Condensed quinoline derivative and use thereof

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

 

The scope of the invention

The present invention relates to a new condensed quinoline compound, with a strong antagonistic effect against thickening receptor, the method thereof, pharmaceutical compositions comprising such a connection, use the connection for obtaining pharmaceuticals, etc.

Background of the invention

Tachykinin is the generic term for a group of neuropeptides, and mammals known substance P (hereinafter SP), neurokinin A (hereinafter abbreviated as specified NKA) and neurokinin B (hereinafter abbreviated as specified NKB). These peptides are known to be associated with their receptors (neurokinin 1, neurokinin 2, neurokinin 3, hereinafter abbreviated listed as NK1, NK2, NK3, respectively)that are present in vivo, for the implementation of different biological activity.

In particular, believe that the NK2 antagonist of the receptor is useful for the prevention or treatment of neurokinin A-dependent pathology and, as it is useful for the prevention or treatment of diseases, such as pulmonary diseases (in particular, bronchospasm in asthma, cough, chronic obstructive pulmonary disease and pulmonary anaphylaxis), diseases of the gastrointestinal tract (in particular, enteropathy syndrome level becomes too low, colon cancer, non-ulcer dis is Asia, esophageal reflux and disorders of the gastrointestinal tract, diseases of the Central nervous system (for example, melancholy, anxiety), diseases of the urinary tract (e.g., dysuria), pain (e.g., neurotic pain, pain associated with inflammatory diseases such as rheumatism, etc.) (Expert Opin. Ther. Targets, (2003) vol. 7(3), p.343).

Up to the present time were known selective peptide antagonists of NK2 receptor (Br. J. Pharmacol., 1990, 100, 588-592 and WO 97/31941). However, these known peptide antagonists of NK2 show weak activity and are metabolically unstable, and therefore, their practical use for the generation of prophylactic or therapeutic agents is difficult.

As selective ones antagonists of NK2 receptor known SR 48968 (Brit. J. Pharmacol. (1992), vol.105, p.77), GR 159897 (Bioorg. Med. Chem. Lett. (1994), vol.4, p.1951), CP 96345 (Science, 1991, vol.251, p.435), RP 67580 (Proc. Nat. Acad. Sci. 1991, vol.88, p.10208), ZD 7944 (Abstracts of Papers, Part 1, 214thNational Meeting of the American Chemical Society, Las Vegas, NV, Sept 7-11, 1997, MEDI 264), WO 02/38547, WO 02/38548, WO 02/083663, WO 02/083664 etc.

In addition, as quinoline derivatives, condensed with the nitrogen-containing heterocycle, known compounds described in J. Org. Chem., 2000, 65, 655-666; J. Org. Chem., 2003, 68, 442-451; Org. Lett., 2001, 3, 2189-2191; Org. Lett., 2001, 3, 4217-4220; Tetrahedron 57, 2001, 5615-5624; Tetrahedron Letters 40, 1999, 1215-1218; Tetrahedron Letters 40, 1999, 3339-3342; Heterocycles, 2004, 63, 1685-1712; US Patent No. 528725 etc.

Description of the invention

Up to now, no connection is found, with a strong antagonistic effect against NK2 receptor, which is safe and excellent in duration (for example, absorbiruyaci, metabolism, in vivo kinetics), as a therapeutic agent for various above-mentioned diseases, which is reputed to be caused by hyperstimulation NK2 receptor. Thus, it is desirable to develop a connection with a new chemical structure different from the structure of the known antagonists of NK2 receptor, and fully meet the requirements of a drug for prevention or treatment of such diseases, and pharmaceutical composition containing such a compound as an active ingredient.

The present invention provides a connection with a new chemical structure different from the structure of the known antagonists of NK2 receptor, which demonstrates a strong antagonistic activity against NK2 receptor and fully meet the clinical requirements concerning safety and duration of action (for example, absorbiruyaci, metabolism, in vivo kinetics) and the like, and pharmaceutical composition containing such compound as active ingredient the A.

Accordingly, the present invention relates to the objects presented in the following paragraphs [1]-[24], etc.

[1] a Compound represented by the formula (I) (hereinafter, in some cases, abbreviated listed as compound (I))

where

R1represents (1) no substitution (i.e., no), (2) hydrogen atom, (3) a hydrocarbon group optionally containing a Deputy(deputies), or (4) acyl;

R2represents (1) hydrogen atom, (2) a hydrocarbon group optionally containing a Deputy(deputies), (3) hydroxy, optionally containing a Deputy, (4) amino, optionally containing a Deputy(deputies), (5) thiol, optionally containing a Deputy, (6) heterocyclic group optionally containing a Deputy(deputies), or (7) acyl;

R3represents (1) no substitution (i.e., no), (2) hydrogen atom, (3) a hydrocarbon group optionally containing a Deputy(deputies), (4) hydroxy, optionally containing a Deputy, (5) amino, optionally containing a Deputy(deputies), (6) thiol, optionally containing a Deputy, or (7) acyl;

R4and R5are the same or different from each other, and each represents (1) hydrogen atom, (2) hydrocarbon group, not battelino containing a Deputy(deputies), (3) hydroxy, optionally containing a Deputy, (4) amino, optionally containing a Deputy(deputies), (5) thiol, optionally containing a Deputy, or (6) acyl;

R6represents (1) (a cyclic group, optionally containing a Deputy(deputies))-carbonyl, (2) alkenylboronic, optionally containing a Deputy(deputies), (3) alkylsulphonyl containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), (ii) amino, optionally containing a Deputy(deputies) and (iii) a heterocyclic group optionally containing a Deputy(deputies), or (4) heterocyclic group optionally containing a Deputy(deputies);

R7, R8, R9and R10are the same or different from each other, and each represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) nitro, (5) hydrocarbon group, optionally containing a Deputy(deputies), (6) hydroxy, optionally containing a Deputy, (7) amino, optionally containing a Deputy(deputies), (8) thiol, optionally containing a Deputy, (9) a heterocyclic group optionally containing a Deputy(deputies), or (10) acyl; or

R7and R8, R8and R9and R9and R10can images is to ring together with adjacent carbon atoms;

n is an integer having a value of from 1 to 5;

--- is the lack of substitution (i.e. is absent) or a simple bond; and

---represents a simple bond or double bond, or its salt.

[2] the Compound according to above item [1], where R6represents (1) (a cyclic group, optionally containing a Deputy(deputies))-carbonyl, (2) alkenylboronic, optionally containing a Deputy(deputies), (3) alkylsulphonyl containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), and (ii) amino, optionally containing a Deputy(deputies), or (4) heterocyclic group optionally containing a Deputy(deputies).

