in W. H. Birkenhager, Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1986, 489-519; Weber, M. A., Am. J. Hypertens., 1992, 5, 247S). Additionally, ACE inhibitors are used to protect the kidneys (Rosenberg M. E. et al, Kidney international 1994, 45, 403; Breyer J. A. et al., Kidney International, 1994, 45, S156), in the prevention of congestive heart failure (Vaughan D. E. et al, Cardiovasc. Res., 1994, 28, 159; Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl 3A), 83) and myocardial infarction (Pfeffer M. A. et al., N. Engl. J. Med, 1992, 327, 669).

The main reason for the development of renin inhibitors lies in the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The only known substrate for renin is angiotensinogen, which can be recycled (under physiological conditions) only by renin. On the contrary, ACE can also cleave bradykinin in addition to Ang I and may be ignored by hemati, representing semipretioase (A. Husain, J. Hypertens., 1993, 11, 1155). Thus patients ingibirovanie ACE leads to the accumulation of bradykinin, calling cough (5-20%) and potentially life-threatening swelling (0,1-0,2%) (Israili, Z. H. et al., Annals of Internal Medicine, 1992, 117, 234). The ACE inhibitors do not inhibit himizu. Therefore, the formation of Ang II is still likely for patients treated with ACE inhibitors. Blocking receptors AT1(for example, using losartan) on the other hand leads to increased action of Ang II on other subtypes at-receptors (e.g., AT2), whose concentration increases significantly when blocking receptors AT1. In summary, it is expected that inhibitors of renin will demonstrate another farmatsevticheskii, than ACE inhibitors and blockers AT1regarding the effectiveness of blocking RAS and from the point of view of safety aspects.

In respect of renin inhibitors, there are only limited clinical experience (Azizi M. et al., J. Hypertens., 1994, 12, 419; Neutel J. M. et al., Am. Heart, 1991, 122, 1094) because of their lack of oral activity due to their coworkers peptide nature (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). Clinical development of several compounds was suspended because of this problem along with the high cost of the products. Only one of the compounds that contains four chiral center, has moved into clinical trials (Rahuel J. et al., Chem. Biol, 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, the necessary renin inhibitors with good oral bioavailability and duration of action. Have been recently described the first ones renin inhibitors, which showed high activity in vitro (C. Oefner et al., Chem. Biol, 1999, 6, 127; patent application WO 97/09311; Marki H. P. et al., Il Farmaco, 2001, 56, 21). However, the state of development of these compounds remains unknown.

The present invention relates to inhibitors of renin ones nature and low molecular weight. Described orally active renin inhibitors of formula (I), which have a long duration of action and are active when the evidence far beyond R the regulation of blood pressure, where can be activated tissue system the renin-chymase, leading to pathophysiologically modified local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. Thus, the present invention describes the data ones renin inhibitors of formula (I).

In particular, the present invention relates to new compounds of the formula (I)

where

the dashed line in 6-membered nitrogen-containing ring Z of formula (I) (a specified ring Z consists of numbered 1 to 6 ring atoms) indicates that the double bond is either present in 3,4 - or 4,5-positions of the ring Z of formula (I), or a double bond is not present in the ring Z of formula (I); and where the

if n = 0, the double bond may be present at the 3,4 - or 4,5-position of the ring Z of formula (I);

or if n = 1, the double bond may be present at the 3,4-position of the ring Z of formula (I);

or: double bond may not be present in the ring Z of formula (I), if:

i) n represents the integer 0, and X represents N or N+-O-or

ii) n represents the integer 0, and V represents-O-CH2-Q-, or

iii) n is an integer 0, W represents a para-substituted phenyl or particularly para-substituted pyridinyl, and V represents pyrrolidinyl formula:/p>

,or

iv) n represents the integer 1, and L represents a-CH2-CH2-, -CH2-CH(R5)-CH2-, -CH2-O-CH2-or-CH2-S-CH2-or

v) n represents the integer 1, L represents a-CH2-N(R6)-CH2-, and X represents N or N+-O-;

X represents CH, N, or N+-O-;

W represents a para-substituted phenyl, para-substituted pyridinyl, or thiazolyl, particularly para-substituted phenyl or para-substituted pyridinyl;

V represents-CH2CH2CH2-, -CH2CH2-A-, -CH2-A-CH2-, -A-CH2CH2-, -CH2CH2CH2CH2-, -A-CH2CH2CH2-, -CH2-A-CH2CH2-, -CH2CH2-A-CH2-, -CH2CH2CH2-A-, -A-CH2CH2-B-, -CH2CH2CH2CH2CH2-, -A-CH2CH2CH2CH2-, -CH2-A-CH2CH2CH2-, -CH2CH2-A-CH2CH2-, -CH2CH2CH2-A-CH2-, -CH2CH2CH2CH2-A-, -A-CH2CH2CH2-B-, -CH2-A-CH2CH2-B-, -A-CH2CH2-B-CH2-, -A-CH2CH2CH2-B-CH2-, -CH2-A-CH2CH2CH2-B-, or-O-CH2-Q-, where Q is related to the group U Faure the uly (I);

or: if (i) n represents the integer 0, or

ii) n represents the integer 1, and X represents N or N+-O-or

iii) L represents-CH2-CH2-or

iv), L represents a-CH2-N(R6)-CH2-, and W represents a para-substituted pyridinyl,

V in addition can be pyrrolidinyl formula:

U represents unsubstituted aryl, especially phenyl; mono-, di-, tri - or Tetra-substituted aryl (especially mono-, di-, tri - or Tetra-substituted phenyl, where the substituents independently selected from C1-7-alkyl, -CF3, halogen and hydroxy-C1-7-alkyl; or a five-membered heteroaryl containing two heteroatoms independently selected from nitrogen, oxygen and sulfur (preferably pyrazolyl or isoxazolyl)where the specified heteroaryl radical optionally is mono-, di - or tri-substituted, where the substituents independently selected from C1-7-alkyl, C1-7-alkoxy, -CF3, -OCF3and halogen;

Q represents a five-membered heteroaryl with two or three heteroatoms independently selected from O and N;

L represents-CH2-CH2-, -CH2-CH(R5)-CH2-, -CH2-N(R6)-CH2-, -CH2-O-CH2- or-CH2-S-CH2-;

A and B independently from the other represent-O - or-S-;

R1represents a C1-7is alkyl or cycloalkyl, preferably cycloalkyl, especially such as cyclopropyl;

R2represents a halogen or1-7-alkyl, preferably chlorine or methyl, in particular chlorine;

R3represents halogen, C1-7-alkyl, C1-7-alkoxy, -CF3or hydrogen, preferably hydrogen;

R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-; CF3-O-(CH2)0-4-CH2-; R R"N-(CH2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl (optionally but preferably substituted by one to three Fermi), cyclopropyl (optionally substituted by one to three Fermi), cyclopropyl-C1-7-alkyl (optionally but preferably substituted by one to three Fermi) and-C(=O)-R'"where R'" represents a C1-4-alkyl, C1-4-alkoxy, -CF3, -CH2-CF3or cyclopropyl; or R12NH-C(=O)-(O)0-1-(CH2)0-4-where R12represents a C1-4-alkyl, C1-4-alkoxy or cyclopropyl; where R' and R" preferably both at the same time does not represent hydrogen;

R5represents-H, -CH2OR8, -CH2NR7R8, -CH2NR7COR8, -CH2NR7SO2R8, -CO2R 8, -CH2OCONR7R8, -CONR7R8, -CH2NR7CONR7'R8, -CH2SO2NR7R8, -CH2SR8, -CH2SOR8or-CH2SO2R8;

R6is a-R8, -COR8, -COOR10, -CONR7R8, -C(NR7)NR7'R8, -CSNR7R8, -SO2R8or-SO2NR7R8; or R6represents a radical of the formula:

where T represents a-CH2-, -NH - or-O-, m represents an integer from 1 to 6, and r represents an integer from 1 to 4;

R7and R7' independently represent hydrogen, C1-7-alkyl, C2-7alkenyl, cycloalkyl or cycloalkyl-C1-7-alkyl, where C1-7-alkyl, cycloalkyl, and cycloalkyl-C1-7the alkyl can be substituted one, two or three Halogens;

R8represents hydrogen, C1-7-alkyl, cycloalkyl or cycloalkyl-C1-7-alkyl, where C1-7-alkyl, cycloalkyl, or cycloalkyl-C1-7-alkyl may be mono-, di - or tri-substituted, where the substituents independently selected from the group consisting of halogen, hydroxy, -OCOR11, -COOR11With1-7-alkoxy, cyano, SO2R11, -CONR11R11', morpholine-4-yl-CO-, ((4-C1-7-alkyl)piperazine-1-yl)-CO-, -NHC(NH)NH2, -NR9 9'and C1-7-alkyl, provided that the carbon atom is connected to not more than one heteroatom in case this carbon atom is sp3-hybridizing;

R9and R9'independently represent hydrogen, C1-7-alkyl, cycloalkyl, cycloalkyl-C1-7-alkyl, hydroxy-C1-7-alkyl, -COOR7or-CONH2;

R10represents halogen, C1-7-alkyl, C1-7-alkoxy, -CF3or hydrogen;

R11and R11'independently represent hydrogen, C1-7-alkyl, C2-7alkenyl, cycloalkyl, or cycloalkyl-C1-7-alkyl, where C1-7-alkyl, cycloalkyl, and cycloalkyl-C1-7the alkyl can be substituted one, two or three Halogens; and

n represents the integer 0 or 1;

and their salts.

Common terms used earlier and later in this description, preferably have, in the framework of this description, the following values, unless otherwise stated.

When the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, it is understood that this also means a single connection, salt and the like.

Any reference to the compounds of formula (I) should be understood as referring also to the salts (in particular pharmaceutically acceptable salts) of compounds of formula is (I), if it is appropriate and expedient.

The term C1-7-alkyl, alone or in combination with other groups, means a linear or branched groups containing from one to seven carbon atoms, preferably from one to four carbon atoms, i.e. C1-4-alkyl. Examples1-7-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyl, tert-butyl, pentyl, hexyl and heptyl. Methyl, ethyl and isopropyl group are preferred.

The term C1-7-alkoxy, by itself or in combination with other groups, refers to the group R-O-, where R represents a C1-7is an alkyl group. Examples1-7the alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, verboeket and tert-butoxy.

The term hydroxy-C1-7-alkyl, alone or in combination with other groups, refers to a group of HO-R, where R represents a C1-7is an alkyl group. Examples of hydroxy-C1-7-alkyl groups are HO-CH2-, HO-CH2CH2-, HO-CH2CH2CH2and CH3CH(OH)-.

The term C2-7alkenyl, by itself or in combination with other groups, means a linear or branched group containing olefinic bond and consisting of two to seven carbon atoms, preferably from two to four atoms of plastics technology : turning & is Yes. Examples of C2-7-alkenyl are vinyl, propenyl and butenyl.

The term halogen, sachet fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. In a more preferred embodiment of the present invention, the term halogen means fluorine or chlorine.

The term cycloalkyl, by itself or in combination with other groups, means saturated cyclic hydrocarbon system with 3-7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclopropyl.

The term aryl by itself or in combination, refers to phenyl, naftilos or indanernas groups, preferably by phenyl group.

The term sp3-heriditary refers to the carbon atom means that the carbon atom forms four bonds with four deputies located tetragonal way around this carbon atom.

The expression "pharmaceutically acceptable salt comprises a salt or inorganic acids or with organic acids, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, oxalic acid, maleic KIS the PTA, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, palmitic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonate acid, econsultancy acid, ethicality acid, p-toluensulfonate acid, salicylic acid, succinic acid, triperoxonane acid and the like, which are non-toxic to living organisms, or, in the case of compounds of formula (I) which is acidic by nature, salt with inorganic base, such as base alkali or alkaline earth metal, e.g. sodium hydroxide, potassium hydroxide, hydroxide calcium and the like. As for other examples of pharmaceutically acceptable salts, then you can refer to the publication "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The compounds of formula (I) may contain asymmetric carbon atoms. The substituents at the double bond or ring can be in the CIS (=Z-) or TRANS (=E-) forms, unless otherwise stated. Therefore, the compounds of formula (I) may exist as mixtures of stereoisomers or, preferably, in the form of pure stereoisomers. Mixture of stereoisomers can be separated by known methods, for example, column chromatography, thin-layer chromatography, HPLC or what estanlizania.

The compounds of this invention also include nitrosated compounds of formula (I), nitrosation of which was conducted on one or more sites such as oxygen (condensation of hydroxyl), sulfur (sulfhydryl condensation) and/or nitrogen.

Nitrosated compounds according to the present invention can be obtained using conventional methods known to experts in this field. For example, known methods of nitrosation of compounds described in U.S. patent No. 5380758, 5703073, 5994294, 6242432 and 6218417; WO 98/19672; and in the publication Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983).

The preferred implementation of the present invention relates to the compound of formula (I), where

if n = 0, the double bond may be present at the 3,4 - or 4,5-position of the ring Z of formula (I); or

if n = 1, the double bond may be present at the 3,4-position of the ring Z of formula (I); or

the double bond may not be present in the ring Z of formula (I), if:

i) n represents the integer 0, and X represents N, or

ii) n represents the integer 0, and V represents-O-CH2-Q-, or

iii) n represents the integer 1, and L represents a-CH2-CH2-, -CH2-CH(R5)-CH2-, -CH2-O-CH2-or-CH2-S-CH2-or

iv) n represents the integer 1, L represents a-CH2-N(R )-CH2-, and X represents N;

X represents CH or N;

V represents-CH2CH2CH2-, -CH2CH2-A-, -CH2-A-CH2-, -A-CH2CH2-, -CH2CH2CH2CH2-, -A-CH2CH2CH2-, -CH2-A-CH2CH2-, -CH2CH2-A-CH2-, -CH2CH2CH2-A-, -A-CH2CH2-B-, -CH2CH2CH2CH2CH2-, -A-CH2CH2CH2CH2-, -CH2-A-CH2CH2CH2-, -CH2CH2-A-CH2CH2-, -CH2CH2CH2-A-CH2-, -CH2CH2CH2CH2-A-, -A-CH2CH2CH2-B-, -CH2-A-CH2CH2-B-, -A-CH2CH2-B-CH2-, -A-CH2CH2CH2-B-CH2-, -CH2-A-CH2CH2CH2-B-, or-O-CH2-Q-, where Q is associated with the group U of formula (I); or:

if

i) n represents the integer 0, or

ii) n represents the integer 1, and X represents N, or

iii) L represents-CH2-CH2-or

iv), L represents a-CH2-N(R6)-CH2-, and W represents a para-substituted pyridinyl, V can in addition be pyrrolidinyl formula:

,and

R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-; CF3-O-(CH2 0-4-CH2or R R N-(CH2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl (optionally substituted by one to three Fermi), cyclopropyl (optionally substituted by one to three Fermi), cyclopropyl-C1-7-alkyl (optionally substituted by one to three Fermi) and-C(=O)-R'"where R'" represents a C1-4-alkyl, -CF3, -CH2-CF3or cyclopropyl.

The preferred implementation of the present invention relates to the compound of formula (I), where X represents CH or N+-O-.

The preferred implementation of the present invention relates to the compound of formula (I), where R6is a-R8, -COR8, -COOR10, -CONR7R8, -C(NR7)NR7'R8, -CSNR7R8, -SO2R8or-SO2NR7R8.

The preferred implementation of the present invention relates to the compound of formula (I), where both A and B represents-O-.

The preferred implementation of the present invention relates to the compound of formula (I), where R5represents-CO2CH3or-CO2H.

The preferred implementation of the present invention relates to the compound of formula (I), where R6represents-H, -COCH3 , -C(NH)NH2, -CONHCH2C(CH3)2CONH2, -CONHCH(CH2)2or-CONHC(CH2)2CN.

The preferred implementation of the present invention relates to the compound of formula (I), where R6is a-H.

The preferred implementation of the present invention relates to the compound of formula (I), where L represents-CH2-CH2- or-CH2-NH-CH2-.

The preferred implementation of the present invention relates to the compound of formula (I), where R1is cyclopropyl.

The preferred implementation of the present invention relates to the compound of formula (I), where W represents a para-substituted phenyl, or

The preferred implementation of the present invention relates to the compound of formula (I), where V represents-O-CH2-CH2-O-, -O-CH2-Q-, -CH2-CH2-O-, where part of the-CH2fragment-CH2-CH2-O - linked to group W of formula (I), or

The preferred implementation of the present invention relates to the compound of formula (I), where V represents-O-CH2-CH2-O - or-O-CH2-Q-.

The preferred implementation of the present invention relates to the compounds is of formula (I), where V-W represents:

The preferred implementation of the present invention relates to the compound of formula (I), where U is a

The preferred implementation of the present invention relates to the compound of formula (I), where U is a

The preferred implementation of the present invention relates to the compound of formula (I), where Q is isoxazolyl or oxadiazolyl.

The preferred implementation of the present invention relates to the compound of formula (I), where Q is isoxazolyl, especially isoxazolyl, which is connected with the remainder of the molecule of formula (I) as follows:

The preferred implementation of the present invention relates to the compound of formula (I), where R2represents Cl, and R3represents hydrogen.

The preferred implementation of the present invention relates to the compound of formula (I), where R4represents CH3-O-(CH2)2-3-, or CH3-C(=O)-NH-CH2-CH2-.

The preferred implementation of the present invention relates to the compound of formula (I), where R4presented yet a-CH 2CH2CH2-O-CH3or-CH2CH2-O-CH3.

The preferred implementation of the present invention relates to the compound of formula (I), where R4represents-CH2CH2-O-CH3.

The preferred implementation of the present invention relates to the compound of formula (I), where the fragment

represents one of the following:

The preferred implementation of the present invention relates to the compound of formula (I), where n is an integer 0.

The preferred implementation of the present invention relates to the compound of formula (I), where the double bond is not present in the ring Z of formula (I), or a double bond is present at the 3,4-position of the ring Z of formula (I).

The preferred implementation of the present invention relates to the compound of formula (I), where the double bond is not present in the ring Z of formula (I), and the substituents in the 3 - and 4-positions of the ring Z of formula (I) are in TRANS-position is obtained at each other.

The preferred implementation of the present invention relates to the compound of formula (I), where the double bond is not present in the ring Z of formula (I), and the absolute configuration at position 3 of the ring Z of formula (I) represents R)-configuration, and the substituent in the 4-position of the ring Z of formula (I) is in the TRANS-position is obtained for the 3-substituent in the ring Z of formula (I).

In a particularly preferred embodiment, the present invention relates to the compound of formula (I), where

X represents CH or N;

W represents a para-substituted phenyl or para-substituted pyridinyl;

V represents-CH2CH2-A-, where part of the-CH2fragment-CH2CH2-A - is associated with a group W of formula (I), A-CH2CH2-B - or-O-CH2-Q-;

U represents a tri-substituted phenyl, where the substituents independently selected from C1-7-alkyl and halogen;

Q represents isoxazolyl;

L represents-CH2-CH2- or-CH2-N(R6)-CH2-;

both A and B represent-O-;

R1is cycloalkyl, preferably cyclopropyl;

R2represents a halogen or1-7-alkyl;

R3represents a halogen or hydrogen;

R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-;

R6is a-R8, -COR8, -CONR7R8or-C(NR7)NR7'R8;

both R7and R7' represent hydrogen;

R8represents hydrogen, C1-7is alkyl or cycloalkyl, where C1-7-alkyl or cycloalkyl to be mono-substituted by cyano or-CONR 11R11'where both R11and R11'represent hydrogen; and

n represents an integer of 0 or 1.

In another particularly preferred embodiment, the present invention relates to the compound of formula (I), where

the double bond may be present at the 3,4-position of the ring Z of formula (I); or:

the double bond may not be present in the ring Z of formula (I), if:

i) n represents the integer 0, and X represents N or N+-O-or

ii) n represents the integer 0, and V represents-O-CH2-Q-, or

iii) n is an integer 0, W represents a para-substituted pyridinyl, and V represents pyrrolidinyl formula:

or

iv) n represents the integer 1, and L represents a-CH2-CH2-;

X represents CH, N, or N+-O-;

W represents a para-substituted phenyl, or para-substituted pyridinyl;

V represents-CH2CH2-A-, -A-CH2CH2-B-, or-O-CH2-Q-, where Q is associated with the group U of formula (I); or:

if

i) n represents the integer 0, or

ii), L represents a-CH2-CH2-or

iii) L represents-CH2-N(R6)-CH2-such as, in particular-CH2-NH-CH2-, and W represents a para-samaden the th pyridinyl,

V in addition can be pyrrolidinyl formula:

U represents a tri-substituted phenyl, where the substituents independently selected from C1-7-alkyl and halogen, in particular methyl and halogen;

Q represents isoxazolyl;

L represents-CH2-CH2- or-CH2-N(R6)-CH2-;

both A and B represent-O-;

R1is cyclopropyl;

R2represents a halogen or C1-7-alkyl, preferably chlorine or methyl, in particular chlorine;

R3represents halogen (in particular chlorine) or hydrogen, preferably hydrogen;

R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-such as, in particular CH3-O-(CH2)1-2-CH2-; R R"N-(CH2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl, substituted by one to three Fermi (in particular F2CH-CH2-), cyclopropyl and-C(=O)-R'"where R'" represents a C1-4-alkyl (in particular methyl or ethyl), C1-4-alkoxy (in particular methoxy), -CH2-CF3or cyclopropyl, such as in particular R NH-(CH2)0-1-CH2-where R' is as previously defined; or R12NH-C(=O)-(O)0-1-(CH2)0-4-(in persons is nasty R 12NH-C(=O)-(O)0-1-(CH2)1-2-), where R12represents a C1-4-alkyl (in particular methyl or ethyl) or cyclopropyl; provided that both R' and R ' cannot simultaneously represent hydrogen;

R6represents-H, C1-7-alkyl-CO-(in particular CH3-CO-), -CONHR8or-C(NH)NH2;

R8is cycloalkyl (especially cyclopropyl); or (C1-7-alkyl (in particular, C4-alkyl) or cycloalkyl (especially cyclopropyl), both of which are monosubstituted cyano or-CONH2; and

n represents an integer of 0 or 1.

The present invention also relates to compounds of formula (I), in which the values of one or more of the substituents and symbols defined for formula(I) or in the preferred embodiment, formula (I)is replaced by defined in this description of preferred values, such as those defined for the above preferred embodiments.

A highly preferred implementation of the present invention relates to the compound of formula (I)selected from the group consisting of:

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

(1R*,5S*)-6-{[2-chloro-5-(2-methoxy-ethyl)Ben is Il]cyclopropyl-carbarnoyl}-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl) benzyl]cyclopropylamine (1S,5R)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

cyclopropyl-[5-(2-methoxy-ethyl)-2-methyl-benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

cyclopropyl-[5-(3-methoxy-propyl)-2-methyl-benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide of (1R,5S)-3-carbamido-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]f the Nile}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

3-[(1-cyano-cyclopropyl)amide] 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid,

3-cyclopropylamino 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid,

3-[(2-carbarnoyl-2-methyl-propyl)amide] 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

(1R,5S)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',5',6'-tetrahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

[5-chloro-2-3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',5',6'-tetrahydro[3,4']bipyridinyl-3'-carboxylic acid, and

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid, and salts of these compounds.

Following a highly preferred implementation of the present invention relates to the compound of formula (I)selected from the group consisting of:

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropa the amide of (1R,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',5',6'-tetrahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1S,5R)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic to the slots,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1S,5R)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1S,5R)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-methoxy-these who)benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine(1S,5R)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3,3,1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3,2,1]octane-2-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-ropyl)pyridine-4-ylmethyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-cyclopropylamino-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)-1-oxypyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

<> (2-chloro-5-cyclopropanecarbonyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine, (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)-1-oxypyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

methyl ester (4-chloro-3-{[((3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carbonyl)cyclopropyl-amino]methyl}benzyl)carbamino acid,

methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl}carbamino acid,

methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexage is o-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl}carbamino acid,

[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-cyclopropanecarbonitrile)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-methylcarbamoylmethyl)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[(cyclopropanecarbonyl)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-is enocsi)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[2-(2,2-diferentiating)ethyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,

[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chlor,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

{2-chloro-5-[2-(2,2-diferentiating)ethyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,

4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl methyl ether-carbamino acid,

2-{4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]phenyl}ethyl methyl ether-carbamino acid,

methyl ester (2-{4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]phenyl}ethyl) - carbamino acid, and

[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropa the amide (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid, and salts of these compounds.

The compounds of formula (I) can be used for the treatment and/or prevention of diseases, such as or associated with hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications of diabetes, such as nephropathy, vasculopathies and neuropathy, glaucoma, elevated intraocular pressure, atherosclerosis, restenosis after angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, with anxiety, confusion, complications of treatment with immunosuppressive agents, and other diseases associated with the system renin-angiotensin.

The compounds of formula (I) are particularly useful for the treatment and/or prevention of hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy heart, fibrosis of the heart, myocardial ischemia, cardiomyopathy, diabetic complications, such to the to nephropathy, vasculopathies and neuropathy.

In one embodiment, the invention relates to a method of treatment and/or prevention of diseases that are associated with impaired regulation of the renin-angiotensin, in particular to a method of treatment and/or prophylaxis of the aforementioned diseases, these methods include the introduction of the patient pharmaceutically active amount of a compound of formula (I).

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier material. Data pharmaceutical compositions can be used for the treatment and/or prevention of the above diseases. The pharmaceutical compositions can be used for enteral, parenteral or topical use. They can be administered, e.g. orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.

The invention also relates to the use of compounds of formula (I) to obtain pharmaceutical compositions for the treatment and/or prophylaxis of the above sableman the th.

Obtaining pharmaceutical compositions can be carried out in ways that will be known to any specialist, skilled in the art (see, for example, Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) through the introduction of the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically important substances in Galanova preparative form of application together with suitable, non-toxic, inert, therapeutically compatible solid or liquid materials-carriers and, if desired, usual pharmaceutical auxiliary additives.

The compounds of formula (I) or the above-mentioned pharmaceutical compositions are also used in combination with other pharmacologically active compounds, such as ACE inhibitors, inhibitors of neutral endopeptidase, aldosterone antagonists, receptor antagonists angiotensin II receptor antagonists endothelin, vasodilators, calcium antagonists, potassium activators, diuretics, antiadrainergicakimi substances, beta-adrenergic antagonists, alpha-adrenergic antagonists, inhibitors beta-hydroxysteroid dehydrogenase type 1, soluble activators is animatrices and/or other drugs, favorable for the prevention or treatment of the above diseases.

The present invention also relates to prodrugs of the compounds of formula (I), which are converted in vivo into a compound of formula (I) as such. Therefore, any reference to the compounds of formula (I) should be understood as referring also to the corresponding prodrugs of the compounds of formula (I), if it is suitable and appropriate.

The compounds of formula (I) can be obtained by methods briefly described below, by the methods described in the examples or by analogous methods.

Connection type A, as indicated in scheme 1, can be obtained as described in patent applications WO 2003/093267, WO 2004/002957, WO 2004/096769, WO 2004/096803, WO 2004/096799 and WO 2004/096366. PG means a suitable protective group, usually carbamate. Rameans suitable ester Deputy, typically methyl, ethyl or benzyl group. L' means the predecessor group L as defined in formula (I). Usually the main chain substituent L is already being fully in the group L', but the group R5and R6- need to build later. Group Raand L' can be modified during the synthesis process. Cross-coupling catalyzed by transition metal, usually palladium, more typically cross-coupling of Negishi and Suzuki, leads to the connection type, where Vameans of predest the INEC Deputy V, as defined for formula (I). Vacan be modified during the synthesis process. The completion of the construction of a fragment of U-V - leads to a connection of type C. it is Sometimes possible to embed the complete fragment U-V-W - in connection type a, obtaining, directly, connection With. the Restoration of the double bond in connection With the subsequent equilibrium conditions leads to the connection type D, where the substituents U-V-W - and RaOCO - often are in TRANS-position to each other. If n = 1, take two diastereoisomer; they can be separated using chromatography. Sometimes it is more convenient to restore the double bond in connection With; in this case, get the connection type E, which transform in the connection type D after creating a Deputy U-V-W-.

Scheme 1

Fragments of U-V-W - or Va-W-, which are introduced by condensation in the connection type And must be obtained separately. Getting some of these substituents are described in the previously mentioned patent applications. Otherwise, pyrolidine Deputy may be attached to the aromatic ring through catalyzed by copper or palladium cross-combination, as described in scheme 2. Under certain circumstances, the transition metal is not necessary for catalysis of this reaction. Connection type F, where PG' oz achet a suitable protective group, will be converted to a compound of type G, where X' is CH or N. If W in the formula (I) represents thiazolyl, can be used the same chemistry.

Scheme 2

If V represents-O-CH2-Q-, isoxazolidine fragment obtained by cyclopentadiene. This cycloaddition can be implemented based on W-Vafragment in the connection type B, leading to connection type C, as described for scheme 1. Or the cycloaddition can be carried out separately as, for example, is presented in scheme 3. Cycloaddition based on the connection type N using (often commercially available aldehydes leads to the connection of the J. of Course, aldehyde fragment can be constructed based on W-Vaslice and can be constructed connection U-CCH, after giving cycloaddition other isoxazolidine fragment. The same principles can be used to obtain oxadiazolidine fragments with the use described in the literature methodologies.

Scheme 3

From aldehyde, labeled 3, and propargilovyh alcohol can also be obtained hydroxymethylimidazole (Scheme 4). Condensation with phenyl or heteroaryl derivative, where X" usually means-OH, -Br or-I, leads to the connection of the J.

the Hema 4

The ester group of compounds of type C or D can be subjected to cleavage with obtaining compounds of type K, as described in scheme 5. If there is a double bond, it may partially be migrated and receive a mixture of two isomeric carboxylic acids. This mixture is subjected to separation. Amide condensation for connection To leads for connection of type L. If you get the mixture of isomers with the double bond in the 3,4 - or 4,5-positions, the mixture is separated at this stage by using chromatographic methods.

Scheme 5

Amines used for such condensations with the formation of amides, must be obtained separately, as described specifically in the examples below.

The final design of the L-group, if necessary, causes the connection type M, as shown in scheme 6. The final removal of the protective group PG leads to the compound of formula (I).

Scheme 6

Enantiomerically pure compounds can be obtained by chromatographic separation of the corresponding racemate using a chiral solid media. Enantioselective synthesis of a number of systems are also known in the literature (Murthy, K. S. K., Rey, A. W., Tjepkema, M., Tetrahedron Lett., 2003, 44, 5355; Cossy, J., Mirguet, O., Pardo, Domingo G., Desmurs, J.-R., European J. Org. Chm., 2002, 21, 3543; Carroll, F. L, Consumer / Patient Information, S. P., Abraham, P., Navarro, H., Kuhar, M. J., Pollard, G. T., Howard, J. L., J. Med. Chem., 2004, 47, 6401; Meltzer, P. C, McPhee, M., Madras, B. K., Bioorg. Med. Chem. Lett, 2003, 13, 4133; Blough, B. E., Keverline, K. L, Nie, Z., Navarro, H., Kuhar, M. J., Carroll, F. I, J. Med. Chem., 2002, 45, 4029). It should also be noted that the separation of 3-tert-butyl ester 6-ethyl ester 9-methyl-7-oxo-3,9-diaza-bicyclo[3.3.1]nonan-3,6-dicarboxylic acid, possibly with the use of tartaric acid.

The following examples serve to further illustrate the present invention. However, they are not intended to limit in any way the scope of the invention.

Chemistry

Reduction(as used in this description)

Acacetyl
AcClacetylchloride
AcOHacetic acid
ADDPazodicarboxylic dipiperidide
Angangiotensin
aq.water
9-BBN9-borabicyclo[3,3,1]nonan
Boctert-butyloxycarbonyl
TCI is. boiling point
BSAbovine serum albumin
Bubutyl
BuLin-utility
CDIcarbonyldiimidazole
ca.about
cat.catalytic
conc.concentrated
Cycyclohexyl
dbadibenzylideneacetone
DIPEAdiisopropylethylamine
DMAP4-N,N-dimethylaminopyridine
DME1,2-dimethoxyethan
DMFN,N-dimethylformamide
DMSOthe sulfoxide
dppp1,3-bis(diphenylphosphino)propane
EDC-HClhydrochloride ethyl-N,N-dim is telemanipulated
EIAenzyme immunoassay
ELSDevaporative light scattering detector
equiv.equivalent(s)
ES+elektrorazpredelenie, positive ionization
ESIelectrospray ionization
Etethyl
EtOActhe ethyl acetate
EtOHethanol
PFflash chromatography
hhour(s)
HOBthydroxybenzotriazole
HPLChigh performance liquid chromatography
LC-MSliquid chromatography - mass spectrometry
MCPBAmeta-chloroperbenzoic acid
Memethyl
MeOHminminute(s)
MCmass spectrometry
NCSN-chlorosuccinimide
NMOoxide N-methylmorpholine
NMRnuclear magnetic resonance
OAcacetate
org.organic
ppair
p-TsOHpair-toluensulfonate acid
PGprotective group
Phphenyl
Q+positive ionization
K.T.room temperature
us.rich
Rast.solution
TBACchloride, Tetra-n-butylamine
TBAF fluoride, Tetra-n-butylamine
TBDMStert-butyl-dimethylsilane
TBMEtert-butyl methyl ether
TBTUtetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea
t-Butert-butyl
Tftrifloromethyl
TFAtriperoxonane acid
THFtetrahydrofuran
TLCthin-layer chromatography
tRretention time (LC-MS or HPLC), given in minutes
UVultraviolet
Visthe visible area
Xanthos4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Temperatures are indicated in degrees centigrade (aboutC). Unless otherwise stated, the reactions take place at room temperature.

Conditions for HPLC or LC-MS-(unless otherwise stated):

The analysis is Kie: column Bond 59 SB Aqua, 4,CH mm) from Agilent Technologies. Eluent: A: acetonitrile; B: H2O + 0.5% TFUCK. Gradient: 90% B → 5% B for 2 minutes. Flow: 1 ml/min Detection: UV-visible region + MS.

Preparative: column Bond SB Aqua, 20×500 mm) from Agilent Technologies. Eluent: A: acetonitrile; B: H2O + 0.05% ammonium hydroxide (25% aq.). Gradient: 80% B → 10% B for 6 minutes. Flow: 40 ml/min Detection: UV + MS or UV + ELSD.

Chiral analytical: a) column Regis Whelk, a 4.6×250 mm, 10 μm. Eluent A: EtOH + 0,05% Et3N. Eluent B: hexane. A flow of 1 ml/min

b) ChiralPak AD, a 4.6×250 mm, 5 μm. Eluent A: EtOH + 0,05% Et3N. Eluent B: hexane. A flow of 1 ml/min

c) ChiralCel OD, a 4.6×250 mm, 10 μm. Eluent A: EtOH + 0.1% Of Et3N. Eluent B: hexane. The flow of 0.8 ml/min

Chiral formulation: (a) column Regis Whelk 01, CH mm and a flow of 100 ml/min

b) ChiralPak AD 20×250 mm, flow 10 ml/min

c) ChiralCel OD, 20 μm, 50 mm × 250 mm, flow 100 ml/min

Experimental part

Bromo-2,3-dichlorobenzaldehyde

In a flame dried round bottom flask with a capacity of 250 ml, equipped with a magnet for stirring on a magnetic stirrer, in an atmosphere of N2added anhydrous THF (75 ml) and Diisopropylamine (3,74 ml of 26.6 mmol). The solution was cooled to 0°C and added dropwise with a syringe BuLi (11.8 ml, to 26.6 mmol, 2,25 M solution in hexano). The obtained yellow solution was stirred at 0°C for 30 minutes and was cooled to -78°C. a Solution of 1-bromo-3,4-dichlorobenzene is (5,00 g, to 22.1 mmol) in 10 ml THF was added via syringe and the resulting solution was stirred at -78°C for 1 hour. After this was added DMF (8,51 ml, 111 mmol) in one portion and the reaction mixture was stirred at -78°C for 2 hours, and then left to warm to room temperature over night. The mixture was suppressed aqueous saturated solution of NH4Cl (15 ml) and poured into a separating funnel with a capacity of 500 ml containing aqueous saturated solution of NH4Cl (250 ml). The mixture was extracted with Et2O (3×50 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude product using PF (hexane → 95:5 hexane/Et2O) gave specified in the header of the connection (of 4.57 g, 82% yield).1H NMR (CDCl3, 500 MHz) δ 10,44 (1H, s), 7,98 (1H, d, J=the 2.5 Hz), 7,87 (1H, d, J=2,5 Hz).

13C NMR (CDCl3, 125 MHz) δ 187,7, 137,7, 135,3, 135,0, 134,7, 130,5, 121,1.

5-Chloro-2-methylbenzaldehyde

In a flame dried round bottom flask with a capacity of 250 ml, equipped with a magnet for stirring on a magnetic stirrer, in an atmosphere of N2was added 2-bromo-4-chlorotoluene (10.0 ml, 75,0 mmol) in anhydrous THF (150 ml). The clear solution was cooled to -78°C and added dropwise BuLi (36,6 ml, and 82.4 mmol, 2,25 M solution in hexano) for 20 minutes. The obtained light-ora the orange region, the solution was stirred at -78°C for 1 hour and was added DMF (30 ml, 375 mmol) in one portion. The resulting mixture was left to warm to room temperature for 4 hours. The reaction was suppressed by addition of aqueous 1M HCl solution (20 ml) and stirred at room temperature overnight. The reaction mixture was poured into a separating funnel with a capacity of 500 ml containing aqueous 1M HCl solution (200 ml). The mixture was extracted with Et2O (3×100 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure, obtaining a yellow oil. Purification by distillation with a short reflux condenser under reduced pressure (~ 1 mm Hg) gave specified in the title compound as a pale yellow oil (7,99 g, 69%). BP.= 70-72°C at 1 mm Hg1H NMR (CDCl3, 500 MHz) δ 10,23 (1H, s), to 7.77 (1H, d, J=the 2.5 Hz), was 7.45 (1H, DD, J=to 8.0, 2.5 Hz), 7,22 (1H, d, J=8.0 Hz), 2,65 (3H, s).

5-Bromo-1-chloro-N-cyclopropylbenzene

In a flame dried round bottom flask with a capacity of 250 ml, equipped with a magnet for stirring on a magnetic stirrer, in an atmosphere of N2was added 5-bromo-2-chlorbenzoyl acid (10.0 g, 42,5 mmol) and DMF (3.9 ml, 51,0 mmol) in toluene (80 ml). The solution was cooled to 0°C was added thereto dropwise over 1 hour oxalicacid (4,4 ml of 51.0 mmol). The resulting mixture was stirred at 0°C for 2 hours and then the volatile components were removed. P is obtained the crude reaction mixture was dissolved in CH 2Cl2(100 ml) and cooled to 0°C in an ice bath. Was added dropwise within 1 hour cyclopropylamine (4,5 ml of 63.7 mmol) followed by addition of DIPEA (11.8 ml, 85,0 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was poured into a separating funnel with a capacity of 1 l containing aqueous 1M HCl solution (600 ml). The mixture was extracted with CH2Cl2(6×250 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The product was led from a mixture of hexane/CH2Cl2and was isolated by filtration, getting mentioned in the title compound (8,24 g, 71%).

N-(5-bromo-2-Chlorobenzyl)cyclopropylamine

A solution of 5-bromo-2-chloro-N-cyclopropylbenzene (12.0 g, 43,7 mmol) in THF (100 ml) were placed in a round bottom flask with a capacity of 250 ml, equipped with a magnet for stirring on a magnetic stirrer, in an atmosphere of N2. The solution was treated by adding dropwise BH3·Me2S (13.1 ml, 131 mmol)and the resulting suspension was stirred at room temperature for 1 hour. The mixture was heated at the boil under reflux for 1 hour, cooled to room temperature and slowly snuffed out by adding dropwise the aqueous 1M HCl solution (25 ml). The suspension is again boiled under reflux in t the value of 1 hour, was cooled to room temperature and was podslushivaet to pH = 10-11 aqueous 1M NaOH solution. The mixture was poured into a separating funnel with a capacity of 500 ml containing aqueous 1M NaOH solution (350 ml). The mixture was extracted with EtOAc (3×100 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The crude amine was used directly in the next stage.

A common way of restorative amination of the substituted benzaldehydes cyclopropylamino:

A solution of the substituted benzaldehyde (17.8 mmol, 1.0 equiv.), cyclopropylamine (3,13 ml of 44.5 mmol, 2.5 equiv.) and cyanoborohydride sodium (1,34 g, with 21.4 mmol, 1.2 equiv.) in MeOH (100 ml) was treated by adding dropwise an ice AcOH (of 3.06 ml, with 53.4 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 16 hours during the night. The reaction mixture was suppressed by adding dropwise the aqueous saturated solution of NaHCO3, and concentrated under reduced pressure to remove MeOH. Neojidanni the residue was poured into a 250 ml separating funnel containing aqueous saturated solution of NaHCO3(150 ml)and was extracted with EtOAc (3×50 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced giving the situation. Cleaning with PF gave benjaminov product.

A common way of introduction of the Boc-protective group in cyclopropylbenzene:

The solution cyclopropylbenzene (43,7 mmol, 1.0 equiv.) in the two-phase mixture of CH2Cl2(50 ml) and 1M aq. NaOH (50 ml) was treated with Boc2O (15.1 ml, 65,6 mmol, 1.5 equiv.). The mixture was intensively stirred at room temperature for 16 hours. The mixture was poured into a separating funnel with a capacity of 500 ml, containing H2O (300 ml)and was extracted with CH2Cl2(3×100 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with PF gave the BOC-protected amine.