[3] the Compound according to above item [1], where

R1represents a

(1) no substitution

(2) a hydrogen atom,

(3) C1-6alkyl,

(4) C7-12aralkyl or

(5) C1-6alkylsulphonyl;

R2represents a

(1) a hydrogen atom,

(2) C1-6alkyl, optionally containing from 1 to 3 substituents selected from (1') hydroxy, (2') C1-6alkoxy, (3') C7-12aralkylated, (4') a mono - or di-C1-6alkylamino, (5') N-C1-6alkoxycarbonyl-N-C1-6alkylamino, (6') amino, (7') C1-6alkylcarboxylic, optional steriade is about 1 to 3 halogen atoms, (8') C7-12arachidonoylethanolamine and (9') C1-6alkoxycarbonyl, optionally containing 1 to 3 halogen atoms,

(3) C3-8cycloalkyl,

(4) C6-10aryl, optionally containing from 1 to 3 substituents selected from (1') halogen, (2') C1-6the alkyl, optionally containing 1 to 3 halogen atoms, (3') cyano, (4') C1-6alkoxycarbonyl and (5') C1-6alkylthio,

(5) C1-6alkoxycarbonyl or

(6) a 5 - or 6-membered heterocyclic group optionally containing a Deputy(deputies)selected from (1') hydroxy, (2') C1-6the alkyl, optionally containing C1-6alkylcarboxylic, (3') C7-19aralkyl, optionally containing C1-6alkoxy, (4') C7-12aralkylated, (5') C7-12orelkinoservisa, (6') a mono-C1-6allylcarbamate and (7') C1-6alkoxycarbonyl;

R3represents a

(1) no substitution

(2) a hydrogen atom, or

(3) C1-6alkyl;

R4represents a hydrogen atom;

R5represents a hydrogen atom;

R6represents a

(1) a group represented by the formula

where ring A is a cyclopentane, cyclohexane or bicyclo[2,2,2]octane;

R11represents a

(1') amino,

(2') C7-12aralkylamines,

(3') C1- alkylcarboxylic, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl, (4”) mono - or di-C1-6alkylamino, optionally substituted hydroxy, (5”) morpholino, (6”) C1-6alkylcarboxylic, (7”) carbamoylating, (8”) 5 - or 6-membered aromatic heterocyclic group, (9”) C6-10arylamino, (10”) (5 - or 6-membered aromatic heterocyclic group)-carbylamine and (11”) C1-6alkoxy,

(4') C2-6alkenylamine, optionally containing a Deputy(deputies)selected from (1”) C6-10aryl, optionally containing a Deputy(deputies)selected from halogen, C1-6of alkyl, C1-6alkoxy and halogen-(C1-6of alkyl, and (2”) 5 - or 6-membered aromatic heterocyclic group, optionally containing C1-6alkyl,

(5') C3-8cycloalkylcarbonyl,

(6') C6-10arylcarboxamide, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3”) C1-6the alkyl, optionally containing amino or C1-6alkylcarboxylic, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy, (7”) carboxy, (8”) C1-6alkoxycarbonyl, (9”) mono - or di-C1-6alkylamino, optionally containing hydroxy or the C 1-6alkoxy, (10) carbamoyl, (11”) halogen-C1-6alkoxy, (12”) C1-6alkylcarboxylic, (13”) aminosulfonyl, (14”) C1-6alkylsulfonyl and (15”) 5 - or 6-membered heterocyclic group or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle, which can contain a Deputy(deputies), selected from C1-6the alkyl and oxo,

(7') C7-12aralkylamines,

(8') C1-6alkoxycarbonyl,

(9') (5 - or 6-membered heterocyclic group, or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle)-carbylamine, which can have a Deputy(deputies)selected from (1”) amino, (2”) C1-6of alkyl, (3) halogen-C1-6of alkyl, (4”) C6-10aryl, (5”) oxo and (6”) 5 - or 6-membered heterocyclic group, optionally containing C1-6alkyl,

(10') C6-10arylsulfonamides,

(11') carbamylcholine,

(12') 3-C1-6alkaluria, optionally containing a Deputy(deputies)selected from (1”) hydroxy, (2”) carboxy, (3”) C1-6alkoxy, (4”) C1-6alkoxycarbonyl, (5”) C1-6alkoxycarbonyl, (6”) amino, (7) halogen, (8) carbamoyl, (9”) C1-6alkylsulfonyl, (10”) heterocyclic group optionally substituted by oxo, and (11”) C1-6 alkylcarboxylic,

(13') 3-C3-8cycloalkylation,

(14') 3-C6-10amiloride, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy, (6”) methylenedioxy, (7”) C1-6alkoxycarbonyl, (8”) of carbamoyl and (9”) 5 - or 6-membered aromatic heterocyclic group,

(15') 3-C1-6alkyl-3-C6-10amiloride,

(16') 3-C7-12aralkylated, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy,

(17') 3-C1-6alkoxyamino,

(18') 3-C6-10arylsulfonamides,

(19') 3-(5 - or 6-membered heterocyclic group, or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle)-ureido, which can contain 5 - or 6-membered heterocyclic group,

(20') piperidylamine, optionally containing C1-6alkylsulphonyl, or

(21') phthalimide,

(2) a group represented by the formula

where R12represents (1') hydrogen atom, (2') C6-10arylcarbamoyl, optionally containing halogen-C1-6alkyl, (3') C7-12Uralelectromed or (4') C6-10allumination; m is 0 or 1; and p is 0 or 1,

(3) a group, provided the by the formula

where R13represents a C6-10arylcarbamoyl,

(4) a group represented by the formula

where ring B is a pyrolidine ring or piperidine ring, each of which is optionally substituted amino; R14represents (1') hydrogen atom, (2') C7-12aralkyl, (3') C1-6alkylsulphonyl, (4') C6-10arylcarbamoyl, (5') C7-12aralkylamines, (6') C1-6alkoxycarbonyl or (7') C7-12aralkylamines,

(5) C2-6alkenylboronic, optionally containing a Deputy(deputies)selected from (1') carboxy, (2') C1-6alkoxycarbonyl and (3') C6-10arylenecarborane,

(6) C1-6alkylsulphonyl containing a Deputy(deputies)selected from (1') amino, (2') C6-10arylcarboxamide, (3') C1-6alkoxycarbonyl and (4') 5 - or 6-membered heterocyclic group, or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle, each of which is optionally substituted by oxo,

(7) 1,2,3,4-tetrahydronaphthalene,

(8) pyrrolidinyl containing C7-12aralkyl, or

(9) a group represented by the formula

where R15represents a C6-10arylcarbamoyl; r is 0 or 1; and s is C Uchenie 0 or 1;

R7represents a hydrogen atom;

R8represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl, optionally containing 1 to 3 halogen atoms, (5) C6-10arylcarbamoyl, (6) C1-6alkoxy, (7) C6-10aryloxy or (8) sulfamoyl;

R9represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl or (5) C1-6alkoxy;

R10represents (1) hydrogen atom, (2) halogen, (3) C1-6alkyl or (4) C1-6alkoxy; and

n has a value of 2 or 3.