A common way to Allilueva the BOC-protected cyclopropylbenzene:

In a flame dried round bottom flask or test tube Slinka in the atmosphere N2was added Pd[PCy3]2(of 0.05 equiv.), CsF (2.0 equiv.) and the corresponding arilbred (1.0 equiv.). If the source Vesela used areshared, instead of the Pd catalyst[PCy3]2used dimer (Pd[PtBu3]Br)2(of 0.025 equiv.). The flask was evacuated under reduced pressure (0.1 mm Hg) and was filled with N2(repeated 3 times). The obtained solid substance was dissolved in anhydrous is GF or dioxane (0.15 M solution) was added in three(n-butyl)allyellow (1.5 equiv.) and the resulting mixture was heated at the boil under reflux for 8-16 hours, up until TLC showed complete depletion of the starting materials. The reaction mixture was cooled to room temperature and filtered through a layer of silica gel on a sintered glass filter, washing Et2O. the Filtrate was concentrated and purified using the PC, receiving the relevant allylbenzene derived.

A common way of hydroporinae/oxidation of allylbenzene:

In a flame dried round bottom flask, equipped with a magnet for stirring on a magnetic stirrer, was added allylbenzenes (1.0 equiv.) and anhydrous THF (0,3 M solution). The solution was cooled to 0°C and added dropwise within 20 minutes BH3·Me2S (1.1 equiv.). The solution was stirred at 0°C for 1 hour, then left to warm to room temperature and stirred additionally for 2 hours. The solution was cooled to 0°C and aqueous 1M NaOH solution was added dropwise (CAUTION - EXOTHERMIC REACTION), followed by adding dropwise 30% aq. H2O2. The mixture was left to warm to room temperature and was stirred for 2 hours. The mixture was poured into a separating funnel containing H2O and was extracted with Et2O (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated the ri reduced pressure. Cleaning with PF gave the target product of alcohol.

A common way of oxidative breakdown/recovery allylbenzenes:

The solution allylbenzene (1.0 equiv.) in CH2Cl2(a 0.4 M solution) was cooled to -78°C and introduced into a solution of gaseous O3using pipes for gas distribution. Gaseous ozone was injected until then, until he trashdolls all the original substance, which was identified by TLC and the reaction mixture is kept slightly bluish color. The reaction mixture was stirred at -78°C for 20 minutes, then was added EtOH (0.5 M solution) and NaBH4(2.5 equiv.). The mixture was left to warm to room temperature overnight (16 hours). The reaction mixture was suppressed by adding dropwise the aqueous saturated solution of NH4Cl (5 ml), and poured into a separating funnel containing aqueous saturated solution of NH4Cl. The mixture was extracted with Et2O (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with PF gave the target alcohol.

The General method of esterification of aromatic primary alcohols idestam the stands:

The suspension of the primary alcohol (1.0 equiv.) in THF (0.25 M solution) was cooled to 0°C obrabatyvali NaH (60% in oil, 2.0 equiv.). The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 30 minutes. The suspension was re-cooled to 0°C and then added in one portion MeI (8,0 equiv.). The reaction mixture was stirred at 0°C for 30 minutes, at room temperature for 30 minutes and then heated at the boil under reflux for 4 hours until, until he trashdolls all starting material, as determined according to TLC. The cooled reaction mixture was suppressed by adding dropwise the aqueous saturated solution of NH4Cl, and poured into a separating funnel containing aqueous saturated solution of NH4Cl, and was extracted with EtOAc (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with PF gave a simple methyl ester.

A common method of removing the protective group of the BOC-protected cyclopropylbenzene:

To a solution of the BOC-protected cyclopropylbenzene (1.0 equiv.) in CH2Cl2(0.1 to 0.5 M solution) was added 4 M HCl in dioxane (5,0 equiv.). The resulting mixture was stirred at room temperature for 8-16 hours, until, while according to TLC there was no complete conversion of the educt. The reaction mixture is poured into a separating funnel, containing 1M aq. NaOH, and was extracted with CH2Cl2(3 times). Cleaning with PF gave the corresponding free amine.

2-(4-Bromo-phenoxy)ethanol

4-Bromophenol (100 g, of 0.58 mol) was dissolved in xylenes (220 ml). Added [1,3]dioxolane-2-on (of 53.7 g, 0.61 mol) and imidazole (592 mg, to 8.70 mmol). The mixture was heated at 140°C for 3 days. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. After drying of the residue in high vacuum has been specified in the title compound (130 g, quantitative yield). LC-MS: tR= 0,81 minutes.

2-(4-Bromo-phenoxy)ethyl ester methanesulfonic acid

2-(4-Bromo-phenoxy)ethanol (125 g, 0,576 mol) was dissolved in CH2Cl2(650 ml) and the solution was cooled to 0°C., Et3N (110 ml, 0,864 mol), and then methylchloride (67,1 ml, 0,864 mol) was bury such a rate that the temperature did not rise above about 10°C (about 60 minutes). The mixture was stirred at 0°C for 1 hour, then at room temperature overnight. The mixture was diluted with CH2Cl2and washed with saturated salt solution (2×). The aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header is the connection (174 g, quantitative yield)which was used without further purification. LC-MS: tR= 0,92 minutes.

1-[2-(4-Bromo-phenoxy)ethoxy]-2,6-dichloro-4-methyl-benzene

K2CO3(29.3 g, 212 mmol) was dissolved in water (162 ml). Was added 1-propanol (150 ml). Solution was added 2,6-dichloro-para-cresol (25 g, 141 mmol) in 1-propanol (150 ml). Was added 2-(4-bromo-phenoxy)ethyl ester methanesulfonic acid (41,6 g, 141 mmol). The mixture was stirred at 85°C for 6 hours. The heating oil bath was removed and added dropwise water (330 ml), when the temperature inside the flask reached 78°C. the Beige suspension was left to cool to room temperature. The mixture was filtered and the precipitate washed with water. After drying the precipitate in a high vacuum at 30°C for 48 hours has been specified in the title compound (43 g, 81 %). LC-MS: tR= 1.15 minutes.

2-(2,6-Dichloro-4-methyl-phenoxy)ethanol

In a three-neck flask, equipped with a meter of gas bubbles and the efficient cooling system, was heated at 160°C for 25 hours a mixture of 2,6-dichloro-p-cresol (20,0 g, 113 mmol), [1,3]dioxolane-2-it (9.95 g, 113 mmol) and imidazole (115 mg, 1.70 mmol). The mixture was left to cool to room temperature. Cleaning with PF (Et2O/heptane 1.1) gave specified in the title compound (18.7 g, 75%). LC-MS: tR= 0,88 minutes.

5-Bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)ATOC and]pyridine

A solution of 2-(2,6-dichloro-4-methyl-phenoxy)ethanol (18.6 g, 84 mmol) in THF (360 ml) was cooled to 0°C. was Added in portions NaH (55% in oil, 6.60 g, approximately 153 mmol) and the mixture was stirred at room temperature for 30 minutes. Was added dropwise a solution of 2,5-dibromopyridine (18.0 g, to 76.3 mmol) in THF (60 ml) and the mixture was heated at the boil under reflux for 90 minutes. The mixture was left to cool to room temperature and carefully added to ice. The solvents were partially removed under reduced pressure and the residue was diluted with EtOAc. This mixture was washed with aqueous saturated solution of NH4Cl. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 3:97) gave specified in the title compound (22.7 g, 79%). LC-MS: tR= 1,13 minutes; ES+: 378,08,

The reaction of 2-chloro-3,6-debtor-benzaldehyde

2-Chloro-3,6-debtor-benzaldehyde (25,0 g, 142 mmol) was dissolved in CH3CN (175 ml). To this solution was added NaHCO3(35,7 g, 424 mmol) and the mixture was intensively stirred for 5 minutes. Was added water (350 ml) and the mixture was stirred for 10 minutes. Added NH2OH·HCl (19.7 g, 283 mmol) and TBAC (1.97 g, was 7.08 mmol) and the reaction mixture was stirred at to the room temperature for 1 hour. Was added dropwise AcOH (20 ml) to pH 6-7. The mixture was extracted with Et2O (3×). The combined organic extracts were washed with saturated salt solution, dried over Na2SO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum has been specified in the header connection (25,0 g, 92%). LC-MS: tR= 0,93 minutes.

[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol

The solution of the oxime of 2-chloro-3,6-debtor-benzaldehyde (21,3 g, 111 mmol) in DMF (66,7 ml) was added dropwise to a solution of NCS (14.9 g, 111 mmol) and pyridine (1,78 ml) in DMF (222 ml). The mixture was stirred for 1 hour at room temperature and was added dropwise a solution of propargilovyh alcohol (4,99 g of 89.1 mmol) in DMF (71 ml). The reaction mixture was heated at 85°C and slowly added to the solution Et3N (15,5 ml, 111 mmol) in DMF (89,3 ml). The reaction mixture was stirred at 85°C for 60 minutes and left to cool to room temperature. The mixture was diluted with water (533 ml) and was extracted with EtOAc (2×). The combined organic extracts were washed with water and saturated salt solution, dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 40:60) gave specified in the title compound (17.0 g, 78%). LC-MS: tR= 0,84 minutes; ES+: 287,12.

1-Bromo-5-chloro-pyridine-4-carbaldehyde

To peremeshivaemogo solution Diisopropylamine (20,9 ml, 148 mmol) in dry THF (350 ml) at -5°C was added dropwise BuLi (1,6M in hexane, to 89.5 ml, 143 mmol) and the resulting solution was stirred for 30 minutes at -5°C. the Solution was cooled to -70°C was added dropwise a solution of 2-bromo-5-chloropyridine (25,0 g, 130 mmol) in THF (100 ml) at -70°C for 15 minutes so that the internal temperature did not exceed -65°C. the Mixture was stirred at -70°C in within 30 minutes. DMF (10.5 ml, 136 mmol) was added dropwise within 20 minutes at such a rate that the internal temperature did not exceed -70°C. the Orange mixture was stirred at -70°C for 40 minutes. The mixture was left to warm to room temperature and was poured into a mixture of water (200 ml) and aqueous 1M NaOH solution (50 ml). The mixture was extracted with EtOAc (2×) and the combined organic extracts were back washed aqueous 1M NaOH solution (2×). The organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 1:8 → 1:6 → 1:4 → 1:2 → 1:1) gave specified in the header connection (21,6 g, 72 %). LC-MS: tR= 0,74 minutes; ES+: 295,01.

2-Bromo-5-chloro-4-dimethoxymethyl-pyridine

To a solution of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43,9 g, 199 mmol) in MeOH (800 ml) was sequentially added at room temperature triethylorthoformate (65,3 ml, 597 mmol) and p-TsOH (1.90 g, 10.0 mmol). This reaction mixture is then n is gravely at boiling under reflux for 3 hours. The mixture was left to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2and the mixture is washed with aqueous 10% solution of K2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header of the connection (of 51.7 g, 97 %)which was used without further purification. LC-MS: tR= 0,92 minutes; ES+: 309,06.

5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)pyridine

To a suspension of Mg (911 mg, 37.5 mmol) and iodine (one crystal) in dry THF (30 ml) was added dropwise to 5% of the total number of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). The mixture was heated at the boil under reflux using a hit-Ghana prior to the formation of the Grignard reagent. The remainder of the 1-bromo-3-methoxypropane was added slowly as flow atterminal reaction. After the addition, the reaction mixture was stirred at the boil under reflux for 20 minutes and left to cool to room temperature. The solution of Grignard reagent (1M in THF, with 23.5 ml, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9,38 mmol) and Ni(dppp)Cl2(495 mg, 0,938 mmol) in THF (50 ml) at 0°C. the Reaction mixture was stirred at room temperature for 30 minutes and then heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and was dissolved in EtOAc. This mixture was washed with aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → EtOAc/heptane 1:1) gave specified in the title compound (1.51 g, 62%). LC-MS: tR= 0,80 min; ES+: 260,15.

5-Chloro-2-(3-methoxy-propyl)pyridine-4-carbaldehyde

5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)pyridine (25,5 g of 98.2 mmol) was dissolved in 1M aqueous HCl solution (500 ml) and the mixture was heated at 80°C for 2 hours. The mixture was left to cool to room temperature and was added EtOAc. The mixture was cooled to 0°C and podslushivaet aq. 2,5M NaOH to pH 10. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (98,1 mmol, 99%)which was used without further purification. LC-MS: tR= 0,62 minutes; ES+: 246,12.

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-Amin

A mixture of 5-chloro-2-(3-methoxy-propyl)pyridine-4-carbaldehyde (21,0 g of 98.2 mmol) and cyclopropylamine (13,8 ml, 196 mmol) in MeOH (450 ml) was stirred at room temperature overnight. NaBH4(4.83 g, 128 mmol) was added at 0°C, and the mixture is displaced is ivali at room temperature over night. Added ice and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and this solution washed with aqueous 1M NaOH solution. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF ( EtOAc/heptane 1:5 → 1:4 → 1:3 → 1:1 → 3:1 → EtOAc) gave specified in the title compound (11.8 g) and [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethylene]cyclopropyl-amine (10.7 g). Given the unreacted Imin was dissolved in MeOH (20 ml) and the solution was cooled to 0°C. was Added NaBH4(3,20 g, and 84.6 mmol) and the mixture was stirred at room temperature overnight. Again, were added NaBH4(3,20 g, and 84.6 mmol) and the mixture was stirred for 3 days. To the reaction mixture were added ice and the mixture was concentrated under reduced pressure. The crude product was dissolved in EtOAc and the resulting mixture was washed with aqueous 1M NaOH solution. The aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:3 → 1:2 → 1:1 → EtOAc) gave specified in the header connection (9,40 g). Fraction specified in the title compounds were mixed together (21.2 g, 85%). LC-MS: tR= 0.55 min; ES+: 296,16.

b> 2-[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine

Et3N (11.3 ml, 79.2 mmol) and PdCl2(PPh3)2(936 mg, 1,31 mmol) was added to a solution of compound J1 (10.6 g of 26.4 mmol) in dioxane (60 ml) and the resulting mixture was stirred at 100°C during the night. The mixture was left to cool to room temperature and diluted with EtOAc. The resulting mixture was washed with water (2×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (9.28 are g, 78%)which was used without further purification.

(5-Bromo-2-chloro-benzyloxy)-tert-butyl-dimethylsilane

TBDMS-Cl (10.6 g, from 66.7 mmol) was added to a solution of (5-bromo-2-chloro-phenyl)methanol (12.8 g, at 55.6 mmol) and imidazole (9,42 g, 138 mmol) in DMF (190 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C was added aqueous saturated solution of NH4Cl. The mixture was extracted with heptane (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → EtOAc/heptane 1:49) gave specified in the title compound (18.0 g, 96%). LC-MS: tR= 1,22 minutes.

3-(tert-Butyl-dimetilglioximatul)-4-chloro-b is soldered

BuLi (1,6M in hexane, 46.6 ml, 74,6 mmol) was added to a solution of (5-bromo-2-chloro-benzyloxy)-tert-butyl-dimethylsilane (16.7 g, 49.7 mmol) in THF (500 ml). The mixture was stirred for 30 minutes at -78°C and DMF (19.2 ml, 249 mmol) was added in such a rate that the temperature did not rise above -70°C. the Mixture was stirred for 30 minutes at -78°C and left to warm to room temperature. The mixture was poured into aqueous saturated solution of NH4Cl. The resulting mixture was extracted with EtOAc several times. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4) gave specified in the title compound (11.2 g, 79%). LC-MS: tR= 1.15 minutes.

The oxime of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde

3-(tert-Butyl-dimetilglioximatul)-4-chloro-benzaldehyde (12.7 g and 44.6 mmol) was dissolved in CH3CN (53 ml). To this solution was added NaHCO3(11.2 g, 134 mmol) and the mixture was intensively stirred for 5 minutes. Was added water (96 ml) and the mixture was stirred for 10 minutes. Was added dropwise NH2OH·HCl (6.20 g, of 89.2 mmol) followed by addition of TBAC (622 mg, 2,24 mmol). The mixture was stirred at room temperature for 1 hour and added dropwise AcOH (4,00 ml) to pH 6-7. The mixture was diluted with water (100 ml) and this mixture extragere what if Et 2O (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (15.1 g, 98%)which was used without further purification. LC-MS: tR= 1.09 min; ES+: 341,13.

3-(tert-Butyl-dimetilglioximatul)-4-chloro-benzylamine

LiAlH4(4.11 g, 108 mmol) was added in portions to a solution of oxime of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (13,0 g, a 43.4 mmol) in Et2O (433 ml). The mixture was stirred for 1 hour at room temperature. To the mixture was carefully added aqueous saturated solution of tartrate of potassium-sodium (400 ml). The mixture was stirred for 3 hours and was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum has been specified in the crude title compound (12.4 g, quantitative yield)which was used without further purification. LC-MS: tR= 0,84 minutes; ES+: 327,37.

N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]ndimethylacetamide

AcCl (0,547 ml of 7.70 mmol) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzylamine (2.00 g, 7,00 mmol) and DIPEA (4,80 ml of 28.0 mmol) in CH2Cl2(70 ml) and 0°C. The mixture was stirred for 1 hour, while it was heated to room temperature. Added CH2Cl2(30 ml) and the mixture washed with aqueous saturated solution of NH4Cl (2×), aqueous 1M NaOH solution (1×) and saturated salt solution (1x). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 60:40) gave specified in the title compound (2.10 g, 91%). LC-MS: tR= 1,07 minutes; ES+: 369,19.

N-(4-Chloro-3-hydroxymethyl-benzyl)ndimethylacetamide

TBAF (1M in THF, 12.0 ml of 12.0 mmol) was added to a solution of N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]ndimethylacetamide (2,05 g, 6,00 mmol) in THF (60 ml) at 0°C. the Mixture was stirred for 2 hours, while it was heated to room temperature. Added EtOAc (100 ml) and the mixture washed with aqueous saturated solution of NH4Cl (1×) and water (4×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 90:10) gave specified in the title compound (750 mg, 59%). LC-MS: tR= 0,63 minutes; ES+: 237,09.

N-(4-Chloro-3-formyl-benzyl)ndimethylacetamide

NMO (1,15 g, compared to 8.26 mmol) was added to a solution of N-(4-chloro-3-hydroxymethyl-benzyl)ndimethylacetamide (588 mg, of 2.75 mmol) in CH3CN (27 ml). The solution p is remedial for 30 minutes at room temperature and was added perruthenate of tetrapropylammonium (97 mg, 0.28 mmol). The mixture was stirred for 1 hour at room temperature and filtered through celite. The precipitate was washed CH3CN. The filtrate was evaporated under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (382 mg, 66%). LC-MS: tR= 0,71 minutes; ES+: 253,07.

N-(4-Chloro-3-cyclopropylamino-benzyl)ndimethylacetamide

A mixture of N-(4-chloro-3-formyl-benzyl)ndimethylacetamide (382 mg, is 1.81 mmol) and cyclopropylamine (0,194 ml, a 2.71 mmol) in MeOH (18 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(102 mg, a 2.71 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. Added EtOAc (50 ml) and the resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (371 mg, 81%). LC-MS: tR= 0,53 minutes; ES+: 253,11.

N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-3,3,3-triptocaine

TBTU (3,37 g, 10.5 mmol) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl) - Rev. in (2.00 g, 7,00 mmol), DIPEA (4,80 ml of 28.0 mmol) and 3,3,3-triptocaine acid (0,927 ml, 10.5 mmol) in CH2Cl2(70 ml). The mixture was stirred at room temperature for 1 hour. Added CH2Cl2(30 ml) and the mixture washed with aqueous saturated solution of NH4Cl (2×), aqueous 1M NaOH solution (1×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 40:60) gave specified in the title compound (1.80 g, 65%). LC-MS: tR= 1,10 minutes; ES+: 396,15.

N-(4-Chloro-3-hydroxymethyl-benzyl)-3,3,3-triptocaine

TBAF (1M in THF, 9,10 ml, 9,10 mmol) was added to a solution of N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-3,3,3-triptocaine (1.80 g, 4,55 mmol) in THF (45 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to room temperature. Added EtOAc (100 ml) and the mixture washed with aqueous saturated solution of NH4Cl (3×) and water (4×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 70:30) gave specified in the title compound (835 mg, 65%). LC-MS: tR= 0,76 minutes; ES+: 323,02.

N-(4-Chloro-3-formyl-benzyl)-3,3,3-triptocaine

MnO2(1.44 g, 14 mmol) was added to a solution of N-(4-chloro-3-hydroxymethyl-benzyl)-3,3,3-triptocaine (841 mg, to 2.99 mmol) in CH3CN (60 ml). The mixture was stirred at room temperature for 3 hours. Again added MnO2(1.44 g, 14.9 mmol) and the mixture was stirred for 90 minutes. The mixture was filtered through celite and the precipitate washed CH3CN and CH2Cl2. The solvents were removed under reduced pressure and the residue was dried in high vacuum, receiving untreated specified in the title compound (840 mg, quantitative yield)which was used without further purification. LC-MS: tR= 0,84 minutes; ES+: 341,21.

N-(4-Chloro-3-cyclopropylamino-benzyl)-3,3,3-triptocaine

A mixture of N-(4-chloro-3-formyl-benzyl)-3,3,3-triptocaine (840 mg, 3.00 mmol) and cyclopropylamine (0,320 ml, 4,51 mmol) in MeOH (30 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature. Added portions NaBH4(170 mg, 4,51 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. The residue was diluted with EtOAc and the resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/MeOH 90:10) gave specified in the header connection (929 mg, 96%). LC-MS: tR= 0,benuty; ES+: 321,05.

tert-Butyl ether 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]cyclopropylamino acid

A mixture of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (1.73 g, the 6.06 mmol) and cyclopropylamine (of 0.64 ml, 9.1 mmol) in MeOH (60 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(344 mg, 9.09 mmol). The mixture was stirred for 1 hour and was added water (20 ml). The solvents were partially removed under reduced pressure. The resulting aqueous suspension was diluted with water (50 ml) and was extracted with EtOAc. The organic extracts washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]cyclopropylamine (1.54 g). This crude substance was dissolved in CH2Cl2(60 ml). Added DIPEA (3.1 ml, 18 mmol), and then Boc2O (1.98 g, 9.09 mmol). The mixture was stirred at room temperature for 2 hours. Added CH2Cl2(40 ml) and the mixture is washed with aqueous 1M HCl solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and dissolve the spruce was removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 5:95) gave specified in the title compound (1.54 g, 78%). LC-MS: tR= 1,26 minutes; ES+: 426,14.

tert-Butyl ester (4-[chloro-3-hydroxymethyl-benzyl)cyclopropylamino acid

Aqueous 1M NaOH solution (16 ml) was added to a solution of tert-butyl methyl ether [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]cyclopropylamino acid (700 mg, of 1.64 mmol) in MeOH (32 ml). The mixture was heated at the boil under reflux for 2 hours and left to cool to room temperature. The solvents were partially removed under reduced pressure and the resulting aqueous layer was diluted with water (100 ml). The mixture was extracted with Et2O (3×). The combined organic layers were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 40:60) gave specified in the title compound (550 mg, quantitative yield). LC-MS: tR= 0,98 minutes; ES+: 312,04.

tert-Butyl ester (4-chloro-3-formyl-benzyl)cyclopropylamino acid

MnO2(815 mg, 8,44 mmol) was added to a solution of tert-butyl methyl ether (4-chloro-3-hydroxymethyl-benzyl)cyclopropylamino acid (526 mg, was 1.69 mmol) in CH3CN (34 ml). The mixture was stirred at room temperature for 3 hours, filter the if through celite and washed with CH 3CN and CH2Cl2. Evaporation of the solvents under reduced pressure gave the crude specified in the title compound (563 mg, quantitative yield)which was used without further purification. LC-MS: tR= 1.05 min; ES+: 310,04.

tert-Butyl ester (4-chloro-3-cyclopropylamino-benzyl)cyclopropylamino acid

A mixture of tert-butyl methyl ether (4-chloro-3-formyl-benzyl)cyclopropylamino acid (563 mg, 1.82 mmol) and cyclopropylamine (of € 0.195 ml, 2,73 mmol) in MeOH (18 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(103 mg, 2,73 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. The resulting oil was diluted with EtOAc (100 ml) and the resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (343 mg, 54%). LC-MS: tR= 0,78 minutes; ES+: 351,39.

tert-Butyl[2-chloro-5-(2-nitro-vinyl)benzyloxy]dimethylsilane

A mixture of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (14.0 g, 49,1 mmol) and acetate of ammo the Oia (3,79 g, 49,1 mmol) in nitromethane (8,19 ml, 152 mmol) and AcOH (39 ml) was heated at the boil under reflux for 3 hours. The mixture was left to cool to room temperature and poured into water. The resulting mixture was extracted with EtOAc several times. The combined organic extracts were washed with water and several times aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The residue was dried in high vacuum overnight and dissolved in DMF (217 ml). The solution was cooled to 0°C was added imidazole (at 8.36 g, 123 mmol) and TBDMS-Cl (8,84 g, 58.6 mmol). The mixture was stirred for 2 hours at 0°C and was poured into aqueous saturated solution of NH4Cl. The resulting mixture was extracted several times EtOAc. The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 2:8) gave specified in the header of the connection (of 9.50 g, 59%). LC-MS: tR= 1,18 minutes.

2-[3-(tert-butyl-dimetilglioximatul)-4-chloro-phenyl]ethylamine

LiAlH4(1,09 g, 28.7 mmol) was added to a solution of tert-butyl[2-chloro-5-(2-nitro-vinyl)benzyloxy]dimethylsilane (3,95 g, 11.5 mmol) in Et2O (115 ml). The mixture was stirred for 1 HR at room temperature was added aqueous saturated solution of tartrate of potassium-sodium. The mixture was stirred for 1 hour and the layers were separated. The aqueous layer was extracted several times Et2O. the combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (3,20 g, 93%)which was used without further purification. LC-MS: tRor = 0.90 min; ES+: 341,18.

N-{2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}ndimethylacetamide

AcCl (0,063 ml, 0.88 mmol) was added to a solution of 2-[3-(tert-butyl-dimetilglioximatul)-4-chloro-phenyl] - ethylamine (252 mg, 0,840 mmol) and DIPEA (0,575 ml, to 3.36 mmol) in CH2Cl2(8,4 ml). The mixture was stirred at room temperature for 30 minutes and was added aqueous saturated solution of NH4Cl. The layers were separated and the organic layer washed with 1M aqueous NaOH solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 19:1) gave specified in the title compound (190 mg, 66%). LC-MS: tR= 1.09 min; ES+: 342,19.

N-[2-(4-Chloro-3-hydroxymethyl-phenyl)ethyl]ndimethylacetamide

TBAF (1M in THF, of 1.12 ml, 1.12 mmol) was added to a solution of N-{2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}ndimethylacetamide (190 mg, 0,555 mmol) in THF (7,10 ml) at 0°C. the Mixture peremeshivayu for 1 hour, while it was heated to room temperature. Was added aqueous saturated solution of NH4Cl and the mixture was extracted with EtOAc (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 19:1) gave specified in the title compound (100 mg, 79%). LC-MS: tR= 0.67 min; ES+: 284,11.

N-[2-(4-Chloro-3-formyl-phenyl)ethyl]ndimethylacetamide

NMO (184 mg, of 1.32 mmol) was added to a solution of N-[2-(4-chloro-3-hydroxymethyl-phenyl)ethyl]ndimethylacetamide (100 mg, 0,439 mmol) in CH2Cl2(which 9.22 ml). The mixture was stirred for 30 minutes and added perruthenate of tetrapropylammonium (15,5 mg, 0,044 mmol). The mixture was stirred for 1 hour at room temperature and filtered through celite. The filtrate was evaporated under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 49:1) gave specified in the title compound (50 mg, 50%). LC-MS: tR= 0.75 min; ES+: 267,10.

N-[2-(4-Chloro-3-cyclopropylamino-phenyl)ethyl]ndimethylacetamide

A mixture of N-[2-(4-chloro-3-formyl-phenyl)ethyl]ndimethylacetamide (50,1 mg, 0,222 mmol), Et3N (0,046 ml of 0.332 mmol) and cyclopropylamine (0,023 ml of 0.332 mmol) in MeOH (0,50 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(1.0 mg, 0,554 mmol). The mixture was stirred for 1 hour and was added aqueous saturated solution of NaHCO3. The mixture was extracted with EtOAc several times and the combined organic extracts were washed with a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (35 mg, 59%). LC-MS: tR= 0,59 minutes; ES+: 267,17.

tert-Butyl(2-chloro-5-vinyl-benzyloxy)dimethylsilane

Pd(PPh3)4(173 mg, 0,149 mmol) was added to a solution of (5-bromo-2-chloro-benzyloxy)-tert-butyl-dimethylsilane (1,00 g, 2,98 mmol) in DME (30 ml). The mixture was stirred at room temperature for 20 minutes and added K2CO3(411 mg, 2,98 mmol), water (10 ml) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan (of 0.53 ml, 2,98 mmol). The mixture was quickly heated to boiling under reflux and stirred at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and diluted with Et2O (100 ml). The mixture was washed with water, and the aqueous layer was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 5:95) gave specified in the title is information connection (822 mg, 98%). LC-MS: tR= 1,22 minutes.

2-[3-(tert-butyl-dimetilglioximatul)-4-chloro-phenyl]ethanol

9-BBN (0,5M in THF, 34,0 ml of 17.0 mmol) was added dropwise during 30 minutes to a solution of tert-butyl(2-chloro-5-vinyl-benzyloxy)dimethylsilane (800 mg, and 2.83 mmol) in THF (28 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 4 hours at room temperature. The mixture was cooled again to 0°C and added dropwise aqueous 1M NaOH solution (39,0 ml) and H2O2(33%, of 9.80 ml, 113 mmol). The mixture was stirred for 2 hours, while it was heated to room temperature, and cooled to 0°C. was Carefully added aqueous saturated solution of Na2S2O3(100 ml) and this mixture was carefully left to warm to room temperature over night. The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc (3×). The combined organic extracts were washed with a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 40:60) gave specified in the title compound (677 mg, 80%). LC-MS: tR= 1,10 minutes; ES+: 301,08.

2-[3-(tert-Butyl-dimetilglioximatul)-4-chlorophenyl]ethyl ester methanesulfonic acid

To a solution of 2-[3-(tert-butyl-dimethylsilane imethyl)-4-chloro-phenyl]ethanol (2.00 g, of 6.65 mmol) in CH2Cl2(66 ml) at 0°C was added dropwise Et3N (of 1.02 ml, 7,31 mmol) and methanesulfonamide (or 0.57 ml, 7,3 mmol). The reaction mixture was stirred at 0°C for 1 hour and was diluted in CH2Cl2(40 ml). The resulting mixture was washed with aqueous saturated solution of NH4Cl (2×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound (2.55 g, quantitative yield)which was used without further purification. LC-MS: tR= 1,13 minutes; ES+: 379,29.

{2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}cyclopropylamine

Cyclopropylamine (1,14 ml, 16.3 mmol) was added to a solution of 2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl ester methanesulfonic acid (1,76 g and 4.65 mmol) in EtOH (46 ml). The mixture was heated at the boil under reflux for 2 hours and again added cyclopropylamine (or 0.57 ml, 8.2 mmol). The mixture was heated at the boil under reflux during the night and left to cool to room temperature. The solvents were removed under reduced pressure and the residue was purified using the PF (EtOAc/heptane 50:50 → 7M NH3/MeOH), getting mentioned in the title compound (865 mg, 68%). LC-MS: tR= 0,92 minutes; ES+: 340,39.

tert-Butyl ether {2-[3-(tert-butyl-dimethylsilane oxymethyl)-4-chlorophenyl]ethyl}cyclopropylamino acid

DIPEA (2,61 ml, the ceiling of 5.60 mmol) and Boc2O (1.22 g, the ceiling of 5.60 mmol) was added to a solution of {2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}cyclopropylamine (1.73 g, 5,09 mmol) in CH2Cl2(50 ml). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with CH2Cl2(50 ml), washed with aqueous saturated solution of NaHCO3, aqueous saturated solution of NH4Cl and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 10:90) gave specified in the title compound (2.14 g, 96%). LC-MS: tR= 1,26 minutes.

tert-Butyl ether [2-(4-chloro-3-hydroxymethyl-phenyl)ethyl]cyclopropyl-carbamino acid

To a suspension of tert-butyl methyl ether {2-[3-(tert-butyl-dimethyl-silyloxy)-4-chlorophenyl]ethyl}cyclopropyl-carbamino acid (2.10 g, 4.77 mmol) in MeOH (96 ml) was added aqueous 1M NaOH solution (48 ml). The mixture was heated at the boil under reflux for 90 minutes. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The resulting aqueous mixture was diluted with water (100 ml) and was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed when below the nom pressure. Purification of the crude product using PF (EtOAc/heptane 40:60) gave specified in the header connection (1,34 g, 86%). LC-MS: tR= 0,98 minutes; ES+: 326,30.

tert-Butyl ether [2-(4-Chloro-3-formyl-phenyl)ethyl]cyclopropyl-carbamino acid

MnO2(1.97 g, of 20.4 mmol) was added to a solution of tert-butyl methyl ether [2-(4-chloro-3-hydroxymethyl-phenyl)ethyl]cyclopropylamino acid (1,33 g, 4,08 mmol) in CH3CN (41 ml). The mixture was stirred over night at room temperature. The mixture was filtered through celite and washed with CH3CN and CH2Cl2. Evaporation of the filtrate under reduced pressure gave the crude specified in the header connection (1,32 g, quantitative yield)which was used without further purification. LC-MS: tR= 1.05 minutes.

tert-Butyl ether [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]cyclopropyl-carbamino acid

A mixture of tert-butyl methyl ether [2-(4-chloro-3-formyl-phenyl)ethyl]cyclopropyl-carbamino acid (1,32 g, 4,08 mmol) and cyclopropylamine (0,438 ml, 6.26 mmol) in MeOH (41 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(232 mg, 6,14 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. Added EtOAc (100 ml) and the mixture was washed water of NASA the military solution of NaHCO 3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/MeOH 95:5) gave specified in the header connection (883 mg, 59%). LC-MS: tR= 0,82 minutes; ES+: 365,38.

tert-Butyl ester of [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbamino acid

To a solution of [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (7,79 g of 30.6 mmol) and DIPEA (13.1 ml of 76.5 mmol) in CH2Cl2(270 ml) was added Boc2O (10.2 g, at 45.9 mmol). The mixture was stirred at room temperature for 1 hour and was cooled to 0°C. the Mixture was neutralized to pH 6 aqueous 1M HCl with efficient stirring and the layers were separated. The aqueous layer was extracted with CH2Cl2(2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:3 → 1:2) gave specified in the header connection (7,83 g, 72%). LC-MS: tR= 0.97 min; ES+: 355,09.

tert-Butyl ester of [5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbamino acid

MCPBA (70%, with 8.33 g, 33.8 mmol) was added to a solution of tert-butyl ester [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbamino acid (7,g, 30.7 mmol) in CH2Cl2(210 ml) and the mixture was stirred for 2 hours at room temperature. The mixture is washed with aqueous 1M NaOH solution and saturated salt solution. The combined aqueous layers was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the header connection (compared to 8.26 g, 72%)which was used without further purification. LC-MS: tR= 0,94 minutes; ES+: 371,14.

[5-Chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine

HCl (4M in dioxane, 83 ml) was added to a solution of tert-butyl ester [5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbamino acid (compared to 8.26 g of 22.3 mmol) in CH2Cl2(83 ml) at 0°C. the Mixture was stirred for 45 minutes at 0°C and for 3 hours at room temperature. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2. The mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the header connection (5,71 g, 95%). LC-MS: tR= 0,46 minutes; ES+: 271,42.

tert-Butyl ether [3-(tert-butyl-dimetilglioximatul)-4-chloro-b is nzyl]-(2-fluoro-ethyl) - carbamino acid

A mixture of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (1.50 g, at 5.27 mmol), DIPEA (1.80 ml, 10.5 mmol) and hydrochloride of 2-foretelling (873 mg, of 7.90 mmol) in MeOH (53 ml) was heated at boiling under reflux for 4 hours. The reaction mixture was left to cool to room temperature and added portions NaBH4(300 mg, to $ 7.91 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. Added EtOAc (100 ml) and the mixture washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-(2-foradil)amine. This crude product was dissolved in CH2Cl2(70 ml). Added DIPEA (2,70 ml, 15.8 mmol), and then Boc2O (1.70 g, to $ 7.91 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2(50 ml) and washed with aqueous 1M HCl solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 10:90) gave specified in the title compound (1.92 g, 85%). LC-MS: tR= 1,22 minutes; ES+: 417,17.

tert-is Hotelowy ether (4-chloro-3-hydroxymethyl-benzyl)-(2-foradil)carbamino acid

TBAF (1M in THF, 8,84 ml, 8,84 mmol) was added to a solution of tert-butyl methyl ether [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-(2-foradil)carbamino acid (1,91 g, was 4.42 mmol) in THF (44,2 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to room temperature. Added EtOAc (100 ml) and the resulting mixture was washed with aqueous saturated solution of NH4Cl (2×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 30:70) gave specified in the header connection (901 mg, 64%). LC-MS: tR= 0,64 minutes; ES+: 318,07.

tert-Butyl ester (4-chloro-3-formyl-benzyl)-(2-foradil)carbamino acid

MnO2(1.22 g, 12.6 mmol) was added to a solution of tert-butyl methyl ether (4-chloro-3-hydroxymethyl-benzyl)-(2-foradil)carbamino acid (801 mg, 2,52 mmol) in CH3CN (50 ml). The mixture was stirred at room temperature for 4.5 hours and was again added MnO2(1.22 g, 12.6 mmol). The mixture was stirred for 1 hour and filtered through celite. The precipitate was washed CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (800 mg, quantitative yield), which use the Wali without additional purification. LC-MS: tR= 1,01 minutes.

tert-Butyl ester (4-chloro-3-cyclopropylamino-benzyl)-(2-foradil)carbamino acid

A mixture of tert-butyl methyl ether (4-chloro-3-formyl-benzyl)-(2-foradil)carbamino acid (850 mg, 2,69 mmol) and cyclopropylamine (0,290 ml of 4.05 mmol) in MeOH (27 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(153 mg, 4.40 mmol). The mixture was stirred for 1 hour. The solvents were removed under reduced pressure and added EtOAc. The resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (845 mg, 88%). LC-MS: tR= 0,76 minutes; ES+: 357,19.

{3-[(tert-Butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}acetic acid

Concentrated H2SO4(98%, 5,80 ml) was carefully added to the suspension CrO3(6,70 g, 67,0 mmol) in water (12.5 ml). Water was slowly added to a total volume of 22.5 ml, at this stage, the mixture was a clear solution. This solution was added dropwise to a solution of tert-butyl methyl ether [2-chloro-5-(2-hydroxy-ethyl)Ben is Il]cyclopropyl-carbamino acid (13,0 g, and 39.9 mmol) in acetone (140 ml) at 0°C. After finishing the addition the mixture was stirred at 0°C for 30 minutes. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc and the resulting mixture was washed with aqueous 1M HCl solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (12.2 g, 90%)which was used without further purification. LC-MS: tR= 0.95 min; ES+: 325,35.

tert-Butyl ether (2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbamino acid

To a solution of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}acetic acid (4,30 g, 12.6 mmol) in CH2Cl2(130 ml) was added 1-chloro-N,N-2-trimethylpsoralen (1,87 ml of 15.2 mmol) and the mixture was stirred for 60 minutes. Solution was added cyclopropylamine (3,62 ml, and 50.6 mmol) in CH2Cl2(50 ml) and the mixture was stirred for 60 minutes. Added CH2Cl2and the mixture was washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3) gave specified in the header connection (3,14 g, 65%). LC-MS: tR= 0.97 min; ES+: 323,29.

2-(4-Chlor-cyclopropylmethyl-phenyl)-N-cyclopropyl-ndimethylacetamide

HCl (4M in dioxane, 31 ml) was added to a solution of tert-butyl methyl ether (2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbamino acid (3,14 g, 8,29 mmol) in CH2Cl2(31 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C and carefully neutralized aqueous 1M NaOH solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the header connection (2,11 g, 91%)which was used without further purification. LC-MS: tR= 0,59 minutes; ES+: 279,32.

tert-Butyl ether (2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbamino acid

To a solution of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}acetic acid (4,30 g, 12.6 mmol) in CH2Cl2(130 ml) was added 1-chloro-N,N-2-trimethylpsoralen (1,87 ml of 15.2 mmol) and the mixture was stirred for 60 minutes. Added methylamine (2M in THF, 25,0 ml, 50.0 mmol) and the mixture was stirred over night. Was added CH2Cl2and the mixture was washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3) gave specified in the header connection (2,01 g, 45%). LC-MS: tsub> R= 0.95 min; ES+: 325,30.

2-(4-Chloro-3-cyclopropylamino-phenyl)-N-methyl-ndimethylacetamide

HCl (4M in dioxane, 20 ml) was added to a solution of tert-butyl methyl ether (2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbamino acid (2,01 g, 5,97 mmol) in CH2Cl2(20 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C and carefully neutralized aqueous 1M NaOH solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound (1.42 g, 99%)which was used without further purification. LC-MS: tR= 0.54 min; ES+: 294,33.

tert-Butyl ether (2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbamino acid

To a solution of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}acetic acid (4,30 g, 12.6 mmol) in CH2Cl2(130 ml) was added 1-chloro-N,N-2-trimethylpsoralen (1,87 ml of 15.2 mmol) and the mixture was stirred for 60 minutes. Added ethylamine (2M in THF, 25,0 ml, 50.0 mmol) and the mixture was stirred over night. Was added CH2Cl2and the mixture was washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product with what omashu PF (EtOAc/heptane 7:3) gave specified in the header connection (2,94 g, 63%). LC-MS: tR= 0.97 min; ES+: 311,28.