[4] the Compound according to above item [1] or [2], where

R1represents a

(1) no substitution

(2) a hydrogen atom,

(3) C1-6alkyl or

(4) C1-6alkylsulphonyl;

R2represents a

(1) a hydrogen atom,

(2) C1-6alkyl, optionally containing from 1 to 3 substituents selected from (1') hydroxy, (2') C1-6alkoxy, (3') C7-12aralkylated, (4') a mono-C1-6alkylamino and

(5') N-C1-6alkoxycarbonyl-N-C1-6alkylamino,

(3) C3-8cycloalkyl,

(4) C6-10aryl, optionally containing from 1 to 3 substituents selected from (1') halogen, (2') C1-6the alkyl, optionally containing 1 to 3 halogen atoms, (3') cyano and (4') C1-6alkoxycarbonyl, or

(5) 5 - or 6-membered aromatic heterocyclic group, not battelino containing a Deputy(deputies), selected from (1') hydroxy, (2') C1-6the alkyl, optionally containing C1-6alkylcarboxylic, (3') C7-12aralkyl, optionally containing C1-6alkoxy and (4') C7-12aralkylated;

R3represents a

(1) no substitution

(2) a hydrogen atom, or

(3) C1-6alkyl;

R4represents a hydrogen atom;

R5represents a hydrogen atom;

R6represents a

(1) a group represented by the formula

where ring A is a cyclopentane, cyclohexane or bicyclo[2,2,2]octane; R11represents (1') amino, (2') C7-12aralkylamines,

(3') C1-6alkylcarboxylic, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl, (4”) CI-C1-6alkylamino and (5) of morpholino, (4') C3-8cycloalkylcarbonyl, (5') C6-10arylcarboxamide, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3”) C1-6of alkyl, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy, (7”) carboxy, and (8”) C1-6alkoxycarbonyl, (6') C7-12aralkylamines, (7') C1-6alkoxycarbonyl, (8') (5 - or 6-membered aromatic heterocyclic group)-carb is ylamino, (9') piperidinecarboxylate, (10') C6-10arylsulfonyl, (11') 3-C1-6alkaluria, optionally containing a Deputy(deputies)selected from (1”) hydroxy, (2”) carboxy, (3”) C1-6alkoxy and (4”) C1-6alkoxycarbonyl, (12') 3-C3-8cycloalkylation, (13') 3-C6-10amiloride, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy and (6) of methylendioxy, (14') 3-C7-12aralkylated, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy, (15') 3-(5 - or 6-membered aromatic heterocyclic group)-ureido, (16') piperidylamine, preferably piperidinomethyl, optionally containing C1-6alkylsulphonyl, or (17') phthalimide,

(2) a group represented by the formula

where R12represents (1') hydrogen atom, (2') C6-10arylcarbamoyl, optionally containing halogen-C1-6alkyl, or (3') C7-12Uralelectromed; m is 0 or 1; and p is 0 or 1,

(3) a group represented by the formula

where R13represents a C6-10arylcarbamoyl,

(4) a group represented by the formula

decalco B is a pyrolidine ring or piperidine ring; R14represents (1') hydrogen atom, (2') C7-12aralkyl, (3') C1-6alkylsulphonyl, (4') C6-10arylcarbamoyl, (5') C7-12aralkylamines or (6') C1-6alkoxycarbonyl,

(5) C2-6alkenylboronic, optionally containing a Deputy(deputies)selected from (1') carboxy, (2') C1-6alkoxycarbonyl and (3') C6-10arylenecarborane,

(6) C1-6alkylsulphonyl containing a Deputy(deputies)selected from (1') amino, (2') C6-10arylcarboxamide and (3') C1-6alkoxycarbonyl,

(7) 1,2,3,4-tetrahydronaphthalene or

(8) pyrrolidinyl containing C7-12aralkyl;

R7represents a hydrogen atom;

R8represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl, optionally containing 1 to 3 halogen atoms, (5) C6-10arylcarbamoyl, (6) C1-6alkoxy or (7) C6-10aryloxy;

R9represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl or (5) C1-6alkoxy;

R10represents (1) hydrogen atom, (2) halogen, (3) C1-6alkyl or (4) C1-6alkoxy; and

n has a value of 2 or 3.

[5] the Compound according to above item [1] or [2], where R1represents a hydrogen atom.

[6] the Compound according to above item [1] or [2], where R2represents (1)C 1-6alkyl, optionally containing a Deputy(deputies)selected from (1') C1-6alkoxy and (2') a mono-C1-6alkylamino, (2) C3-8cycloalkyl, (3) C6-10aryl, optionally containing halogen, or (4) a 5 - or 6-membered aromatic heterocyclic group, optionally containing C1-6alkyl.

[7] the Compound according to above item [1] or [2], where R3represents (1) hydrogen atom or (2) C1-6alkyl.

[8] the Compound according to above item [1] or [2], where R6represents a

(1) a group represented by the formula

where ring A is a cyclohexane or bicyclo[2,2,2]octane, R11'represents (1') C1-6alkylaryl, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl and (4) of morpholino, (2') C6-10arylcarbamoyl, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3”) C1-6of alkyl, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy and (7”) C1-6alkoxycarbonyl, (3') C7-12aralkylamines, (4') (5 - or 6-membered aromatic heterocyclic group-carbonyl, (5') C1-6alkylaminocarbonyl, optionally containing a Deputy(deputies), selected the from (1”) hydroxy, (2”) C1-6alkoxy and (3”) C1-6alkoxycarbonyl, (6') C3-8cycloalkylcarbonyl, (7') C6-10allumination, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy and (6) of methylendioxy, (8') C7-12aralkylamines, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy, (9') (5 - or 6-membered aromatic heterocyclic group)-aminocarbonyl or (10') piperidinylcarbonyl, preferably piperidinylcarbonyl, optionally containing C1-6alkylsulphonyl, or

(2) a group represented by the formula

where R12' represents a C6-10arylcarbamoyl.

[9] the Compound according to above item [1] or [2], where R8represents a hydrogen atom or a halogen.

[10] the Compound according to above item [1] or [2], where R9represents a hydrogen atom or a halogen.

[11] the Compound according to above item [1] or [2], where R10represents a hydrogen atom or a halogen.

[12] the Compound according to above item [1] or [2], where n has a value of 2.

[13] N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzo the Ministry of foreign Affairs,

N-phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea,

2-methyl-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamid,

4-(1H-imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(1H-pyrazole-1-yl)phenyl]urea or

4-cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide.