2-(4-Chloro-3-cyclopropylamino-phenyl)-N-ethyl-ndimethylacetamide

HCl (4M in dioxane, 29 ml) was added to a solution of tert-butyl methyl ether (2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbamino acid (2,94 g, 8,01 mmol) in CH2Cl2(29 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C and carefully neutralized aqueous 1M NaOH solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound (1.90 g, 89%)which was used without further purification. LC-MS: tR= 0,58 minutes; ES+: 308,03.

N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]propionamide

Chloride propionyl (2,02 ml of 23.1 mmol) and DIPEA (14.4 ml, 84,0 ml) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzylamine (6,00 g of 20.9 mmol) in CH2Cl2(195 ml). The mixture was stirred for 15 minutes at room temperature and was additionally added CH2Cl2. The mixture is washed with aqueous saturated solution of NH4Cl (2×), aqueous 1M NaOH solution (1×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Cleaning neozhidannostyu using PF (EtOAc/heptane 1:9 → 3:2) gave specified in the header connection (5,08 g, 71%). LC-MS: tR= 1.09 min; ES+: 383,41.

N-(4-Chloro-3-hydroxymethyl-benzyl)propionamide

Aqueous 1M NaOH solution (92 ml) was added to a solution of N-[3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]propionamide (5,08 g, 14.9 mmol) in MeOH (184 ml). The mixture was heated up to 80°C and stirred at this temperature for 30 minutes. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The aqueous residue was diluted with water and was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave specified in the header connection (2,99 g, 88%). LC-MS: t = 0.67 min; ES+: 269,31.

N-(4-Chloro-3-formyl-benzyl)propionamide

MnO2(5,61 g, and 65.7 mmol) was added to a solution of N-(4-chloro-3-hydroxymethyl-benzyl)propionamide (2,99 g of 13.1 mmol) in CH3CN (255 ml) at room temperature. The mixture was stirred for 3 hours at room temperature and again added MnO2(2.24 g, to 26.2 mmol). The mixture was stirred for 1 hour at room temperature and the mixture was filtered through celite. The filtrate was evaporated under reduced pressure and the residue was dried in high vacuum, receiving untreated listed is in the title compound (2,74 g, 93%)which was used without further purification. LC-MS: tR= 0,76 minutes; ES+: 267,27.

N-(4-Chloro-3-cyclopropylamino-benzyl)propionamide

Cyclopropylamine (1,28 ml, 18.2 mmol) was added to a solution of N-(4-chloro-3-formyl-benzyl)propionamide (2,74 g, 12.1 mmol) in MeOH (42 ml). The mixture was stirred over night and added portions NaBH4(918 mg, 24,3 mmol). The mixture was stirred for 4 hours and was added aqueous 1M NaOH solution (70 ml). The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc (2×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave specified in the header connection (2,62 g, 81%). LC-MS: tR= 0,58 minutes; ES+: 267,38.

3-(tert-Butyl-dimetilglioximatul)-4-chloro-benzylamine cyclopropanecarbonyl acid

Cyclopropanecarbonitrile (2,88 ml, was 31.0 mmol) and Et3N (of 4.38 ml, was 31.0 mmol) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzylamine (6,00 g of 20.9 mmol) in CH2Cl2(125 ml). The mixture was stirred for 30 minutes at room temperature and was additionally added CH2Cl2. The mixture is washed with aqueous saturated solution of NH4Cl (2×),aqueous 1M NaOH solution (2×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the header connection (6,10 g, 82%). LC-MS: tR= 1.09 min; ES+: 395,42.

4-Chloro-3-hydroxymethyl-benzylated cyclopropanecarbonyl acid

Aqueous 1M NaOH solution (111 ml) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzylamine cyclopropanecarbonyl acid (6,10 g, and 17.2 mmol) in MeOH (222 ml). The mixture was heated up to 80°C and stirred at this temperature for 30 minutes. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The aqueous residue was diluted with water and was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave specified in the header connection (3,47 g, 84%). LC-MS: tR= 0,71 minutes; ES+: 281,31.

4-Chloro-3-formyl-benzylated cyclopropanecarbonyl acid

MnO2(6,29 g, 72.0 mmol) was added to a solution of 4-chloro-3-hydroxymethyl-benzylamino cyclopropanecarbonyl acid (3,47 g, 14.0 mmol) in CH3CN (300 ml) at room temperature is E. The mixture was stirred for 3 hours at room temperature and again added MnO2(2,52 g, 29,0 mmol). The mixture was stirred for 1 hour at room temperature and again added MnO2(1.26 g, 14.0 mmol). The mixture was stirred for 1.5 hours and filtered through celite. The filtrate was evaporated under reduced pressure and the residue was dried in high vacuum, receiving untreated specified in the title compound (3.13 g, 91%)which was used without further purification. LC-MS: tR= 0,80 min; ES+: 279,31.

4-Chloro-3-cyclopropylamino-benzylated cyclopropanecarbonyl acid

Cyclopropylamine (1.39 ml of 19.8 mmol) was added to a solution of 4-chloro-3-formyl-benzylamine cyclopropanecarbonyl acid (3.13 g, 13,2 mmol) in MeOH (28 ml). The mixture was stirred over night and added portions NaBH4(996 mg, 26.0 mmol). The mixture was stirred for 3 hours and was added aqueous 1M NaOH solution (70 ml). The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc (2×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave specified in the header connection (3,37 g, 92%). LC-MS: tR= 0,62 minutes; ES+: 279,35.

p> Methyl ester [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]carbamino acid

Methylchloroform (1,98 ml of 25.2 mmol) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzylamine (6,00 g of 20.9 mmol) and DIPEA (7,33 ml, 42.0 mmol) in CH2Cl2(100 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and was additionally added CH2Cl2. The mixture is washed with aqueous saturated solution of NH4Cl, 1M aqueous NaOH solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:5) gave specified in the header of the connection (of 5.39 g, 75%). LC-MS: tR= 1,02 minutes; ES+: 344,38.

Methyl ester of (4-chloro-3-hydroxymethyl-benzyl)carbamino acid

A mixture of methyl ester [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]carbamino acid (5,39 g, 15.7 mmol) in MeOH (160 ml) and aqueous 1M NaOH solution (80 ml) was heated at 80°C for 1.5 hours. The mixture was left to cool to room temperature and was partially evaporated under reduced pressure. The aqueous residue was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high the vacuum received untreated specified in the header connection (3,53 g, 98%)which was used without further purification. LC-MS: tR= 0.72 min; ES+: 230,25.

Methyl ester of (4-chloro-3-formyl-benzyl)carbamino acid

MnO2(of 6.68 g, 76.9 mmol) was added to a solution of methyl ester (4-chloro-3-hydroxymethyl-benzyl)carbamino acid (3,53 g of 15.4 mmol) in CH3CN (300 ml). The mixture was stirred at room temperature for 3 hours and again added MnO2(2.67 g, 30.7 mmol). The mixture was stirred for 1 hour and again added MnO2(1,34 g of 15.4 mmol). The mixture was stirred for 2 hours and filtered through celite. The precipitate was washed CH2Cl2and the filtrate was evaporated under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (3,22 g, 92%)which was used without further purification.

Methyl ester of (4-chloro-3-cyclopropylamino-benzyl)carbamino acid

A mixture of methyl ester and (4-chloro-3-formyl-benzyl)carbamino acid (3,22 g, 14.1 mmol) and cyclopropylamine (1,49 ml and 21.2 mmol) in MeOH (50 ml) was stirred at room temperature overnight. Added portions NaBH4(1.07 g, 28.3 mmol) and the mixture was stirred at room temperature for 3 hours. Was added aqueous 1M NaOH solution (90 ml) and the solvents were partially removed under reduced pressure. The aqueous residue was extracted with EtOAc (3×). Joint the United organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1) gave specified in the header connection (3,24 g, 85%). LC-MS: tR= 0,59 minutes; ES+: 310,31.

3-(4-Chloro-3-hydroxymethyl-phenyl)propionic acid

A mixture of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (1.84 g, 6,46 mmol), acid Meldrum (931 mg, 6,46 mmol) and the complex of formic acid-triethylamine 5:2 (1,62 ml of 23.4 mmol) in DMF (6,00 ml) was heated at 100°C for 3.5 hours. Again added acid Meldrum (466 mg, 3,23 mmol) and the mixture was stirred for 1 hour at 100°C. the Mixture was left to cool to room temperature and was diluted mixture of water and ice. The resulting mixture was extracted with EtOAc several times. The combined organic extracts were washed with water, dried over MgSO4was filtered and the solvents were removed under reduced pressure. The residue was dissolved in Et2O, and the resulting mixture was extracted several times aqueous 1M NaOH solution. The combined aqueous extracts were acidified to pH 2 aqueous 1M HCl solution and this aqueous mixture was extracted several times Et2O. the combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified the title compound (1.20 g, 87%)which was used without further purification. LC-MS: tR= 0,71 minutes.

3-(4-Chloro-3-hydroxymethyl-phenyl)-N-methyl-propionamide

MeNH2(2M in THF, of 28.0 ml, or 56.1 mmol) and TBTU (1.98 g, 6,17 mmol) was added to a solution of 3-(4-chloro-3-hydroxymethyl-phenyl)propionic acid (1.20 g, 5,59 mmol) in CH2Cl2(42 ml). The mixture was stirred at room temperature for 2.5 hours and was added CH2Cl2(150 ml). The mixture was washed with a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:9) gave specified in the title compound (250 mg, 20%). LC-MS: tR= 0.67 min; ES+: 269,34.

3-(4-Chloro-3-formyl-phenyl)-N-methyl-propionamide

MnO2(10.6 g, 110 mmol) was added to a solution of 3-(4-chloro-3-hydroxymethyl-phenyl)-N-methyl-propionamide (2.50 g, 11.0 mmol) in CH3CN (223 ml). The mixture was stirred for 1 hour at room temperature. The mixture was filtered through celite and washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure and the residue was dried in high vacuum, receiving untreated specified in the title compound (2.30 g, 93%)which was used without further purification. LC-MS: tR= 0,76 minutes; ES+: 267,30.

3-(4-Chloro-3-cyclopropylamino-phenyl)-N-methyl-impregnated shall name

A mixture of 3-(4-chloro-3-formyl-phenyl)-N-methyl-propionamide (2.30 g, 10.2 mmol) and cyclopropylamine (1,09 ml of 15.3 mmol) in MeOH (109 ml) was stirred for 2 hours. Added cyclopropylamine (0,364 ml, 5,09 mmol) and the mixture was heated at the boil under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(771 mg, of 20.4 mmol). The mixture was stirred for 2 hours at room temperature. The solvents were removed under reduced pressure and the resulting oil was diluted with EtOAc (500 ml). The resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl25:95) gave specified in the header connection (2,05 g, 75%). LC-MS: tR= 0,58 minutes; ES+: 267,39.

tert-Butyl ether {2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}-(2,2-dottorati)carbamino acid

A mixture of 2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl ester methanesulfonic acid (7.50 g, and 19.8 mmol) and 2,2-differetiation (of 5.05 g of 62.3 mmol) in EtOH (20 ml) was stirred at 60°C over night. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was dried in the high vacuum and dissolved in CH 2Cl2(200 ml). The mixture was cooled to 0°C was added Et3N (for 9.64 ml, of 69.2 mmol) and Boc2O (6,05 g, 27.7 mmol). The mixture was stirred overnight while it was heated to room temperature. Added CH2Cl2(120 ml) and the mixture is washed with aqueous 1M HCl solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 1:19) gave specified in the title compound (8.00 g, quantitative yield), which still contained tert-butanol as an impurity. LC-MS: tR= 0,91 minutes; ES+: 364,49.

tert-Butyl ether [2-(4-chloro-3-hydroxymethyl-phenyl)ethyl]-(2,2-dottorati)carbamino acid

tert-Butyl ether (2-[3-(tert-butyl-dimetilglioximatul)-4-chlorophenyl]ethyl}-(2,2-dottorati)carbamino acid (7.50 g, 16.2 mmol) was dissolved in MeOH (323 ml). Was added aqueous 1M NaOH solution (161 ml) and the mixture was heated at the boil under reflux for 1 hour. The solvents were partially removed under reduced pressure and the aqueous residue was diluted with water (900 ml). The mixture was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, getting neojidanno is specified in the header connection (4,60 g, 81%)which was used without further purification. LC-MS: tR= 1.00 min; ES+: 317,31.

tert-Butyl ether [2-(4-chloro-3-formyl-phenyl)ethyl]-(2,2-dottorati)carbamino acid

MnO2(6,35 g, and 65.7 mmol) was added to a solution of tert-butyl methyl ether [2-(4-chloro-3-hydroxymethyl-phenyl)ethyl]-(2,2-dottorati)carbamino acid (4,60 g, 13,2 mmol) in CH3CN (133 ml). The mixture was stirred at room temperature for 4 hours. The mixture was filtered through celite and the precipitate washed CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure, obtaining the crude specified in the header connection (4,30 g, 94%)which was used without further purification. LC-MS: tR= 1,06 minutes.

tert-Butyl ether [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]-(2,2-dottorati)carbamino acid

A mixture of tert-butyl methyl ether [2-(4-chloro-3-formyl-phenyl)ethyl]-(2,2-dottorati)carbamino acid (4,30 g, 12.4 mmol) and cyclopropylamine (1.77 ml, 12.4 mmol) in MeOH (125 ml) was stirred for 2 hours at room temperature. Added cyclopropylamine (of 0.44 ml, 6.2 mmol) and the mixture was heated at the boil under reflux for 4 hours. The mixture was left to cool to room temperature. NaBH4(935 mg, of 24.7 mmol) was added in portions. The mixture was stirred for 1 hour. The solvents were removed under reduced pressure the residue was placed in EtOAc (800 ml). The resulting mixture was washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl25:95) gave specified in the header connection (3,53 g, 73%). LC-MS: tR= 0,83 minutes; ES+: 389,52.

tert-Butyl ether (2-chloro-5-vinyl-benzyl)cyclopropyl-carbamino acid

To a solution of tert-butyl methyl ether (5-bromo-2-chloro-benzyl)cyclopropyl-carbamino acid (105 g, 0,292 mol) in DME (800 ml) in an atmosphere of N2at room temperature was added Pd(PPh3)4(16,9 g, 14.6 mmol). The mixture was stirred at room temperature for 30 minutes and was added K2CO3(40,7 g, 292 mmol), water (350 ml) and 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]dioxaborolan (52,0 ml, 292 mmol). The mixture was heated at the boil under reflux for 3 hours. The mixture was left to cool to room temperature and added to water (500 ml). The mixture was extracted with Et2O (4×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 9:1) gave specified in the header connection (70,9 g, 79%). LC-MS: tR= 1,10 minutes; ES+: 293,38.

tert-Butyl ether (2-chloro-5-formyl-b is nil)cyclopropyl-carbamino acid

The mixture Of3/About2(poluchennuyu using sonalization Fisher) carefully barbotirovany through a solution of tert-butyl methyl ether (2-chloro-5-vinyl-benzyl)cyclopropyl-carbamino acid (10.0 g, 32.5 mmol) in CH2Cl2(356 ml) and MeOH (44 ml) at -78°C for 60 minutes. The mixture was bought reduced-blue color, and after the mixture was barbotirovany pure O2until then, until it became colorless. The mixture was purged by a stream of nitrogen for 60 minutes and add Me2S (44,0 ml). The mixture was stirred at -78°C for 2 hours. The solvents were removed under reduced pressure and the residue was dried in high vacuum over night, receiving untreated specified in the title compound (11.7 g, quantitative yield)which was used without further purification. LC-MS: tR= 1,04 minutes; ES+: 295,34.

tert-Butyl ether (2-chloro-5-hydroxymethyl-benzyl)cyclopropyl-carbamino acid

NaBH4(1.48 g, of 37.7 mmol) was added to a solution of tert-butyl methyl ether (2-chloro-5-formyl-benzyl)cyclopropyl-carbamino acid (11.7 g, of 37.7 mmol) in CH3CN (113 ml) in an atmosphere of N2. The mixture was stirred at room temperature for 1 hour and was added water (113 ml). The mixture was stirred at room temperature for 5 minutes and was extracted with CH2Cl2(3×). The combined organic layers were dried over MgSO4that filter is Ali and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 7:3) gave specified in the header connection (6,53 g, 56%). LC-MS: tR= 0.96 min; ES+: 297,37.

tert-Butyl methyl ether(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbamino acid

4-Nitrophenylphosphate (5,08 g, 24.4 mmol) and DIPEA (of 8.37 ml, for 48.9 mmol) was added to a solution of tert-butyl methyl ether (2-chloro-5-hydroxymethyl-benzyl)cyclopropyl-carbamino acid (3,05 g, 9,78 mmol) in CH3CN (50 ml). The mixture was stirred at 60°C for 20 hours and left to cool to room temperature. Added MeNH2(2M in THF, 49,0 ml, 98,0 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was distributed between CH2Cl2and water. The organic layer was washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Et2O 9:1) gave specified in the title compound (2.67 g, 74%). LC-MS: tR= 1,01 minutes; ES+: 313,37/

4-Chloro-3-cyclopropylamino-benzyl methyl ether-carbamino acid

HCl (4M in dioxane, 35 ml) was added to a solution of tert-butyl methyl ether (2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbamino acid (3,48 g, 9.43 mmol) in CH2Cl2(35 ml) at 0°C. the Mixture was stirred during 2 hours at 0°C and was additionally added CH 2Cl2. The mixture is washed with aqueous 1M NaOH solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the header connection (2,48 g, 98%)which was used without further purification. LC-MS: tR= 0,61 minutes; ES+: 310,38.

tert-Butyl methyl ether[2-chloro-5-(2-methylcarbamoylmethyl)benzyl]cyclopropyl-carbamino acid

4-Nitrophenyl chloroformate (3.25 g, 15.7 mmol) and DIPEA (7,88 ml, 46,0 mmol) was added to a solution of tert-butyl methyl ether [2-chloro-5-(2-hydroxy-ethyl) - benzyl]cyclopropyl-carbamino acid (3.00 g, of 9.21 mmol) in CH3CN (46 ml). The mixture was stirred at 60°C for 20 hours and left to cool to room temperature. Added MeNH2(2M in THF, 46,0 ml, 92.0 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was distributed between CH2Cl2and water. The organic layer was washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Et2O 9:1) gave specified in the header connection (1,76 g, 50%). LC-MS: tR= 1,02 minutes; ES+: 283,42.

2-(4-Chloro-3-cyclopropylamino-phenyl)ethyl methyl ether-carbamino acid

HCl (4M in di is the Ksan, 18 ml) was added to a solution of tert-butyl methyl ether [2-chloro-5-(2-methylcarbamoylmethyl)benzyl]cyclopropyl-carbamino acid (1,76 g, 4,60 mmol) in CH2Cl2(18 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C and was additionally added CH2Cl2. The mixture is washed with aqueous 1M NaOH solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the header connection (1,46 g, quantitative yield)which was used without further purification. LC-MS: tR= 0,64 minutes; ES+: 283,40.

2-{3-[(tert-Butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}ethyl ester toluene-4-sulfonic acid

Et3N (2,56 ml, 18.4 mmol) and DMAP (153 mg, of 1.23 mmol) was added to a solution of tert-butyl methyl ether [2-chloro-5-(2-hydroxy-ethyl) - benzyl]cyclopropyl-carbamino acid (4,00 g, 12.3 mmol) in CH2Cl2(110 ml) at 0°C. was Added dropwise a solution of p-toluensulfonate (2,80 g, 14.7 mmol) in CH2Cl2(18 ml) and the mixture was stirred for 3 days, during which time it was warmed to room temperature. The mixture was distributed between CH2Cl2and water and the aqueous layer was extracted with CH2Cl2(3×). The combined organic layers were washed with saturated salt solution, dried over MgSO4that filtered the solvent was removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 8:2) gave specified in the header connection (4,90 g, 83%). LC-MS: tR= 1,13 minutes; ES+: 480,53.

tert-Butyl ester of [5-(2-azido-ethyl)-2-chloro-benzyl]cyclopropyl-carbamino acid

NaN3(1,17 g, 18.0 mmol) was added to a solution of 2-{3-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-4-chlorophenyl}ethyl ester toluene-4-sulfonic acid (2.16 g, 4,50 mmol) in DMF (45 ml). The mixture was heated to 65°C and stirred at this temperature for 1.5 hours. The mixture was left to cool to room temperature and poured into water. The mixture was extracted with TBME (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 95:5) gave specified in the header connection (1,49 g, 94%). LC-MS: tR= 1,11 minutes; ES+: 336,43.

tert-Butyl ester of [5-(2-amino-ethyl)-2-chloro-benzyl]cyclopropyl-carbamino acid

Me3P (1M in toluene, 4,20 ml, 4.20 mmol) was added to a solution of tert-butyl ester [5-(2-azido-ethyl)-2-chloro-benzyl]cyclopropyl-carbamino acid (1,49 g of 4.25 mmol) in THF (13,0 ml) and the mixture was stirred at room temperature for 5 hours. Added phosphate buffer (pH 7,4, DPBS Gibco 14200, diluted 10×) and the mixture several times to AXT who was agarawala CH 2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (1,34 g, 97%)which was used without further purification. LC-MS: tR= 0,81 minutes; ES+: 325,18.

Methyl ether (2-{3-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-4-chloro-phenyl}ethyl) - carbamino acid

Methylchloroform (1,72 ml, 21.9 mmol) and K2CO3(of 7.65 g of 54.8 mmol) was added to a solution of tert-butyl ester [5-(2-amino-ethyl)-2-chloro-benzyl]cyclopropyl-carbamino acid (1.78 g, of 5.48 mmol) in acetone (8,00 ml). The mixture was heated at boiling with bartnum fridge over night and left to cool to room temperature. The mixture was distributed between water and CH2Cl2and the aqueous layer was extracted with CH2Cl2(3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 6:4) gave specified in the header connection (1,41 g, 67%). LC-MS: tR= 1,03 min; ES+: 383,50.

Methyl ester [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]carbamino acid

HCl (4M in dioxane, 17 ml) was added to a solution of methyl ester (2-{3-[(tert-butoxycarbonyl-C is chlorophyl-amino)methyl]-4-chloro-phenyl}ethyl) - carbamino acid (1.73 g, to 4.52 mmol) in CH2Cl2(17 ml) at 0°C. the Mixture was stirred at 0°C for 2.5 hours and washed with aqueous 1M NaOH solution. The aqueous layer was extracted with CH2Cl2.The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (1.27 g, 99%)which was used without further purification. LC-MS: tR= 0,64 minutes; ES+: 283,41.

tert-Butyl ether [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-(2,2-dottorati)carbamino acid

Hydrochloride of 2,2-differetiation (1.70 g, 14.4 mmol) and DIPEA (2,47 ml, 14.4 mmol) was added to a solution of 3-(tert-butyl-dimetilglioximatul)-4-chloro-benzaldehyde (2,74 g, 9,62 mmol) in MeOH (80 ml). The mixture was heated at the boil under reflux for 5 hours and left to cool to room temperature. NaBH4(546 mg, 14.4 mmol) was added in portions and the mixture was stirred for 2 hours at room temperature. The solvents were removed under reduced pressure and the residue was placed in EtOAc. The mixture is washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The remainder of the Rast is oral in CH 2Cl2(53 ml) was added DIPEA (4,94 ml of 28.9 mmol) and Boc2O (3,15 g, 14.4 mmol). The mixture was stirred for 1 hour at room temperature and washed with aqueous 1M HCl solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound (4.35 g, quantitative yield)which was used without further purification. LC-MS: tR= 1.25 min; ES+: 394,08.

tert-Butyl ester (4-chloro-3-hydroxymethyl-benzyl)-(2,2-dottorati)carbamino acid

tert-Butyl ether [3-(tert-butyl-dimetilglioximatul)-4-chloro-benzyl]-(2,2-dottorati)carbamino acid (4.35 g, 9,67 mmol) suspended in MeOH (100 ml) was added aqueous 1M NaOH solution (50 ml). The mixture was heated at the boil under reflux for 3 hours and the solvents were partially removed under reduced pressure. The aqueous residue was diluted with water (100 ml) and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 2:8 → 3:7) gave specified in the title compound (2.70 g, 83%). LC-MS: tR= 0.99 min; ES+: 302,96.

tre the-Butyl ester (4-chloro-3-formyl-benzyl)-(2,2-dottorati)carbamino acid

MnO2(to 3.89 g, with 40.2 mmol) was added to a solution of tert-butyl methyl ether (4-chloro-3-hydroxymethyl-benzyl)-(2,2-dottorati)carbamino acid (2,71 g, 18.2 mmol) in CH3CN (85 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and again added MnO2(2,71 g, 18.2 mmol). The mixture was stirred over night. The mixture was filtered through celite and the precipitate washed CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure, obtaining the crude specified in the header connection (2,80 g, quantitative yield)which was used without further purification. LC-MS: tR= 1,03 min; ES+: not visible.

tert-Butyl ester (4-chloro-3-cyclopropylamino-benzyl)-(2,2-dottorati)carbamino acid

tert-Butyl ester (4-chloro-3-formyl-benzyl)-(2,2-dottorati)carbamino acid (563 mg, was 1.69 mmol) was dissolved in MeOH (18 ml). Added cyclopropylamine (0,181 ml of 2.53 mmol) and the mixture was heated at the boil under reflux for 4 hours. The mixture was left to cool to room temperature and added portions NaBH4(96 mg, or 95.7 mg of 2.53 mmol). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. The residue was placed in EtOAc and the mixture is washed with aqueous saturated solution of NaHCO3(1×) and saturated salt solution (1×). The organic layer of sushiland MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (558 mg, 88%). LC-MS: tR= 0,76 minutes; ES+: 375,15.

(S)-1-(4-Bromo-phenyl)pyrrolidin-3-ol

A mixture of 1-bromo-4-iodine-benzene (50.0 g, 177 mmol), (S)pyrrolidin-3-ol (28,6 ml, 353 mmol), CuI (of 6.73 g, 35,3 mmol) and K3PO4·H2O (81,4 g, 353 mmol) in N,N-dimethylaminoethanol (177 ml) was stirred at 55°C for 60 hours. The mixture was left to cool to room temperature and added water. The mixture was extracted several times CH2Cl2. The combined organic extracts were washed with a mixture of aqueous concentrated solution of NH3and water in the ratio 1:1. Containing NH3the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Crystallization of the crude product from a mixture of EtOAc/heptane gave specified in the header connection (36,1 g, 84%).

(S)-1-(4-Bromo-phenyl)-3-(tert-butyl-dimethylsiloxy)pyrrolidin

(S)-1-(4-Bromo-phenyl)pyrrolidin-3-ol (14.0 g, 57,7 mmol) was dissolved in DMF (100 ml) and was added TBDMS-Cl (10.4 g, of 69.2 mmol) and imidazole (9.81 g, 144 mmol). The mixture was stirred at room temperature overnight. Was added aqueous saturated RA is creative NH 4Cl (100 ml) and the mixture was extracted with heptane (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:15 → 1:4) gave specified in the title compound (17.3 g, 84%).

(R)-5-Bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine

ADDP (11,7 g of 45.4 mmol) was added to a solution of G1 (8,82 g of 36.3 mmol) and 2,6-dichloro-p-cresol (7,37 g, 40.0 mmol) in toluene (200 ml). The mixture was degirolami nitrogen for 5 minutes and added a PBu3(of 85%to 15.8 ml, 46.2 mmol). The mixture was quickly heated to 100°C and stirred at this temperature for 2 hours. The mixture was left to cool to room temperature and was diluted with heptane (200 ml). The mixture was filtered, and the filtrate was evaporated under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:7) gave specified in the crude title compound, which was diluted in CH2Cl2. This mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum has been specified in segalove compound in pure form (13.5 g, 93%). LC-MS: tR= 0,92 minutes; ES+: 402,98.

(S)-5-Bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine

ADDP (11.4 g, a 44.2 mmol) was added to the solution with the unity G3 (8,61 g, of 35.4 mmol) and 2,6-dichloro-p-cresol (7,19 g of 39.0 mmol) in toluene (200 ml). The mixture was degirolami nitrogen for 5 minutes and added a PBu3(85%, of 15.4 ml of 45.0 mmol). The mixture was quickly heated to 100°C and stirred at this temperature for 2 hours. The mixture was left to cool to room temperature and was diluted with heptane (200 ml). The mixture was filtered and the filtrate was evaporated under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:7) gave specified in the crude title compound, which was diluted in CH2Cl2. This mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum has been specified in the title compound in pure form (13,4 g, 94%). LC-MS: tR= 0,93 minutes; ES+: 402,97.

tert-Butyl ester 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid

A mixture of 8-methyl-8-azabicyclo[3.2.1]Octan-3-one (50.5 g, 359 mmol) and 1-chloroethylphosphonic (117 ml of 1.08 mol) in CH2ClCH2Cl (500 ml) was heated at 80°C for 5 hours. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 3 hours was added in portions to a MeOH (250 ml) for 30 minutes. The mixture was stirred at 75°C for 1 hour and left to cool until anatoy temperature. The solvents were removed under reduced pressure. The residue was diluted with Et2O (250 ml) and the mixture was subjected to ultrasonic treatment for 15 minutes. The mixture then was stirred for 30 minutes and filtered. The precipitate was rinsed Et2O (125 ml) and dried in high vacuum. The residue was diluted with dioxane (400 ml) and the mixture was cooled to 0°C. was Added aqueous 1M NaOH solution (400 ml). Added Boc2O (82.3 g, 377 mmol) and the mixture was stirred overnight, during which time it was warmed to room temperature. The mixture was extracted with Et2O (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 3:7) gave specified in the header connection (59.0 g, 73%). LC-MS: tR= 0,83 minutes.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-hydroxy-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid

To a suspension of NaH (55-65% in mineral oil, 9,82 g, approximately 225 mmol) in cyclohexane (87,5 ml) was added dimethylcarbonate (21,0 ml, 250 mmol). The mixture was heated at boiling under reflux was added over 35 minutes to a solution of tert-butyl ester 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid (25.6 g, 113 mmol) in MeOH (0.25 ml) and cyclohexane (62.5 ml). The mixture was heated at the boil under reflux for 3 hours and Oh what was Adali to 0°C. Added carefully aqueous saturated solution of NH4Cl to phase separation. The organic layer was extracted several times CH2Cl2. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 3:7) gave specified in the header connection (29,7 g, 93%). LC-MS: tR= 0.96 minutes.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*, tripterocalyx-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (A1)

NaH (55-65% suspension in oil, 6,69 g, approximately 153 mmol) was added over 35 minutes to a solution of 8-tert-butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-hydroxy-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (34,7 g, 123 mmol) in THF (600 ml) at 0°C. the Mixture was stirred for 75 minutes and was added PhN(Tf)2(52,5 g, 147 mmol). The mixture was stirred overnight while it was heated to room temperature. The mixture was poured into a mixture of ice-water. The solvents were partially removed under reduced pressure and the residue several times was extracted with EtOAc. The combined organic extracts were washed with water, saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 2:8) gave the decree is Noah in the title compound (52,0 g, quantitative yield). LC-MS: tR= 1,07 minutes.

1-tert-Butyl ester 3-ethyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (A2)

1-tert-Butyl ester 3-ethyl ester 4-oxo-piperidine-1,3-dicarboxylic acid (30,9 g, 114 mmol) was dissolved in CH2Cl2(800 ml). Added DIPEA (48.7 per ml, 285 mmol) and the reaction mixture was cooled to -78°C. was Slowly added a solution Tf2O (24,4 ml, 148 mmol) in CH2Cl2(25 ml), maintaining the temperature at -78°C. the Mixture was stirred for 30 minutes at -78°C. the Mixture was left to warm to room temperature and was added aqueous 10% solution of Na2CO3(400 ml) and ice. The layers were separated and the aqueous layer was extracted with CH2Cl2(2×). The combined organic layers were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → EtOAc/heptane 25:75) gave specified in the header connection (44,0 g, 91%). LC-MS: tR= 1.05 min; ES+: 404,44.

1-tert-Butyl ester 3-methyl ester 4-[4-(tert-butyl-dimethylsiloxy)phenyl]-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (B1)

BuLi (1,6M in hexano, to 27.0 ml, to 43.1 mmol) was added to a solution of (4-bromophenoxy)-tert-butyldimethylsilyl (12.4 g, to 43.1 mmol) in THF (300 ml) at -78°C. the Mixture was stirred for 30 minutes at -78°C and added ZnCl2(1M in THF, to 52.4 ml, 524 mmol). The mixture was left to warm to room temperature and the solution was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 12.0 g, for 30.8 mmol) in THF (20 ml) and Pd(PPh3)4(1,00 g, 0,863 mmol). The mixture was stirred at room temperature over night and was added aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 1:1) gave specified in the title compound (13.3 g, 96%). LC-MS: tR=1.20 min; ES+: 448,35.

1-tert-Butyl ester 3-methyl ester 4-(4-hydroxy-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (B2)

TBAF (9,50 g, 30 mmol) was added to a solution of compound B1 (13,4 g, 30 mmol) in THF (100 ml) at 0°C. the Mixture was stirred at 0°C for 1 hour. Added CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl, water, and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (10.0 g, quantitative yield)which was used without further purification. LC-MS: t = 0,92 minutes; ES+: 334,23.

1-tert-Butyl ester 3-methyl ester 4-(4-benzyloxy-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (B3)

To a solution of 4-benzoxa-bromo-benzene (18,4 g, 70,0 mmol) in THF (450 ml) at -78°C was added BuLi (1,6M in hexane, to 50.0 ml, 80,0 mmol). The mixture was stirred for 30 minutes at -78°C and added ZnCl2(1M in THF, 86 ml, 86 mmol). The mixture was left to warm to room temperature. Solution was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 19.5 g, 50.0 mmol) in THF (20 ml) and Pd(PPh3)4(1,43 g of 1.23 mmol). The mixture was quickly heated up to 50°C and stirred at this temperature for 40 minutes. Was added aqueous saturated solution of NH4Cl and the mixture was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:9 → 2:8) gave specified in the header connection (20,8 g, 98%). LC-MS: tR= 1.12 min; ES+: 424,25.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-(4-hydroxy-phenyl)-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B4)

Aqueous 2M solution of Na2CO3(90,0 ml) was added to a mixture of compound A1 (10.1 g, 24.4 mmol) and 4-hydroxybenzophenone acid is (3,37 g, 24.4 mmol) in DME (180 ml). The mixture was degirolami N2within 3 minutes and was added Pd(PPh3)4(1.42 g, of 1.23 mmol). The mixture was quickly heated up to 80°C and stirred at this temperature for 1 hour. The mixture was left to cool to room temperature and distributed between EtOAc (250 ml) and water (250 ml). The organic phase is washed with water. The combined aqueous layers was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1) gave specified in the header connection (7,27 g, 83%). LC-MS: tR= 0,94 minutes; ES+: 360,29.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-7-[4-(tert-butyl-dimethylsiloxy)phenyl]-9-methyl-3,9-diazabicyclo[3.3.1]non-7-ene-3,6-dicarboxylic acid (B9)

BuLi (1,6M in hexane, 31.9 per ml, of 51.0 mmol) was added to a solution of (4-bromo-phenoxy)-tert-butyl-dimethylsilane (12.8 g, to 44.5 mmol) in THF (150 ml) at -78°C. the Mixture was stirred for 60 minutes at -78°C and added ZnCl2(1,1M, and 50.5 ml, at 55.6 mmol). The mixture was left to warm to room temperature and the solution was added 3-tert-butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-9-methyl-7-tripterocalyx-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (WO 2003/093267; 17.0 g, 37,1 mmol) in THF (10 ml) and Pd(PPh3)4(1.07 g, 0,927 mmol). The mixture plumage is shivali at 50°C for 25 minutes and left to cool to room temperature. Was added aqueous saturated solution of NH4Cl and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 6:4) gave specified in the title compound (15.9 g, 83%). LC-MS: tR= 0.95 min, ES+: 517,25.

3-tert-Butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-[4-(tert-butyl-dimethylsiloxy)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (B10)

A mixture of compound B9 book (6.16 g, to 11.9 mmol) and 2,2,2-trichloro-1,1-dimethylethanamine (3,15 g of 13.1 mmol) in 1,2-dichloroethane (200 ml) was heated at 60°C for 20 hours. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 8:2) gave specified in the header connection (7,58 g, 90%). LC-MS: tR= 1,29 min, ES+: 707,36.

3-tert-Butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-(4-hydroxy-phenyl)-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (B11)

Compound B10 (7,58 g of 10.7 mmol) was dissolved in MeOH (110 ml) was added p-TsOH (2,03 g of 11.8 mmol). The mixture was stirred at room temperature for 2 hours and was added 10% aq. a solution of Na2CO3(200 ml). The solvent was partially removed, propanganda pressure, and the resulting suspension was extracted with EtOAc. The organic extracts were filtered and washed with 10%aqueous solution of Na2CO3and a saturated solution of salt. The organic layer was dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane) gave specified in the title compound (2.10 g, 33%). LC-MS: tR= 1.09 min, ES+: 593,25.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-(6-bromo-pyridin-3-yl)-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B12)

6-Bromopyridin-3-Bronevoy acid (5,00 g of 24.8 mmol), Pd(OAc)2(278 mg, 1,24 mmol) and PPh3(650 mg, 2.48 mmol) suspended in EtOH (67 ml). Was added a solution of Na2CO3(3.15 g, 29.7 mmol) in water (25,3 ml). Was added a solution of compound A1 (10.3 g, 24,8 mmol) in THF (25 ml) and the mixture was heated at the boil under reflux for 4 hours. Again, was added 6-bromopyridin-3-Bronevoy acid (5,00 g of 24.8 mmol) and 1 hour later were added Pd(OAc)2(278 mg, 1,24 mmol) and PPh3(650 mg, 2.48 mmol) and Na2CO3(3.15 g, 29.7 mmol). The mixture is stirred at the boil under reflux for 1 hour and left to cool to room temperature. The solvents were removed under reduced pressure. Added EtOAc and the mixture is washed with aqueous saturated solution of NaHCO3(2×), aqueous saturated solution of NH4Cl and saturated solution is Oli. The organic layer was dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 20:80) gave specified in the header connection (4,24 g, 40%). LC-MS: tR= 1,01 min, ES+: 423,19.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,5S)-3-{4-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1S,5R)-3-{4-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B13)

BuLi (1,6M in hexane, to 30.5 ml, 48.8 mmol) was added during 20 minutes to a solution of (S)-1-(4-bromo-phenyl)-3-(tert-butyl-dimethylsiloxy)pyrrolidine (8,40 g, 23.6 mmol) in THF (350 ml) at -78°C. the Mixture was stirred for 1.75 h at -78°C again, was added BuLi (a 7.85 ml, 12.7 mmol). The mixture was stirred for 15 minutes at -78°C and added ZnCl2(1M in THF, 53,6 ml, 53.6 mmol). The mixture was left to warm to room temperature and was added to a solution of compound A1 (6,53 g, 15.7 mmol) in THF (20 ml), and Pd(PPh3)4(451 mg, 0,390 mmol). The mixture was rapidly heated to 45°C and stirred at this temperature for 45 minutes. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl (200 ml). The layers were separated and the aqueous layer was extragere is whether CH 2Cl2(2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 2:8) gave a mixture of the mentioned in the title compounds (7,17 g, 84%). LC-MS: tR= 1,24 min, ES+: 543,26.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,5S)-3-[4-((S)-3-hydroxy-pyrrolidin-1-yl)phenyl]-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1S,5R)-3-[4-((S)-3-hydroxy-pyrrolidin-1-yl)phenyl]-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B14)

TBAF (4,87 g of 15.5 mmol) was added to a solution of compounds B13 (7,22 g, 13.3 mmol) in THF (75 ml) at 0°C. the Mixture was stirred overnight while it was heated to room temperature. Added EtOAc (185 ml)and the mixture was washed with saturated salt solution (4×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl2with 1% Et3N) gave a mixture of the mentioned in the title compounds (5,51 g, 97%). LC-MS: tR= 0.96 min, ES+: 429,32.

A mixture of 3-tert-butyl ester 6-ethyl ester (1R,5S)-7-{6-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]pyridine-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (1S,5R)-7-{6-[(S)-3-(t is et-butyl-dimethylsiloxy)pyrrolidin-1-yl]pyridine-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (B15)

BuLi (1,6M in hexane, to 20.6 ml, a 33.2 mmol) was added to a solution of compound G2 (of 9.30 g, 26.0 mmol) in THF (300 ml) at -78°C. the Mixture was stirred for 60 minutes at -78°C and added ZnCl2(1M in THF, 41,4 ml, up 41.4 mmol). The mixture was left to warm to room temperature and stirred at this temperature for 30 minutes. Was added a solution of 3-tert-butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-9-methyl-7-tripterocalyx-3,9-diaza-bicyclo[3,3,1]non-6-ene-3,6-dicarboxylic acid (WO 2003/093267; of 9.50 g of 20.7 mmol) in THF (50 ml) and Pd(PPh3)4(578 mg, 0,500 mmol) in THF (10 ml) and the reaction mixture was heated at 70°C for 2 hours. The mixture was left to cool to room temperature and extinguished aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 5:1 → 3:1 → 1:1 → 1:3 → EtOAc/MeOH 49:1) gave a mixture of the mentioned in the title compound (12.1 g, 99%). LC-MS: tR= 0,81 min, ES+: 587,56.