[14] the Method of obtaining the compound represented by formula (Ic)

where R6'represents (1) (a cyclic group, optionally containing a Deputy(deputies))-carbonyl, (2) alkenylboronic, optionally containing a Deputy(deputies), or (3) alkylsulphonyl containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), and (ii) amino, optionally containing a Deputy(deputies), and other symbols are defined in paragraph [1] above, or it is salt, which includes

(1) the reaction of condensation of the compound represented by formula (II)

where each symbol is defined in paragraph [1] above, or its salt,

compounds represented by formula (III)

R2-CHO (III)

where R2defined in paragraph [1] above, or its salt, and

compounds represented by formula (IV)

where P represents a protective group, and other symbols are defined in paragraph [1] above, or its salt to obtain the compound represented by formula (Ia)

where each symbol is defined above, or its salt with subsequent removal of the protective group P, or

(2) the reaction of condensation of the compound represented by formula (II)

where each symbol is defined above, or its salt,

compounds represented by formula (III)

R2-CHO (III)

where R2defined above, or its salt, and

compounds represented by formula (V)

where all R are the same or different from each other, and each represents a C1-6alkyl, P' is a protective group, and n is defined in paragraph [1] above, or its salt to obtain the compound represented by formula (Ib)

where each character is definitely the linen above, or its salt with subsequent removal of the protective group P', and

the interaction of the compounds represented by formula (VI)

where each symbol is defined above, or its salt obtained above in (1) or (2)with the compound represented by formula (VII)

R6'-OH (VII)

where R6'defined above, or its salt.

[15] the NK2 receptor Antagonist comprising a compound having a partial structure represented by the formula

where n is an integer having a value of from 1 to 5; and

---represents a simple bond or double bond, or its salt.

[16] the Prodrug compounds according to the above item [1] or [2].

[17] a Pharmaceutical agent comprising the compound according to above item [1] or [2] or its prodrug.

[18] the Pharmaceutical agent according to the above item [17], which is a NK2 receptor antagonist.

[19] the Pharmaceutical agent according to the above item [17], which is an agent for the prevention or treatment of functional gastrointestinal diseases.

[20] the Pharmaceutical agent according to the above item [17], which is an agent for the prevention or treatment of irritable bowel syndrome or non-ulcer dyspepsia.

[21] the Method antag is nozirovania receptor NK2, which includes the introduction of an effective amount of compound according to the above item [1] or [2] or its prodrug to the mammal.

[22] a Method for prevention or treatment of functional gastrointestinal diseases, which includes the introduction of an effective amount of compound according to the above item [1] or [2] or its prodrug to the mammal.

[23] the Use of compounds according to the above item [1] or [2] or its prodrug to get the NK2 receptor antagonist.

[24] the Use of compounds according to the above item [1] or [2] or its prodrug to obtain funds for the prevention or treatment of functional gastrointestinal diseases.

Detailed description of the invention

Since the compound (I), its salt and its prodrug of the present invention have an antagonistic action on the receptor NK2 and demonstrate reduced toxicity, they are particularly useful as a means for the prevention or treatment of functional gastrointestinal disorders (e.g. irritable bowel syndrome or non-ulcer dyspepsia and the like).

The best way of carrying out the invention

The present invention is explained in more detail below.

As the “halogen”, you can specify, for example, fluorine, chlorine, bromine, iodine atom and the like,

1, R2, R3, R4, R5, R7, R8, R9or R10you can specify, for example,

(1) C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and so on), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(2) C2-6alkenyl (for example, ethynyl, 1-propenyl, 2-propenyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(3) C2-6quinil (for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, etc.), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(4) C3-8cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (i.e. C3-6cycloalkyl), cycloheptyl, cyclooctyl, bicyclo[2,2,2]octyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(5) C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(6) C7-12aralkyl (for example, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl etc), optionally containing from 1 to 5 substituents selected from the groups of the substituents A, described below, etc.

As the “acyl” for R1, R2, R3, R4, R5, R7, R8, R9or R10you can specify, for example,

(1) C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl, propylmalonic, isopropylcarbonate, butylcarbamoyl, isobutylketone, second-butylcarbamoyl, tert-butylcarbamoyl, internabonal, hexylcaine etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(2) C2-6alkenylboronic (for example, EtherChannel, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(3) C2-6alkenylboronic (for example, tinykernel, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(4) C3-6cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(5) C6-10arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(6) C7-12 aralkylamines (for example, benzylcarbamoyl, ventilkappen, 1-naphthylmethyl, 2-naphthylmethyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(7) C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(8) C2-6alkenylbenzenes (for example, ethinylestradiol, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(9) C2-6alkyloxyaryl (for example, ethinylestradiol, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(10) C3-6cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(11) C6-10aryloxyalkyl (for example, toxicarol, 1-naphthaleneboronic, 2-naphthaleneboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(12) C7-12Uralelectromed (for example, benzyloxycarbonyl, ventilatsioonil, 1-naphthylenediamine, 2-naphthylenediamine etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below,

(13) carbarnoyl, optionally mono - or di-substituted (1') C1-6the alkyl (for example, stands, ethyl, propylene, isopropyl, bootrom, isobutyl, second-bootrom, tert-bootrom, Pentium, hexyl and so on), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (2') C2-6alkenyl (for example, atenolol, 1-propanolol, 2-propanolol etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (3') C2-6the quinil (for example, atenolol, 1-PROPYNYL, 2-PROPYNYL, etc.), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (4') C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (5') C6-10the aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl and d), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (6') C7-12aralkyl (for example, benzyl, Venetian, 1-naphthylmethyl, 2-naphthylmethyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (7') C1-6alkylcarboxylic (for example, acetyl, ethylcarbonate, propellerblades, isopropylcarbonate, butylcarbamoyl, isobutylamino, second-butylcarbamoyl, tert-butylcarbamoyl, intercambios, vexillaria etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (8') C2-6alkenylboronic (for example, tanikabaylor, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (9') C2-6alkylammonium (for example, etinilestradiol, 1-propylammonium, 2-propylammonium etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (10') C3-6cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (11') C6-10Arica what Bonilla (for example, the benzoyl, 1-naftilan, 2-naftilan etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (12')

C7-12aralkylamines (for example, benzylcarbamoyl, venaticorum, 1-naphthylethylene, 2-naphthylethylene etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (13') C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (14') C2-6alkanolammonium (for example, ethinylestradiol, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (15') C2-6alkyloxyaryl (for example, ethinylestradiol, 1-propeciacitalopram, 2-propeciacitalopram etc), optionally containing from 1 to 5 substituents selected from the group of substituents A, described below, (16') C3-6cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclobutanecarbonyl, C is kleintraktoren, cyclohexyloxycarbonyl etc), optionally containing from 1 to 5 substituents selected from the group of substituents As described below, (17')6-10aryloxyalkyl (for example, phenoxycarbonyl, 1-naphthalocyanine, 2-naphthalocyanine etc), optionally containing from 1 to 5 substituents selected from the group of substituents As described below, and (18') C7-12orelkinoservisa (for example, benzyloxycarbonyl, ventilatsioonile, 1-aftermarketcellular.com, 2-aftermarketcellular.com etc), optionally containing from 1 to 5 substituents selected from the group of substituents As described below

(14) sulfamoyl

etc.