A mixture of 3,9-di-tert-butyl ester 6-ethyl ester (1R,5S)-7-[6-((S)-3-hydroxy-pyrrolidin-1-yl)pyridine-3-yl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (1S,5R)-7-[6-((S)-3-hydroxy-pyrrolidin-1-yl)pyridine-3-yl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic key is lots of (B16)

To a solution of compounds B15 (12.0 g, 20,5 mmol) in CH2ClCH2Cl (250 ml) was added NaHCO3(17,2 g, 204 mmol) and 1-chloroethylphosphonic (22,3 ml, 204 mmol). The mixture was heated at the boil under reflux during the night and left to cool to room temperature. The mixture was filtered and the filtrate was carefully evaporated under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in MeOH (200 ml). The mixture was stirred at 60°C for 3 hours and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 5 hours. The residue was dissolved in CH2Cl2(250 ml) and cooled to 0°C. was Added DIPEA (21,0 ml, 122 mmol) and Boc2O (13,4 g, with 61.3 mmol). The mixture was stirred at 0°C for 30 minutes and at room temperature over night. The mixture was diluted with CH2Cl2and washed with aqueous 1M HCl solution and aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 99:1 → 98:2 → 97:3 → 96:4 → 95:5) gave a mixture of the mentioned in the title compounds (7,31 g, 64%). LC-MS: tR= 0,82 min, ES+: 559,43.

1'-tert-Butyl ether 3'-methyl ether (S)-6-[3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (B17)

BuLi (1,mW hexane, 32,8 ml, to 52.4 mmol) was added to a solution of compound G2 (13,2 g, 37,0 mmol) in THF (300 ml) at -78°C. the Mixture was stirred at -78°C for 1 hour and added ZnCl2(1M in THF, 61,6 ml of 61.6 mmol). The mixture was left to warm to room temperature and was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 12.0 g, for 30.8 mmol) in THF (20 ml) and Pd(PPh3)4(887 mg, 0,768 mmol). The mixture was quickly heated up to 70°C and stirred at this temperature for 90 minutes. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc. The organic extracts washed with aqueous saturated solution of NH4Cl, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 9:1 with 1% Et3N → heptane/EtOAc 5:5 c 1% Et3N) gave specified in the header connection (27,3 g, 89%). LC-MS: tR= 0.97 min, ES+: 518,50.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-(4-hydroxy-phenyl)-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B18)

To a solution of compound A1 (10.0 g, 24,1 mmol) and 4-hydroxybenzophenone acid (3.42 g, 24,1 mmol) in DME (171 ml) was added aq. 2 M Na2CO3(86 ml). The mixture was stirred at room temperature for carried the channels at minutes and was added Pd(PPh 3)4(1.39 g, 1.20 mmol). The mixture was quickly heated up to 80°C and stirred at this temperature for 60 minutes. The mixture was distributed between EtOAc and water and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 6:4) gave specified in the header of the connection (of 7.70 g, 89%). LC-MS: tR= 0.95 min, ES+: 360,18.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-(4-benzyloxy-phenyl)-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (B19)

To a solution of compound B18 (of 7.70 g, with 21.4 mmol) in CH3CN (54 ml) was added K2CO3(2,96 g, with 21.4 mmol) followed by the addition of LiBr (catalytic amount). The mixture was heated at the boil under reflux for 60 minutes and was added dropwise a solution of benzylbromide (2.55 ml, with 21.4 mmol) in CH3CN (54 ml). The mixture was heated at the boil under reflux for 3 hours. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. Added CH2Cl2the mixture is washed with aqueous saturated solution of NH4Cl. The aqueous layer was extracted with CH2Cl2(3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and Rast is oriali was removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 7:3) gave specified in the header connection (9,36 g, 97%). LC-MS: tR= 1,13 min, ES+: 450,17.

Methyl ether (rat.)-(1R*,5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-methyl-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid (C1)

1-[2-(4-Bromo-phenoxy)ethoxy]-2,6-dichloro-4-methyl-benzene (10.5 g, of 28.0 mmol) was dissolved in THF (90 ml) and the solution was cooled to -78°C. was Added BuLi (1,6M in hexane, 18.2 ml of 29.1 mmol) and the solution was stirred at -78°C for 1 hour. Added ZnCl2(1M in THF, 30,8 ml, for 30.8 mmol) and the mixture was left to warm to room temperature. Solution was added methyl ether (rat.)-(1R*,5S*-8-methyl-3-tripterocalyx-8-azabicyclo[3.2.1]]Oct-2-ene-2-carboxylic acid (WO 2004/096799; 4,60 g, 14.0 mmol) in THF (10 ml) and then Pd(PPh3)4(324 mg, 0,280 mmol). The mixture was rapidly heated to 55°C and stirred at this temperature for 30 minutes. The mixture was cooled to 0°C and was added EtOAc (250 ml). This mixture was washed with cold 1M aqueous solution of NaOH (1×) and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl25:95) gave specified in the header connection (5,77 g, 87%). LC-MS: tR= 0,86 minutes; ES+: 476,26.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C2)

NaHCO3(4,65 g, 55.3 mmol) and 1-chloroethylphosphonic (6,03 ml, 55.3 mmol) was added to a solution of compound C1 (5,27 g, 11.1 mmol) in CH2ClCH2Cl (100 ml). The mixture was heated at the boil under reflux for 4 hours and left to cool to room temperature. The mixture was filtered, the precipitate washed with CH2ClCH2Cl and the filtrate was evaporated under reduced pressure. The residue was dried in high vacuum overnight and dissolved in MeOH (100 ml). The mixture was quickly heated up to 50°C and stirred at this temperature for 20 minutes. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2Cl2(100 ml) was added DIPEA (for 9.47 ml, 55.3 mmol). The mixture was cooled to 0°C and was added Boc2O (3,62 g of 16.6 mmol). The mixture was stirred at 0°C for 2 hours and diluted with CH2Cl2. This mixture is washed with aqueous 1M HCl solution (2×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Cleaning with PF (EtOAc/heptane 1:8 → 1:4 → 1:1 → EtOAc) gave specified in the header of the connection (of 3.56 g, 57%). LC-MS: tR= 1,19 minutes; ES+: 562,34.

1-tert-Butyl ester 3-methyl ester 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (C3)

1-[2-(4-Bromo-phenoxy)this is XI]-2,6-dichloro-4-methyl-benzene (16.6 g, a 44.2 mmol) was dissolved in THF (150 ml) and the solution was cooled to -78°C. was Added BuLi (1,6M in hexane, to 31.4 ml, 50.3 mmol) and the mixture was stirred at -78°C for 30 minutes. Added ZnCl2(1M in THF, 56,0 ml, 56.0 mmol) and the mixture was left to warm to room temperature. The mixture was stirred at room temperature for 1 hour. Solution was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 14.3 g, to 36.7 mmol) in THF (30 ml) and then a solution of Pd(PPh3)4(1.23 g, 1.06 mmol) in THF (30 ml). The mixture was stirred at 50°C for 20 minutes and cooled to 0°C. was Added aqueous 10% solution of NH4Cl. The mixture was extracted with EtOAc. The organic extracts washed with aqueous 10% solution of NH4Cl, water, and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4 → EtOAc) gave specified in the title compound (19.7 g, quantitative yield). LC-MS: tR= 1.20 min; ES+: 536,77.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (C4)

A solution of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine (790 mg, 2.10 mmol) in THF (18 ml) was cooled to -78°C. was Added BuLi (1.6 in hexane, 2.65 ml, 4.20 mmol). The mixture was stirred at -78°C for 1 hour and added ZnCl2(1M in THF, 6.30 ml, 6,30 mmol). The mixture was left to warm to room temperature. Was added a solution of 3-tert-butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-9-methyl-7-tripterocalyx-3,9-diaza-bicyclo[3,3,1]non-6-ene-3,6-dicarboxylic acid (WO 2003/093267; 641 mg, of 1.40 mmol) in THF (3,00 ml) and then Pd(PPh3)4(40 mg, 0.035 mmol). The mixture was rapidly heated to 55°C and stirred at this temperature for 20 minutes. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl. The solvents were partially removed under reduced pressure and the residue was diluted with EtOAc. This mixture was washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:3 → EtOAc) gave specified in the title compound (444 mg, 52%). LC-MS: tR= 0,94 minutes; ES+: 606,28.

3-tert-Butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C5)

2,2,2-Trichloro-1,1-dimethylethylamine (2,77 g, 11.6 mmol) was added to a solution of compound C4 (1.40 g, 2,31 mmol) in CH 2ClCH2Cl (30 ml) and the mixture was heated at the boil under reflux for 2 hours. Again, was added 2,2,2-trichloro-1,1-dimethylethylamine (1.40 g, 5.5 mmol) and the mixture was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was diluted with EtOAc and washed with aqueous 1M NaOH solution (2×). The combined aqueous layers was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4) gave specified in the title compound (815 mg, 44%). LC-MS: tR= 1.25 min; ES+: 796,32.

1'-tert-Butyl ether 3'-methyl ester 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (C6)

BuLi (1,6M in hexane, to 39.3 ml of 45.2 mmol) was added to a solution of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine (11,0 g, 28.3 mmol) in THF (700 ml) at -78°C. the Mixture was stirred for 1 hour and added ZnCl2(0,71M in THF, 78,6 ml of 56.5 mmol). This solution was left to warm to room temperature. Solution was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 13,0 g, 34.5 mmol) in THF (30 ml) and Pd(PPh3)4 (814 mg, 0,704 mmol). The mixture was stirred for 30 minutes at room temperature. Was added aqueous saturated solution of NH4Cl and the mixture was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 1:1) gave specified in the title compound (10.7 g, 70%). LC-MS: tR= 1.16 min; ES+: 537,33.

1-tert-Butyl ester 3-methyl ester 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (C7)

To a solution of compound B2 (10.0 g, 30 mmol) and [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (8,84 g, 30 mmol) in toluene (60 ml) was added ADDP (15,1 g, 60 mmol) and PBu3(90%, and 30.0 ml, 108 mmol). The mixture was stirred for 2 hours at 80°C and left to cool to room temperature. The solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4 → EtOAc) gave specified in the header connection (8,64 g, 51%). LC-MS: tR= 1.15 min; ES+: 561,25.

1'-tert-butyl ether 3'-methyl ester 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5,6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (C8)

Preparing a mixture of 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO2004/002957; 6,04 g of 15.5 mmol), 2-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (9.28 are g, of 20.7 mmol) and aq. 2M Na2CO3(br93.1 ml, 186 mmol) in DME (150 ml) was added in portions Pd(PPh3)4(1,00 g, 0,866 mmol). The mixture was heated up to 80°C and stirred at this temperature for 1 hour. The mixture was left to cool to room temperature and diluted with EtOAc. The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:2 → 2:1) gave specified in the header connection (with 4.64 g, 40%). LC-MS: tR= 1.34 min; ES+: 562,34.

6-Ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (C9)

HCl (4M in dioxane, 30 ml) was added to a solution of compound C5 (3,34 g, 4.20 mmol) in CH2Cl2(30 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C, then for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2Cl2(30 ml) was added DIPEA (2,88 ml of 16.8 mmol). The mixture was cooled to -20°C and carefully added AcCl (0,315 ml, to 4.41 mmol). The mixture was stirred to use the f for 20 minutes at -20°C and added CH 2Cl2. The mixture is washed with aqueous 1M HCl and 1M aqueous NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4 → 1:3 → 1:2) gave specified in the title compound (3.03 g, 98%). LC-MS: tR= 1,18 minutes; ES+: 738,14.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C10)

A mixture of compound B4 (6,80 g of 18.9 mmol), [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (6,97 g, 28.3 mmol), ADDP (of 9.55 g, 37.8 mmol) and PBu3(85%, to 13.8 ml, at 56.6 mmol) in toluene (280 ml) was heated at boiling under reflux for 1 hour. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:1) gave specified in the header connection (11,0 g, 99%). LC-MS: tR= 1,14 minutes; ES+: 587,30.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-9-methyl-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (C11)

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-9-methyl-7-tripterocalyx-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (WO 2003/093267; 1,00 g of 2.18 mmol) and 2-[3-(2-chloro-3,6-debtor-phenyl)isoxazol the-5-ylethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (1,41 g, with 3.27 mmol) was dissolved in DME (14,5 ml) was added aq. 2M Na2CO3(11,0 ml). The mixture was degirolami N2(5 minutes). Was added Pd(PPh3)4(126 mg, 0,109 mmol) and the mixture was rapidly heated to 80°C. the Mixture was stirred at this temperature for 1 hour and left to cool to room temperature. The mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/MeOH 95:5) gave specified in the title compound (1.12 g, 81%). LC-MS: tR= 0,91 minutes; ES+: 631,34.

3-tert-Butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C12)

The mixture of compounds C11 (1.10 g, of 1.74 mmol) and 2,2,2-trichloro-1,1-dimethylethanamine (4,18 g of 17.4 mmol) in 1,2-dichloroethane (18,0 ml) was stirred at 70°C for 2 hours. The mixture was left to cool to room temperature, the solvents were removed under reduced pressure and the crude product was purified using PF (EtOAc/heptane 40:60), receiving specified in the title compound (1.04 g, 73%). LC-MS: tR= 1,22 minutes; ES+: 821,16.

6-Ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[3-(2-chloro-3,6-gift the R-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (C13)

To a solution of compound C12 (4,14 g 5,04 mmol) in CH2Cl2(41 ml) at 0°C was added HCl (4M in dioxane, 41 ml). The mixture was stirred at 0°C for 90 minutes and at room temperature for 30 minutes. The solvents were removed under reduced pressure and the residue was dried in high vacuum. This residue was dissolved in CH2Cl2(41 ml) was added DIPEA (of 3.45 ml, at 20.2 mmol). The mixture was cooled to 0°C and added dropwise acetyl chloride (0,376 ml of 5.29 mmol). The mixture was stirred at room temperature for 30 minutes and was added CH2Cl2. This mixture was washed with aqueous saturated solution of NH4Cl. The organic extracts washed with aqueous 1M NaOH solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 7:3) gave specified in the header of the connection (at 3.35 g, 87%). LC-MS: tR= 1.15 min; ES+: 763,07.

3-tert-Butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C20)

A mixture of compound B11 (2.10 g, 3,55 mmol), [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (5.32 g, 10.1 mmol), ADDP (1,79 g, 7,10 mmol) and PBu3(85%, 2,60 ml, 10.5 mmol) in toluene (70 ml) was heated at boiling under reflux for 1 cha is and. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane: 1:1) gave specified in the header connection (2,87 g, 99%). LC-MS: tR= 1,22 minutes; ES+ not visible.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C21)

BuLi (of 1.6 M in hexane, 12.0 ml, 19.2 mmol) was added to a solution of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine (of 5.45 g, 14.4 mmol) in THF (120 ml) at -78°C. the Mixture was stirred at -78°C for 60 minutes and was added ZnCl2(1M in THF, 28,9 ml of 28.9 mmol). The mixture was left to warm to room temperature and was added compound A1 (4,00 g, 9,63 mmol) in dry THF (50 ml) and Pd(PPh3)4(277 mg, 0,240 mmol) in THF ( 2 ml). The mixture was heated at 70°C for 1 hour and extinguished aqueous saturated solution of NH4Cl (70 ml). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 99:1 → 98:2 → 97:3 → 96:4 → 95:5) gave specified in the header connection (4,25 g, 78%). LC-MS: tR= 1.16 min; ES+: 563,11.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,5S*)-3-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-8-Aza icicle[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C22)

Connection B12 (2,49 g, 5,88 mmol) and [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (1.88 g, the 7.65 mmol) was dissolved in toluene (58 ml). To the mixture was added tert-BuONa (848 mg, 8,83 mmol), Xanthos (204 mg, 0,353 mmol) and Pd2(dba)3(110 mg, 0,120 mmol). The reaction mixture was heated at the boil under reflux for 1 hour and left to cool to room temperature. The mixture was evaporated to dryness under reduced pressure. Purification of the residue using PF (EtOAc/heptane 25:75) gave specified in the header connection (1,71 g, 50%). LC-MS: tR= 1,13 minutes; ES+: 588,23.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1S,5R)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C23)

The mixture of compounds B14 (2,75 g, 6.42 per mmol), 2,6-dichloro-p-cresol (2,27 g, 12.8 mmol), ADDP (2,43 g, 9,63 mmol) and PBu3(3,90 g, 19.2 mmol) in toluene (43 ml) was heated at boiling under reflux for 1 hour. The mixture was left to cool to room temperature and was added EtOAc (65 ml). The mixture is washed with aqueous 1M NaOH solution (2×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the TATKO using PF (EtOAc/heptane 1:5) gave the mixture specified in the title compounds (2,54 g, 67%). LC-MS: tR= 1,23 minutes; ES+: 587,26.

A mixture of 3,9-di-tert-butyl ester 6-ethyl ester (1R,5S)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (1S,5R)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C24)

The mixture of compounds B16 (5,00 g of 8.95 mmol), 2,6-dichloro-p-cresol (3,17 g of 17.9 mmol), ADDP (4.52 g, to 17.9 mmol) and PBu3(85%, 6,97 ml, 26.8 mmol) in toluene (80 ml) was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and diluted with EtOAc (200 ml). The mixture is washed with aqueous 1M NaOH solution (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:19 → 1:1) gave a mixture specified in the header connections (the ceiling of 5.60 g, 87%). LC-MS: tR= 1,01 min, ES+: 717,33.

A mixture of 3,9-di-tert-butyl ester 6-ethyl ester (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester 6-ethyl ester (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C25)

The mixture of compounds B16 (5,g, of 8.95 mmol), 2-chloro-3,6-differenoe (2,95 g of 17.9 mmol), ADDP (4.52 g, to 17.9 mmol) and PBu3(85%, 6,97 ml, 26.8 mmol) in toluene (80 ml) was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and diluted with EtOAc (200 ml). The mixture is washed with aqueous 1M NaOH solution (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:19 → 1:1) gave a mixture of the mentioned in the title compounds (4,96 g, 79%). LC-MS: tR= 0,98 min, ES+: 705,37.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (C26)

Zn (2.00 g, 30.7 mmol) was added to a solution of compound C20 (2.50 g, of 3.05 mmol) in THF (31 ml) and AcOH (3,80 ml) and the mixture is efficiently stirred at room temperature for 6.5 hours. The mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was diluted with CH2Cl2and the mixture is washed with aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the title compound (1.52 g, 81%). LC-MS: tRor = 0.90 min, ES+: 657,21.

3,9-Di tre the-butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C27)

A solution of compound C26 (1.52 g, 2,47 mmol), DIPEA (2,11 ml, 12.3 mmol) and Boc2O (1,62 g, 7.40 mmol) in CH2Cl2(12 ml) was stirred at room temperature overnight. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 7:3) gave specified in the header connection (1,58 g, 59%). LC-MS: tR= 1.16 min, ES+: 716,20.

6-Ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo [3.3.1]non-6-ene-6,9-dicarboxylic acid (C28)

HCl (4M in dioxane, 15 ml) was added to a solution of compound C20 (1.50 g, to 1.83 mmol) in CH2Cl2(15 ml) and the mixture was stirred at room temperature for 90 minutes. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CH2Cl2(15 ml) was added DIPEA (1.25 ml, 7,33 mmol) and AcCl (0,136 ml, 1.92 mmol). The mixture was stirred at room temperature for 30 minutes and was added CH2Cl2. The mixture is washed with aqueous 1M HCl and 1M aqueous NaOH solution. The organic layer was dried over MgSO4was filtered and RA is the founders were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 1:1) gave specified in the title compound (1.10 g, 79%). LC-MS: tR= 1,14 min, ES+: 761,99.

Ethyl ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid (C29)

Powder Zn (944 mg, 14.4 mmol) was added to a solution of compound C28 (1.10 g, 1,45 mmol) in THF (15 ml) and glacial AcOH (1,30 ml). The mixture was stirred at room temperature for 3 hours. The mixture was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was distributed between CH2Cl2and aqueous saturated solution of NaHCO3and the organic layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 95:5) gave specified in the title compound (640 mg,79%). LC-MS: tR= 0,84 min, ES+: 599,48.

9-tert-Butyl ester 6-ethyl ester (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (C30)

A mixture of compound C29 (640 mg, 1.15 mmol), DIPEA (0,983, 5,74 mmol) and Boc2O (753 mg, of 3.45 mmol) in CH2Cl2(6,00 ml) was stirred at room temperature overnight. The mixture distribution is Yali between CH 2Cl2water and a saturated solution of NH4Cl. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc) gave specified in the title compound (750 mg, 99%). LC-MS: tR= 1.09 min, ES+: 658,15.

3,9-Di-tert-butyl ester 6-methyl ester (rat.)-(1R*,5S*)-7-{6-[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (C31)

3,9-Di-tert-butyl ester 6-methyl ester (rat.)-(1R*,5S*)-7-tripterocalyx-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (WO 2006/021402, 4,72 g of 8.90 mmol) and 2-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (5,77 g of the crude product, about 13.4 mmol) was dissolved in a mixture of DME (59.3 ml) and aqueous 2M solution of Na2CO3(44,5 ml). The mixture was degirolami N2was added Pd(PPh3)4(514 mg, 0,445 mmol). The mixture was quickly heated up to 80°C and stirred at this temperature for 1 hour. The mixture was diluted with EtOAc (100 ml) and washed with water (100 ml). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc 100% → EtOAc/MeOH 95:5) gave specified in zag is lowke connection (4,56 g, 73%). LC-MS: tR= 1.15 min, ES+: 703,25.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1S,5R)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (C32)

A solution of (R)-5-bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine (charged 8.52 g of 21.2 mmol) in THF (212 ml) at -78°C was treated with BuLi (1,6M in hexane, 22,1 ml). After 30 minutes stirring at -78°C was added ZnCl2(1,03M in THF, 41,1 ml, 42,4 mmol). The mixture was left to warm to room temperature. Added connection A1 (9,78 g, 23.5 mmol) in THF (5 ml) and Pd(PPh3)4(816 mg, 0,706 mmol). The mixture was quickly heated up to 75°C and stirred at this temperature for 1 hour. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc. The organic extracts washed with aqueous saturated solution of NH4Cl, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → heptane/EtOAc 60:40) gave a mixture of the mentioned in the title compounds (6,18 g, 45%). LC-MS: tR= 0.96 min, ES+: 588,19.

1'-tert-Butyl ether 3'-methyl ether (S)-6-[3-(2,6-dichloro-4-methyl-is enocsi)pyrrolidin-1-yl]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (C33)

A solution of (S)-5-bromo-2-[3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine (charged 8.52 g of 21.2 mmol) in THF (212 ml) at -78°C was treated with BuLi (1,6M in hexane, to 22.1 ml, was 35.3 mmol). The mixture was stirred at -78°C for 30 minutes and was added ZnCl2(1,03M in THF, 41,1 ml, 42,4 mmol). The mixture was left to warm to room temperature. Solution was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957; 9,17 g, 23.5 mmol) in THF (5 ml), and Pd(PPh3)4(816 mg, 0,701 mmol). The mixture was quickly heated up to 75°C and stirred at this temperature for 1 hour. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc. The organic extracts washed with aqueous saturated solution of NH4Cl, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → heptane:EtOAc 65:35) gave specified in the header connection (6,83 g, 52%). LC-MS: tR= 0,92 min, ES+: 562,36.

1'-tert-Butyl ether 3'-ethyl ester 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (C34)

Compound A2 (9,52 g, 23.6 mmol) and 2-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (13, g, 29.5 mmol) was dissolved in DME (164 ml) was added 2M aqueous solution of Na2CO3(118 ml). The mixture was degirolami N2(5 minutes) was added Pd(PPh3)4(1,36 g, 1.18 mmol). The mixture was quickly heated up to 80°C and stirred at this temperature for 1 hour. The mixture was left to cool to room temperature and diluted with EtOAc (200 ml). The mixture was washed with water (200 ml). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 30:70) gave specified in the header connection (8,45 g, 62%). LC-MS: tR= 1,13 min, ES+: 576,41.

1-tert-Butyl ester 3-methyl ester (rat.)-(3R*, 4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1,3-dicarboxylic acid (D1)

ADDP (2,78 g, 11.0 mmol) was added to a solution of compound E3 (1.85 g, 5,52 mmol) and [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (1.63 g, 6.62 mmol) in toluene (20 ml). Added a PBu3(90%, 5,44 ml, 20.0 mmol) and the mixture was stirred for 2 hours at 80°C. the Mixture was left to cool to room temperature and diluted with EtOAc. The resulting mixture was washed with water (1×) and saturated salt solution (2×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 2:8 → EtOAc) gave the University the data in the title compound (2.67 g, 86%). LC-MS: tR= 1,14 minutes; ES+: 563,26.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*, 2R*, 3S*, 5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (D2)

Mg (1,02 g of 41.8 mmol) was added to a solution of compound C2 (4,70 g, at 8.36 mmol) in MeOH (230 ml). The reaction mixture was stirred at room temperature for 2 hours. Again added Mg (1,02 g of 41.8 mmol) and the mixture was again stirred for 2 hours. The reaction mixture was heated at 70°C and stirred at this temperature for 16 hours. The mixture was left to cool to room temperature and extinguished aqueous saturated solution of NH4Cl (5 ml). Added EtOAc and the mixture was washed with water (2×) and saturated salt solution (1×). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 5:45 → 6:44 → 7:43 → 8:42) gave specified in the title compound (595 mg, 13%). LC-MS: tR= 1,18 minutes; ES+: 564,18.

The mixture of all possible stereoisomers of 1'-tert-butyl ester, 3'-methyl ester 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D3)

Compound C6 (7,00 g, 13,0 mmol) was dissolved in MeOH (130 ml). Was slowly added Mg (500 mg, of 20.6 mmol). The mixture was stirred for 1 hour and again added Mg (608 mg, 25,0 mmol). The mixture is eremetical 3 hours. Was slowly added aqueous 1M HCl solution and the mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the mixture was extracted with EtOAc. The organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum, received untreated specified in the title mixture of compounds (4,92 g, 70%), which was used without further purification. LC-MS: tR= 1.16 min, ES+ = 539,43.

3'-Methyl ether (rat.)-(3R*,4S*)-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D4)

The mixture of compounds D3 (of 5.40 g, 10.0 mmol) and MeONa (540 mg, 10.0 mmol) in MeOH (250 ml) was stirred overnight at 70°C. Again) was added MeONa (54 mg, 1.00 mmol) and the mixture was stirred for 5 hours at 70°C. Again) was added MeONa (54 mg, 1.00 mmol) and the mixture was stirred overnight at 70°C. was Added a 1M aqueous solution of HCl to achieve a pH of 6-7. The solvent was evaporated under reduced pressure and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 8:2 with 1% Et3N) gave specified in the header connection (4,92 g, 91%). LC-MS: tR= 1.16 min, ES+ = 539,43.

p> A mixture of all four possible steroisomers 1-tert-butyl ester 3-methyl ester 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (D5)

Mg (2,21 g, 91 mmol) was added in portions to a solution of compound C3 (22,5 g, 42 mmol) in MeOH (200 ml) at 0°C. the Mixture was stirred for 1.5 hours at 0°C was added EtOAc. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum was obtained mixture specified in the header of the compounds in crude form (22,6 g, quantitative yield). LC-MS: tR= 1,19 min, ES+ = 538,39.

1-tert-Butyl ester 3-methyl ester (rat.)-(3R*,4S*)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (D6)

MeONa (2,27 g, 42 mmol) was added to a solution of compounds D5 (22,6 g, 42 mmol) in MeOH (200 ml). The mixture was stirred at 70°C for 6 hours and again was added MeONa (2,27 g, 42 mmol). The mixture was stirred at 70°C for 2 days and left to cool to room temperature. Added EtOAc and the resulting mixture was washed with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl25:95 → 10:90) gave specified in the title compound (10.7 g, 47%). LC-MS: tR= 1,19 min, ES+ = 538,39.

1-tert-Butyl ester 3-methyl ester (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (D7)

Compound D6 (24.2 g, 45 mmol) was separated by HPLC (Regis R, R Whelk, isocratic conditions, eluent B 65%). Has been specified in the header of the connection (of 6.61 g, 27%). LC-MS: tR= 1,19 min, ES+ = 538,39. Chiral column HPLC: tR= 13,8 minutes.

8-tert-butyl ester 2-methyl ester (rat.)-(1R*,2R*,3S*,5S*)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (D8)

Mg (600 mg, or 24.7 mmol) was added to a solution of compound C21 (6,48 g, 11.5 mmol) in MeOH (350 ml). The mixture was intensively stirred at room temperature for 2 hours and again added Mg (1.20 g, 49.4 mmol). The mixture was stirred for 4 hours and again added Mg (600 mg, or 24.7 mmol). The mixture was stirred over night and again was added Mg (300 mg, 12.3 mmol). The mixture was stirred for 3 hours at room temperature and was heated at the boil under reflux overnight. The mixture was left to cool to room temperature and was added EtOAc (400 ml). The mixture was washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:19 � 3:47 → 6:75 → 1:9 → 9:75 → 2:15) gave specified in the title compound (1.12 g, 17%). LC-MS: tR= 1.16 min, ES+ = 565,33.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,2R,3S,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1S,2S,3R,5R)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (D9)

Mg (1.01 g, up 41.4 mmol) was added to a solution of compounds C23 (a 4.86 g of 8.27 mmol) in MeOH (83 ml). The mixture was stirred at room temperature for 2 hours. Again added Mg (1.01 g, up 41.4 mmol) and the mixture was stirred at room temperature until until proreagirovali all the amount of Mg. The mixture was heated at 70°C for 16 hours and left to cool to room temperature. Was added aqueous 1M HCl solution to pH 6-7 and the solvent was partially evaporated under reduced pressure. The aqueous residue was extracted with EtOAc. The organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Re-purification of the crude product using PF (heptane → heptane/EtOAc 90:10) gave a mixture of the mentioned in the title compound (820 mg, 17%). LC-MS: tR= 1,21 min, ES+ = 589,16.

A mixture of 8-tert-butyl ester 2-methyl ester (1R,2R,3S,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[.2.1]octane-2,8-dicarboxylic acid, 8-tert-butyl ester 2-methyl ester (1S, 2S, 3R, 5R)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester (1R,2R,3S,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (D10)

Mg (1.27 g, 52,3 mmol) was added in portions to a solution of compounds C32 (x 6.15 g, 10.5 mmol) in MeOH (105 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. Again added Mg (1.27 g, 52,3 mmol) and the mixture was stirred until then, while Mg is not reacted completely. The mixture was heated at 70°C and stirred at this temperature for 16 hours. The mixture was left to cool to room temperature and was added aqueous 1M HCl solution to pH 6-7. The solvent was partially evaporated under reduced pressure and the aqueous residue was poured into aqueous saturated solution of NH4Cl, diluted with EtOAc and intensively stirred. The mixture then was extracted with EtOAc and the combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → heptane/EtOAc 6:4) gave the mixture specified in the title compounds (3,26 g, 53%).

A mixture of 1'-tert-butyl EPE is a 3'-methyl ether (3'R,4'R)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid, 1'-tert-butyl ether 3'-methyl ether (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S, 4'R)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S, 4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-Il]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D11)

The mixture of compounds E5 (7,02 g, 17.3 mmol), 2,6-dichloro-p-cresol (3,68 g of 20.8 mmol), ADDP (6,56 g, 26.0 mmol) and PBu3(90%, 8,55 ml of 31.1 mmol) in toluene (340 ml) was stirred at 65°C for 5 hours. The mixture was left to cool to room temperature and was added EtOAc. The mixture was washed with water (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 4:6) gave a mixture of the mentioned in the title compounds (6,54 g, 67%). LC-MS: tR= 0.95 min, ES+ = 564,51.

A mixture of 1'-tert-butyl ether 3'-methyl ether (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid and (1'-tert-butyl ether 3'-methyl ether (3'S,4'R)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicar is about acid (D12)

MeONa (851 mg, 15.8 mmol) was added to a solution of compounds D11 (6,54 g, 12.1 mmol) in MeOH (250 ml). The mixture was stirred overnight at 70°C and was added MeONa (196 mg, 3.63 mmol)and the mixture was stirred for 3 days at 70°C. was Added aqueous 1M HCl solution to pH 6-7 and the solvents were partially removed under reduced pressure. The aqueous residue was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 8:2 → heptane/EtOAc 5:5 with a constant amount of 1% Et3N) gave a mixture of the mentioned in the title compounds (2,74 g, 42%).

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid(D13)

To a solution of compound E7 (590 mg, and 1.63 mmol) in toluene (10 ml) was added ADDP (824 mg, of 3.27 mmol), [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (441 mg, of 1.80 mmol) and PBu3(85%, 1,19 ml, is 4.85 mmol). The mixture was heated at the boil under reflux for 3 hours and left to cool to room temperature. The mixture was distributed between EtOAc and aqueous 10% solution of Na2CO3and the aqueous layer was extracted with EtOAc. The combined organic layers washed with aqueous saturated solution of Na2CO3the saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 8:2) gave specified in the header connection (772 mg, 80%). LC-MS: tR= 1,14 min, ES+ = 589,20.

A mixture of 1'-tert-butyl ether 3'-methyl ether (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S,4'R)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D 14)

Mg (1,03 g of 42.6 mmol) was added in four portions to a solution of compound C33 (5,00 g, 8,51 mmol) in MeOH (85 ml) at room temperature in a flask equipped with a reflux condenser and a bubble counter to control the allocation of H2. The mixture was stirred at room temperature for 2 hours. The mixture was heated to 70°C and stirred at this temperature for 16 hours. The mixture was left to cool to room temperature and was added aqueous 1M HCl solution to pH=6 to 7. The solvents were partially removed under reduced pressure and the aqueous mixture was poured into aqueous saturated solution of NH4Cl. Added EtOAc and the mixture was intensively stirred. The mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution, dried over MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → heptane/EtOAc 70:30) gave a mixture of the mentioned in the title compound (1.60 g, 33%).

1'-tert-Butyl ether 3'-ethyl ester (rat.)-(3'R,4'R)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D 15)

In dvuhgolosy flask with a capacity of 5 ml, dried hit gun and three insulated and filled with an inert atmosphere, was added chloride 1,3-bis(2,6-di-isopropylphenyl)imidazole copper (I) (Buchwald, S. L., et al, Org. Lett. 2003, 5, 2417, 466 mg, 0,955 mmol), NaOtBu (91,8 mg, 0,955 mmol) and toluene (9.5 ml). The suspension was stirred at room temperature for 10 minutes while she was turned into a clear solution. Added poly(methylhydrosiloxane) (6,89 ml, 115 mmol) and the resulting yellow-orange solution was stirred at room temperature for 5 minutes. Connection C34 (550 mg, of 9.55 mmol) in toluene (9.5 ml) was added in one portion at room temperature and the mixture was stirred for 1 minute. Undiluted tBuOH (10,8 ml, 115 mmol) was added dropwise within 15 minutes to control the evolution of a gas and the reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into a saturated solution of salt and mix several times was extracted with EtOAc. United organizes the e layers were dried over Na 2SO4was filtered and the solvents were removed under reduced pressure. The residue was dissolved in MeOH, while the precipitated poly(methylhydrosiloxane) and the mixture was filtered through celite. Purification of the residue using PF (heptane → heptane/EtOAc 70:30) gave specified in the title compound, contaminated with poly(methylhydrosiloxane) (7,32 g, quantitative yield). LC-MS: tR= 1,13 minutes; ES+: 578,57.

1'-tert-Butyl ether 3'-ethyl ester (rat.)-(3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (D 16)

A mixture of compound D15 (7,32 g, 12.7 mmol) and NaOEt (1.29 g, 19.0 mmol) in EtOH (253 ml) was stirred at 70°C during the night. The mixture was left to cool to room temperature. Aqueous 1M HCl solution was added until reaching pH 6-7 and the solvent was partially evaporated under reduced pressure. The mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvent was evaporated under reduced pressure. Purification of the crude product using PF (heptane → heptane/EtOAc 70:30) gave specified in the header connection (2,45 g, 33%). LC-MS: tR= 1,14 minutes; ES+: 578,42.

A mixture of 1-tert-butyl ester 3-methyl ester (rat.)-(3R*, 4R*)-4-(4-benzyloxy-phenyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl is the first ether (rat.)-(3R*, 4S*)-4-(4-benzyloxy-phenyl)piperidine-1,3-dicarboxylic acid (E1)

Mg (3,96 g, 163 mmol) was carefully added to a solution of compound B3 (20.6 g, 46 mmol) in MeOH (20 ml). The mixture was stirred for 2 hours and diluted with EtOAc. The resulting mixture was washed with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Drying under high vacuum gave specified in the title compound (19.7 g, 95%), which was used without further purification.

1-tert-Butyl ester 3-methyl ester (rat.)-(3R*,4S*)-4-(4-benzyloxy-phenyl)piperidine-1,3-dicarboxylic acid (E2)

MeONa (382 mg, 7,07 mmol) was rapidly added to a solution of compounds E1 (3,01 g, 7,07 mmol) in MeOH (20 ml). The mixture was stirred at 70°C for 6 hours. Again was added MeONa (382 mg, 7,07 mmol) and the mixture was stirred at 70°C for 3 days. Added EtOAc and the resulting mixture was washed with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc) gave specified in the header connection (2,88 g, 96%).

1-tert-Butyl ester 3-methyl ester (rat.)-(3R*,4S*)-4-(4-hydroxy-phenyl)piperidine-1,3-dicarboxylic acid (E3)

Received a solution of compound E2 (2,61 g, 6.12 mmol) in THF (20 ml). The mixture of products is Wali Ar was added Pd(OH) 2(20% coal-5,00 mg). The mixture was purged H2and stirred at room temperature overnight. The mixture was filtered through celite and the filtrate was evaporated under reduced pressure. After drying in high vacuum, received untreated specified in the title compound (1.85 g, 90%)which was used without further purification. LC-MS: tR= 0,93 minutes; ES+: 336,26.

A mixture of 1'-tert-butyl ether 3'-methyl ether (3'R,4'S)-6-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'R,4'R)-6-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S,4'S)-6-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S,4'R)-6-[(S)-3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (E4)

Mg (1,00 g, 41.2 mmol) was added to a solution of compounds B17 (15.5 g, 30.0 mmol) in MeOH (300 ml). The mixture was stirred for 1 hour, and the evolution of gas occurred after 30 minutes. Again added Mg (1,00 g, 41.2 mmol) and the mixture was again stirred for 2 hours. Was slowly added aqueous 1M of rest the p HCl and the mixture was stirred for 1 hour at room temperature. The mixture was extracted with EtOAc (5×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/MeOH 19:1 → CH2Cl2/Meon/Et3N 9:1:0,015) gave a mixture of the mentioned in the title compounds (5,65 g, 36%). LC-MS: tR= 0.97 min; ES+: 520,41.

A mixture of 1'-tert-butyl ether 3'-methyl ether (3'R,4'R)-6-((S)-3-hydroxy-pyrrolidin-1-yl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'R,4'S)-6-((S)-3-hydroxy-pyrrolidin-1-yl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S,4'R)-6-((S)-3-hydroxy-pyrrolidin-1-yl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether 3'-methyl ether (3'S,4'S)-6-((S)-3-hydroxy-pyrrolidin-1-yl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (E5)

TBAF (3,22 g, 10.2 mmol) was added to a solution of compounds E4 (5.30 g, 10.2 mmol) in THF (110 ml) at 0°C. the Mixture was stirred for 5 hours at 0°C and again was added TBAF (3,22 g, 10.2 mmol). The mixture was stirred for 2 hours at 0°C. was Added EtOAc and the mixture was washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Cleaning neocidin the CSO product using PF (EtOAc/heptane 2:1 → EtOAc) gave the mixture specified in the title compounds (2,80 g, 68%). LC-MS: tR= 0,71 minutes; ES+: 406,41.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,2R*,3S*,5S*)-3-(4-benzyloxy-phenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (E6)

Mg (1.35 g, at 55.6 mmol) was added to a solution of compound B19 (5,00 g, 11.1 mmol) in MeOH (310 ml) at 0°C. the Mixture was stirred for 2 hours at room temperature and again added Mg (1.35 g, at 55.6 mmol). The mixture was stirred for 4 hours at room temperature and in boiling under reflux for 19 hours. The mixture was left to cool to room temperature and was added aqueous saturated solution of NH4Cl. The mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 85:15) gave specified in the title compound (760 mg, 15%). LC-MS: tR= 1,13 minutes; ES+: 452,23.

8-tert-Butyl ester 2-methyl ester (rat.)-(1R*,2R*,3S*,5S*)-3-(4-hydroxy-phenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (E7)

Pd(OH)2-on-coal (20%, 76 mg) was added to a solution of compound E6 (760 mg, 1,68 mmol) in MeOH (5,00 ml) and THF (5 ml). The mixture was purged with N2then H2. The mixture was stirred in an atmosphere of H2throughout the night. The mixture was filtered through celite and the filtrate was evaporated under reduced on the no. After drying the residue under high vacuum, received untreated specified in the title compound (590 mg, 97%)which was used without further purification. LC-MS: tR= 0.95 min; ES+: 347,36.