The group of substituents As:

(1) C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and so on), optionally containing from 1 to 3 substituents selected from (1') halogen (e.g. fluorine, chlorine, bromine, iodine), (2') hydroxy, (3') amino, (4')6-10arylcarboxamide (for example, phenylcarbonylamino, nattermannallee etc), strykersville, optionally containing halogen-C1-6alkyl (e.g. trifluoromethyl, etc.), (5')7-12arachidonoylethanolamine (for example, benzyloxycarbonylamino etc.), (6') C1-6alkylcarboxylic (for example, acetoxy, ethylcarbonate, propylmalonate, isopropylcarbonate and, BUTYLCARBAMATE, isobutyryloxy, sec-butylcarbamoyl, tert-BUTYLCARBAMATE, intercorporate, hexylcaine etc.),

(2) C2-6alkenyl (for example, ethynyl, 1-propenyl, 2-propenyl etc.),

(3) C2-6quinil (for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL, etc.),

(4) C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.),

(5) C7-19aralkyl (for example, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, trail etc), optionally containing from 1 to 3 C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc.),

(6) hydroxy,

(7) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc.),

(8) C6-10aryloxy (for example, phenoxy, 1 naphthyloxy, 2-naphthyloxy etc.),

(9) C7-12Arakelots (for example, benzyloxy, penetrate, 1 aftermatket, 2-aftermatket etc.),

(10) C1-6alkylcarboxylic (for example, acetoxy, ethylcarbonate, propylmalonate, isopropylcarbonate, BUTYLCARBAMATE, isobutyryloxy, sec-butylcarbamoyl, tert-BUTYLCARBAMATE, intercorporate, hexylcaine etc.),

(11) C2-6alkenylboronic (for example, etherchannels, 1-propenylboronic and, 2 propanecarboxylate etc.),

(12) C2-6alkylcarboxylic (for example, tinycorelinux, 1 propanecarboxylate, 2-propanecarboxylate etc.),

(13) C1-6alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc.),

(14) C6-10aaltio (for example, phenylthio, 1 naphthylthio, 2-naphthylthio etc.),

(15) C7-12Uralkali (for example, benzylthio, penetito, 1 naphthylmethyl, 2-naphthylmethyl etc.),

(16) carboxy,

(17) C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl, propylmalonic, isopropylcarbonate, butylcarbamoyl, isobutylketone, second-butylcarbamoyl, tert-butylcarbamoyl, internabonal, hexylcaine etc.),

(18) C2-6alkenylboronic (for example, EtherChannel, 1-propenylboronic, 2-propenylboronic etc.),

(19) C2-6alkenylboronic (for example, tinykernel, 1-propenylboronic, 2-propenylboronic etc.),

(20) C6-10arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol etc.),

(21) C7-12aralkylamines (for example, benzylcarbamoyl, ventilkappen, 1-naphthylmethyl, 2-naphthylmethyl etc.),

(22) C1-6alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, sec-butoxy arbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc.),

(23) C2-6alkenylbenzenes (for example, ethinylestradiol, 1-propenylboronic, 2-propenylboronic etc.),

(24) C2-6alkyloxyaryl (for example, ethinylestradiol, 1-propenylboronic, 2-propenylboronic etc.),

(25) C6-10aryloxyalkyl (for example, phenoxycarbonyl, 1-naphthaleneboronic, 2-naphthaleneboronic etc.),

(26) C7-12Uralelectromed (for example, benzyloxycarbonyl, ventilatsioonil, 1-naphthylenediamine, 2-naphthylenediamine etc.),

(27) carbarnoyl,

(28) mono-C1-6allylcarbamate (for example, methylcarbamoyl, ethylcarbitol, propellerblades, isopropylcarbamate, butylcarbamoyl, isobutylbarbituric, second-butylcarbamoyl, tert-butylcarbamoyl, intercalator, exaltabitur etc.),

(29) di-C1-6allylcarbamate (for example, dimethylcarbamoyl, diethylcarbamoyl, dipropylamino, N-ethyl-N-methylcarbamoyl etc.),

(30) C6-10arylcarbamoyl (sometimes abbreviated as specified in this application as C6-10allumination) (for example, phenylcarbamoyl, afterburner etc.),

(31) C7-12aralkylamines (for example, benzylcarbamoyl, phenetically, naphthylethylene etc.),

(32) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, p is operalional, isopropylphenyl, butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl etc.),

(33) C2-6alkanesulfonyl (for example, atenololbuy, 1-propylsulfonyl, 2-propanesulfonyl etc.),

(34) C2-6alkylsulfonyl (for example, ethnicolor, 1-propylsulfonyl, 2-propylsulfonyl etc.),

(35) amino,

(36) mono-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, hexylamine etc.),

(37) di-C1-6alkylamino (for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-ethyl-N-methylamino etc.),

(38) mono-C2-6alkanolamine (for example, ethanolamine, 1 propanolamine, 2-propylamino etc.),

(39) di-C2-6alkanolamine (for example, diethanolamine, di(1-propenyl)amino, di(2-propenyl)amino etc.),

(40) mono-C2-6alkynylamino (for example, ethynylene, 1 propylamino, 2-propylamino etc.),

(41) di-C2-6alkynylamino (for example, diethylamino, di(1-PROPYNYL)amino, di(2-PROPYNYL)amino etc.),

(42) C6-10arylamino (for example, phenylamino etc.),

(43) C7-12aralkylamines (for example, benzylamino etc.),

(44) C1-6alkylcarboxylic (for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, butyl is arbolino, isobutylamino, sec-butylcarbamoyl, tert-butylcarbamoyl, intelcorporation, paxilonline etc), optionally containing from 1 to 3 substituents selected from (1') halogen (e.g. fluorine, chlorine, bromine, iodine), (2') C1-6alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc.), (3') a mono - or di-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, hexylamine, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-ethyl-N-methylamino), optionally substituted hydroxy, (4') hydroxy, (5') C1-6alkylcarboxylic (for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, BUTYLCARBAMATE, isobutylamino, sec-butylcarbamoyl, tert-butylcarbamoyl, intelcorporation, paxilonline etc.), (6') carbamoylating, (7') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies), Oprah is elenai below) (8') C6-10arylamino (for example, phenylamino etc.), (9') (heterocyclic group)-carbylamine (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below), and (10') C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc.),

(45) C3-8cycloalkylcarbonyl (for example, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbodiimide etc.),