(S)-1-(5-Bromo-pyridine-2-yl)pyrrolidin-3-ol (G1)

A mixture of 2,5-dibromopyridine (12.2 g, 51,5 mmol) and (S)-hydroxypyrrolidine (2,80 g, 32.1 mmol) in toluene (50 ml) was heated at boiling under reflux overnight. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (150 ml)and the mixture is washed with aqueous 10% solution of K2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → heptane/EtOAc 1:2) gave specified in the header connection (3,62 g, 46%). LC-MS: tR= 0.48 minutes; ES+: 243,15.

(S)-5-Bromo-2-[3-(tert-butyl-dimethylsiloxy)pyrrolidin-1-yl]pyridine (G2)

To a solution of G1 (20,9 g, to 85.8 mmol) in DMF (350 ml) at 0°C was added imidazole (14.6 g, 215 mmol) and TBDMS-Cl (19,4 g, 129 mmol). This mixture was stirred at room temperature for 1.5 hours and was added aqueous 10% solution of K2CO3(150 ml). The mixture was extracted with heptane (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Cleaning OST the ka using PF (heptane/EtOAc 5:1 → 4:1 → 3:1 → 1:1) gave specified in the title compound (30.5 g, 99%).

(R)-1-(5-Bromo-pyridine-2-yl)pyrrolidin-3-ol (G3)

A mixture of 2,5-dibromopyridine (10.0 g, 42.2 per mmol) and (R)-hydroxypyrrolidine (11,0 g, 126 mmol) in toluene (50 ml) was heated at boiling under reflux overnight. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (150 ml) and the mixture is washed with aqueous 10 % solution of K2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane → heptane/EtOAc 1:2) gave specified in the header connection (8,63 g, 84%). LC-MS: tR= 0.48 minutes; ES+: 243,15.

5-Bromo-2-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine (J1)

2.5-Dibromopyridine (12,6 g, to 53.0 mmol) and [3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-yl]methanol (10.0 g, up 40.7 mmol) was dissolved in toluene (400 ml). To the solution was added tBuONa (by 5.87 g, with 61.1 mmol), Xanthos (1.42 g, 2.45 mmol) and Pd2(dba)3(732 mg HDI, 0.800 mmol). The resulting mixture was heated at the boil under reflux during the night and left to cool to room temperature. The mixture was filtered through celite (washed with EtOAc and washed with aqueous saturated solution of NaHCO3(1×) and saturated salt solution (2×). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Clean n the purified product using PF (EtOAc/heptane 10:90) gave specified in the title compound (10.6 g, 65%). LC-MS: tR= 1,10 minutes; ES+: 400,66.

8-tert-Butyl ether (rat.)-(1R*,5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (K1)

Connection C2 (3,82 g, to 6.80 mmol) was dissolved in EtOH (100 ml). The solution was heated to 70°C and was added aqueous 1M NaOH solution (80 ml, 80 mmol). The mixture was stirred at 80°C for 3 hours and left to cool to room temperature. The solvents were partially removed under reduced pressure and the residue was poured into a separating funnel, filled with EtOAc. Added a 1M aqueous solution of HCl until the aqueous phase became acidic and the phases were shaken and separated. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 8-tert-butyl ether (rat.)-(1R*,5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-3-ene-2,8-dicarboxylic acid (3,45 g, 93%)which was used without further purification. LC-MS: tR= 1,13 minutes; ES+: 548,25.

1-tert-Butyl ester 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (K2)

Aqueous 1M LiOH solution (to 11.1 ml, 11.1 mmol) was added to a solution of compound C3 (1.50 g, of 2.72 mmol) in THF (0 ml). The mixture was stirred at 60°C for 3 days. The mixture was left to cool to room temperature and was added aqueous 1M HCl solution, until then, until the mixture became acidic. The mixture was extracted with EtOAc. The organic extracts washed with aqueous 1M HCl solution and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 1:2) gave specified in the title compound in a mixture of 1-tert-butyl ester 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (1,41 g, 99%). LC-MS: tR= 1,10 minutes; ES+: 522,30.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K3)

Compound C5 (1,02 g, 1.3 mmol) was dissolved in EtOH (14 ml)was added aqueous 1M NaOH solution (6 ml). The mixture was heated up to 80°C and stirred at this temperature for 3 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The residue was mixed with EtOAc and the mixture was acidified using 1M aqueous HCl solution. Phase distributed and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents UD is ranged under reduced pressure. After drying in high vacuum, received untreated specified in the title compound in a mixture of 3-tert-butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (864 mg, 87%), which is further used without purification. LC-MS: tR= 1.15 min; ES+: 768,23.

1'-tert-butyl ester 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K4)

A mixture of compound C6 (1,00 g of 1.86 mmol) and 1M aqueous solution of LiOH (7,00 ml of 7.00 mmol) in THF (7,00 ml) was stirred at 70°C during the night. Added a 1M aqueous solution of HCl to reach pH 4 and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum, received untreated specified in the title compound in a mixture of 1'-tert-butyl ester 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1,3'-dicarboxylic acid (850 mg, 87%)which was used without further purification.

1-tert-Butyl ester 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (K5)

Aqueous 1M LiOH solution (15.0 ml, 15.0 mmol) was added to a solution of compound C7 (2,04 g of 3.64 mmol) in THF (15 ml). The mixture is eremetical at 60°C for 3 days and was added aqueous 1M HCl solution. The mixture was extracted with EtOAc (2×). The combined organic extracts washed with aqueous 1M HCl solution and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc) gave the crude specified in the title compound in a mixture of 1-tert-butyl ester 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (600 mg, 30%). LC-MS: tR= 1,08 minutes; ES+: 547,20.

(1-tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1,3-dicarboxylic acid (K6)

A solution of compound D1 (2.00 g, 3.72 mmol) in THF (30 ml) and aqueous 1M NaOH solution (30 ml) was stirred at 70°C during the night. Added a 1M aqueous solution of HCl to reach pH 4. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum, received untreated specified in the header connection (2,04 g, quantitative yield)which was used without further purification. LC-MS: tR= 1,08 minutes; ES+: 549,31.

1'-tert-butyl ester 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K7)

A mixture of compound C8 (1,00 g, 1.78 mmol) and water is about 1M solution of LiOH (7,00 ml, 7,00 mmol) in THF (7,00 ml) was stirred overnight at 70°C. was Added a 1M aqueous solution of HCl to reach pH 4. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum has been specified in the title compound in a mixture of 1'-tert-butyl ester 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (976 mg, quantitative yield)which was used without further purification. LC-MS: tR= 1,06 minutes; ES+: 548,30.

9-(2,2,2-Trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (K8)

To a solution of compound C9 (3.03 g, 3,81 mmol) in EtOH (30 ml) was added aqueous 1M NaOH solution (15 ml). This mixture was heated up to 80°C and stirred at this temperature for 2.5 hours. The mixture was partially concentrated under reduced pressure. The residue was acidified using 2M aqueous HCl solution and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 9-(2,2,2-trichloro-1,1-dimethylethylamine) e is Il (rat.)-(1R*,5S*)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3,3,1]non-7-ene-6,9-dicarboxylic acid (2.70 g, quantitative yield)which was used without further purification. LC-MS: tR= 1,08 minutes; ES+: 710,09.

8-tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (K9)

To a solution of compound D2 (595 mg, 1.05 mmol) in EtOH (6,00 ml) was added aqueous 1M NaOH solution (2.0 ml) and the resulting mixture was stirred at room temperature for 1 hour and at 70°C during the night. The mixture was partially concentrated under reduced pressure and the aqueous residue was acidified using 2M aqueous HCl solution. The mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (573 mg, 98 %)which was used without further purification. LC-MS: tR= 1,11 minutes; ES+: 534,91.

8-tert-Butyl ether (rat.)-(1R*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (K10)

A solution of compound C10 (1.06 g, of 1.80 mmol) in EtOH (26,4 ml) was heated to 70°C. was Added aqueous 1M NaOH solution (20,6 ml) and the mixture was stirred for 2 hours at 70°C. the Mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The residue was acidified to p is 1 1M aqueous HCl solution and was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying in high vacuum, received untreated specified in the title compound in a mixture of 8-tert-butyl ether (rat.)-(1R*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3,2,1]Oct-3-ene-2,8-dicarboxylic acid (1,00 g, 95%)which was used without further purification.

9-(2,2,2-Trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (K11)

The mixture of compounds C13 (762 mg, 1.00 mmol) in EtOH (30 ml) and aqueous 1M NaOH solution (10 ml) was stirred at 75°C for 2 hours. The mixture was left to cool to room temperature. The solvents were partially removed under reduced pressure, and the residue was acidified using 1M aqueous HCl solution to pH 2-3. The mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-6,9-dicarboxylic acid (690 mg, 94%), which COI is litovali without additional purification. LC-MS: tR= 1,06 minutes; ES+: 735,00.

1'-tert-Butyl ether (rat.)-(3R*,4S*)-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K16)

A mixture of compound D4 (4,92 g, 9,12 mmol) in aqueous 1M NaOH solution (75 ml) and MeOH (75 ml) was stirred for 4.5 hours at 70°C. Aqueous 1M HCl solution was added until reaching a pH of about 4. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (4,63 g, 97%)which was used without further purification. LC-MS: tR= 1,08 min, ES+: 525,40.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K17)

The mixture of compounds C20 (1.29 g, 1.57 mmol) in EtOH (16 ml) and aqueous 1M NaOH solution (16 ml) was heated at boiling under reflux overnight. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The residue was acidified using 1M aqueous HCl solution and the resulting mixture was extracted with EtOAc (3×). The combined organic extracts were washed with saturated R is the target salt, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 3-tert-butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3,3,1]non-7-ene-3,6,9-tricarboxylic acid (1.24 g, 99%)which was used without further purification. LC-MS: tR= 1.15 min, ES+: 792,38.

8-tert-Butyl ether (rat.)-(1R*,5S*)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (K18)

Connection C21 was dissolved in a mixture of 1:1 MeOH and THF (50 ml). Added 2M aqueous NaOH (27 ml) and the mixture was stirred at room temperature overnight. The solvents were partially removed under reduced pressure and the residue was acidified to pH 1 aqueous 1M HCl solution. The mixture was extracted with EtOAc. The organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 8-tert-butyl ether (rat.)-(1R*,5S*)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-3-ene-2,8-dicarboxylic acid (1,91 g, 98%)which was used without further purification. LC-MS: tR= 1.09 min, ES+: 548,96

8-tert-Butyl ether (rat.)-(1R*,5S*)-3-{6-[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (K19)

Connection C22 (588 mg, 1.00 mmol) was dissolved in MeOH (30 ml) was added aqueous 1M NaOH solution (10 ml). The resulting suspension was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The aqueous residue was treated with aqueous 1M HCl solution to achieve a pH of about 2-3. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 8-tert-butyl ether (rat.)-(1R*,5S*)-3-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-3-ene-2,8-dicarboxylic acid (581 mg, quantitative yield)which was used without further purification. LC-MS: tR= 1,06 min, ES+: 574,16.

A mixture of 8-tert-butyl ether (1R,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ether (1S,5R)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2,8-dicarboxylic acid (K20)

Su is pensio compounds C23 (587 mg, 1.00 mmol) in MeOH (30 ml) and aqueous 1M NaOH solution (10 ml) was heated at boiling under reflux for 24 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The aqueous residue was treated with aqueous 1M HCl solution to achieve a pH of about 2-3, and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Drying of the residue over night under high vacuum gave the crude specified in the connection header in a mixture of 8-tert-butyl ester (1R,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-3-ene-2,8-dicarboxylic acid 8-tert-butyl ester (1S,5R)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-3-ene-2,8-dicarboxylic acid (592 mg, quantitative yield)that was used without additional purification. LC-MS: tR= 1.15 min, ES+: 573,20.

A mixture of 3,9-di-tert-butyl ether (1R,5S)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ether (1S,5R)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K21)

The mixture of compounds C24 (1.20 g, 1,67 mmol) in EtOH (18 ml) and aqueous 1M races the thief NaOH (6,00 ml) was stirred at room temperature for 1 hour and at 70°C for 5.5 hours. The mixture was left to cool to room temperature and partially concentrated under reduced pressure. The aqueous residue was acidified using 2M aqueous HCl solution and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated listed in the connection header in a mixture of 3,9-di-tert-butyl ester (1R,5S)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (1S,5R)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (1,15 g, quantitative yield)which was used without further purification. LC-MS: tR= 0,94 min, ES+: 689,19.

A mixture of 3,9-di-tert-butyl ether (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ether (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K22)

The mixture of compounds C25 (1.18 g, 1,67 mmol) in EtOH (18 ml) and aqueous 1M NaOH solution (to 6.00 ml) was stirred at room temperature for 1 hour and at 70°C for 5.5 hours. The mixture was left to cool until it is matney temperature and partially concentrated under reduced pressure. The aqueous residue was acidified using 2M aqueous HCl solution and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated listed in the connection header in a mixture of 3,9-di-tert-butyl ester (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (1.13 g, quantitative yield)which was used without further purification. LC-MS: tR= 0,92 min, ES+: 677,21.

1-tert-Butyl ether (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (K23)

A mixture of compound D7 (or 4.31 g, 8 mmol) in MeOH (50 ml) and aqueous 1M of NaOH it is (79 ml) was stirred at 80°C for 8 hours. The mixture was left to cool to room temperature and was added aqueous 2M HCl (50 ml). The mixture was extracted with EtOAc. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (4,18 g, the amount the state output). LC-MS: tR= 1.12 min, ES+: 524,41.

8-tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (K24)

Aqueous 1M NaOH solution (6,50 ml) was added to a solution of compound D8 (1.19 g, 2.10 mmol) in EtOH (12 ml). The mixture was heated at 70°C for 2 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The resulting mixture was distributed between EtOAc and aqueous 2M HCl solution. The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (1.07 g, 92%)which was used without further purification. LC-MS: tR= 1,08 min, ES+: 551,33.

3,9-di-tert-Butyl ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K25)

The mixture of compounds C27 (1,58 g, 2.21 mmol) in EtOH (22 ml) and aqueous 1M NaOH solution (22 ml) was heated at boiling under reflux for 4 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The residue was distributed between aqueous 1M HCl solution and EtOAc. layer was extracted with EtOAc. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection together with 3,9-di-tert-butyl ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (1,49 g, 98%)which was used without further purification. LC-MS: tR= 1,08 min, ES+: 688,1.

9-tert-Butyl ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6,9-dicarboxylic acid (K26)

The mixture of compounds C30 (750 mg, to 1.14 mmol) in EtOH (11 ml) and aqueous 1M NaOH solution (11 ml) was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and the solvents were removed under reduced pressure. The residue was distributed between aqueous 1M HCl and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection together with 9-tert-butyl ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-d is fluoro-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-6,9-dicarboxylic acid (720 mg, quantitative yield)which was used without further purification. LC-MS: tR= 1.00 min, ES+: 630,15.

3,9-Di-tert-butyl ether (rat.)-(1R*,5S*)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (K27)

A mixture of compound C31 (703 mg, 1.00 mmol) in MeOH (30 ml) and aqueous 1M NaOH solution (10 ml) was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. The aqueous residue was treated with aqueous 1M HCl solution to achieve a pH of about 2-3, and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound in a mixture of 3,9-di-tert-butyl ether (rat.)-(1R*,5S*)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (726 mg, quantitative yield)which was used without further purification. LC-MS: tR= 1,08 min, ES+: 689,50.

A mixture of 8-tert-butyl ester (1R,2R,3S,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ether (1S,2S,3R,5R)-3-{4-[(R)-3-(2,6-d is chloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (K28)

The mixture of compounds D9 (778 mg, 1,32 mmol) in EtOH (7.5 ml) and aqueous 1M NaOH solution (2.5 ml) was heated at 70°C during the night. The mixture was left to cool to room temperature and was added EtOAc. The mixture was acidified using 2M aqueous HCl and was extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum was obtained the crude mixture indicated in the title compound (740 mg, 97%), which was used without further purification. LC-MS: tR= 1,17 min, ES+: 575,21.

A mixture of 8-tert-butyl ester (1R,2R,3S,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ether (1S,2S,3R,5R)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ether (1R,2S,3R,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ether (1S,2R,3S,5R)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (K29)

The mixture of compounds D10 (1.24 g, 2.10 mmol) in EtOH (12 ml) and aqueous 1M NaOH solution (6,50 ml) was stirred at 70°C for 2 hours. The mixture was left to cool to room temperature and the solvent is partially what dalali under reduced pressure. The aqueous residue was distributed between EtOAc and aq. 2M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received neojidannyy mixture specified in the title compounds (1,17 g, 97%), which was used without further purification.

A mixture of 1'-tert-butyl ether (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether (3'S,4'R)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K30)

The mixture of compounds D12 (2,74 g, 5.08 mmol) in MeOH (50 ml) and aqueous 1M NaOH solution (50 ml) was stirred for 4 hours at 70°C. the Mixture was left to cool to room temperature and was added aqueous 1M HCl solution to pH~7. The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum was obtained the crude mixture indicated in the title compound (2.10 g, 75%)which was used without further purification. LC-MS: tR= 091 minutes ES+: 550,15.

8-tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2,8-dicarboxylic acid (K31)

To a solution of compound D13 (772 mg, 1,31 mmol) in EtOH (7,00 ml) was added aqueous 1M NaOH solution (2,60 ml) and the mixture was stirred at 70°C for 2 hours. The mixture was partially evaporated under reduced pressure and distributed between water and EtOAc. The aqueous layer was acidified using 1M aqueous HCl solution and was extracted with EtOAc. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the header connection (706 mg, 94%)which was used without further purification. LC-MS: tR= 1,07 min, ES+: 575,17.

A mixture of 1'-tert-butyl ether (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid 1'-tert-butyl ether (3'S,4'R)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K32)

Connection D14 (1.55 g, 2.82 mmol) was dissolved in MeOH (28 ml). Aqueous 1M NaOH solution (14 ml) was added and the mixture was heated at the boil under reflux for 2 hours. The mixture was left to cool to room temperature and aqueous 1 is a solution of HCl was added to achieve a pH of 5-6. The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc. The organic extracts washed with aqueous saturated solution of NH4Cl, dried over MgSO4, filtered and the solvents were removed under reduced pressure. Drying of the crude product under high vacuum gave the crude mixture indicated in the title compounds (1,38 g, 89%), which was used without further purification. LC-MS: tR= 0,89 min, ES+: 550,35.

1'-tert-Butyl ether (rat.)-(3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (K33)

A mixture of compound D16 (800 mg, 1.38 mmol) in 1M aqueous solution of NaOH (14 ml) and EtOH (28 ml) was stirred at 80°C for 2 hours. The mixture was left to cool to room temperature and the solvents were partially removed under reduced pressure. Aqueous 1M HCl solution was added to achieve pH 7 and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (757 mg, 99%)which was used without further purification. LC-MS: tR= 1.05 min, ES+: 550,38.

Di-tert-butyl ether (rat.)-(1R*,5S*)-6-{[2-chloro-5-(3-methoxy-propyl)benzo is l]cyclopropyl-carbarnoyl}-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L1)

3,9-Di-tert-butyl ether (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (300 mg, 0,463 mmol) was dissolved in toluene (10 ml). Was added DMF (1,8 ml) and oxacillin (52,7 μl, 0.6 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was carefully removed under reduced pressure and the residue was dissolved in CH2Cl2(7.5 ml). Within 10 minutes was added a solution of [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (176 mg, 0,693 mmol) and Et3N (97 μl, 0,693 mmol) in CH2Cl2(7.5 ml), then the mixture was stirred for 30 minutes. The mixture was evaporated and the residue was distributed between Et2O and aqueous 1M HCl solution. The organic fraction washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The solution of this residue (402 mg, 0,455 mmol) and NaOEt (21% in EtOH, 0,257 ml, 0,683 mmol) in EtOH (2,84 ml) was heated at 80°C during the night. The mixture was evaporated under reduced pressure and the residue was dissolved in Et2O. This mixture is washed with aqueous 1M HCl solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue with the help of the FG gave specified in the title compound (300 mg).

tert-Butyl ether (1R,5S)-6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]carbarnoyl}-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (L2)

To a solution of compound of example 4 (6,77 mmol) in THF (67,7 ml) was added triterpane (2,298 g, 7,11 mmol) and Et3N (2,85 ml, 20,31 mmol). The mixture was stirred overnight, then added to the time interval of 2 additional portions of reagents for 10% each. The solvent was evaporated under reduced pressure and the residue was purified using PF, getting cyclopropyl-[2,3-dichloro-5-(3-methoxypropyl)benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3-trityl-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid (to 5.21 mmol). To a solution of this compound (a total of 5.21 mmol) in CH2Cl2(52.1 ml) was added Boc2O (2,84 g, 13,0 3 mmol) and DIPEA (2,73 ml, 15,63 mmol). The mixture was stirred overnight and the solvent was evaporated under reduced pressure. The residue was purified using the PC, receiving tert-butyl ether (1R,5S)-6-{cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)benzyl]carbarnoyl}-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3-trityl-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (4,46 mmol). A solution of this compound (4,46 mmol) in AcOH (34,9 ml) and water (3,48 ml) was heated at 60°C for 1 hour 17 minutes. The solvent was evaporated and again azeotrope was evaporated with heptane (2×) and was purified chromatography the raffia on silica gel, getting listed at the beginning of the connection.

tert-Butyl ether (rat.)-(1R*,5S*)-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-carboxylic acid (L3)

The mixture of compounds K1 (3,15 g of 5.75 mmol), DIPEA (2,97 ml, 23,0 mmol), DMAP (175 mg, 1.44 mmol), HOBt (970 mg, 7.19 mmol) and EDC·HCl (1.65 g, 8,63 mmol) in CH2Cl2(110 ml) was stirred for 1 hour at room temerature. Was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-Amin (of 4.38 g, 17.3 mmol) and the mixture was stirred at room temperature for 8 days. The mixture was diluted with CH2Cl2and washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 3:7) gave specified in the header connection (3,45 g, 77%). LC-MS: tR= 1,28 minutes; ES+: 785,38.

tert-Butyl ester 5-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (L4)

To a solution of compound K2 (400 mg, 0,766 mmol) in CH2Cl2(8 ml) was added HOBt (129 mg, 0,957 mmol), DIPEA (0,524 ml of 3.06 mmol), DMAP (23,3 mg, 0,191 mmol), [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (291 mg, 1.15 mmol) and EDC·HCl (mg, 1.15 mmol). The mixture was stirred for 24 hours and diluted with CH2Cl2. The mixture is washed with aqueous 1M HCl solution and water, dried over Na2SO4was filtered and the solvent was evaporated under reduced pressure. Cleaning with PF (EtOAc/heptane/CH2Cl23:6:1 with 1% Et3N) gave specified in the title compound (406 mg, 70%). LC-MS: tR= 1,27 minutes; ES+: 759,42.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L5)

A mixture of compound K3 (805 mg, 1.05 mmol), DIPEA (to 0.72 ml, 4.20 mmol), DMAP (32.1 mg, to 0.263 mmol), HOBt (177 mg, 1,31 mmol) and EDC·HCl (302 mg, was 1.58 mmol) in CH2Cl2(15 ml) was stirred at room temperature for 1 hour. Was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (535 mg, 2.10 mmol) and the mixture was stirred for 4 days. Again, was added EDC·HCl (140 mg, 0,709 mmol), HOBt (100 mg, of 0.741 mmol) and [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (270 mg, 1.06 mmol). The mixture was stirred for 6 days and was added EDC·HCl (100 mg, 0,506 mmol) and HOBt (30 mg, 0,222 mmol). The mixture was stirred for 24 hours and diluted with additional CH2Cl2. The mixture is washed with aqueous 1M HCl solution (2×), aqueous 10% solution of Na2CO3(×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9) gave specified in the title compound (580 mg, 55%). LC-MS: tR= 1,32 minutes; ES+: 1003,40.

tert-Butyl ether 5'-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L6)

A mixture of compound K4 (484 mg, 0,925 mmol), [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (352 mg, of 1.39 mmol), HOBt (156 mg, of 1.16 mmol), DMAP (28,3 mg, 0,232 mmol), DIPEA (0,631 ml of 3.69 mmol) and EDC·HCl (265 mg, 1.38 mmol) in CH2Cl2(8 ml) was stirred overnight at room temperature. Added CH2Cl2and the mixture was stirred with aqueous 1M HCl solution (1×), water (1×) and saturated salt solution (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl21:49 → 1:19 c 2% Et3N) gave specified in the title compound (570 mg, 81%). LC-MS: tR= 1,28 minutes; ES+: 607,46.

tert-Butyl ether 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-5-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (L7)

A mixture of compound K5 (6004 mg, 1.10 mmol), [2-chloro-5-(3-methoxy-propyl)be the ZIL]cyclopropyl-amine (334 mg, of 1.32 mmol), HOBt (185 mg, 1.37 mmol), DMAP (33.6 mg, 0,285 mmol), DIPEA (0,751 ml, 4,39 mmol) and EDC·HCl (315 mg, of 1.64 mmol) in CH2Cl2(4 ml) was stirred for 2 days at room temperature. The mixture was filtered through an Isolute® (0.6 g), previously washed with aqueous 1M HCl solution. The organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure. Purification of the residue using PF (EtOAc/heptane/CH2Cl23:1:6 1% Et3N) gave specified in the header connection (784 mg, 91%). LC-MS: tR= 1,22 minutes; ES+: 782,54.

tert-Butyl ester 5-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (L8)

A mixture of compound K2 (500 mg, 0,957 mmol), [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (300 mg, 1.18 mmol), DIPEA (0,655 ml, a 3.83 mmol), DMAP (29.3 mg, 0,240 mmol), HOBt (162 mg, 1.20 mmol) and EDC·HCl (275 mg, 1,43 mmol) in CH2Cl2(2 ml) was stirred at room temperature for 48 hours. The mixture was filtered through an Isolute® (0.6 g), previously washed with aqueous 1M HCl solution (1 ml). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane/CH2Cl23:1:6 1% Et3N) gave specified in the title compound (650 mg, 89%). LC-MS: tR= 1.20 min; E+: 758,52.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}piperidine-1-carboxylic acid (L9)

A mixture of compound K6 (1,00 g, 1.82 mmol), [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (694 mg, to 2.94 mmol), HOBt (307 mg, 2.28 mmol), DMAP (55,1 mg, 0,456 mmol), DIPEA (1,24 ml, 7,26 mmol) and EDC·HCl (1,49 g of 2.72 mmol) in CH2Cl2(16 ml) was stirred for 24 hours. The mixture was diluted with CH2Cl2and washed with aqueous 1M HCl solution, water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane/CH2Cl2with 1% Et3N) gave specified in the title compound (1.24 g, 87%). LC-MS: tR= 1,23 minutes; ES+: 784,40.

tert-Butyl ester 6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-5'-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L10)

A mixture of compound K7 (500 mg, 0,913 mmol), [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (347 mg, 1.37 mmol), HOBt (154 mg, to 1.14 mmol), DMAP (27.9 mg, 0,228 mmol), DIPEA (0,623 ml, 3.63 mmol) and EDC·HCl (261 mg, and 1.63 mmol) in CH2Cl2(8.0 ml) was stirred for 24 hours. The mixture was diluted with CH2Cl2and the mixture is washed with aqueous 1M HCl solution, water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (acetone/heptane 3:1 → acetone, always with the addition of 1% Et3N) gave specified in the title compound (344 mg, 48%). LC-MS: tR= 1.20 min; ES+: 783,39.

2,2,2-Trichloro-1,1-dimethylethylamine ether (rat.)-(1R*,5S*)-3-acetyl-6-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (L11)

To a solution of compound K8 (1,00 g of 1.41 mmol) in CH2Cl2(17 ml) was sequentially added at room temperature DIPEA (0,965 ml, 5,64 mmol), DMAP (to 43.1 mg, 353 mmol), HOBt (238 mg, of 1.76 mmol) and EDC·HCl (675 mg, of 3.53 mmol). This mixture was stirred at room temperature for 45 minutes and was added [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (664 mg, 2,61 mmol). The mixture was stirred at room temperature for 3 days. To the mixture was added EDC·HCl (270 mg, 1.37 mmol) and HOBt (190 mg, of 1.41 mmol) was stirred at room temperature for 2 days. To the reaction mixture was added EDC·HCl (135 mg, 0,684 mmol) and stirred for 2 days. To the reaction mixture was added EDC·HCl (135 mg, 0,684 mmol), HOBt (95 mg, 0,704 mmol) and [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (359 mg, of 1.41 mmol), which was stirred for 6 DN is th at room temperature. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and NaHCO3(1×). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:4 → 1:3 → 1:2 → 1:1 → 2:1 → EtOAc) gave specified in the title compound (722 mg, 54%). LC-MS: tR= 1.20 min; ES+: 783,39.

tert-Butyl methyl ether(rat.)-(1R*,2R*,3S*,5S*)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L12)

To a solution of compound K9 (573 mg, 1.04 mmol) in CH2Cl2(10 ml) was sequentially added DIPEA (0,713 ml of 4.16 mmol), DMAP (31.8 mg, is 0.260 mmol), HOBt (176 mg, of 1.30 mmol) and EDC·HCl (499 mg, 2,60 mmol). This reaction mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (462 mg, of 1.93 mmol). The mixture was stirred over night. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:5 → 1:3 → 1:1 → 2:1) gave specified in the title compound (448 mg, 56%). LC-MS: tR= 1.25 min; ES+: 771,16.

tert-Butyl methyl ether(rat.)-(1R*,2R*,3S*,5S*)-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L13)

To a solution of compound K9 (130 mg, 0,236 mmol) in CH2Cl2(1.5 ml) was sequentially added DIPEA (0,122 ml, 0,945 mmol), DMAP (7,09 mg, 0,058 mmol), HOBt (and 39.7 mg, 0,294 mmol) and EDC·HCl (113 mg, 0,592 mmol). This mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (111 mg, 0,437 mmol). The mixture was stirred at room temperature overnight. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:5 → 1:3 → 1:1 → 2:1) gave specified in the title compound (137 mg, 73 %). LC-MS: tR= 1,27 minutes; ES+: 787,16.

tert-Butyl ether (rat.)-(1R*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-carboxylic acid (L14)

To a solution of compound K10 (573 mg, 1.00 mmol) in dry DMF (15 ml) was sequentially added at room temperature DIPEA (0,685 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol) and EDC·HCl (479 mg, of 2.50 mmol). The mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (381 mg, 1.50 mmol). A mixture of AC is stirred for 6 days. The reaction mixture was diluted with EtOAc and washed with aqueous 1M HCl solution (3×), and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 30:70) gave specified in the title compound (492 mg, 61%). LC-MS: tR= 1,22 minutes; ES+: 808,22.

2,2,2-Trichloro-1,1-dimethylethylamine ether (rat.)-(1R*,5S*)-3-acetyl-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid(L15)

To a solution of compound K11 (680 mg, 0,926 mmol) in dry DMF (13,9 ml) was sequentially added at room temperature DIPEA (0,634 ml, 3,70 mmol), DMAP (28,2 mg, 0,231 mmol), HOBt (156 mg, of 1.16 mmol) and EDC·HCl (444 mg, 2.32 mmol). The reaction mixture was stirred at room temperature for 75 minutes, then was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-amine (352 mg, of 1.39 mmol). The mixture was stirred for 6 days and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc and the resulting mixture was washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using the PF (EtOAc/heptane 1/1) gave specified in the title compound (373 mg, 42%). LC-MS: tR= 1,27 minutes; ES+: 970,38.

tert-Butyl ether 5'-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',6'-dihydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L20)

A mixture of compound K4 (700 mg, of 1.34 mmol), [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (409 mg, 1,60 mmol), DIPEA (0,915 ml, to 5.35 mmol), DMAP (of 40.9 mg, 0,335 mmol), HOBt (226 mg, 1,67 mmol) and EDC·HCl (384 mg, 2.00 mmol) in CH2Cl2(2.00 ml) was stirred for 48 hours at room temperature. The mixture was filtered through an Isolute®, pre-washed with aqueous 1M HCl solution, elwira CH2Cl2. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by HPLC (x-Bridge column, acetonitrile/H2O + 0.05% of formic acid 10:90 → 90:10, for 6 minutes) gave specified in the title compound (249 mg, 25%). LC-MS: tR= 1,29 minutes; ES+: 1004,42.

tert-Butyl ether (rat.)-(3'R*,4'S*)-3'-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L21)

The mixture of compounds K16 (1,00 g, 1,90 mmol), [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (485 mg, 1,90 mmol), DIPEA (1,30 ml, to 7.61 mmol), DMAP (58,1 mg, 0,476 mmol), HOBt (221 mg, of 2.38 mmol) and EDC·HCl (547 mg, of 2.86 mmol who) in CH 2Cl2(4,00 ml) was stirred for 24 hours at room temperature. Added EDC·HCl (250 mg, of 1.27 mmol) and the mixture was again stirred for 24 hours. Added EDC·HCl (100 mg, 0,506 mmol) and the mixture was again stirred for 24 hours. Added CH2Cl2and the solution washed with aqueous 1M HCl solution, water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/MeOH 98:2% → 95:5) gave specified in the title compound (414 mg, 29%). LC-MS: tR= 1,19 minutes; ES+:763,60.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-6-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L22)

The mixture of compounds K17 (1.24 g, 1.57 mmol), DIPEA (1.07 ml, 6,27 mmol), DMAP (47,9 mg, 0,392 mmol), HOBt (300 mg, a 1.96 mmol) and EDC·HCl (751 mg, to 3.92 mmol) in CH2Cl2(24,00 ml) was stirred for 3 hours at room temperature. Added [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (738 mg, 2,90 mmol) and the mixture was stirred for 11 days. Added CH2Cl2and the solution washed with aqueous 1M HCl solution, water and saturated salt solution. The organic layer was dried n the l MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 9:1) gave specified in the title compound (850 mg, 53%). LC-MS: tR= 1,24 minutes; ES+: 1028,60.

tert-Butyl ether 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-5-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (L23)

A mixture of compound K5 (700 mg, 1.28 mmol), [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (391 mg, 1.54 mmol), DIPEA (0,876 ml, 5,12 mmol), DMAP (39,2 mg, 0,321 mmol), HOBt (216 mg, 1,60 mmol) and EDC·HCl (368 mg, 1.92 mmol) in CH2Cl2(2.00 ml) was stirred for 2 days at room temperature. The mixture was filtered through an Isolute®, pre-washed with aqueous 1M HCl solution using CH2Cl2as eluent. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 2:8) gave specified in the title compound (548 mg, 55%). LC-MS: tR= 1,16 minutes.

tert-Butyl ether (rat.)-(1R*,5S*)-3-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropanecarbonyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-carboxylic acid (L24)

To a solution of compound K19 (574 mg, 1.00 mmol) in dry DMF (15 ml) placentas is tion was added at room temperature DIPEA (0,685 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol) and EDC·HCl (479 mg, of 2.50 mmol). The reaction mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (381 mg, 1.50 mmol). The mixture was stirred for 6 days. The mixture was diluted with EtOAc and washed with aqueous 1M HCl solution (3x) and aqueous saturated solution of NaHCO3(1x). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 40:60) gave specified in the title compound (486 mg, 60%). LC-MS: tR= 1,21 minutes; ES+:809,21.

A mixture of tert-butyl methyl ether (1R,5S)-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-carboxylic acid tert-butyl ester (1S,5RS)-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-carboxylic acid (L25)

To a solution of compounds K20 (574 mg, 1.00 mmol) in CH2Cl2(15 ml) was sequentially added at room temperature: DIPEA (0,685 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol) and EDC·HCl (479 mg, of 2.50 mmol). The mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(3-methoxy-propyl)benzyl]qi is sapropel-amine (381 mg, 1.50 mmol). The mixture was stirred for 6 days. The mixture was diluted with EtOAc and washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 30:70) gave the mixture specified in the title compound (525 mg, 65%). LC-MS: tR= 1,31 minutes; ES+:810,26.

A mixture of di-tert-butyl ether (1R,5S)-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ether (1S,5R)-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L26)

To a solution of compounds K21 (1,15 g, 1,67 mmol) in CH2Cl2(25 ml) was sequentially added at room temperature: DIPEA (1,14 ml, to 6.67 mmol), DMAP (50,8 mg, 0,416 mmol), HOBt (282 mg, of 2.08 mmol) and EDC·HCl (799 mg, of 4.17 mmol). The mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (719 mg, 3.00 mmol). The mixture was stirred at room temperature for 18 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and water nassen is m solution of NaHCO 3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 1:7 → 1:5 → 1:3 → 1:1 → 2:1) gave a mixture of the mentioned in the title compound (559 mg, 37%). LC-MS: tR= 1,08 minutes; ES+:912,08.

A mixture of di-tert-butyl ether (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ether (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L27)

To a solution of compounds K22 (1.13 g, 1,67 mmol) in CH2Cl2(25 ml) was sequentially added at room temperature: DIPEA (1,14 ml, to 6.67 mmol), DMAP (50,8 mg, 0,416 mmol), HOBt (282 mg, of 2.08 mmol) and EDC·HCl (799 mg, of 4.17 mmol). The mixture was stirred at room temperature for 45 minutes and was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (719 mg, 3.00 mmol). The mixture was stirred at room temperature for 18 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. the cleaning of the crude product using PF (EtOAc/heptane 1:9 → 1:7 → 1:5 → 1:3 → 1:1 → 2:1) gave a mixture of the mentioned in the title compound (581 mg, 39%). LC-MS: tR= 1,04 minutes; ES+:898,10.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-6-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L28)

To a solution of compound K3 (894 mg, of 1.16 mmol) in CH2Cl2(15 ml) was sequentially added at room temperature: DIPEA (0,797 ml of 4.66 mmol), DMAP (35.6 mg, 0,292 mmol), HOBt (197 mg, of 1.46 mmol) and EDC·HCl (558 mg, only 2.91 mmol). This mixture was stirred at room temperature for 45 minutes and was added [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (548 mg, of 2.15 mmol). The mixture was stirred for 18 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:4 → 1:3 → 1:2 → 1:1 → 2:1 → EtOAc) gave specified in the title compound (325 mg, 28%). LC-MS: tR= 1,29 minutes; ES+: 1004,42.

tert-Butyl ether (3R,4S)-3-{[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (L29)

The mixture of compounds K23 (399 mg, 0,761 mmol), [5-chloro-2-(3-methoxy-propyl)is iridin-4-ylmethyl]cyclopropyl-amine (194 mg, 0,761 mmol), HOBt (129 mg, 0,952 mmol), DMAP (23,2 mg, 0,190 mmol), DIPEA (0,521 ml of 3.05 mmol) and EDC·HCl (219 mg, to 1.14 mmol) in CH2Cl2(8,00 ml) was stirred at room temperature for 24 hours. Again, was added HOBt (129 mg, 0,952 mmol), DMAP (23,2 mg, 0,190 mmol), DIPEA (0,521 ml of 3.05 mmol) and EDC·HCl (219 mg, to 1.14 mmol) and the mixture was stirred for 6 hours. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19 with 1% Et3N) gave specified in the title compound (105 mg, 18%). LC-MS: tR= 1,21 minutes; ES+: 762,49.

tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L30)

The mixture of compounds K24 (1.08 g, of 1.95 mmol), DIPEA (of 1.34 ml, 7,80 mmol), DMAP (to 59.6 mg, 0,488 mmol), HOBt (329 mg, 2,44 mmol) and EDC·HCl (561 mg, at 2.93 mmol) in CH2Cl2(30 ml) was stirred at room temperature for 15 minutes. Was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (701 mg, at 2.93 mmol) and the mixture was stirred for 4 days at room temperature. Added CH2Cl2(250 ml) and the mixture is washed with aqueous 1M HCl solution (2×), water and saturated Rast is a PR NaHCO 3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:10) gave specified in the title compound (710 mg, 47%). LC-MS: tR= 1,24 minutes; ES+: 774,41.

3-tert-Butyl ester 9-(2,2,2-trichloro-1,1-dimethylethylamine) ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L31)

The mixture of compounds K17 (940 mg, 1,19 mmol), EDC·HCl (569 mg, to 2.67 mmol), HOBt (227 mg, 1,49 mmol), DMAP (36,3 mg, 0,297 mmol) and DIPEA (0,814 ml of 4.75 mmol) in CH2Cl2(18 ml) was stirred at room temperature for 3 hours. Was added [2-chloro-5-(2-methoxy-propyl)benzyl]cyclopropyl-amine (558 mg, of 2.20 mmol) and the mixture was stirred at room temperature for 2 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 65:35 → EtOAc) gave specified in the title compound (560 mg, 45%). LC-MS: tR= 1,30 minutes; ES+: 1027,30.

Di-tert-butyl ether (rat.)-(1R*,5S*)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]t is chlorophyl-carbarnoyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L32)

The mixture of compounds K25 (1.45 g, 2,17 mmol), EDC·HCl (1.04 g, 5,42 mmol), HOBt (414 mg, a 2.71 mmol), DMAP (66,1 mg, 0,541 mmol) and DIPEA (1,48 ml, 8,67 mmol) in CH2Cl2(32 ml) was stirred at room temperature for 3 hours. Was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (961 mg, 4,01 mmol) and the mixture was stirred at room temperature for 24 hours. Again, was added EDC·HCl (1.04 g, 5,42 mmol), HOBt (414 mg, a 2.71 mmol) and DMAP (cat. number), and the mixture was stirred at room temperature for 6 days. Again, was added EDC-HCl (1.04 g, 5,42 mmol), HOBt (414 mg, a 2.71 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 6 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 7:3) gave specified in the title compound (990 mg, 50%). LC-MS: tR= 1,22 minutes; ES+: 909,39.

tert-Butyl ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (L33)

The mixture of compounds K26 (720 mg, to 1.14 mmol), EDC·HCl (548 mg, of 2.86 mmol), HOBt (219 mg, 1,43 mmol), DMAP (34,9 mg, 0,286 mmol) and DIPEA (0,783 ml of 4.75 mmol) in CH2Cl2(1 ml) was stirred at room temperature for 3 hours. Was added [2-chloro-5-(2-methoxy-propyl)benzyl]cyclopropyl-amine (537 mg, 2,12 mmol) and the mixture was stirred at room temperature for 24 hours. EDC·HCl (548 mg, of 2.86 mmol). Again, was added HOBt (219 mg, 1,43 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 1 day. Again, was added EDC-HCl (548 mg, of 2.86 mmol), HOBt (219 mg, 1,43 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 1 day. Again, was added EDC-HCl (548 mg, of 2.86 mmol), HOBt (219 mg, 1,43 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 6 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc) gave specified in the title compound (550 mg, 56%). LC-MS: tR= 1.20 min; ES+: 865,11.

tert-Butyl ether (rat.)-(1R*,5S*)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-6-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-9-carboxylic acid (L34)

The mixture of compounds K26 (1.13 g, to 1.79 mmol), EDC·HCl (860 mg, of 4.49 mmol), HOBt (343 mg, 2,24 mmol), DMAP (54.9 mg, 0,449 mmol) and DIPEA (1.23 ml, 7,18 mmol) in CH2Cl2(27 ml) was stirred at room temperature for 3 hours. Added [-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (795 mg, of 3.32 mmol) and the mixture was stirred at room temperature for 3 days. Again, was added EDC·HCl (354 mg, to 1.79 mmol), HOBt (242 mg, to 1.79 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 2 days. Again, was added EDC·HCl (354 mg, to 1.79 mmol), HOBt (242 mg, to 1.79 mmol), and DMAP (cat. number) and the mixture was stirred at room temperature for 1 day. Again, was added EDC·HCl (177 mg, 0.90 mmol), HOBt (121 mg, 0.90 mmol) and DMAP (cat. number) and the mixture was stirred at room temperature for 5 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 7:3 → EtOAc → MeOH/CH2Cl21:9) gave specified in the title compound (560 mg, 37%). LC-MS: tR= 1,19 minutes; ES+: 851,36.

Di-tert-butyl ether (rat.)-(1R*,5S*)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid (L35)

The mixture of compounds K27 (689 mg, 1.00 mmol), DIPEA (0,685 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol) and EDC·HCl (479 mg, of 2.50 mmol) in DMF (15 ml) was stirred at room temperature for 45 minutes. Was added [2-chloro-5-(2-methoxy-propyl)benzyl]ecoprofile-amine (381 mg, 1.50 mmol) and the mixture was stirred for 6 days. The mixture was diluted with EtOAc and washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 40:60) gave specified in the title compound (452 mg, 49%). LC-MS: tR= 1,23 minutes; ES+: 924,18.

A mixture of tert-butyl methyl ether (1R,2R,3S,5S)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1S,2S,3R,5R)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L36)

The mixture of compounds K28 (742 mg, 1,29 mmol), DIPEA (0,883 ml, 5,16 mmol), DMAP (39,5 mg, 0,323 mmol), HOBt (218 mg, of 1.61 mmol), EDC·HCl (371 mg, 1.94 mmol) and [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (464 mg, 1.94 mmol) in CH2Cl2(20 ml) was stirred at room temperature for 24 hours. Was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (155 mg, 0,647 mmol) and the mixture was stirred for 3 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4, who was intervali and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:9 → 1:1) gave a mixture of the mentioned in the title compound (470 mg, 46%). LC-MS: tR= 1,31 minutes; ES+: 798,29.

A mixture of tert-butyl methyl ether (1R,2R,3S,5S)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1S,2S,3R,5R)-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L37)

The mixture of compounds K29 (577 mg, 1.00 mmol), DIPEA (0,684 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol), EDC·HCl (288 mg, 1.50 mmol) and [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (240 mg, 1.00 mmol) in CH2Cl2(20 ml) was stirred at room temperature for 7 days. Added DIPEA (0,171 ml, 1.00 mmol), HOBt (135 mg, 1.00 mmol) and EDC·HCl (197 mg, 1.00 mmol) and the mixture was stirred for 3 days. Added EDC·HCl (98 mg, 0.50 mmol) and the mixture was stirred for 3 days. The mixture was diluted with CH2Cl2(80 ml) and washed with aqueous 1M HCl solution (2×) and aqueous 10% solution of Na2CO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:3 → 1:1) gave a mixture specified in the header of the connection is on (150 mg, 19%). LC-MS: tR= 1,01 minutes; ES+: 799,41.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L38)

The mixture of compounds K30 (600 mg, of 1.09 mmol), DIPEA (0,746 ml, 4,36 mmol), DMAP (33.3 mg, 0,273 mmol), HOBt (184 mg, of 1.36 mmol), EDC·HCl (313 mg, of 1.64 mmol) and [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (261 mg, of 1.09 mmol) in CH2Cl2(10 ml) was stirred at room temperature for 3 days. Added EDC·HCl (200 mg, of 1.02 mmol) and the mixture was stirred for 6 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution, water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave a mixture of the mentioned in the title compound (624 mg, 74%). LC-MS: tR= 1.05 min; ES+: 771,30.

tert-Butyl ether (rat.)-(1R*,5S*)-2-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-8-karbonvansty (L39 are effective)

To a solution of compound K1 (548 mg, 1.00 mmol) in DMF (15 ml) was sequentially added at room temperature: DIPEA (0,685 ml, 4.00 mmol), DMAP (30,5 mg of 0.250 mmol), HOBt (169 mg, 1.25 mmol) and EDC·HCl (479 mg, of 2.50 mmol). The reaction mixture was stirred at room temperature for 45 minutes and was added [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (361 mg, 1.50 mmol). The mixture was stirred for 6 days. The mixture was diluted with EtOAc and washed with aqueous 1M HCl solution (3×) and aqueous saturated solution of NaHCO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane → EtOAc/heptane 50:50) gave specified in the title compound (190 mg, 24%). LC-MS: tR= 1,22 minutes; ES+: 786,19.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5'6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ether (3'S,4'R)-3'-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L40)

The mixture of compounds K30 (600 mg, of 1.09 mmol), DIPEA (0,746 ml, 4,36 mmol), DMAP (33.3 mg, 0,273 mmol), HOBt (184 mg, of 1.36 mmol), EDC·HCl (313 mg, of 1.64 mmol) and [5-chloro-2-(3-methoxy-propyl)PI is one-4-ylmethyl]cyclopropyl-amine (333 mg, to 1.31 mmol) in CH2Cl2(10 ml) was stirred at room temperature for 2 days. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution, water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2→ MeOH/CH2Cl21:9) gave a mixture of the mentioned in the title compound (330 mg, 39%). LC-MS: tR= 1,01 minutes; ES+: 788,67.

tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-2-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L41)

To a solution of compound K31 (706 mg, of 1.23 mmol) in CH2Cl2(18 ml) was added EDC·HCl (589 mg, of 3.07 mmol), HOBt (235 mg, 1.53 mmol), DIPEA (0,841 ml, 4,91 mmol) and DMAP (37,3 mg, 0,306 mmol). The mixture was stirred at room temperature for 2 hours and was added [2-chloro-5-(2-methoxy-propyl)benzyl]cyclopropyl-amine (530 mg, of 2.09 mmol). The mixture was stirred at room temperature for 3 days. To the reaction mixture was added EDC·HCl (118 mg, 0,614 mmol), HOBt (82,9 mg, 0,614 mmol), DMAP (15,0 mg, 0,123 mmol) and DIPEA (0,420 ml of 2.46 mmol) and the mixture was stirred for 7 days. The mixture was diluted with CH2Cl2and washed with aqueous 1M HCl solution. The aqueous layer was extracted with CH2Cl2. The combined organic is their extracts are washed with aqueous saturated solution of NaHCO 3, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/EtOAc 2:8) gave specified in the title compound (360 mg, 36%). LC-MS: tR= 1,22 minutes; ES+: 810,45.

tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-2-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L42)

To a solution of compound K31 (1,16 g, 2.02 mmol) in CH2Cl2(20 ml) was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (484 mg, 2.02 mmol), DIPEA (1.04 million ml, 6.05 mmol) and TBTU (968 mg, to 3.02 mmol). The mixture was stirred at room temperature for 3 days. The mixture was distributed between CH2Cl2and water and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 2:3) gave specified in the header connection (1,00 g, 62%). LC-MS: tR= 1,21 minutes; ES+: 796,44.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-f is noxi)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L43)

A solution of compounds K32 (1.19 g, 2,17 mmol) in CH2Cl2(22 ml) was treated with TBTU (833 mg, 2,60 mmol) and DIPEA (1,11 ml of 6.49 mmol) and the resulting solution was stirred for 30 minutes at room temperature. Was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (649 mg, a 2.71 mmol) and the resulting solution was stirred at room temperature for 3 hours. Was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (162 mg, 0,678 mmol). The mixture was stirred for 2 hours and was poured into aqueous saturated solution of NaHCO3. The resulting mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 50:50) gave a mixture of the mentioned in the title compounds (2,34 g, quantitative yield). LC-MS: tR= 1,01 minutes; ES+: 773,46.

tert-Butyl ether (rat.)-(1R*,2R*,3S*,5S*)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-2-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-8-azabicyclo[3.2.1]octane-8-carboxylic acid (L44)

To a solution of compound K31 (620 mg, of 1.08 mmol) in CH2Cl2(6,00 ml) was added [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (275 mg, of 1.08 mmol), DIPEA (3,24 mmol) and TBTU (1,61 mmol). The mixture was stirred at room temperature for 3 days. EXT is ulali CH 2Cl2and the mixture was washed with water. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 1:1) gave specified in the title compound (450 mg, 51%). LC-MS: tR= 1.16 min; ES+: 811,48.

tert-Butyl methyl ether(rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-piperidine-1-carboxylic acid (L45)

A mixture of compound K6 (700 mg, 1.28 mmol), DMF (cat. number) and oxalicacid (0,140 ml, by 1.68 mmol) in toluene (20 ml) was stirred for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dissolved in CH2Cl2(20 ml). Added Et3N (0,267 ml, 1.92 mmol) and [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (488 mg, 1.92 mmol) and the mixture was stirred for 30 minutes at room temperature. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound (670 mg, 67%)which was used without further purification. LC-MS: tR= 1.16 min; ES+: 785,31.

tert-Butyl methyl ether(RA is.)-(3R*,4S*)-3-{[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L46)

Oxalicacid (0,140 ml of 1.66 mmol) was added to a solution of compound K6 (700 mg, 1.28 mmol) in toluene (22 ml) and DMF (0,020 ml). The mixture was stirred at room temperature for 1 hour and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(17 ml) was added Et3N (0,266 ml, at 1.91 mmol). The mixture was stirred for 5 minutes and the solution was added N-(4-chloro-3-cyclopropylamino-benzyl)ndimethylacetamide (484 mg, at 1.91 mmol) in CH2Cl2(7.0 ml). The mixture was stirred at room temperature overnight and washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:49) gave specified in the title compound (502 mg, 50%). LC-MS: tR= 1.15 min; ES+: 783,27.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4 'R)-3'-{[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L47)

Oxalicacid (0,136 ml, 1.57 mmol) was added to a solution of compounds K30 (720 m is, to 1.31 mmol) in toluene (20 ml) and DMF (3 drops). The mixture was stirred at room temperature for 80 minutes. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2(30 ml). Added Et3N (0,540 ml, 3.90 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)ndimethylacetamide (489 mg, 1.94 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc → MeOH/EtOAc 1:9) gave a mixture of the mentioned in the title compound (778 mg, 77%). LC-MS: tR= 0.99 min; ES+: 784,23.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-(acetylamino-methyl)-2-Chlorobenzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methylphenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L48)

Oxalicacid (0,136 ml, 1.57 mmol) was added to a solution of compounds K32 (720 is g, to 1.31 mmol) in toluene (20 ml) and DMF (3 drops). The mixture was stirred at room temperature for 80 minutes. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2(30 ml). Added Et3N (0,540 ml, 3.90 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)ndimethylacetamide (489 mg, 1.94 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc → MeOH/EtOAc 1:9) gave a mixture of the mentioned in the title compound (671 mg, 66%). LC-MS: tR= 0.99 min; ES+: 784,23.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({2-chloro-5-[(3,3,3-Cryptor-propionamido)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ether (3'S,4'R)-3'-({2-chloro-5-[(3,3,3-Cryptor-propionamido)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L49)

Oxalicacid (0,136 ml, 1.57 mmol) we use the and to the solution of compounds K30 (720 mg, to 1.31 mmol) in toluene (20 ml) and DMF (3 drops). The mixture was stirred at room temperature for 80 minutes. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2(30 ml). Added Et3N (0,540 ml, 3.90 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)-3,3,3-triptocaine (621 mg, 1.94 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc → MeOH/EtOAc 1:9) gave a mixture of the mentioned in the title compound (870 mg, 79%). LC-MS: tR= 1,02 minutes; ES+: 854,24.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({2-chloro-5-[(3,3,3-Cryptor-propionamido)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid tert-butyl ether (3'S,4'R)-3'-({2-chloro-5-[(3,3,3-Cryptor-propionamido)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L50)

Oxalicacid (0,136 ml, 1,mol) was added to a solution of compounds K32 (720 mg, to 1.31 mmol) in toluene (20 ml) and DMF (3 drops). The mixture was stirred at room temperature for 80 minutes. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2(30 ml). Added Et3N (0,540 ml, 3.90 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)-3,3,3-triptocaine (625 mg, of 1.95 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc → MeOH/EtOAc 1:9) gave a mixture of the mentioned in the title compound (840 mg, 76%). LC-MS: tR= 1,02 minutes; ES+: 854,28.

tert-Butyl ether (rat.)-(3R*,4S*)-3-({5-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L51)

Oxalicacid (0,122 ml, 1.44 mmol) was added to a solution of compound K6 (659 mg, 1.20 mmol) in toluene (25 ml) and DMF (3 drops). The mixture was stirred at room temperature for 80 minutes. The solvents were removed under reduced pressure and the residue Rabaul is whether CH 2Cl2(30 ml). Added Et3N (0,540 ml, 3.90 mmol) and the mixture was stirred for 5 minutes. Solution was added tert-butyl ester (4-chloro-3-cyclopropylamino-benzyl)cyclopropyl-carbamino acid (463 mg, 1,32 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc → MeOH/EtOAc 1:9) gave specified in the title compound (600 mg, 62%). LC-MS: tR= 1,23 minutes; ES+: 881,76.

tert-Butyl methyl ether(rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}piperidine-l-carboxylic acid (L52)

MCPBA (332 mg, of 1.34 mmol) was added to a solution of compound L45 (960 mg, 1,22 mmol) in CH2Cl2(12 ml). The mixture was stirred at room temperature over night and again was added MCPBA (50 mg, 0,290 mmol). The mixture was stirred for 5 hours and was added EtOAc. The mixture is washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents in which alali under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:9) gave specified in the header of the connection is still in the mix with the connection L45. This mixture was dissolved in CH2Cl2(12 ml) and again was added MCPBA (100 mg, 0,406 mmol). The mixture was stirred for 4 hours at room temperature and washed with aqueous saturated solution of NaHCO3and water. The organic layer was dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl22,5:97,5 → 5:95, 1% Et3N) gave specified in the title compound (660 mg, 66%). LC-MS: tR= 1.15 min; ES+: 800,75.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({5-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl ether (3'S,4'R)-3'-({5-[(tert-butoxycarbonyl-cyclopropyl-amino)methyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L53)

To a solution of compounds K32 (623 mg, 1.13 mmol) in toluene (18 ml) was sequentially added at room temperature and DMF (one drop) and oxacillin (0,117 ml of 1.36 mmol). The mixture was stirred at room temperature is within 1 hour. The solvents were removed under reduced pressure and neojidannoe substance was dried in high vacuum. The crude product was dissolved in CH2Cl2(20 ml). Added Et3N (of 0.47 ml, 3,39 mmol) and the mixture was stirred for 5 minutes at room temperature. Solution was added tert-butyl ester (4-chloro-3-cyclopropylamino-benzyl)cyclopropyl-carbamino acid (475 mg, 1.35 mmol) in CH2Cl2(4 ml) and the mixture was stirred at room temperature for 45 minutes. Added CH2Cl2(20 ml) and the mixture washed with aqueous saturated solution of NH4Cl (1×) and water 10% solution of Na2CO3(1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (heptane/EtOAc 1:1 → EtOAc) gave the mixture specified in the title compound (860 mg, 86%). LC-MS: tR= 1,08 minutes; ES+: 884,86.

tert-Butyl ether (rat.)-(3R*,4S*)-3-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L54)

Oxalicacid (0,211 ml, 2.49 mmol) was added to a solution of compound K6 (1,14 g 2,07 mmol) and DMF (3 drops) in toluene (65 ml). The mixture was stirred at room temperature for 45 minutes and the solvent was removed under reduced pressure. The residue was thoroughly dried in the eye of the vacuum and dissolved in CH 2Cl2(35 ml). Added Et3N (0,710 ml, 5,10 mmol) and the mixture was stirred for 5 minutes at room temperature. Solution was added N-[2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]ndimethylacetamide (540 mg, 2.04 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:1 → EtOAc) gave specified in the title compound (490 mg, 36%). LC-MS: tR= 1,14 minutes; ES+: 797,52.

tert-Butyl ether (rat.)-(3R*,4S*)-3-({5-[2-(tert-butoxycarbonyl-cyclopropyl-amino)ethyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L55)

Oxalicacid (0,120 ml of 1.42 mmol) was added to a solution of compound K6 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (15 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(10 ml) was added Et3N (0,221 mmol, of 1.59 mmol). The mixture was stirred for 5 minutes and was added tert-butyl ether [2-(4-chloro-3-cyclopropylamino the o-methyl phenyl)ethyl]cyclopropyl-carbamino acid (386 mg, 1.06 mmol). The mixture was stirred for 30 minutes at room temperature and washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:4 → EtOAc) gave specified in the title compound (620 mg, 49%). LC-MS: tR= 1.25 min; ES+: 895,57.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({5-[2-(tert-butoxycarbonyl-cyclopropyl-amino)ethyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl ether (3'S,4'R)-3'-({5-[2-(tert-butoxycarbonyl-cyclopropyl-amino)ethyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L56)

Oxalicacid (0,120 ml of 1.42 mmol) was added to a solution of compounds K30 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (15 ml). The mixture was stirred for 30 minutes at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(10 ml) was added Et3N (0,221 ml of 1.59 mmol). The mixture was stirred for 5 minutes and was added tert-butyl ether [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]cyclopropyl-carbamino acid (405 mg, 1,11 the mol). The mixture was stirred for 30 minutes at room temperature and washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc) gave the mixture specified in the title compound (240 mg, 24%). LC-MS: tR= 1.09 min; ES+: 898,60.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({5-[2-(tert-butoxycarbonyl-cyclopropyl-amino)ethyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl ether (3'S,4'R)-3'-({5-[2-(tert-butoxycarbonyl-cyclopropyl-amino)ethyl]-2-chloro-benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L57)

Oxalicacid (0,150 ml, 1.77 mmol) was added to a solution of compounds K32 (750 mg, about 1.36 mmol) and DMF (1 drop) in toluene (33 ml). The mixture was stirred for 90 minutes at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(26 ml) was added Et3N (0,227 ml of 1.63 mmol). The mixture was stirred for 5 minutes and was added tert-butyl ether [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]cyclopropyl-carbamino acid (398 mg, 1,09 IMO is b). The mixture was stirred for 30 minutes at room temperature and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1) gave a mixture of the mentioned in the title compounds (796 mg, 65%). LC-MS: tR= 1,08 minutes; ES+: 898,61.

tert-Butyl ether (rat.)-(3'R*,4'S*)-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L58)

Oxalicacid (0,147 ml of 1.73 mmol) was added to a solution of compound K16 (700 mg, of 1.33 mmol) and DMF (0,02 ml) in toluene (29 ml). The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 30 minutes and diluted with CH2Cl2(38 ml). Added Et3N (0,345 ml, 2.48 mmol) and [5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (448 mg, of 1.66 mmol). The mixture was stirred at room temperature for 1.5 hours and was added an additional amount of CH2Cl2. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:49) gave specified in the title compound (480 mg, 47%). LC-MS: tR= 1.16 minutes is; ES+: 779,56.

tert-Butyl ether (rat.)-(3R*,4S*)-3-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L59)

Oxalicacid (0,120 ml of 1.42 mmol) was added to a solution of compound K6 (600 mg, of 1.09 mmol) and DMF (one drop) in toluene (15 ml). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(10 ml) was added Et3N (0,221 ml of 1.59 mmol). The mixture was stirred for 5 minutes and the solution was added tert-butyl ester (4-chloro-3-cyclopropylamino-benzyl)-(2,2-dottorati)carbamino acid (458 mg, of 1.27 mmol) in CH2Cl2(5 ml). The mixture was stirred for 30 minutes at room temperature and was extracted with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:4 → EtOAc) gave specified in the title compound (700 mg, 71%). LC-MS: tR= 1,22 minutes; ES+: 905,53.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carbon is acid and tert-butyl methyl ether (3'S,4'R)-3'-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L60)

Oxalicacid (0,150 ml, 1.77 mmol) was added to a solution of compounds K32 (750 mg, about 1.36 mmol) and DMF (one drop) in toluene (33 ml). The mixture was stirred for 1 hour and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(20 ml) was added Et3N (0,227 ml of 1.63 mmol). The mixture was stirred for 5 minutes and the solution was added tert-butyl ester (4-chloro-3-cyclopropylamino-benzyl)-(2,2-dottorati)carbamino acid (409 mg, of 1.09 mmol) in CH2Cl2(6 ml). The mixture was stirred for 30 minutes at room temperature and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1) gave a mixture of the mentioned in the title compound (759 mg, 62%). LC-MS: tR= 1,06 minutes; ES+: 908,57.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L61)

Oxalicacid (0,150 ml, 1.77 mmol) was added to a solution of compounds K32 (750 mg, about 1.36 mmol) and DMF (one drop) in toluene (33 ml). The mixture was stirred is for 1 hour and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(20 ml) was added Et3N (0,227 ml of 1.63 mmol). The mixture was stirred for 5 minutes and the solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-cyclopropyl-ndimethylacetamide (304 mg, of 1.09 mmol) in CH2Cl2(6 ml). The mixture was stirred for 30 minutes at room temperature and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc) gave the mixture specified in the title compounds (737 mg, 72%). LC-MS: tR= 1.00 min; ES+: 812,57.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L62)

Oxalicacid (0,143 ml, was 1.69 mmol) was added to a solution of compounds K32 (716 mg, of 1.30 mmol) and DMF (0,02 ml) in toluene (30 ml). The mixture was stirred for 2.5 hours at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(32 ml) was added Et3N (0,378 ml, 2,70 mmol). Solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-methyl-ndimethylacetamide (455 mg, of 1.80 mmol) in CH2Cl 2(10 ml) and the mixture was stirred for 1 hour at room temperature. Added additional amount of CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:49) gave a mixture of the mentioned in the title compound (810 mg, 79%). LC-MS: tR= 0,94 minutes; ES+: 786,60.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbarnoyl]-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L63)

Oxalicacid (0,119 ml, 1.37 mmol) was added to a solution of compounds K32 (630 mg, to 1.14 mmol) and DMF (one drop) in toluene (25 ml). The mixture was stirred for 2 hours and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(31 ml) was added Et3N (0,580 ml of 4.17 mmol). The mixture was stirred for 5 minutes and the solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-ethyl-ndimethylacetamide (370 mg, of 1.39 mmol) in CH2Cl2(5 ml). The mixture is PE is amasyali for 2 hours at room temperature and the solvents were removed under reduced pressure. Added additional amount of CH2Cl2and the mixture is washed with aqueous 10% solution of Na2CO3.The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 4:1) gave a mixture of the mentioned in the title compound (700 mg, 77%). LC-MS: tR= 1,01 minutes; ES+: 800,70.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(propionamido-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S, 4'R)-3'-{[2-chloro-5-(propionamido-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L64)

Oxalicacid (0,152 ml of 1.80 mmol) was added to a solution of compounds K32 (761 mg, 1.38 mmol) and DMF (one drop) in toluene (32 ml). The mixture was stirred for 75 minutes and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(42 ml) was added Et3N (0,378 ml, 2,70 mmol). The mixture was stirred for 5 minutes and the solution was added N-(4-chloro-3-cyclopropylamino-benzyl)propionamide (480 mg, of 1.80 mmol) in CH2Cl2(10 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced on the no. Added additional amount of CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:49) gave a mixture of the mentioned in the title compound (990 mg, 90%). LC-MS: tR= 0.99 min; ES+: 798,74.

tert-Butyl ether (rat.)-(3R*,4S*)-3-({2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropyl-carbarnoyl)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L65)

Oxalicacid (0,211 ml, 2.49 mmol) was added to a solution of compound K6 (1,14 g 2,07 mmol) and DMF (one drop) in toluene (65 ml). The mixture was stirred for 45 minutes, the solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2Cl2(35 ml) was added Et3N (0,710 ml, 5,10 mmol). The mixture was stirred for 5 minutes and the solution was added 4-chloro-3-cyclopropylamino-benzylamine cyclopropanecarbonyl acid (474 mg, 1.70 mmol) in CH2Cl2(4 ml). The mixture was stirred for 1 hour at room temperature and was added an additional amount of CH2Cl2. The mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. Organic with the Oh was dried over MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:3 → 1:1) gave specified in the title compound (610 mg, 36%). LC-MS: tR= 1,14 minutes; ES+: 809,54.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-({2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L66)

Oxalicacid (0,141 ml of 1.66 mmol) was added to a solution of compounds K32 (704 mg, 1.28 mmol) and DMF (one drop) in toluene (30 ml). The mixture was stirred for 2.5 hours, the solvent was removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2Cl2(39 ml) was added Et3N (0,347 ml, 2.48 mmol). The mixture was stirred for 5 minutes and the solution was added 4-chloro-3-cyclopropylamino-benzylamine cyclopropanecarbonyl acid (461 mg, of 1.65 mmol) in CH2Cl2(10 ml). The mixture was stirred for 1 hour at room temperature and was added an additional amount of CH2Cl2. The mixture is washed with aqueous 1M HCl solution and saturated R is the target salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:49) gave a mixture specified in the header connections (of 1.03 g, 99%). LC-MS: tR= 1.00 min; ES+: 812,64.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[2-chloro-5-(methoxycarbonylamino-methyl)benzyl]cyclopropyl-carbarnoyl}piperidine-1-carboxylic acid (L67)

Oxalicacid (0,211 ml, 7,46 mmol) was added to a solution of compound K6 (1,14 g 2,07 mmol) and DMF (1 drop) in toluene (65 ml). The mixture was stirred at room temperature for 45 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum and dissolved in CH2Cl2(35 ml). Added Et3N (0,710 ml, 5,10 mmol) and the mixture was stirred at room temperature for 5 minutes. Solution was added methyl ether (4-chloro-3-cyclopropylamino-benzyl)carbamino acid (457 mg, 1.70 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 1 hour. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure is I. Purification of the crude product using PF (EtOAc/heptane 1:3 → 1:1 → EtOAc) gave specified in the title compound (620 mg, 37%). LC-MS: tR= 1.15 min; ES+: 799,50.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(methoxycarbonylamino-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(methoxycarbonylamino-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L68)

Oxalicacid (0,113 ml of 1.31 mmol) was added to a solution of compounds K30 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (20 ml). The mixture was stirred at room temperature for 1.5 hours and the solvent was removed under reduced pressure. The residue was dried in high vacuum and dissolved in CH2Cl2(26 ml). Added Et3N (0,455 ml of 3.27 mmol) and the mixture was stirred for 5 minutes. Solution was added methyl ether (4-chloro-3-cyclopropylamino-benzyl)carbamino acid (293 mg, of 1.09 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 45 minutes. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. Organic the ski layer was dried over MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc) gave the mixture specified in the title compound (860 mg, 89%). LC-MS: tR= 0,98 minutes; ES+: 802,55.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(methoxycarbonylamino-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(methoxycarbonylamino-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L69)

Oxalicacid (0,113 ml of 1.31 mmol) was added to a solution of compounds K32 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (20 ml). The mixture was stirred at room temperature for 1.5 hours and the solvent was removed under reduced pressure. The residue was dried in high vacuum, and dissolved in CH2Cl2(26 ml). Added Et3N (0,455 ml of 3.27 mmol) and the mixture was stirred for 5 minutes. Solution was added methyl ether (4-chloro-3-cyclopropylamino-benzyl)carbamino acid (293 mg, of 1.09 mmol) in CH2Cl2(4,00 ml) and the mixture was stirred at room temperature for 45 minutes. Added additional amount of CH2Cl2and the mixture is washed with water nasyscennosti NH 4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → EtOAc) gave the mixture specified in the title compound (630 mg, 72%). LC-MS: tR= 0,98 minutes; ES+: 802,55.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and (3'S,4'R)-3'-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L70)

Oxalicacid (0,240 ml of 2.83 mmol) was added to a solution of compounds K30 (1.20 g, to 2.18 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature, the solvents were removed under reduced pressure and the residue was dried in high vacuum for 15 minutes. The residue was dissolved in CH2Cl2(10 ml) was added Et3N (0,456 ml of 3.28 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added N-[2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]ndimethylacetamide (611 mg, to 2.29 mmol) in CH2Cl2(5 ml). The mixture was stirred for 30 minutes at room temperature and the solvents were removed when eigendom pressure. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 1:1 → 7:3) gave the mixture specified in the title compounds (1,36 g, 78%). LC-MS: tR= 0.99 min; ES+: 798,37.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L71)

Oxalicacid (0,143 ml, was 1.69 mmol) was added to a solution of compounds K32 (716 mg, of 1.30 mmol) and DMF (1 drop) in toluene (15 ml). The mixture was stirred for 1 hour at room temperature, the solvents were removed under reduced pressure and the residue was dried in high vacuum for 15 minutes. The residue was dissolved in CH2Cl2(13 ml) was added Et3N (0,362 ml, 2,60 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added N-[2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]ndimethylacetamide (364 mg, 1.37 mmol) in CH2Cl2(5 ml). The mixture was stirred is for 30 minutes at room temperature and the solvents were removed under reduced pressure. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave a mixture of the mentioned in the title compound (550 mg, 53%). LC-MS: tR= 0,98 minutes; ES+: 798,36.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L72)

Oxalicacid (0,120 ml of 1.42 mmol) was added to a solution of compounds K30 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature, the solvents were removed under reduced pressure and the residue was dried in high vacuum for 15 minutes. The residue was dissolved in CH2Cl2(10 ml) was added Et3N (0,221 ml, 1,49 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added (tert-butyl ether 4-chloro-3-cyclopropylamino the methyl-benzyl)-(2,2-dottorati)carbamino acid (400 mg, 1.11 mmol) in CH2Cl2(5 ml). The mixture was stirred for 30 minutes at room temperature and the solvents were removed under reduced pressure. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The residue is triturated with a mixture of heptane and EtOAc ratio of 8:2 and filtered. The filtrate was evaporated under reduced pressure. Purification of the crude product using two PF (EtOAc/heptane 1:4 → EtOAc; the second time MeOH/CH2Cl21:19) gave a mixture of the mentioned in the title compound (230 mg, 24%). LC-MS: tR= 1,10 minutes; ES+: 908,32.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L73)

Oxalicacid (0,146 ml of 1.65 mmol) was added to a solution of compounds K30 (700 mg, of 1.27 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The remainder of restore and in CH 2Cl2(30 ml) was added Et3N (0,266 ml, at 1.91 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-cyclopropylacetylene (355 mg, of 1.27 mmol) in CH2Cl2(5 ml). The mixture was stirred for 90 minutes at room temperature and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave a mixture of the mentioned in the title compounds (742 mg, 72%). LC-MS: tR= 1.00 min; ES+: 812,67.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L74)

Oxalicacid (0,146 ml of 1.65 mmol) was added to a solution of compounds K30 (700 mg, of 1.27 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(30 m is) and was added Et 3N (0,266 ml, at 1.91 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-methylacetamide (322 mg, of 1.27 mmol) in CH2Cl2(5 ml). The mixture was stirred for 2 hours at room temperature and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave a mixture of the mentioned in the title compound (637 mg, 64%). LC-MS: tR= 0,98 minutes; ES+: 786,62.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-({2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropyl-carbarnoyl)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3 'S, 4'R)-3'-({2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropyl-carbarnoyl-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L75)

Oxalicacid (0,146 ml of 1.65 mmol) was added to a solution of compounds K30 (700 mg, of 1.27 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(30 ml) was added Et 3N (0,266 ml, at 1.91 mmol). The mixture was stirred at room temperature for 5 minutes and the solution was added cyclopropanecarbonyl acid 4-chloro-3-cyclopropylamino-benzylated (355 mg, of 1.27 mmol) in CH2Cl2(5 ml). The mixture was stirred for 1 hour at room temperature and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave a mixture of the mentioned in the title compound (496 mg, 48%). LC-MS: tR= 0.99 min; ES+: 812,68.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L76)

Oxalicacid (0,156 ml, 1.77 mmol) was added to a solution of compounds K30 (750 mg, about 1.36 mmol) and DMF (one drop) in toluene (30 ml). The mixture was stirred at room temperature for 1 hour and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl220 ml) was added Et 3N (0,284 ml, 2.04 mmol). The mixture was stirred for 5 minutes at room temperature was added a solution of [5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-amine (369 mg, of 1.36 mmol) in CH2Cl2(10 ml). The mixture was stirred for 1 hour at room temperature and was added an additional amount of CH2Cl2. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by chromatography in a thick layer (MeOH/CH2Cl21:15) gave a mixture of the mentioned in the title compound (418 mg, 38%). LC-MS: tR= 0.95 min; ES+: 804,31.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L77)

Oxalicacid (is 0.135 ml, 1.54 mmol) was added to a solution of compounds K32 (650 mg, 1.18 mmol) and DMF (one drop) in toluene (30 ml). The mixture was stirred at room temperature for 1 hour and the solvents deletion is whether under reduced pressure. The residue was dissolved in CH2Cl2(20 ml) was added Et3N (0,247 ml, 1.77 mmol). The mixture was stirred for 5 minutes at room temperature was added a solution of [5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-amine (320 mg, 1.18 mmol) in CH2Cl2(10 ml). The mixture was stirred for 1 hour at room temperature and was added an additional amount of CH2Cl2. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by chromatography in a thick layer (MeOH/CH2Cl21:15) gave a mixture of the mentioned in the title compound (402 mg, 42%). LC-MS: tR= 0.96 min; ES+: 804,29.

tert-Butyl ether (rat.)-(3R*,4S*)-3-[(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropyl-carbarnoyl]-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L78)

Oxalicacid (0,184 ml of 1.42 mmol) was added to a solution of compound K6 (650 mg, 1,19 mmol) and DMF (3 drops) in toluene (20 ml) at room temperature. The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,495 ml of 3.56 mmol) and the mixture was stirred during 5 minutes. Solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-cyclopropyl-ndimethylacetamide (331 mg, 1,19 mmol) in CH2Cl2(5 ml) and the mixture was stirred over night. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3) gave specified in the title compound (667 mg, 69%). LC-MS: tR= 1,13 minutes; ES+: 809,17.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]piperidine-1-carboxylic acid (L79)

Oxalicacid (0,184 ml of 1.42 mmol) was added to a solution of compound K6 (650 mg, 1,19 mmol) and DMF (3 drops) in toluene (20 ml) at room temperature. The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,495 ml of 3.56 mmol) and the mixture was stirred for 5 minutes. Solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-methylacetamide (300 mg, 1,19 mmol) in CH2Cl2(5 ml)and the mixture was stirred over night. Added dopolnitelnost CH 2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 4:1) gave specified in the title compound (597 mg, 64%). LC-MS: tR= 1.12 min; ES+: 783,70.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-[(2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbarnoyl]piperidine-1-carboxylic acid (L80)

Oxalicacid (0,184 ml of 1.42 mmol) was added to a solution of compound K6 (650 mg, 1,19 mmol) and DMF (3 drops) in toluene (20 ml) at room temperature. The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,495 ml of 3.56 mmol) and the mixture was stirred for 5 minutes. Solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-ethyl-ndimethylacetamide (316 mg, 1,19 mmol) in CH2Cl2(5 ml) and the mixture was stirred over night. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents removed the ri reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3) gave specified in the title compound (441 mg, 47%). LC-MS: tR= 1,13 minutes; ES+: 797,77.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[2-chloro-5-(propionamido-methyl)benzyl]cyclopropyl-carbarnoyl}piperidine-1-carboxylic acid (L81)

Oxalicacid (0,184 ml of 1.42 mmol) was added to a solution of compound K6 (650 mg, 1,19 mmol) and DMF (3 drops) in toluene (20 ml) at room temperature. The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,495 ml of 3.56 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)propionamide (316 mg, 1,19 mmol) in CH2Cl2(5 ml) and the mixture was stirred over night. Added additional amount of CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3) gave specified in the title compound (640 mg, 68%). LC-MS: tR= 1,13 minutes; ES+: 797,75.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-the ENT-5-ethylcarboxylate-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-ethylcarboxylate-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L82)

Oxalicacid (0,120 ml of 1.42 mmol) was added to a solution of compounds K30 (600 mg, of 1.09 mmol) and DMF (1 drop) in toluene (26 ml). The mixture was stirred at room temperature for 2 hours and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2(20 ml) was added Et3N (0,227 ml of 1.63 mmol). The mixture was stirred for 5 minutes and the solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)-N-ethyl-ndimethylacetamide (291 mg, of 1.09 mmol) in CH2Cl2(6,00 ml). The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure. Purification of the residue using PF (EtOAc) gave the mixture specified in the title compound (560 mg, 64%). LC-MS: tR= 1,03 min; ES+: 798,32.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(propionamido-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(propionamido-methyl)benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L83)

Oxalicacid (0,152 ml of 1.80 mmol) was added to a solution of compounds K30 (760 mg, 1.38 mmol) and DMF (1 drop) in toluene (32 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under decreased the pressure. The residue was dried in high vacuum for 15 minutes and was dissolved in CH2Cl2(24 ml). Added Et3N (0,292 ml of 2.08 mmol) and the mixture was stirred for 5 minutes. Solution was added N-(4-chloro-3-cyclopropylamino-benzyl)propionamide (370 mg, of 1.39 mmol) in CH2Cl2(10 ml) and the mixture was stirred at room temperature for 1 hour. Added CH2Cl2(50 ml) and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:49) gave a mixture of the mentioned in the title compound (530 mg, 48%). LC-MS: tR= 0.99 min; ES+: 800,69.

tert-Butyl ether (rat.)-(3R*,4S*)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3-{[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropyl-carbarnoyl}piperidine-1-carboxylic acid (L84)

Oxalicacid (0,177 ml, a 2.01 mmol) was added to a solution of compound K6 (850 mg, 1.55 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 15 minutes and was dissolved in CH2Cl2(20 ml). Added Et3N (0,323 ml, 2.32 mmol) and the mixture was stirred for 5 minutes. Solution was added 3-(-chloro-3-cyclopropylamino-phenyl)-N-methyl-propionamide (413 mg, 1.55 mmol) in CH2Cl2(10 ml) and the mixture was stirred at room temperature for 1 hour. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:99 → 1:49 → 3:97) gave specified in the title compound (780 mg, 63%). LC-MS: tR= 1,14 minutes; ES+: 797,69.

tert-Butyl ether (rat.)-(3R*,4S*)-3-[(5-{2-[tert-butoxycarbonyl-(2,2-dottorati)-amino]ethyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-1-carboxylic acid (L85)

Oxalicacid (0,177 ml, a 2.01 mmol) was added to a solution of compound K6 (850 mg, 1.55 mmol) and DMF (1 drop) in toluene (30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 15 minutes and was dissolved in CH2Cl2(20 ml). Added Et3N (0,323 ml, 2.32 mmol) and the mixture was stirred for 5 minutes. Solution was added tert-butyl ester [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]-(2,2-dottorati)carbamino acid (602 mg, 1.55 mmol) in CH2Cl2(10 ml) and the mixture was stirred at room temperature for 90 minutes. Added the CH 2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:99 → 1:49 → 3:97) gave specified in the title compound (530 mg, 37%). LC-MS: tR= 1,24 minutes; ES+: 919,78.

tert-Butyl ether (rat.)-(3'R*,4'S*)-3'-{[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropyl-carbarnoyl}-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L86)

Oxalicacid (0,078 ml, 0,886 mmol) was added to a solution of compound K33 (375 mg, 0,682 mmol) and DMF (1 drop) in toluene (15 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 15 minutes and was dissolved in CH2Cl2(15 ml). Added Et3N (0,190 ml of 1.36 mmol) and the mixture was stirred for 5 minutes. Solution was added N-[2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]ndimethylacetamide (182 mg, 0,682 mmol) in CH2Cl2(2 ml) and the mixture was stirred at room temperature for 1 hour. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed at igenom pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:99 → 1:49 → 3:97 → 5:95) gave specified in the title compound (776 mg, 99%). LC-MS: tR= 1,14 minutes; ES+: 798,69.

tert-Butyl ether (rat.)-(3'R*,4'S*)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3'-{[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L87)

Oxalicacid (0,175 ml of 1.98 mmol) was added to a solution of compound K33 (840 mg, 1.53 mmol) and DMF (1 drop) in toluene (33 ml). The mixture was stirred for 45 minutes at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,425 ml of 3.05 mmol) and the mixture was stirred for 5 minutes. Was added a solution of [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (389 mg, 1.53 mmol) in CH2Cl (3 ml) and the mixture was stirred at room temperature for 1.5 hours. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:99 → 1:49) gave specified in the title compound (619 mg, 52%). LC-MS: tR= 1,14 minutes; S+: 786,67.

tert-Butyl methyl ether(rat.)-(3'R*,4'S*)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-3'-{[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropyl-carbarnoyl}-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L88)

MCPBA (85%, 212 mg, 0,860 mmol) was added to a solution of compound L87 (615 mg, 0,782 mmol) in CH2Cl2(19 ml) at room temperature. The mixture was stirred for 4.5 hours and was added an additional amount of CH2Cl2. The mixture is washed with aqueous 1M NaOH solution and saturated salt solution. The combined aqueous layers was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the title compound (621 mg, 82%). LC-MS: tR= 1.12 min; ES+: 802,67.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[3-(R)-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[3-(R)-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L89)

Oxalicacid (0,178 ml, 2.10 mmol) was added to the races the thief compounds K30 (890 mg, of 1.62 mmol) and DMF (1 drop) in toluene (45 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,327 ml of 2.35 mmol) and the mixture was stirred for 5 minutes. Was added a solution of 3-(4-chloro-3-cyclopropylamino-phenyl)-N-methyl-propionamide (470 mg, of 1.76 mmol) in CH2Cl2(15 ml) and the mixture was stirred at room temperature for 1.5 hours. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl23:97) gave a mixture of the mentioned in the title compound (230 mg, 18%). LC-MS: tR= 1.00 min; ES+: 800,70.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(5-{2-[tert-butoxycarbonyl-(2,2-dottorati)amino]ethyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(5-{2-[tert-butoxycarbonyl-(2,2-dottorati)amino]ethyl}-2-chloro-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic KIS is the notes (L90)

Oxalicacid (0,166 ml, a 1.96 mmol) was added to a solution of compounds K30 (830 mg and 1.51 mmol) and DMF (1 drop) in toluene (50 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(20 ml). Added Et3N (0,282 ml, 1.35 mmol) and the mixture was stirred for 5 minutes. Solution was added tert-butyl ester [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]-(2,2-dottorati)carbamino acid (526 mg, 1.35 mmol) in CH2Cl2(20 ml)and the mixture was stirred at room temperature for 1.5 hours. Added CH2Cl2and the mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl23:97) gave a mixture of the mentioned in the title compound (670 mg, 54%). LC-MS: tR= 1.09 min; ES+: 922,88.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-[(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropyl-carbarnoyl]-6-[(R)-3-(2,6-dichloro-4-methyl-dryer is XI)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L91)

Oxalicacid (0,376 ml, 4,36 mmol) was added to a solution of compounds K30 (2.00 g, 3,66 mmol) and DMF (1 drop) in toluene (85 ml). The mixture was stirred for 4 hours at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(50 ml). Added Et3N (0,932 ml, 6,70 mmol) and the mixture was stirred for 5 minutes. Solution was added 4-chloro-3-cyclopropylamino-benzyl methyl ether-carbamino acid (660 mg, of 2.46 mmol) in CH2Cl2(5 ml)and the mixture was stirred at room temperature overnight. Added CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 4:1) gave a mixture of the mentioned in the title compound (920 mg, 51%). LC-MS: tR = 1.00 min; ES+: 802,73.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahed the o-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L92)

Oxalicacid (0,376 ml, 4,36 mmol) was added to a solution of compounds K30 (2.00 g, 3,66 mmol) and DMF (1 drop) in toluene (85 ml). The mixture was stirred for 4 hours at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(50 ml). Added Et3N (0,932 ml, 6,70 mmol) and the mixture was stirred for 5 minutes. Solution was added 2-(4-chloro-3-cyclopropylamino-phenyl)ethyl methyl ether-carbamino acid (687 mg, 2,43 mmol) in CH2Cl2(5 ml) and the mixture was stirred at room temperature overnight. Added CH2Cl2and the mixture is washed with aqueous saturated solution of NH4Cl and aqueous 10% solution of Na2CO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 4:1) gave a mixture of the mentioned in the title compound (920 mg, 51%). LC-MS: tR= 1.00 min; ES+: 816,75.