(46) C2-6alkenylamine (for example, ethanolgasoline, 1 propionylcarnitine, 2-propionylcarnitine etc), optionally containing from 1 to 3 substituents selected from (1') C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl), optionally containing from 1 to 3 substituents selected from halogen (e.g. fluorine, chlorine, bromine, iodine), C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl etc.), C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc) and halogen-C1-6the alkyl (for example, trifloromethyl, 2,2,2-triptorelin is), and (2') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below), optionally containing C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl),

(47) C2-6alkylcarboxylic (for example, tinycorelinux, 1 propionylcarnitine, 2-propionylcarnitine etc.),

(48) C6-10arylcarboxamide (for example, phenylcarbonylamino, strykersville, nattermannallee etc), optionally containing from 1 to 3 substituents selected from (1') halogen (e.g. fluorine, chlorine, bromine, iodine), (2') C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl etc), optionally containing from 1 to 3 substituents selected from halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, amino, and C1-6alkylcarboxylic (for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, BUTYLCARBAMATE, isobutylamino, sec-butylcarbamoyl, tert-butylcarbamoyl, intelcorporation, paxilonline), (3') C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isoprop the si, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc), optionally containing 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (4') C1-6alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc.), (5') cyano, (6') carboxy, (7') a mono - or di-C1-6alkylamino (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, hexylamine, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-ethyl-N-methylamino), optionally containing from 1 to 3 substituents selected from hydroxy and C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy), (8') of carbamoyl, (9') C1-6alkylcarboxylic (for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, BUTYLCARBAMATE, isobutylamino, sec-butylcarbamoyl, tert-butylcarbamoyl, intelcorporation, paxilonline), (10') aminosulfonyl, (11') C1-6alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, and propylsulfonyl, butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl, pentasulphide, hexylsilane) and (12') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below), optionally containing from 1 to 3 substituents selected from C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl) and oxo(=O)

(49) C7-12aralkylamines (for example, benzylmorphine, fenethylline etc.),

(50) (heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below))-carbylamine (for example, taylorsville, pyridylcarbonyl, piperidinecarboxylate (for example, piperidinecarboxylate etc), pyrazinecarboxamide, imidazolecarboxamide, benzimidazolecarboxylate, 1H-benzothiazolylsulfenamide, indolealkylamine, paranychianakis, furanocoumarin, 1,2,3,6-tetrahydropyrimidine, tetrachloroaniline, pyrazolecarboxylate, genoxal is ylcarbonyl, hinolincarbonova, imidazo[1,2-a]pyridylcarbonyl, benzothiazolylsulfenamide, 3,4-dihydro-2H-1,4-benzoxazinones, pyrimidinecarbonitrile, 1,2,4-thiazolecarboxamide, 2,3-dihydro-1-benzogermanorbornadiene, 2,1-antitotalitarian etc), which may contain from 1 to 3 substituents selected from (1') amino, (2') C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl), (3') a halogen-C1-6the alkyl (for example, trifloromethyl, 2,2,2-triptoreline), (4') C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl), (5') oxo(=O) and (6') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below), optionally containing C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl),

(51) C1-6alkylsulfonyl (for example, methylsulfonylamino, ethylsulfonyl, propylsulfonyl, isopropylbenzylamine, butylmethylamine, isobutylamino, sec-butylsulfonyl, tert-butylsulfonyl, pentylaniline, hexylaniline etc.),

(52) C2-6alkanesulfonyl is (for example, atenololonline, 1 propanesulfonate, 2-propanesulfinamide etc.),

(53) C2-6alkylsulfonyl (for example, etenilsililidin, 1 propylsulfonyl, 2-propanesulfinamide etc.),

(54) C6-10arylsulfonyl (for example, phenylcarbonylamino, naphthylamine etc.),

(55) C7-12Arakishvili (for example, benzylmethylamine etc.),

(56) C1-6alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, solutionline, sec-butoxycarbonylamino, tert-butoxycarbonylamino, phenoxycarbonylamino, hexyloxyphenyl etc), optionally containing 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine),

(57) N-C1-6alkoxycarbonyl-N-C1-6alkylamino (for example, N-tert-butoxycarbonyl-N-methylamino, N-methoxycarbonyl-N-methylamino etc.),

(58) C6-10aryloxypropanolamine (for example, phenoxycarbonylamino etc.),

(59) C7-12arachidonoylethanolamine (for example, benzyloxycarbonylamino etc.),

(60) carbamylcholine,

(61) 3-C1-6alkaluria (for example, 3-methylurea, 3 amiloride, 3 propylurea, 3 isopropylamino, 3 butylurea, 3 pentyurina, 3 isopentylamine, 3 hexylamino etc), neobyazatel which contains from 1 to 3 substituents, selected from (1') C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc.), (2') C1-6alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc.), (3') carboxy, (4') hydroxy, (5') C1-6alkoxycarbonyl (for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylamino, solutionline, sec-butoxycarbonylamino, tert-butoxycarbonylamino, phenoxycarbonylamino, hexyloxyphenyl), (6') amino, (7') halogen (e.g. fluorine, chlorine, bromine, iodine), (8') of carbamoyl, (9')

C1-6alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl etc.), (10') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below), optional replaced oxo, and (11') C1-6alkylcarboxylic is but (for example, acetylamino, ethylcarbodiimide, propylnitrosamine, isopropylcarbodiimide, BUTYLCARBAMATE, isobutylamino, sec-butylcarbamoyl, tert-butylcarbamoyl, intelcorporation, paxilonline etc.),

(62) 3-C3-8cycloalkylation (for example, 3-cyclopentylamine, 3 cyclobutylamine, 3 cyclopentylamine, 3 cyclohexylurea, 3 cycloheptylamine, 3 cyclooctylamino etc.),

(63) 3-C6-10amiloride (for example, 3-phenylurea, 3 naphthylurea etc), optionally containing from 1 to 3 substituents selected from (1') halogen (e.g. fluorine, chlorine, bromine, iodine), (2') cyano, (3') C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl etc), optionally containing 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (4') C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc.), (5') C1-4alkylenedioxy (e.g.,- OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -OCH2CH2CH2CH2O - etc.), (6') C1-6alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, is ethoxycarbonyl, hexyloxybenzoyl), (7') of carbamoyl and (8') heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below),

(64) 3-C1-6alkyl-3-C6-10amiloride (where as C1-6alkyl groups can be specified, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like, and as C6-10aryl group, you can specify, for example, phenyl, 1-naphthyl, 2-naphthyl and the like, in particular, you can specify, for example, 3-methyl-3-phenylurea etc.),

(65) 3-C7-12arancelario (for example, 3-benzylurea, 3 ventilerede etc), optionally containing from 1 to 3 substituents selected from (1') halogen (e.g. fluorine, chlorine, bromine, iodine), (2') cyano, (3') C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl etc), optionally containing 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (4') C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentox, hexyloxy etc), and (5') C1-4alkylenedioxy (e.g.,- OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -OCH2H 2CH2CH2O - etc),