A mixture of tert-butyl methyl ether (3'R,4'S)-3'-{[2-chloro-5-(2-methoxycarbonylamino-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid and tert-butyl methyl ether (3'S,4'R)-3'-{[2-chloro-5-(2-methoxycarbonylamino-ethyl) - benzyl]cyclopropyl-carbarnoyl}-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L93)

Oxalicacid (of 0.182 ml of 2.15 mmol) was added to a solution of compounds K30 (910 mg, of 1.65 mmol) and DMF (1 drop) in toluene (40 ml). The mixture was stirred for 2 hours at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(30 ml). Added Et3N (0,341 ml, 2.45 mmol) and the mixture was stirred for 5 minutes. Solution was added methyl ester [2-(4-chloro-3-cyclopropylamino-phenyl)ethyl]carbamino acid (597 mg, of 1.64 mmol) in CH2Cl2(6 ml) and the mixture was stirred at room temperature for 30 minutes. The solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:1) gave a mixture of the mentioned in the title compound (830 mg, 62%). LC-MS: tR= 1,01 minutes.

tert-Butyl ether (rat.)-(3'R*,4'S*)-6-[3-(2-chloro-3,6-differenl)isoxazol-5-ylethoxy]-3'-{[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1'-carboxylic acid (L94)

Oxalicacid (0,078 ml, 0,886 mmol) was added to a solution of compound K33 (375 mg, 0,682 mmol) and DMF (1 drop) in toluene (15 ml). The mixture was stirred for 40 minutes at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum for 1 hour and dissolved in CH2Cl2(13 ml). Added Et3N(0,190 ml, of 1.36 mmol) and the mixture was stirred for 5 minutes. Solution was added [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine (164 mg, 0,682 mmol) in CH2Cl2(2 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture is washed with aqueous 1M HCl solution and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2→ MeOH/CH2Cl21:99 → 1:49) gave specified in the title compound (377 mg, 48%). LC-MS: tR= 1,19 minutes; ES+: 771,66.

2,2,2-Trichloro-1,1-dimethylethylamine ether (rat.)-(1R*,5S*)-3-acetyl-6-{[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropyl-carbarnoyl}-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-9-carboxylic acid (M1)

HCl (4M in dioxane, 10 ml) was added to a solution of compound 5 (582 mg, of 0.58 mmol) in CH2Cl2(10 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum over night. Foamed residue was dissolved in CH2Cl2(10 ml) was added DIPEA (0,397 ml, 2.32 mmol). The mixture was cooled to -20°C and was added AcCl (45 μl, 0.64 mmol). The mixture was stirred for 15 minutes and diluted with additional CH2Cl2. The mixture was washed in the s ' 1M HCl and 1M aqueous NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 1:4 → 1:3 → 1:2 → EtOAc → MeOH/EtOAc 1:19) gave specified in the title compound (456 mg, 53%). LC-MS: tR= 1,27 minutes; ES+: 946,37.

EXAMPLES

Example 1

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

Connection L1 (300 mg, 0.34 mmol) and HCl (4,0M in 1,4-dioxane, 2.55 ml, 10.2 mmol) was mixed at 21°C and stirred at 21°C during the night. The mixture was evaporated under reduced pressure and the residue was distributed between EtOAc and aqueous 1M NaOH solution. The organic phase was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF gave specified in the title compound (68 mg). MC (M+1) ESI 684.

Example 2

(rat.)-(1R*,5S*)-6-{[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-carbarnoyl}-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene

The target compound was obtained from 3,9-di-tert-butyl ether (rat.)-( 1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethyl]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid, as for the connection of L1, but using N-[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine instead of N-[2-chloro-5-(3-methoxypropyl the l)benzyl]cyclopropylamine, then, as described for example 1. MS (M+l) ESI 668.

Example 3

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (WO 2005/040165) and N-[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine how to connect L1, and as described for example 1. MS (ESI, Q+) m/z 697,9.

Example 4

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was obtained by separation of the compound of example 3 using chiral HPLC (column Chiracel AD). Optical rotation: [α]D23= +53,2 (c = 0,47, CHCl3). MS (ESI, Q+) m/z 700,1.

Example 5

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was obtained by separation of the compound of example 3 using chiral HPLC (column Chiracel AD). Optical rotation: [α]D23= -60,1 (c = 0,34, CHCl3). MS (ESI, Q+) m/z 698,3.

Example 6

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]Cyclops pyramid (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (rat.)-(1R*,5S*)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (WO 2005/040165) and [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine as to connect the L1, and then as described for example 1. MS (ESI, Q+) m/z 686,0.

Example 7

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid and [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropyl-amine as to connect the L1, and then as described for example 1. MS (ESI, Q+) m/z 686,1.

Example 8

Cyclopropyl-[5-(2-methoxy-ethyl)-2-methyl-benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid and cyclopropyl-[5-(2-methoxy-ethyl)-2-methyl-benzyl]amine as to connect the L1, and then as described for example 1. MS (ESI, Q+) m/z 664,1.

Example 9

Cyclopropyl-[5-(3-methoxy-propyl)-2-methyl-benzyl]amide of (1R,5S)-7-{4-[2-(2,-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid and cyclopropyl-[5-(3-methoxy-propyl)-2-methyl-benzyl]amine as to connect the L1, and then as described for example 1. MS (ESI, Q+) m/z 678,2.

Example 10

Cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)benzyl]amide of (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid

This compound was synthesized from 3,9-di-tert-butyl ether (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid and cyclopropyl-[2,3-dichloro-5-(3-methoxy-propyl)benzyl]amine as to connect the L1, and then as described for example 1. MS (ESI, Q+) m/z 733,9.

Example 11

Cleaners containing hydrochloride salt cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide of (1R,5S)-3-carbamimidoyl-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

A solution of N,N'-bis(tert-butylcarbamoyl)urea (112 mg, 0,406 mmol) in DMF (5 ml) was treated with EDC·HCl (121 mg, 0,405 mmol) and DIPEA (164 μl, 0,936 mmol). The resulting solution was stirred at room temperature for 1 hour and then treated with compound L2 (250 mg, 0,312 mmol). The resulting solution was stirred at room temperature for 3 hours, ZAT is poured into a separating funnel with a capacity of 250 ml, containing H2O (150 ml)and was extracted with Et2O (3×50 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with PF (hexane/EtOAc 7:3) gave the protected urea in the form of a clear oil. For protected substances were removing the protective group and purification as previously described for example 1. MS (ESI, Q+) m/z 740,2.

Example 12

3-[(1-Cyano-cyclopropyl)amide] 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid

A solution of CDI (5 equiv.), 1-amino-cyclopropanecarbonitrile (5 equiv.) and Et3N (5 equiv.) in DMF was stirred for 30 minutes at room temperature. Solution was added connection L2 in DMF and the mixture was stirred over night. The mixture was suppressed aqueous saturated solution of NH4Cl and extracted with EtOAc. The organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Cleaning with PF gave a secure connection, which is then processed as described in example 1. Characterization using mass spectrometry (ESI, Q+) m/z 806,4.

Example 13

3-Cyclopropylamino 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propylbenzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid

Received as described in example 12, but using cyclopropylamine instead of 1-amino-cyclopropanecarbonitrile. MS (ESI, Q+) m/z 783,0.

Example 14

3-[(2-Carbarnoyl-2-methyl-propyl)amide] 6-{cyclopropyl-[2-chloro-5-(3-methoxy-propyl)benzyl]amide} (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-3,9-diazabicyclo [3.3.1]non-6-ene-3,6-dicarboxylic acid

Received as described in example 12, but using 3-amino-2,2-dimethyl-propionamide instead of 1-amino-cyclopropanecarbonitrile. MS (ESI, Q+) m/z 841,8.

Example 15

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3,2,1]Oct-2-ene-2-carboxylic acid

Compound L3 (3,45 g, 4.40 mmol) was dissolved in CH2Cl2(60 ml) and the mixture was cooled to 0°C. was Added HCl (4M in dioxane, 15 ml). The mixture was stirred for 1 hour at 0°C, then for 2.5 hours at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum over night. The residue was dissolved in CH2Cl2and the mixture is washed with aqueous 1M NaOH solution (2H). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl24:96 0.5% Et3N) gave specified in the title racemic compound (2,18 g, 72%). This rat is at separated using HPLC (Regis Whelk column, isocratic conditions using 85% of eluent B), receiving specified in the title compound (420 mg, 19%). LC-MS: tR= 0.97 min; ES+: 683,31. Chiral column HPLC: tR= 36,97 minutes.

Example 16

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid

To a solution of compound L4 (405 mg, 0,535 mmol) in CH2Cl2(5.2 ml) was added HCl (4M in dioxane, to 1.34 ml, are 5.36 mmol) at 0°C. the Mixture was stirred for 1.5 hours at 0°C and the solvent was evaporated under reduced pressure without heating. The residue was diluted with CH2Cl2and washed with aqueous saturated solution of NaHCO3and water, dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl21:19) gave specified in the title compound (168 mg, 48%). LC-MS: tR= 0.96 min; ES+: 657,24.

Example 17

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

Zn (powder, 160 mg, 2,43 mmol) was added to the intensively stirred solution of compound M1 (458 mg, 0,485 mmol) in THF (6 ml) and AcOH (2 ml). The mixture was stirred for 3 hours and filtered. The precipitate washed with THF and the filtrate was evaporated under lowered the second pressure. The residue was dried in high vacuum and diluted with CH2Cl2. This mixture is washed with aqueous 1M NaOH solution (4×) and the organic layer was dried over MgSO4and filtered. The solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl21:49) gave specified in the racemic title compound (210 mg, 61%). This racemate was separated by HPLC (Chiralcel OD, isocratic conditions using 70% of eluent B), receiving specified in the title compound (63 mg, 30%). LC-MS: tR= 0,927 minutes; ES+: 743,33. Chiral column HPLC: tR= 7.6 minutes.

Example 18

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',5',6'-tetrahydro-[3,4']bipyridinyl-3'-carboxylic acid

To a solution of compound L6 (570 mg, 0,752 mmol) in CH2Cl2(5 ml) at 0°C was added HCl (4M in dioxane, a 1.88 ml, 7,52 mmol). The mixture was stirred for 30 minutes at 0°C and for 2 hours at room temperature. Was added aqueous 1M NaOH solution and the alkaline mixture was poured into a syringe with a dry Isolute® (HM-N, 5 g) and 1 g of Na2SO4The product was suirable CH2Cl2until then, until he stopped the release of the product. The solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl23:97 → 5:95 c 1% Et3N) gave specified in the title compound (157 mg, 32%). LC-MS: tR= 0,95 is displaced; ES+: 659,98.

Example 19

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid

HCl (4M in dioxane, 4,70 ml) was added to a solution of compound L7 (730 mg, 0,931 mmol) in CH2Cl2(4 ml) at 0°C. the Mixture was stirred at 0°C for 90 minutes, and was added aqueous 1M NaOH solution to achieve a slightly alkaline pH. The mixture was filtered through an Isolute® and suirable CH2Cl2. The organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by HPLC gave specified in the title compound (130 mg, 20%). LC-MS: tR= 0.95 min; ES+: 682,18.

Example 20

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid

A solution of compound L8 (150 mg, 0,198 mmol) in CH2Cl2(3 ml) was cooled to 0°C. was Added HCl (4M in dioxane, 0,247 ml, 0,988 mmol). The mixture was stirred for 1 hour at 0°C. was Again added HCl (4M in dioxane, 0,247 ml, 0,988 mmol) and the mixture was stirred for 2 hours at room temperature. Again, was added HCl (4M in dioxane, 0,247 ml, 0,988 mmol) and the mixture was stirred for 2 hours at room temperature. Was added aqueous 1M NaOH solution to obtain a slightly alkaline with the art. The mixture was filtered through an Isolute® and suirable CH2Cl2and the organic phase was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl25:95) gave specified in the title compound (57 mg, 44%). LC-MS: tR= 0,91 minutes; ES+: 660,40.

Examples 21 and 22

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, to 3.00 ml) was added to a solution of compound 5 (819 mg, 0,816 mmol) in CH2Cl2(9 ml) at 0°C. the Mixture was stirred at 0°C for 30 minutes and left to warm to room temperature over 1 hour. The mixture was concentrated under reduced pressure and the residue was dried in high vacuum over night. The residue was dissolved in CH2Cl2and the resulting mixture was washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. This substance was dissolved in a mixture of THF (9 ml) and AcOH (3 ml). Was added Zn powder (534 mg, 8.16 mmol) and the mixture was stirred intensively for 4 hours. The mixture was filtered through celite and actuarialy was removed under reduced pressure. The residue was dissolved in CH2Cl2and the resulting mixture was washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 98:2 → 96:4 → 94:6 → 92:8, always with the addition of 1% Et3N) gave a mixture of the mentioned in the title compound (439 mg, 76 %). This mixture was separated by HPLC (Chiralcel OD, isocratic conditions using 85% of eluent B), getting listed in the title compound (84 mg, 18%, and 53 mg, 12%, respectively). LC-MS: tR= 0,85 minutes; ES+: 701,23. Chiral column HPLC: tR= 11,9 and 20.0 minutes, respectively.

Example 23

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 4,90 ml of 19.5 mmol) was added to a solution of compound L9 (1,02 g of 1.31 mmol) in CH2Cl2(5.5 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature. The mixture was diluted with CH2Cl2and washed with aqueous saturated solution of NaHCO3and water. The organic layer was dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/heptane 7:3 → EtOAc → MeOH/acetone 1:9) gave specified in the racemic title compound (328 mg, 37%). This rat is t divided by HPLC (Regis Whelk, eluent B from 65% → 40% for 10 minutes, then isocratically), getting mentioned in the title compound (100 mg, 29%). LC-MS: tR= 0.95 min; ES+: 684,49. Chiral column HPLC: tR= 20.4 minutes.

Example 24

[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 6-[3-(2-[ENT-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',5',6'-tetrahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 1,10 ml, 4,39 mmol) was added to a solution of compound 10 (344 mg, 0,439 mmol) in CH2Cl2(1.20 ml) at 0°C. the Mixture was stirred for 3 hours at room temperature and the solvents were removed under reduced pressure. Added CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (heptane/CH2Cl2/Meon 3:6:1 with 1% Et3N → heptane/CH2Cl2/Meon 2:7:1 with 1% Et3N) gave specified in the title compound (31 mg, 10%). LC-MS: tR= 0,94 minutes; ES+: 683,46.

Example 25

[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-3-acetyl-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

To a solution of compound L11 (722 mg, 0,763 mmol) in THF (9 ml) and AcOH (3 ml) was added by portions at room temperature powder Zn (500 mg, 7,63 mmol). This mixture is tensive was stirred at room temperature for 1 hour. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2and washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 98:2 → 96:4 → 94:6 → 92:8 always with the addition of 1% Et3N) gave specified in the racemic title compound (305 mg, 54%). This racemate was separated by HPLC (Chiralcel OD, isocratic conditions using 80% of eluent B), receiving specified in the title compound (100 mg, 29%). LC-MS: tR= 0,86 minutes; ES+: 744,19. Chiral column HPLC: tR= 10.8 minutes.

Example 26

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3,2,1]octane-2-carboxylic acid

To a solution of compound L12 (448 mg, 0,570 mmol) in CH2Cl2(6,00 ml) at 0°C was added HCl (4M in dioxane, 2.00 ml). The mixture was stirred for 30 minutes at 0°C for 90 minutes at room temperature. The solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2and washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue using PF (CH2Cl2/MeOH 96:4 → 95:5 → 94:6 → 93:7 always with EXT is the effect of 0.5% Et 3N) gave specified in the racemic title compound (358 mg, 93%). This racemate was separated by HPLC (Regis Whelk, the gradient of eluent B from 75% → 30% within 30 minutes), getting mentioned in the title compound (114 mg, 30%). LC-MS: tR= 1.00 min; ES+: 673,52. Chiral column HPLC: tR= 16,6 minutes.

Example 27

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3,2,1]octane-2-carboxylic acid

To a solution of compound L13 (137 mg, 0,174 mmol) in CH2Cl2(2.00 ml) at 0°C was added HCl (4M in dioxane, 0,70 ml). The mixture was stirred for 30 minutes at 0°C for 90 minutes at room temperature. The solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2and washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue using PF (CH2Cl2/MeOH 96:4 → 95:5 → 94:6 → 93:7 always with the addition of 0.5% Et3N) gave specified in the racemic title compound (113 mg, 95%). This racemate was separated by HPLC (Regis Whelk, the gradient of eluent B from 75% → 30% within 30 minutes), getting mentioned in the title compound (114 mg, 30%). LC-MS: tR= 0.99 min; ES+: 687,20. Chiral column HPLC: tR= 18,3 minutes.

Example 28

[2-Chloro-5-(3-methoxy-propyl)Ben is Il]cyclopropylamine (1R,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid

To a solution of compound L14 (492 mg, 0,627 mmol) in CH2Cl2(6.30 ml) at 0°C was added HCl (4M in dioxane, 6.30 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2and washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue using PF (CH2Cl2→ CH2Cl2/MeOH 9:1) gave specified in the racemic title compound (296 mg, 67%). This racemate was separated by HPLC (Chiracel OD, isocratic, eluent B 85%), getting mentioned in the title compound (80 mg, 28%). LC-MS: tR= 0,94 minutes; ES+: 708,20. Chiral column HPLC: tR= 17.0 minutes.

Example 29

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

Zn (powder, 192 mg, to 2.94 mmol) was added to a solution of compound L15 (569 mg, 0,587 mmol) in THF (8,01 ml) and AcOH (or 2.67 ml). The mixture was intensively stirred at room temperature for 3 hours and again was added Zn (192 mg, to 2.94 mmol). The mixture was stirred for 1 hour and filtered through celite. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2l 2and the mixture is washed with aqueous 1M NaOH solution (4×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 9:1) gave specified in the racemic title compound (160 mg, 36%). This racemate was separated by HPLC (Chiracel OD, gradient eluent B from 95% → 50% within 30 minutes), getting mentioned in the title compound (80 mg, 28%). LC-MS: tR= 0,91 minutes; ES+: 766,17. Chiral column HPLC: tR= 19,3 minutes.

Example 30

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',5',6'-tetrahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, and 0.50 ml) was added to a solution of compound L20 (249 mg, 0,328 mmol) in CH2Cl2(2.00 ml) at 0°C. the Mixture was stirred for 1.5 hours at 0°C was added aqueous 1M NaOH solution until until the mixture was alkaline. The mixture was filtered through an Isolute® and the organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by HPLC (x-Bridge column, acetonitrile/H2O + 0.05% of NH4OH, 10:90 → 90:10, for 6 minutes) gave specified in the title compound (20 mg, 9%).

Example 31

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4S')-6-[2-(2,6-dichloro-4-methyl-phenoxy)ATOC and]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, of 1.36 ml) was added to a solution of compound L21 (414 mg, 0,543 mmol) in CH2Cl2(1.50 ml) at 0°C. the Mixture was stirred for 3 hours at room temperature. Added CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave specified in the racemic title compound (211 mg, 59%). This racemate was separated by HPLC (Regis Whelk, 70% B → 30% B over 30 minutes), getting mentioned in the title compound (52 mg, 24%). LC-MS: tR= 0,88 minutes; ES+: 663,51. Chiral column HPLC: tR= 18.9 minutes.

Examples 32 and 33

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1S,5R)-7-{4-[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, and 8.50 ml) was added to a solution of compound L22 (850 mg, 0,827 mmol) in CH2Cl2(8,50 ml) at 0°C. the Mixture was stirred at room temperature for 60 minutes. The solvents were removed under reduced pressure and the residue was diluted with CH2Cl2. The resulting mixture was washed with aqueous 1M solution of NaO and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 98:2 → 95:5) gave a brown oil. This oil was dissolved in THF (4,00 ml) and AcOH (0,50 ml). Added Zn (261 mg, 3,99 mmol) and the reaction mixture was then intensively stirred at room temperature for 3 hours. The mixture was filtered through celite and the filtrate was diluted with EtOAc. This mixture was washed with aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 8:2 → CH2Cl2/ NH37M in methanol 8:2) gave specified in the racemic title compound (90 mg, 11%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting listed in the title compound (21 mg, 18 mg, 23% and 20%, respectively). LC-MS: tR= 0,80 min; ES+: 724,22. Chiral column HPLC: tR= of 18.3 minutes and 20.9 minutes, respectively.

Example 34

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydropyridine-3-carboxylic acid

HCl (4M in dioxane, and 1.00 ml) was added to a solution of compound L23 (548 mg, 0,699 mmol) in CH2Cl2(4,00 ml) at 0°C. the Mixture is eremetical for 1.5 hours at 0°C. Aqueous 1M NaOH solution was added until the mixture was alkaline. The organic layer was separated, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave specified in the title compound (27 mg, 6%). LC-MS: tR= 0,88 minutes; ES+: 683,50.

Example 35

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid

The mixture of compounds K18 (500 mg, 0,910 mmol), EDC·HCl (209 mg, of 1.09 mmol) and HOBt (135 mg, 1.00 mmol) in DMF (5 ml) was stirred at room temperature for 30 minutes. Was added N-methylmorpholine (0,502 ml, 4,55 mmol) and [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (462 mg, 1.82 mmol). The mixture was stirred at room temperature for 3 days and again was added EDC·HCl (210 mg, of 1.09 mmol), HOBt (135 mg, 1.00 mmol), N-methylmorpholin (0,500 ml of 4.54 mmol) and 5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropyl-amine (230 mg, of 0.91 mmol). The mixture was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and washed with aqueous 10% citric acid solution, aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (EtOAc/g is plan 1:3) gave the amide condensation product, which was dried in high vacuum. This product was dissolved in HCl (4M in dioxane, 2 ml) and the mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure and the residue was diluted with EtOAc. This mixture was washed with aqueous saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title racemic compound. This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 60%), getting mentioned in the title compound (41 mg, 20%). LC-MS: tR= 0.96 min; ES+: 686,18. Chiral column HPLC: tR= 12.6 minutes.

Example 36

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid

Connection L24 (486 mg, 0,600 mmol) was dissolved in CH2Cl2(6,00 ml). HCl (4M in dioxane, to 6.00 ml) was added at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the resulting oil was dried under high vacuum. Purification of the residue using PF (CH2Cl2→ CH2Cl2/Meon 90:10) gave specified in the header of racemic the connection. This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 60%), getting mentioned in the title compound (71 mg, 17%). LC-MS: tR= 0,93 minutes; ES+: 709,18. Chiral column HPLC: tR= 16.3 minutes.

Example 37

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo [3.2.1]Oct-2-ene-2-carboxylic acid

Connection L25 (525 mg, 0,649 mmol) was dissolved in CH2Cl2(6,50 ml). HCl (4M in dioxane, 6,50 ml) was added at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the resulting oil was dried under high vacuum. Purification of the residue using PF (CH2Cl2→ CH2Cl2/Meon 90:10) gave specified in the title compound, together with its corresponding (1S,5R)-diastereoisomer (348 mg, 76%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (92 mg, 20%). LC-MS: tR= 1,01 minutes; ES+: 708,21. Chiral column HPLC: tR= 9,83 minutes.

Examples 38 and 39

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1S,5R)-7-{6-[(R)-3-(2,6-dichloro--methyl-phenoxy)-pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, 2.00 ml) was added to a solution of compound L26 (559 mg, 0,570 mmol) in CH2Cl2(6,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and overnight at room temperature. The solvents were removed under reduced pressure and the resulting oil was dried under high vacuum. The residue was diluted with CH2Cl2and the resulting mixture was washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 96:4 → 94:6 → 98:2 → 90:10) gave a mixture of the mentioned in the title compound (402 mg, 99%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting listed in the title compound (70 mg, 68 mg, 23% and 22%, respectively). LC-MS: tR= 0,80 min; ES+: 712,59. Chiral column HPLC: tR= 19.7 minutes and 24.6 minutes, respectively.

Examples 40 and 41

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1S,5R)-7-{6-[(R)-3-(2-chloro-3,6-debtor-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, 2.00 ml) was added to a solution of compounds L27 (581 mg, 0,646 mmol) in CH2Cl2(6,00 ml) PR is 0°C. The mixture was stirred for 30 minutes at 0°C and overnight at room temperature. The solvents were removed under reduced pressure and the resulting oil was dried under high vacuum. The residue was diluted with CH2Cl2and the resulting mixture was washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 96:4 → 94:6 → 98:2 → 90:10) gave a mixture of the mentioned in the title compound (344 mg, 76%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting listed in the title compound (53 mg and 60 mg, 18% and 20%, respectively). LC-MS: tR= 0,78 minutes; ES+: 698,57. Chiral column HPLC: tR= 15,5 minutes and 20.3 minutes, respectively.

Examples 42 and 43

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid [5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1S,5R)-7-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl/dioxane (4M, 5,00 ml) was added to a solution of compound L28 (764 mg, 0,760 mmol) in CH2Cl2(5,00 ml). The mixture was stirred for 1 hour at room temperature and the mixture was evaporated under reduced pressure. About what's headed the remainder was dried in high vacuum. The residue was dissolved in a mixture of THF (6,00 ml) and AcOH (2.00 ml). Added Zn (497 mg, 7,60 mmol) and the mixture was stirred for 3 hours. The mixture was filtered, washed with THF and the solvent was removed under reduced pressure. The residue was dried in high vacuum. The residue was diluted with EtOAc and washed with aqueous 1M NaOH solution (3×). The combined aqueous layers was extracted with EtOAc (1×). The combined organic layers were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (MeOH/CH2Cl21:9 → 2:8, always with the addition of 1% Et3N) gave specified in the racemic title compound (109 mg, 20%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting listed in the title compound (4.5 mg and 4.1 mg, 5% and 4%, respectively). LC-MS: tR= 0,80 min; ES+: 702,10. Chiral column HPLC: tR= 15,5 minutes and 17.9 minutes, respectively.

Example 44

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 5,00 ml) was added to a solution of compound L29 (103 mg, is 0.135 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the resulting oil was dried in high vacuo the E. The residue was diluted with CH2Cl2and the resulting mixture was washed with 1M aqueous NaOH solution (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/MeOH 98:2 → 96:4 c 1% Et3N) gave specified in the title compound (52 mg, 58%). LC-MS: tR= 0,89 minutes; ES+: 662,17.

Example 45

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

HCl (4M in dioxane, 18 ml) was added to a solution of compound L30 (711 mg, 0,920 mmol) in CH2Cl2(18 ml). The mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The remaining substance was dissolved in CH2Cl2and this mixture is washed with aqueous 1M NaOH solution (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying of the residue in high vacuum was obtained the crude racemic compound (580 mg, 94%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (200 mg, 35%). LC-MS: tR= 0.97 min; ES+: 674,24. Chiral column HPLC: tR= 10.5 minutes.

Examples 46 and 47

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

Zn (powder, 356 mg of 5.45 mmol) was added to a solution of compound L31 (560 mg, 0,545 mmol) in THF (5,00 ml) and glacial AcOH (0,700 ml). The mixture was intensively stirred at room temperature for 5 hours. The mixture was filtered through celite and was combined with EtOAc. The resulting mixture was washed with aqueous saturated solution of NaHCO3. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. This crude substance was dissolved in CH2Cl2(4,00 ml), was added HCl (4M in dioxane, 4,00 ml). The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was diluted with EtOAc and the resulting mixture was washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:4) gave the racemic mixture specified in the title compound (150 mg, 38%). This racemate was separated by HPLC (Regis Whelk, isocrates the second eluent B 50%), getting listed in the title compound (45 mg and 46 mg, 30% and 30%, respectively). LC-MS: tR= 0,85 minutes; ES+: 723,23. Chiral column HPLC: tR= 18,7 minutes and 22.9 minutes, respectively.

Examples 48 and 49

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1S,5R)-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, 10 ml) was added to a solution of compound L32 (991 mg, of 1.09 mmol) in CH2Cl2(10 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and for 2 hours at room temperature. The solvents were removed under reduced pressure, and the residue was distributed between CH2Cl2and aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/7M NH3in MeOH 9:1 → 8:2) gave a mixture of the mentioned in the title compound (574 mg, 74%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting listed in the title compound (185 mg 188 mg, 36% and 37%, respectively). LC-MS: tR= 0,83 minutes; ES+: 709,33. Chiral column HPLC: tR= 19.7 minutes and 23.3 min is you, respectively.

Example 50

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, 5.50 ml) was added to a solution of compound L33 (551 mg, 0,636 mmol) in CH2Cl2(5.50 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and for 2 hours at room temperature. The solvents were removed under reduced pressure and the residue was distributed between CH2Cl2and aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/7M NH3in MeOH 9:1) gave specified in the racemic title compound (270 mg, 55%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (135 mg, 31%). LC-MS: tR= 0,91 minutes; ES+: 765,14. Chiral column HPLC: tR= 27,4 minutes.

Example 51

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,5S)-3-acetyl-7-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, the ceiling of 5.60 ml) was added to a solution of compound L34 (560 mg, 0,657 mmol) in CH2Cl2(the ceiling of 5.60 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and in accordance with the s 2 hours at room temperature. The solvents were removed under reduced pressure and the residue was distributed between EtOAc and aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/7M NH3in MeOH 9:1) gave specified in the racemic title compound (385 mg, 78%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (102 mg, 26%). LC-MS: tR= 0,89 minutes; ES+: 751,37. Chiral column HPLC: tR= 27,8 minutes.

Examples 52 and 53

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,5S)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid [2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1S,5R)-7-{6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]pyridine-3-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-6-carboxylic acid

HCl (4M in dioxane, 9,80 ml) was added to a solution of compound L35 (452 mg, 489 mmol) in CH2Cl2(4,90 ml) at room temperature. The mixture was stirred for 1 hour at room temperature and the solvents were removed under reduced pressure. The residue was dried in high vacuum. Purification of the crude product using PF (CH2Cl2→ CH2Cl2/Meon 80:20) gave the racemic mixture specified in the header connection is s (277 mg, 78%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting listed in the title compound (24 mg and 30 mg, 9% and 11%, respectively). LC-MS: tR= 0,85 minutes; ES+: 724,19. Chiral column HPLC: tR= 13.7 minutes and 16.9 minutes, respectively.

Example 54

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

HCl (4M in dioxane, at 8.00 ml) was added to a solution of compounds L36 (474 mg, 0,595 mmol) in CH2Cl2(8,00 ml). The mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CH2Cl2and the mixture is washed with aqueous 1M NaOH solution (3). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (2M NH3in MeOH/CH2Cl21:30 → 13:300 → 15:300 → 36:300) gave specified in the title compound, together with its corresponding (1S,2S,3R,5R)-diastereoisomer (295 mg, 71%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (85 mg, 29%). LC-MS: tR= 1,03 min; ES+: 698,27. Chiral column HPLC: tR= 18,6 minutes.

Example 55/b>

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]pyridine-3-yl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

HCl (4M in dioxane, 10.0 ml) was added to a solution of compounds L37 (152 mg, 0,190 mmol) in CH2Cl2(10.0 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CH2Cl2and the mixture is washed with aqueous 1M NaOH solution (3×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude mixture indicated in the title compound, together with its corresponding (1S, 2S, 3R, 5R)-diastereoisomer (125 mg, 94%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (24 mg, 21%). LC-MS: tR= 0,78 minutes; ES+: 697,39. Chiral column HPLC: tR= 13.7 minutes.

Example 56

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 2.00 ml) was added to a solution of compounds L38 (624 mg, 0,793 mmol) in CH2Cl2(2,50 ml) at 0°C. the Mixture was stirred for 3 hours at room temperature and p is storytale was removed under reduced pressure. Added CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (EtOAc/heptane 7:3 → EtOAc/MeOH 9:1) gave specified in the title compound mixed with its (3'S, 4'R)-diastereoisomer (380 mg, 71%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (78 mg, 21%). LC-MS: tR= 0,82 minutes; ES+: 671,22. Chiral column HPLC: tR= 18,3 minutes.

Example 57

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,5S)-3-{4-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]phenyl}-8-azabicyclo[3.2.1]Oct-2-ene-2-carboxylic acid

HCl (4M in dioxane, is 2.40 ml) was added to a solution of compound L39 are effective (190 mg, 0,242 mmol) in CH2Cl2(2,40 ml). The mixture was stirred for 1 hour at room temperature. The solvents were removed under reduced pressure and the resulting oil was dried under high vacuum. Purification of the residue using PF (CH2Cl2→ CH2Cl2/Meon 90:10) gave specified in the racemic title compound (148 mg, 89%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 70%), receiving specified in the header connection (7,1 mg, 5%). LC-MS: tR= 0,92 minutes; ES+: 684,23. Chiral column HPLC: tR= 20,9 minutes.

Example 5

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 1,10 ml) was added to a solution of compounds L40 (360 mg, 0,457 mmol) in CH2Cl2at 0°C. the Mixture was stirred for 3 hours at room temperature and the solvents were removed under reduced pressure. Added CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining mentioned in the title compound, together with its corresponding (3'S,4'R)-diastereoisomer (310 mg, 99%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 70%), getting mentioned in the title compound (49 mg, 16%). LC-MS: tR= 0,76 minutes; ES+: 688,20. Chiral column HPLC: tR= 19,3 minutes.

Example 59

[2-Chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

To a solution of compound L41 (360 mg, 0,444 mmol) in CH2Cl2(4,00 ml) at room temperature was added HCl (4M in dioxane, 4,00 ml). The mixture was stirred at room temperature for 2 hours and the mixture was evaporated under reduced pressure. Added CH2Cl2and mesh washed with aqueous 1M NaOH solution. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 9:1) gave specified in the racemic title compound (120 mg, 38%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (17 mg, 17%). LC-MS: tR= 0.96 min; ES+: 710,37. Chiral column HPLC: tR= 15,1 minutes.

Example 60

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

To a solution of compound L42 (1,00 g of 1.26 mmol) in CH2Cl2(10 ml) at room temperature was added HCl (4M in dioxane, 10 ml). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness, then added CH2Cl2. The mixture is washed with aqueous 1M NaOH solution. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/7M NH3in MeOH 9:1) gave specified in the racemic title compound (760 mg, 87%). This racemate was separated by HPLC (Regis Whelk, isocratic e is uent B 50%), getting listed in the title compound (17 mg, 17%). LC-MS: tR= 0,94 minutes; ES+: 696,40. Chiral column HPLC: tR= 15,1 minutes.

Example 61

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

A solution of compound L43 (2.14 g, 2.77 mmol) in CH2Cl2(27 ml) at 0°C was treated with HCl (4M in dioxane, and 13.5 ml) and the mixture was stirred for 2 hours, while it was heated to room temperature. The mixture was poured into 1M aqueous NaOH solution and the resulting mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure. Purification of the residue using PF (CH2Cl2/Meon 85:15) gave specified in the title compound, together with its corresponding (3'S,4'R)-diastereoisomer (904 mg, 48%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (42 mg, 5%). LC-MS: tR= 0,80 min; ES+: 673,47. Chiral column HPLC: tR= 19.7 minutes.

Example 62

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (1R,2R,3S,5S)-3-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-8-azabicyclo[3.2.1]octane-2-carboxylic acid

To a solution of compound L44 (450 mg, 0,555 mmol) is CH 2Cl2(4,50 ml) at room temperature was added HCl (4M in dioxane, 4,50 ml). The mixture was then stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and added CH2Cl2. The organic layer is washed with aqueous 1M NaOH solution. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (CH2Cl2/Meon 9:1) gave specified in the racemic title compound (270 mg, 68%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (88 mg, 33%). LC-MS: tR= 0,89 minutes; ES+: 711,39. Chiral column HPLC: tR= 15.7 minutes.

Example 63

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-Chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, to 2.13 ml) was added to a solution of compound L45 (670 mg, 0,853 mmol) in CH2Cl2(2.00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C for 1.5 hours at room temperature. The mixture is washed with aqueous 10% solution of Na2CO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents udaleniya reduced pressure. Purification of the crude product by HPLC (acetonitrile/0.05% aq. NH310:90 → 90:10, column X-bridge) gave specified in the racemic title compound (406 mg, 69%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (90 mg, 23%). LC-MS: tR= 0,86 minutes; ES+: 685,59. Chiral column HPLC: tR= 18,6 minutes.

Example 64

[5-(Acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 1.60 ml) was added to a solution of compound L46 (500 mg, 0,638 mmol) in CH2Cl2(1.50 ml) at 0°C. the Mixture was stirred at 0°C for 90 minutes and was diluted with additional CH2Cl2. The mixture is washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (430 mg, 99%). This crude racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (115 mg, 27%). LC-MS: tR= 0,87 minutes; ES+: 683,21. Chiral column HPLC: tR= 25,1 minutes.

Example 65

[5-(Acetylamino-methyl)-2-Chlorobenzyl]cyclopropylamine(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-ethyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,90 ml) was added to a solution of compounds L47 (770 mg, 0,990 mmol) in CH2Cl2(9,90 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into the intensively stirred mixture of aqueous 10% solution of Na2CO3(40 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (510 mg, 76%). This crude mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (160 mg, 32%). LC-MS: tR= 0.77 min; ES+: 684,30. Chiral column HPLC: tR= 25,0 minutes.

Example 66

[5-(Acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, of 4.25 ml) was added to a solution of compounds L48 (667 mg, 0,850 mmol) in CH2Cl2(8,50 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into the intensively stirred mixture of aqueous 10% solution of Na2CO3(40 ml) and EtOAc (100 ml). The phase section is whether and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (515 mg, 88%). This crude mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (160 mg, 32%). LC-MS: tR= 0.77 min; ES+: 684,30. Chiral column HPLC: tR= 26,3 minutes.

Example 67

{2-Chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 5,10 ml) was added to a solution of compounds L49 (870 mg, of 1.02 mmol) in CH2Cl2(10,2 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into the intensively stirred mixture of aqueous 10% solution of Na2CO3(40 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (610 mg, 79%). This crude mixture was separated by HPLC (Regis Whek, isocratic eluent B 50%), getting mentioned in the title compound (200 mg, 33%). LC-MS: tR= 0,81 minutes; ES+: 752,31. Chiral column HPLC: tR= 21.5 minutes.

Example 68

{2-Chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,80 ml) was added to a solution of compounds L50 (828 mg, 0,970 mmol) in CH2Cl2(9,70 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into the intensively stirred mixture of aqueous 10% solution of Na2CO3(40 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S, 4'R)-diastereoisomer (715 mg, 98%). This crude mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (215 mg, 29%). LC-MS: tR= 0,81 minutes; ES+: 754,23. Chiral column HPLC: tR= 20,9 minutes.

Example 69

(2-Chloro-5-cyclopropylamino-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}Piperi the Jn-3-carboxylic acid

HCl (4M in dioxane, 3,40 ml) was added to a solution of compound L51 (600 mg, 0,680 mmol) in CH2Cl2(6,80 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into the intensively stirred mixture of aqueous 10% solution of Na2CO3(40 ml) and EtOAc (100 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (410 mg, 88%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (117 mg, 29%). LC-MS: tR= 0,78 minutes; ES+: 681,66. Chiral column HPLC: tR= 15.6 minutes.

Example 70

[5-Chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 5,00 ml) was added to a solution of compound L52 (660 mg, 0,823 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was diluted with CH2Cl2off , washed with aqueous saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over Na2SO4, filters the if and the solvent was evaporated under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:9 → 3:7) gave specified in the racemic title compound (528 mg, 91%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 30%), getting mentioned in the title compound (65 mg, 13%). LC-MS: tR= 0,85 minutes; ES+: 701,18. Chiral column HPLC: tR = 25.4 minutes.

Example 71

(2-Chloro-5-cyclopropylamino-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

To a solution of compounds L53 (860 mg, 0,mol) in CH2Cl2(9.7 ml) at 0°C was added HCl (4M in dioxane, is 4.85 ml). The mixture was stirred at 0°C for 30 minutes and within 45 minutes at room temperature. The mixture was poured into a mixture of aqueous 10% solution of Na2CO3(28 ml) and EtOAc (140 ml) under stirring. The layers were separated. The organic extract was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (631 mg, 95%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (175 mg, 29%). LC-MS: tR= 0,70 minutes; ES+: 683,10. Chiral column HPLC: tR= 16,9 minutes.

Example 72

[5-(2-Acetylamino-ethyl)-2-chloro-benzylchloride (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, to 3.00 ml) was added to a solution of compound L54 (486 mg, 0,610 mmol) in CH2Cl2(6,10 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The mixture was poured into intensively mixed aqueous 10% solution of Na2CO3(20 ml) and was added EtOAc (100 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (500 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (60 mg, 12%). LC-MS: tR= 0,89 minutes; ES+: 697,26. Chiral column HPLC: tR= 22,8 minutes.

Example 73

[2-Chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 1.73 ml) was added to a solution of compound L55 (620 mg, 0,692 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C was added aqueous saturated solution of NaHCO3to neutral pH. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with water and saturated salt solution, who left the house taking over MgSO 4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (485 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (85 mg, 17%). LC-MS: tR= 0,79 minutes; ES+: 695,22. Chiral column HPLC: tR= 16.7 minutes.

Example 74

[2-Chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3'R, 4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 2.00 ml) was added to a solution of compounds L56 (227 mg, 0,253 mmol) in CH2Cl2(4,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and neutralized aqueous saturated solution of NaHCO3. The layers were separated and the organic layer was extracted with CH2Cl2. The combined organic extracts washed with aqueous 10% solution of Na2CO3and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (174 mg, 98%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting mentioned in the title compound (18 mg, 11%). LC-MS: tR= 0.72 min; ES+: 696,28. Hee the social column HPLC: t R= 15,0 minutes.

Example 75

[2-Chloro-5-(2-cyclopropylamino)benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 2,50 ml) was added to a solution of compounds L57 (796 mg, 0,887 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and neutralized aqueous saturated solution of NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2(2×). The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (582 mg, 93%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (127 mg, 24%). LC-MS: tR= 0.72 min; ES+: 696,30. Chiral column HPLC: tR= 17.9 minutes.

Example 76

[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[2-(2,6-dichloro-4-methyl-phenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 11,00 ml) was added to a solution of compound L58 (780 mg, 1.00 mmol) in CH2Cl2(11,00 ml) at 0°C. the Mixture was stirred for 1.5 hours at 0°C and alibali in intensively mixed aqueous 1M NaOH solution. The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (428 mg, 63%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (42 mg, 11%). LC-MS: tR= 0,85 minutes; ES+: 677,26. Chiral column HPLC: tR= 40.2 minutes.

Example 77

{2-Chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 1,93 ml) was added to a solution of compound L59 (700 mg, 0,773 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and neutralized aqueous 10% solution of Na2CO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (410 mg, 75%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (83 mg, 18%). LC-MS: tR= 079 minutes; ES+: 705,18. Chiral column HPLC: tR= 15,5 minutes.

Example 78

(2-Chloro-5-[(2,2-diferentiating)-methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, and 2.83 ml) was added to a solution of compounds L60 (739 mg, 0,814 mmol) in CH2Cl2(5,66 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature and was added aqueous 10% solution of Na2CO3to neutralize the mixture. The layers were separated and the aqueous layer was extracted with CH2Cl2(2×). The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (534 mg, 93%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (118 mg, 23%). LC-MS: tR= 0.72 min; ES+: 708,27. Chiral column HPLC: tR= 16.2 minutes.

Example 79

(2-Chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, and 2.83 ml) was added to a solution of compounds L61 (637 mg, 0,785 mmol) VSN 2Cl2(5,66 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature and was added aqueous saturated solution of NaHCO3to achieve pH 7. The layers were separated and the aqueous layer was extracted with CH2Cl2(2×). The combined organic extracts were washed with water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (466 mg, 83%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting mentioned in the title compound (55 mg, 13%). LC-MS: tR= 0,80 min; ES+: 710,21. Chiral column HPLC: tR= 36,7 minutes.

Example 80

(2-Chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, and 11.0 ml) was added to a solution of compounds L62 (810 mg, of 1.03 mmol) in CH2Cl2(11,0 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C was added aqueous 1M NaOH solution (40 ml). The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining neocis the TES specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (670 mg, 95%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (112 mg, 17%). LC-MS: tR= 0.75 min; ES+: 686,59. Chiral column HPLC: tR= 40.5 minutes.

Example 81

(2-Chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 7,0 ml) was added to a solution of compounds L63 (700 mg, 0,876 mmol) in CH2Cl2(7.0 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C was added aqueous 1M NaOH solution to achieve a pH >12. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (605 mg, 99%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 45%), getting mentioned in the title compound (110 mg, 19%). LC-MS: tR= 0,80 min; ES+: 698,32. Chiral column HPLC: tR= 39.1 minutes.

Example 82

[2-Chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbon is Oh acid

HCl (4M in dioxane, 13,0 ml) was added to a solution of compounds L64 (990 mg, 1,24 mmol) in CH2Cl2(13,0 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C was added aqueous 1M NaOH solution (40 ml). The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (571 mg, 66%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (100 mg, 18%). LC-MS: tR= 0,78 minutes; ES+: 698,60. Chiral column HPLC: tR= 27,5 minutes.

Example 83

{2-Chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 3,70 ml) was added to a solution of compound L65 (607 mg, 0.75 mmol) in CH2Cl2(7,50 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature and was poured into the intensively stirred aqueous 10% solution of Na2CO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2 SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (530 mg, 99%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (53 mg, 10%). LC-MS: tRor = 0.90 min; ES+: 709,22. Chiral column HPLC: tR= 27,1 minutes.

Example 84

{2-Chloro-5-[(cyclopropanecarbonyl)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 14 ml) was added to a solution of compounds L66 (1030 mg, of 1.27 mmol) in CH2Cl2(14 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature and was poured into the intensively stirred aqueous 10% solution of Na2CO3. The layers were separated and added aqueous 1M NaOH solution (40 ml). The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (630 mg, 70%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (140 mg, 22%). LC-MS: R= 0,79 minutes; ES+: 712,56. Chiral column HPLC: tR= 27,0 minutes.

Example 85

Methyl ester of (4-chloro-3-{[((3R,4S)-4-{4-[3-(2-chloro-3,6-differenl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carbonyl)cyclopropylamino]methyl}benzyl)carbamino acid

HCl (4M in dioxane, 4,80 ml) was added to a solution of compound L67 (616 mg, 0,770 mmol) in CH2Cl2(7,70 ml) at 0°C. the Mixture was stirred for 1 hour at room temperature, and was poured into the intensively stirred aqueous 10% solution of Na2CO3(20 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (530 mg, 98%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (50 mg, 10%). LC-MS: tR= 0,89 minutes; ES+: 699,17. Chiral column HPLC: tR= 27,4 minutes.

Example 86

Methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl}carbamino acid

HCl (4M in dioxane, 1.25 ml) was added to a solution of compounds L68 (190 mg, 0,237 mmol) in CH2Cl2(2.37 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C is within 80 minutes at room temperature and was poured into the intensively stirred aqueous 10% solution of Na 2CO3(7,00 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S, 4'R)-diastereoisomer (163 mg, 98%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (23 mg, 14%). LC-MS: tR= 0,80 min; ES+: 702,25. Chiral column HPLC: tR= 23.5 minutes.

Example 87

Methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl}carbamino acid

HCl (4M in dioxane, at 3.25 ml) was added to a solution of compounds L69 (630 mg, 0.786 mmol) in CH2Cl2(of 7.90 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C for 80 minutes at room temperature and was poured into the intensively stirred aqueous 10% solution of Na2CO3(23,0 ml). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over Na2SO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (550 mg, 99%). This mixture R is sdelali by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (120 mg, 22%). LC-MS: tR= 0,78 minutes; ES+: 702,48. Chiral column HPLC: tR= 26,6 minutes.

Example 88

[5-(2-Acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 6.4 ml) was added to a solution of compounds L70 (1,36 g, 1.70 mmol) in CH2Cl2(6 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and was added to neutralize the aqueous saturated solution of NaHCO3. Added CH2Cl2and the mixture was extracted with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification by HPLC gave specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (658 mg, 55%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (184 mg, 28%). LC-MS: tR= 0,76 minutes; ES+: 700,58. Chiral column HPLC: tR= 21,0 minutes.

Example 89

[5-(2-Acetylamino-ethyl)-2-Chlorobenzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 2.35 ml) dobavlyali solution of compounds L71 (500 mg, 0,626 mmol) in CH2Cl2(to 3.00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and was added to neutralize the aqueous saturated solution of NaHCO3. Added CH2Cl2and the mixture was extracted with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification by HPLC gave specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (209 mg, 48%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (60 mg, 30%). LC-MS: tR= 0,78 minutes; ES+: 700,66. Chiral column HPLC: tR= 22,8 minutes.

Example 90

{2-Chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,00 ml) was added to a solution of compounds L72 (460 mg, 0,506 mmol) in CH2Cl2(8,00 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C and was added to neutralize the aqueous saturated solution of NaHCO3. Added CH2Cl2and the mixture was extracted with 1M aqueous HCl solution and a saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Ochistka by HPLC gave specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (270 mg, 75%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (34 mg, 15%). LC-MS: tR= 0.72 min; ES+: 706,23. Chiral column HPLC: tR= 14,0 minutes.

Example 91

(2-Chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, at 8.00 ml) was added to a solution of compounds L73 (740 mg, 0,912 mmol) in CH2Cl2(8,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (707 mg, quantitative yield). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (180 mg, 28%). LC-MS: tR= 0,78 minutes; ES+: 712,60. Chiral column HPLC: tR= 38,5 minutes.

Example 92

(2-Chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrole the Jn-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 7,00 ml) was added to a solution of compounds L74 (632 mg, 0,805 mmol) in CH2Cl2(7,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (544 mg, 99%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (62 mg, 12%). LC-MS: tR= 0,78 minutes; ES+: 684,66. Chiral column HPLC: tR= 38,6 minutes.

Example 93

{2-Chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 5,00 ml) was added to a solution of compounds L75 (491 mg, 0,605 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M what astora NaOH. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (544 mg, 99%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (71 mg, 16%). LC-MS: tR= 0,79 minutes; ES+: 712,63. Chiral column HPLC: tR= 24,6 minutes.

Example 94

[5-Chloro-2-(3-methoxy-propyl)-1-oxypyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,20 ml) was added to a solution of compounds L76 (414 mg, 0,515 mmol) in CH2Cl2(4,20 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (383 mg, quantitative yield). This mixture was separated by HPLC (Chiralcel OD, isocratic eluent B 80%), getting listed in the title the information connection (107 mg, 30%). LC-MS: tR= 0,74 minutes; ES+: 704,27. Chiral column HPLC: tR= 22,1 minutes.

Example 95

[5-Chloro-2-(3-methoxy-propyl)-1-oxypyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,00 ml) was added to a solution of compounds L77 (398 mg, 0,496 mmol) in CH2Cl2(4,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (360 mg, quantitative yield). This mixture was separated by HPLC (Chiralcel OD, isocratic eluent B 80%), getting mentioned in the title compound (80 mg, 26%). LC-MS: tR= 0.75 min; ES+: 704,27. Chiral column HPLC: tR= 19,1 minutes.

Example 96

(2-Chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 7,00 ml) was added to a solution of compound L78 (667 mg 0,824 mmol) in CH 2Cl2(7,00 ml) at 0°C. the Mixture was stirred at 0°C for 3 hours and was added aqueous 1M NaOH solution up until the aqueous layer showed a pH of 14. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (581 mg, 99%). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (142 mg, 25%). LC-MS: tR= 0,88 minutes; ES+: 709,54. Chiral column HPLC: tR= 34,6 minutes.

Example 97

(2-Chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, to 6.00 ml) was added to a solution of compound L79 (597 mg, 0,762 mmol) in CH2Cl2(6,00 ml) at 0°C. the Mixture was stirred at 0°C for 3 hours and was added aqueous 1M NaOH solution up until the aqueous layer showed a pH of 14. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (518 mg, 99%). This racemate was separated by HPLC (Regis Whelk, and ocratically eluent B 50%), getting listed in the title compound (130 mg, 26%). LC-MS: tR= 0,86 minutes; ES+: 683,55. Chiral column HPLC: tR= 32,4 minutes.

Example 98

(2-Chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 5,00 ml) was added to a solution of compound L80 (441 mg, 0,553 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred at 0°C for 3 hours and was added aqueous 1M NaOH solution up until the aqueous layer showed a pH of 14. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (398 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (82 mg, 21%). LC-MS: tR= 0,87 minutes; ES+: 697,56. Chiral column HPLC: tR= 32,2 minutes.

Example 99

[2-Chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, 7,00 ml) was added to a solution of compound L81 (640 mg, 0,802 mmol) in CH2Cl2(7,00 ml) at 0°C. the Mixture was stirred at 0°C at the tip is of 3 hours and was added aqueous 1M NaOH solution until until the aqueous layer showed a pH of 14. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (584 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (141 mg, 25%). LC-MS: tR= 0,88 minutes; ES+: 697,55. Chiral column HPLC: tR= 24,0 minutes.

Example 100

(2-Chloro-5-ethylcarboxylate-benzyl)cyclopropylamine (3'R, 4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 2,50 ml) was added to a solution of compounds L82 (560 mg, 0,701 mmol) in CH2Cl2(5,00 ml) at 0°C. the Mixture was stirred at 0°C for 1 hour and was added aqueous saturated solution of NaHCO3. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (300 mg, 61%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), receiving specified in the header with the Association (75 mg, 27%). LC-MS: tR= 0,81 minutes; ES+: 700,27. Chiral column HPLC: tR= 18,4 minutes.

Example 101

[2-Chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 7,00 ml) was added to a solution of compounds L83 (530 mg, 0,663 mmol) in CH2Cl2(7,00 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C and was poured into aqueous 1M NaOH solution. The layers were separated and the aqueous layer was extracted with CHCl3. The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S, 4'R)-diastereoisomer (410 mg, 88%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (50 mg, 12%). LC-MS: tR= 0.77 min; ES+: 698,62. Chiral column HPLC: tR= 24,6 minutes.

Example 102

[2-Chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, at 8.00 ml) was added to a solution of compound L84 (775 mg, 0,972 mmol) in CH2Cl2(8,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C for 1.5 hours at room Tempe is the atur. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title racemic compound (792 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (227 mg, 30%). LC-MS: tR= 0,87 minutes; ES+: 697,62. Chiral column HPLC: tR= 21,4 minutes.

Example 103

{2-Chloro-5-[2-(2,2-diferentiating)ethyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid

HCl (4M in dioxane, to 6.00 ml) was added to a solution of compound L85 (525 mg, 0,571 mmol) in CH2Cl2(6,00 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C for 1.5 hours at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was dissolved in CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (460 mg, quantitative yield). This racemate was separated using the HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (122 mg, 30%). LC-MS: tR= 0,78 minutes; ES+: 719,60. Chiral column HPLC: tR= 14.4 minutes.

Example 104

[5-(2-Acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 8 ml) was added to a solution of compound L86 (770 mg, 0,964 mmol) in CH2Cl2(8 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title racemic compound (692 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (211 mg, 31%). LC-MS: tR= 0,86 minutes; ES+: 698,60. Chiral column HPLC: tR= 18.9 minutes.

Example 105

[5-chloro-2-(3-methoxy-propyl)-1-oxypyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 6 the l) was added to a solution of compound L88 (550 mg, 0,685 mmol) in CH2Cl2(6 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title racemic compound (692 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (83 mg, 17%). LC-MS: tR= 0,81 minutes; ES+: 702,54, chiral HPLC column: tR= 41,4 minutes.

Example 106

[5-Chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 6 ml) was added to a solution of compound L87 (600 mg, 0,763 mmol) in CH2Cl2(6 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed when below the nom pressure, receiving untreated specified in the racemic title compound (534 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (164 mg, 31%). LC-MS: tR= 0,84 minutes; ES+: 686,61. Chiral column HPLC: tR= 15.8 minutes.

Example 107

[2-Chloro-5-(2-methylcarbamoylmethyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 10 ml) was added to a solution of compounds L89 (230 mg, in 0.288 mmol) in CH2Cl2(10 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (130 mg, 65%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (30 mg, 21%). LC-MS: tR= 0,78 minutes; ES+: 700,63. Chiral column HPLC: tR= 22,1 minutes.

Example 108

2-Chloro-5-[2-(2,2-diferentiating)this is]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 16 ml) was added to a solution of compounds L90 (772 mg, 0,838 mmol) in CH2Cl2(16 ml) at 0°C. the Mixture was stirred for 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product using PF (MeOH/CH2Cl21:19) gave specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (210 mg, 35%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (80 mg, 37%). LC-MS: tR= 0,70 minutes; ES+: 722,65. Chiral column HPLC: tR= 14,0 minutes.

Example 109

4-Chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl methyl ether-carbamino acid

HCl (4M in dioxane, 10 ml) was added to a solution of compounds L91 (920 mg, 1.15 mmol) in CH2Cl2(10 ml) at 0°C. the Mixture was stirred for 3 hours at 0°C. the Mixture was diluted with additional CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgO 4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (850 mg, quantitative yield). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (175 mg, 22%). LC-MS: tR= 0,78 minutes; ES+: 700,61. Chiral column HPLC: tR= 26,1 minutes.

Example 110

2-{4-Chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]phenyl}ethyl methyl ether-carbamino acid

HCl (4M in dioxane, 10 ml) was added to a solution of compounds L92 (920 mg, 1.13 mmol) in CH2Cl2(10 ml) at 0°C. the Mixture was stirred for 3 hours at 0°C. the Mixture was diluted with additional CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (730 mg, 90%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (159 mg, 22%). LC-MS: tR= 0,79 m the chickpeas; ES+: 716,61. Chiral column HPLC: tR= 21,4 minutes.

Example 111

Methyl ether (2-{4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]phenyl}ethyl) - carbamino acid

HCl (4M in dioxane, 3,70 ml) was added to a solution of compounds L93 (830 mg, about 1.47 mmol) in CH2Cl2(6,00 ml) at 0°C. the Mixture was stirred for 1.5 hours at room temperature. The mixture was diluted with additional CH2Cl2and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. After drying the residue under high vacuum, received untreated specified in the title compound mixed with its corresponding (3'S,4'R)-diastereoisomer (496 mg, 47%). This mixture was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (83 mg, 18%). LC-MS: tR= 0,80 min; ES+: 716,66. Chiral column HPLC: tR= 20,7 minutes.

Example 112

[2-Chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid

HCl (4M in dioxane, 4,00 ml) was added to a solution of compound L94 (370 mg, 0,479 mmol) in CH2Cl2(4,00 ml) at 0°C. the Mixture was stirred those which begins 30 minutes at 0°C and for 1 hour at room temperature. The solvents were removed under reduced pressure and the residue was dried in high vacuum. The residue was diluted with CHCl3and the mixture is washed with aqueous 1M NaOH solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining the crude specified in the racemic title compound (344 mg, quantitative yield). This racemate was separated by HPLC (Regis Whelk, isocratic eluent B 50%), getting mentioned in the title compound (70 mg, 22%). LC-MS: tRor = 0.90 min; ES+: 671,61. Chiral column HPLC: tR= 15.2 minutes.

Biological tests

1. Enzyme-linked immunosorbent assay (EIA) to assess the accumulation of AngI and inhibition of renin.

1.1 Getting conjugate AngI-BSA

1.3 mg (1 mmol) AngI [1-10 (Bachem, H-1680)] and 17 mg (0.26 mmol) of BSA (Fluka, 05475) was dissolved in 4 ml 0,1M phosphate buffer, pH of 7.4, and then was added dropwise 2 ml diluted in H2O 1:100 glutaraldehyde (Sigma G-5882). The mixture is incubated over night at 4°C and then dialyzed against 2 liters of 0.9% NaCl, twice for 4 hours at room temperature, followed by dialysis against 2 liters of 1X PBS overnight at room temperature. The solution is then filtered through syringe filter, 0.45 µm (Nalgene, Cat. No. 194-2545). The conjugate can be stored in polypropylene tubes in a 0.05% solution of sodium azide at 4°C for at the end is th least 12 months.

1.2 Getting MTP (tablets for micrometrology)coated with BSA-AngI

Tablets for micrometrology (MPT384, MaxiSorpTM, Nunc) were incubated over night at 4°C with 80 ál conjugate AngI(1-1O)/BSA (diluted 1:100,000 in 1X PBS in a Teflon beaker (the exact breeding depends on the portion of the conjugate), poured, filled with 90 µl of blocking solution [0.5% of BSA (Sigma A-2153) in 1X PBS, 0.02% of NaN3] and incubated for at least 2 hours at room temperature or over night at 4°C. In 96-well MTP (MaxiSorp™, Nunc) was applied 200 ál conjugate and blocked with 250 μl of blocking solution as described above, except that the blocking solution contained 3% BSA. The tablets can be stored in the blocking solution at 4°C for 1 month.

1.3 AngI-EIA in 384-well MTP

Tablet MTP covered Angl (1-10)/BSA, washed 3 times with buffer wash (1X PBS, 0.01% of Tween 20) and were filled with 75 μl of primary antibody solution (anti-AngI antibiotiky, pre-diluted 1:10 in serum of a horse), diluted to a final concentration of 1:100,000 in the buffer for analysis (1X PBS, 1 mm EDTA, 0,1% BSA, pH 7,4). 5 ál of renioval the reaction mixture (or standards in the buffer for analysis) (see below) was added to a solution of primary antibody and the plates were incubated overnight at 4°C. After incubation the tablets were washed 3 times with buffer for washing and incubated with secondary the m antibody [IgG against rabbit, linked to horseradish peroxidase (Amersham Bioscience, NA 934V)diluted 1:2000 in buffer for washing] for 2 hours at room temperature. The tablets were washed 3 times with buffer for washing and then incubated for 1 hour at room temperature with substrate solution [1,89 mm ABTS (2,2'-Azino-di(3-ethyl-benzothiazolesulfonamide)] (Roche Diagnostics, 102 946) and 2.36-mm H2O2[30%, (Fluka, 95300] buffer substrate (0,1M sodium acetate, 0,05M of sodium dihydrophosphate, pH of 4.2). The optical density (OD) of the tablet was then read at 405 nm in a microplate reader for (FLUOStar Optima from BMG). Production AngI during the reaction renin was evaluated quantitatively by comparing the OD of the sample with OD measured parallel to the standard curve AngI(1-10).

2. Initial analysis of renin inhibition: IC50in the buffer, 384-well plate MTP

Applied analysis of renin adapted based on the previously described analysis (W. Fischli et al, Hypertension, 1991, 18:22-31), which consists of two stages: the first stage of recombinant human renin incubated with its substrate (commercial tetradecapeptide renin substrate person) to obtain the product of Angiotensin I (AngI). In the second stage was measured by the number of accumulated AngI (enzyme-linked immunosorbent assay (EIA). A detailed description of this analysis below. The EIA analysis is highly sensitive and well suited to measure the activity of renin in the buffer or plasma. Due to the low concentration of renin used in this analysis (2 fmol per tube for analysis or 10 PM), it is possible to measure the affinity of the inhibitor in this primary analysis for concentate below PM.

2.1 Methodology

Recombinant human renin (3 PG/ml) in buffer for analysis (1X PBS, 1 mm EDTA, 0,1% BSA, pH 7,4), the substrate tetradecapeptide (1-14) of the person (Bachem, M-1120) [5 μm in 10 mm HCl], sulfate hydroxyquinoline solution (Fluka, 55100) [30 mm in H2O] and buffer for analysis of pre-mixed at 4°C in the ratio of 100:30:10:145, and 47.5 μl per well of this mixture was transferred into a polypropylene plates (MTP384, Nunc). Test compounds were dissolved and diluted in 100% DMSO and 2.5 μl was added to the pre-mixture, and then incubated at 37°C for 3 hours. At the end of the incubation period, 5 μl of renioval the reaction mixture (or standards in the buffer for analysis) carried in the EIA analyses (as described above) and estimated the number AngI produced by renin. Expected percentage of inhibition of renin (decrease AngI) for each concentration of the compound and determining the concentration of the inhibitor of renin, which caused 50% inhibition of enzyme activity (IC50). Compounds of the present invention also showed a very good bioavailability, and they are metabolically more stable than the previous connection, Ural branch of the Nude in the development of this field.

Examples of inhibition

Compound of example No.IC50 values [nm]Compound of example No.IC50 values [nm]
10,2500,24
40,2600,26
110,3670,63
130,8770,22
180,5830,18
260,14930,38
340,11020,08
420,261100,39

1. The compound of formula (I)

where paragraph the IRNA line 6-membered nitrogen-containing ring Z of formula (I) (a specified ring Z consists of numbered 1 to 6 ring atoms) indicates that the double bond is either present in 3,4-position of the ring Z of formula (I), or a double bond is not present in the ring Z of formula (I); and
where the double bond may be present at the 3,4-position of the ring Z of formula (I); or
the double bond may not be present in the ring Z of formula (I), if:
i) X represents N or N+-O-or
ii) V is a-O-CH2-Q-, or
iii) W represents a para-substituted phenyl or para-substituted pyridinyl, and V represents pyrrolidinyl formula:

X represents CH, N, or N+-O-;
W represents a para-substituted phenyl or para-substituted pyridinyl;
V represents-O-CH2-Q-, where Q is related to the group U of formula (I), or V is pyrrolidinyl formula:

U is a mono-, di-, tri - or Tetra-substituted aryl, where the substituents independently selected from C1-7-alkyl and halogen;
Q represents a five-membered heteroaryl with two or three heteroatoms independently selected from O and N;
R1represents a C1-7is alkyl or cycloalkyl;
R2represents a halogen or1-7-alkyl;
R3represents a halogen or hydrogen;
R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-; R R"N-(C 2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl (optionally substituted by one to three Fermi), cyclopropyl (optionally substituted by one to three Fermi), cyclopropyl-C1-7the alkyl (optionally substituted by one to three Fermi) and-C(=O)-R'"where R'" represents a C1-4alkyl, C1-4-alkoxy, -CH2-CF3or
cyclopropyl;
or R12NH-C(=O)-(O)0-1-(CH2)0-4-where R12represents a C1-4is alkyl or cyclopropyl; and
n represents the integer 0;
and its salts.

2. The compound according to claim 1,
where the double bond may be present at the 3,4-position of the ring Z of formula (I); or
the double bond may not be present in the ring Z of formula (I), if:
i) X represents N or
ii) V is a-O-CH2-Q-;
X represents CH or N; and
R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-; or R R N-(CH2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl (optionally substituted by one to three Fermi), cyclopropyl (optionally substituted by one to three Fermi), cyclopropyl-C1-7-alkyl (optionally substituted by one to three Fermi) and-C(=O)-R'"where R'" represents a C1-4-alkyl, -CH2-CF3or qi is sapropel;
or a salt of this compound.

3. The compound according to claim 1, where X represents CH or N+-O-or a salt of this compound.

4. The compound according to any one of claims 1 to 3,
where R1is cyclopropyl or salt of this compound.

5. The compound according to any one of claims 1 to 3,
where W represents a para-substituted phenyl, or

or a salt of this compound.

6. The compound according to any one of claims 1 to 3,
where V represents-O-CH2-Q -, or a salt of this compound.

7. The compound according to any one of claims 1 to 3, where V-W is a:

or a salt of this compound.

8. The compound according to any one of claims 1 to 3,
where U is a

or a salt of this compound.

9. The compound according to any one of claims 1 to 3, where Q is isoxazolyl or oxadiazolyl, or a salt of this compound.

10. The connection according to claim 9,
where Q represents isoxazolyl or salt of this compound.

11. The compound according to any one of claims 1 to 3 and 10, where R2represents CL, and R3represents hydrogen, or a salt of this compound.

12. The compound according to any one of claims 1 to 3 and 10, where R4represents CH3-O-(CH2)2-3-, or CH3-C(=O)-NH-CH2-CH2-or salt of this compound.

13. Connection on any and what items 1-3 and 10, where
R4represents-CH2CH2CH2-O-CH3or-CH2CH2-O-CH3or a salt of this compound.

14. The connection indicated in paragraph 13
where R4represents-CH2CH2-O-CH3or a salt of this compound.

15. The compound according to any one of claims 1 and 10, where the fragment

represents one of the following features:

or a salt of this compound.

16. The compound according to claim 1,
where the double bond may be present at the 3,4-position of the ring Z of formula (I); or
the double bond may not be present in the ring Z of formula (I), if:
i) X represents N or N+-O-or
ii) V is a-O-CH2-Q-, or
iii) W represents a para-substituted pyridinyl, and V represents pyrrolidinyl formula:

U represents a tri-substituted phenyl, where the substituents independently selected from C1-7-alkyl and halogen;
Q represents isoxazolyl;
R1is cyclopropyl; and
R4represents a C1-7-alkyl-O-(CH2)0-4-CH2-, R R"N-(CH2)0-4-CH2-, where R' and R" independently are selected from the group consisting of hydrogen, C1-7-alkyl, substituted by one to three Fermi, cyclopropyl and-C(=O)-R'"where R'" before the hat is C 1-4-alkyl, C1-4-alkoxy, -CH2-CF3or cyclopropyl, or R12NH-C(=O)-(O)0-1-(CH2)0-4-where R12represents a C1-4is alkyl or cyclopropyl; provided that both R' and R ' cannot simultaneously represent hydrogen;
or a salt of this compound.

17. The compound according to any one of claims 1 to 3, 10, 14, and 16, where there is no double bond in the ring Z of formula (I), and the substituents in the 3 - and 4-positions of the ring Z of formula (I) are in TRANS-position relative to each other, or a salt of this compound.

18. The compound according to any one of claims 1 to 3, 10, 14, and 16, where there is no double bond in the ring Z of formula (I), and position 3 of the ring Z of formula (I) has the absolute configuration (R), and the substituent in the 4-position of the ring Z of formula (I) is in the TRANS-position to the substituent at the 3-position of the ring Z of formula (I), or a salt of this compound.

19. The compound according to claim 1, selected from the group consisting of:
[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine 4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid,
[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid, and
[2-chloro-5-(3-methoxy-propyl)benzyl]cyclopropylamino-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',5',6'-tetrahydro the-[3, 4']bipyridinyl-3'-carboxylic acid, and salts of these compounds.

20. The compound according to claim 1, selected from the group consisting of:
[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamino-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid,
[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4'] bipyridinyl-3'-carboxylic acid,
[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy] phenyl} piperidine-3-carboxylic acid,
[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-(acetylamino-methyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-is ALOR-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
{2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid {2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-cyclopropylamino-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy] phenyl }piperidine-3-carboxylic acid,
(2-chloro-5-cyclopropylamino-benzyl)cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy] phenyl} piperidine-3-carboxylic acid,
[2-chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(2-cyclopropylamino-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
{2-chloro-5-[(2-diferentiating)methyl]benzyl}cyclopropylamine
(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy] phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine
(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine
(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine(3'R,4'S)-6-[(S)-3 -(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
{2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[(cyclopropanecarbonyl)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
methyl ester (4-chloro-3-{((3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy] phenyl} piperidine-3-carbonyl)-cyclopropyl-amino]methyl} benzyl)carbamino acid,
methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl} amino)methyl] benzyl} carbamino acid,
methyl ester {4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl}carbamino acid,
[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine
(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
{2-chloro-5-[(cyclopropanecarbonyl-amino)methyl]benzyl}cyclopropylamine(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-Fe is hydroxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine (3'R,4'S)-6-[(S)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
(2-chloro-5-cyclopropanecarbonyl-benzyl)cyclopropylamine
(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
(2-chloro-5-methylcarbamoylmethyl-benzyl)cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
(2-chloro-5-ethylcarboxylate-benzyl)cyclopropylamine(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[2-chloro-5-(propionamido-methyl)benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[2-chloro-5-(2-metalcarbon the Il-ethyl) - benzyl]cyclopropylamine(3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[2-(2,2-diferentiating)ethyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]phenyl}piperidine-3-carboxylic acid,
[5-(2-acetylamino-ethyl)-2-chloro-benzyl]cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4', 5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)-1-oxy-pyridine-4-ylmethyl]cyclopropylamine(3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4'] bipyridinyl-3'-carboxylic acid,
[5-chloro-2-(3-methoxy-propyl)pyridine-4-ylmethyl] cyclopropylamine (3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4'] bipyridinyl-3'-carboxylic acid,
[2-chloro-5-(2-methylcarbamoyl-ethyl) - benzyl]cyclopropylamine (3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4'] bipyridinyl-3'-carboxylic acid,
{2-chloro-5-[2-(2,2-diferentiating)ethyl]benzyl}cyclopropylamine
(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid,
4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]benzyl methyl ether-carbamino acid,
2-{4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine the l-3'-carbonyl} amino)methyl] phenyl} ethyl methyl ether-carbamino acid,
methyl ester (2-{4-chloro-3-[(cyclopropyl-{(3'R,4'S)-6-[(R)-3-(2,6-dichloro-4-methyl-phenoxy)pyrrolidin-1-yl]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carbonyl}amino)methyl]phenyl}ethyl) - carbamino acid, and
[2-chloro-5-(2-methoxy-ethyl) - benzyl]cyclopropylamine(3'R,4'S)-6-[3-(2-chloro-3,6-debtor-phenyl)isoxazol-5-ylethoxy]-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-3'-carboxylic acid, and salts of these compounds.

21. Pharmaceutical composition, which has inhibitory activity against renin-containing compound according to any one of claims 1 to 20, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier material.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there described are diazabicyclic aryl derivatives of general formula I , their enantiomers or any mixture of those enantiomers, or their pharmaceutically acceptable salts, where radical values A, L, B and n are given in the description, and pharmaceutical composition containing the above diazabicyclic aryl derivatives.

EFFECT: new compounds represent cholinergic ligands of nicotinic receptors of acetylcholine and modulators of receptors and carrying agents of monoamines, and can be used for treatment of diseases and illnesses related to cholinergic system of central nervous system and periphery nervous system, which are related to activity of muscles, endocrine diseases, inflammatory diseases, and neurodegenerative diseases.

12 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): , where: R1 is selected from -ORa, -C(O)NRaRb, -NHS(O)2Rc, -C(O)ORa; A means C1-4alkylenyl; R2 means C3-12cycloalkyl or C6-10aryl which is optionally substituted by one -ORa, one or two halogen atoms, one or two C1-3alkyls substituted by two or three halogen atoms; or one, two, three or four C1-3alkyls; G means C1-4alkylenyl; R3 is selected from hydrogen, -C(O)R4, -C(O)NHR5, -S(O)2Rc and -S(O)2NRaRb; R4 means C3-6cycloalkyl or C1-6alkyl, C3-6cycloalkyl is optionally substituted by one -ORa, and C1-6alkyl is optionally substituted by one or two substitutes selected from -ORa, -C(O)ORa, -S(O)2R6, -C(O)NRaRb, -NRaRb, -CN, C3-6cycloalkyl and phenyl; or by one -D-(CH2)j-R7 where D means , j is equal to 1, n is equal to 1 or 2; R6 means C1-3alkyl optionally substituted by R7; R7 means -C(O)ORa; R5 means C1-6alkyl, benzo[1.3]dioxole or -(CH2)q-phenyl; where phenyl is optionally substituted by one or two substitutes selected from halogen, -ORa, C1-3alkiyl and C1-3alkoxy where C1-3alkyl and C1-3alkoxy optionally substituted by 2 or 3 halogen atoms, and q is equal to 0, 1; Ra and Rb independently mean hydrogen or C1-4alkyl; and Rc means C1-3alkyl; provided when R2 means phenyl substituted in position 4, R3 is not -C(O)R4 where R4 means C1-4alkyl substituted by C(O)ORa; to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, to a method of preparing the compound of formula (I), to compounds of formula (II), (III), to application of the compounds on any claim 1-14, to a method of analysing a biological system or a sample containing a mu-opioid receptor, and also to a method of treating a mammal suffering a disease caused by mu-opioid receptor activity.

EFFECT: production of the new biologically active compounds exhibiting mu-opioid receptor antagonist activity.

26 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new tartrate salts of (1R,2R,3S,5S)-2-methoxymethyl-3-(3,4-difluorophenyl)-8-azabicyclo[3.2.1]octane, such as L-tartrate monohydrates and anhydrates.

EFFECT: application as inhibitors of monoamine neurotransmitter reuptake.

8 cl, 8 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 8-ethyl-6,7-fullero[60]-3-oxa-8-azabicyclo[3.2.1]octane of the general formula (1): . Method involves interaction of fullerene[60] with N-ethylmorpholine in the mole ratio fullerene-C60 : N-ethylmorpholine = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% with respect to fullerene[60], in toluene medium as a solvent at temperature ˜20°C for 18-30 h. The yield of the end product is 73-90%. Synthesized compound can be used as chelating agent, sorbent, biologically active compound and in creature of novel materials with desired electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with dipiperidine methane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 15-25 hours. Yield of target product is 70-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

The invention relates to 2-substituted 4,5-dailyedition General formula (I), where R1- 4-pyridyl; R2- phenyl, naphthas-1-yl or naphthas-2-yl, which optionally can contain up to 5 substituents selected from halogen; R3is hydrogen; R4- pyridyl, optionally substituted with halogen or amino group

The invention relates to new derivatives of 8-azabicyclo[3.2.1]Octan-3-methanamine in the form of pure geometric-isomers of General formula I, where U represents the formula (A) or (B) in which V is hydrogen or halogen, (C1-C3)alkyl group or one or two (C1-C3)alkoxygroup, W and X each represents either two oxygen atom or the oxygen atom and the group CH2or the group CH2and the oxygen atom or the oxygen atom and the group WITH n = 0 or 1, R is through the band when U denotes the formula (a), or hydrogen or (C1-C3)alkyl, when U denotes the formula (I), Y represents one or more atoms or a group comprising hydrogen, halogen and t

The invention relates to new derivatives of 8-azabicyclo[3,2,1]Oct-2-ene and-octane, which are cholinergic ligands at the nicotinic Ach (acetylcholine) receptors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R1 is a phenyl group (said phenyl group is substituted with one or more C1-6alkyl groups, one C1-3alkyl group (said C1-3alkyl group is substituted with one or more halogen atoms), one C1-3alkoxy group (said C1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R2 is a C1-3alkyl group, R3 is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R5' group (where R5' is NR6'R7', (where R6' is a hydrogen atom, and R7' is a C1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R5 group (where R5 is NR6R7 (where R6 is a hydrogen atom or a C1-3alkyl group, and R7 is a C1-6alkyl group (said C1-6alkyl group can be substituted with one or more hydroxyl groups, one C1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C1-3alkyl groups, one or more C1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR6R7 is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C1-6alkyl group, one or more hydroxyl groups)) or C1-6alkyl group (said C1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R4 is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

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