(66) 3-C1-6alkoxide (for example, 3-metaxourgeio, 3 elixiride, 3 proporcionado, 3 isopropoxide, 3 butoxide, 3 isobutoxide, 3-(sec-butoxy)ureido, 3-(tert-butoxy)ureido, 3 pentoxyverine, 3 getselectionend),

(67) 3-C6-10arylsulfonyl (for example, 3-(phenylsulfonyl)ureido, 3-(1-naphthylmethyl)ureido, 3-(2-naphthylmethyl)ureido),

(68) 3-(heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below))-ureido (for example, 2-pyridylamino, 3 pyridylamino, 4-pyridylamino, 3-(1H-benzotriazolyl)-ureido), optionally containing from 1 to 3 substituents selected from C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, penttila, hexyl etc) and heterocyclic groups (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below),

(69) piperidylamine, optionally containing from 1 to 3 groups C1-6alkylcarboxylic (for example, acetyl, ethylcarbonate, propellerblade, isopropylcarbonate, b is tinkerballa, isobutylketone, second-butylcarbamoyl, tert-butylcarbamoyl, internabonal, hexylcaine),

(70) phthalimide:

(71) heterocyclic group (where specified heterocyclic group has the same meaning as the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies)”defined below, and you can specify, for example, 5 - or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc. and 8-12-membered aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, 3H-indolyl, indolinyl, isoindolyl, isoindolyl, 1H-indazole, benzimidazole, benzoxazolyl, 1,2-benzisoxazole, 2,1-benzisoxazole, benzothiazole, benzopyranyl, 1,2-benzisothiazolin, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, purinol, pteridinyl, carbazolyl, α-carbonyl, β-carbolines, γ-carbolines, acridine is, phenoxazines, phenothiazines, phenazines, phenoxathiin, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, benzoxazolyl and the like, and a 3-8-membered saturated or unsaturated non-aromatic heterocyclic group, such as oxiranyl, azetidine, oxetane, titanyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tylenol, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil, 3-hexahydrotriazine[c]pyrrolyl, homopiperazin, homopiperazine, 1,2,3,6-tetrahydropyrimidine etc., etc., or non-aromatic heterocyclic group, where the double bonds of the aforementioned aromatic monocyclic heterocyclic group or condensed aromatic heterocyclic group is partially or fully saturated, such as dihydropyridin, dihydropyrimidin, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1-benzofuranyl, 1,3-benzodioxolyl, bromanil etc., etc.),

(72) halogen (e.g. fluorine, chlorine, bromine, iodine),

(73) azide,

(74) nitro,

(75) cyano,

(76) oxo(=O),

(77) C1-6alkylene (for example, C 1-4alkylene, such as-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- etc),

(78) C1-4alkylenedioxy (e.g.,- OCH2O-, -OCH2CH2O-, -och2CH2CH2O-, -och2CH2CH2CH2O - etc),

(79) a group represented by the formula: R12-NH-(CH2)p-

where R12represents (1') hydrogen atom, (2') C6-10arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol), optionally containing from 1 to 3 groups

halogen-C1-6the alkyl (for example, trifloromethyl, 2,2,2-triptoreline), (3') C7-12Uralelectromed (for example, benzyloxycarbonyl, ventilatsioonil, 1-naphthylenediamine, 2-naphthylenediamine) or (4')6-10arellanobond (for example, phenylenecarbonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl), and p is 0 or 1.

(80) a group represented by the formula: R15-NH-(CH2)r-

where R15represents a C6-10arylcarbamoyl (for example, benzoyl, 1-naphtol, 2-naphtol), and r is 0 or 1.

The above group of substituents And, optionally, further comprises from 1 to 3 substituents selected from the group of substituents A, defined above, in a position which is replaced.

As a Deputy in hydrox is, optionally containing a substitute for R2, R3, R4, R5, R7, R8, R9or R10you can specify, for example, “Uglevodorody group, optionally containing a Deputy(deputies)”above for R1, R2, R3, R4, R5, R7, R8, R9or R10.

As the substituent of the “amino, optionally containing a Deputy(deputies)for R2, R3, R4, R5, R7, R8, R9or R10you can specify, for example, “Uglevodorody group, optionally containing a Deputy(deputies)”above for R1, R2, R3, R4, R5, R7, R8, R9or R10and the number of substituents is 1 or 2.

As a thiol, optionally containing a substitute for R2, R3, R4, R5, R7, R8, R9or R10you can specify, for example, a group represented by the formula-SR20(where R20represents a hydrocarbon group, optionally containing a Deputy(deputies)), a group represented by the formula-S(O)R21(where R21represents a hydrocarbon group, optionally containing a Deputy(deputies), and the group represented by the formula-S(O)2R22(where R22pre whom represents a hydrocarbon group, optionally containing a Deputy(deputies)). As the “hydrocarbon group optionally containing a Deputy(deputies),for R20, R21or R22you can specify, for example, groups similar to the “hydrocarbon group optionally containing a Deputy(deputies)”above for R1, R2, R3, R4, R5, R7, R8, R9or R10.

As the “heterocyclic group” of the “heterocyclic group optionally containing a Deputy(deputies),for R2, R6, R7, R8, R9or R10in the present description, unless otherwise specified, you can specify, for example, 5 to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic group or non-aromatic heterocyclic group containing as constituents of the ring atoms besides carbon atoms, 1 to 3 kinds of heteroatoms in the amount of from 1 to 5 (preferably 1 to 3)selected from nitrogen atom, sulfur atom and oxygen atom.

As the “aromatic heterocyclic group”, you can specify, for example, 5 - or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxa is azolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc. and 8-12-membered aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, 3H-indolyl, indolinyl, isoindolyl, isoindolyl, 1H-indazole, benzimidazole, benzoxazolyl, 1,2-benzisoxazole, 2,1-benzisoxazole, benzothiazole, benzopyranyl, 1,2-benzisothiazolin, 1H-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthyridine, purinol, pteridinyl, carbazolyl, α-carbonyl, β-carbolines, γ-carbolines, acridines, phenoxazines, phenothiazines, phenazines, phenoxathiin, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, 1,4-benzoxazines and the like (preferably a heterocycle, where the above-mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group is condensed with benzene ring or a heterocycle, where the same or different from each other, two of the heterocycle mentioned 5-or 6-membered aromatic monocyclic heterocyclic groups are condensed, more preferably, the heterocycle, where the above-mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group is condensed with benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo[b]thienyl etc., etc.

As a “non-aromatic heterocyclic group”, you can specify, for example, a 3-8-membered saturated or unsaturated non-aromatic heterocyclic group, such as oxiranyl, azetidine, oxetane, titanyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tylenol, piperidyl (containing piperidine), tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil, 3-hexahydrotriazine[c]pyrrolyl, homopiperazin, homopiperazine, 1,2,3,6-tetrahydropyrimidine etc., etc., or non-aromatic heterocyclic group, where the double bonds of the aforementioned aromatic monocyclic heterocyclic group or condensed aromatic heterocyclic group is partially or fully saturated, such as dihydropyridin, dihydropyrimidin, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1-benzofuranyl, 1,3-dioxindole, bromanil etc., etc.

From the above-mentioned "heterocyclic group" as the "5 - or 6-membered heterocyclic group, you can specify, for example, furyl, t is Anil, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tylenol, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil, etc. and as a "5 - or 6-membered aromatic heterocyclic group", you can specify for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl etc.

From the above-mentioned "heterocyclic group" as the "condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle, you can specify, for example, isoindolyl, benzimidazolyl, 1,3-dioxindole, 1H-benzotriazolyl, indolyl, honokalani, 2,3-dihydro-1-benzofuranyl, 1,2-benzisoxazole, benzothiazole, 1,4-benzoxazines, isobenzofuranyl, bromanil, 3H-indolyl, lH-indazole, ethanolic, hinely, phthalazine, hintline, cinnoline, indolinyl, isoindolyl, benzop the wounded, etc.

As a "Deputy" in the "heterocyclic group optionally containing a Deputy(deputies),for R2, R6, R7, R8, R9or R10you can specify, for example, substituents selected from the above group of substituents A, etc. the Number of substituents is from 1 to 5.

As the "cyclic group, optionally containing a Deputy(deputies),in the definition of" (a cyclic group, optionally containing a Deputy(deputies))-carbonyl" for R6you can specify, for example, (1) homocyclic ring group optionally containing a Deputy(deputies), and (2) heterocyclic group optionally containing a Deputy(deputies).

As gamecycledelay ring group" of the "gamecycledelay ring group optionally containing a Deputy(deputies), you can specify, for example, (1) C3-8cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2,2,2]octyl etc.), (2) C6-10aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, etc.) and (3) group, where C3-8cycloalkyl in (1) and C6-10the aryl in (2) are condensed (for example, 1,2,3,4-tetrahydronaphthyl).

As the “substituent” in the “gamecycledelay ring group optionally containing replace the ü(deputies)”, you can specify, for example, substituents similar to the above group of substituents A. the Number of substituents is from 1 to 5.

As the “heterocyclic group optionally containing a Deputy(deputies), you can specify, for example, groups similar to the “heterocyclic group optionally containing a Deputy(deputies),” above for R2, R6, R7, R8, R9or R10.

As alkenylboronic, optionally containing a Deputy(deputies),for R6you can specify, for example, C2-6alkenylboronic (for example, EtherChannel, 1-propenylboronic, 2-propenylboronic etc), optionally containing from 1 to 5 substituents selected from the above group of substituents A, etc.

As alkylcarboxylic” from “alkylcarboxylic containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), (ii) amino, optionally containing a Deputy(deputies), and (iii) a heterocyclic group optionally containing a Deputy(deputies),for R6you can specify, for example, C1-6alkylsulphonyl (for example, acetyl, ethylcarboxyl, propylmalonic, isopropylcarbonate, butylcarbamoyl, isobutylketone, second-butylcarbamoyl, tert-butylcarbamoyl, penciler the Nile, hexylcaine etc., etc.

As cycloalkyl, optionally containing a Deputy(deputies)” from “alkylcarboxylic containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), (ii) amino, optionally containing a Deputy(deputies), and (iii) a heterocyclic group optionally containing a Deputy(deputies)for R6you can specify, for example, C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally containing from 1 to 5 substituents selected from the above group of substituents A, etc.

As amino, optionally containing a Deputy(deputies)” from ”alkylcarboxylic containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), (ii) amino, optionally containing a Deputy(deputies), and (iii) a heterocyclic group optionally containing a Deputy(deputies)for R6you can specify, for example, groups of similar amino, optionally containing a Deputy(deputies)”above for R2, R3, R4, R5, R7, R8, R9or R10.

As the “heterocyclic group optionally containing a substituent(the Deputy is)” from “alkylcarboxylic, containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), (ii) amino, optionally containing a Deputy(deputies), and (iii) a heterocyclic group optionally containing a Deputy(deputies)for R6you can specify, for example, groups similar to the “heterocyclic group optionally containing a Deputy(deputies)”above for R2, R6, R7, R8, R9or R10and “Deputy” is chosen from the group of substituents A.

The number of substituents, which contains the above alkylaryl, is from 1 to 3.

As a ring which R7and R8, R8and R9or R9and R10form together with the adjacent carbon atoms, can be specified, for example, (1) homolliella ring, optionally containing from 1 to 5 substituents selected from the above group of substituents A, or (2) a heterocycle, optionally containing from 1 to 5 substituents selected from the above group of substituents A.

As homozygotesare ring” of the “homozygotesare ring, optionally containing from 1 to 5 substituents selected from the above group of substituents A', you can specify, for example, C3-6cycloalkyl ring (for example, cyclopropane ring cyclobutanone ring, cyclopentane ring, cyclohexane ring, etc.), C6-10aryl ring (e.g., benzene ring, naphthalene ring, etc. etc.

As the “heterocycle” of the “heterocycle, optionally containing from 1 to 5 substituents selected from the above group of substituents A, unless otherwise specified, you can specify, for example, 5 to 14-membered (monocyclic, bicyclic or tricyclic) aromatic heterocyclic group or non-aromatic heterocyclic group containing as constituents of the ring atoms in addition to carbon atoms, from 1 to 5 (preferably 1 to 3) heteroatoms 1-3 species selected from nitrogen atom, sulfur atom and oxygen atom.

As the “aromatic heterocycle”, you can specify, for example, 5 - or 6-membered aromatic monocyclic heterocycle such as furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazol ring, imidazole ring, pyrazole nucleus ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazoline ring, furazane ring, 1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring is, pyrazinone ring, triazine ring and the like, and 8-12-membered aromatic condensed heterocycle, such as benzofuranol ring, isobenzofuran ring, benzo[b]thiophene ring, indole ring, isoindole ring, 1H-indazol ring, benzimidazole ring, benzoxazole ring, 1,2-benzisoxazole ring, 2,1-benzisoxazole ring, benzothiazoline ring, benzopyrene ring, 1,2-benzisothiazole ring, 1H-benzotryazolyl ring, quinoline ring, isoquinoline ring, cinnoline ring, hintline ring, hinoksolinov ring, phthalazinone ring, naphthyridine ring, purine ring, pteridine ring, carbazole ring, α-carolynowoe ring, β-carolynowoe ring, γ-carolynowoe ring, acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenoxathiin ring, thianthrene ring, phenanthridinium ring, phenanthroline ring, indolizine ring, pyrrolo[1,2-b]pyridazinone ring, pyrazolo[1,5-a]pyridine ring, imidazo[1,2-a]pyridine ring, imidazo[1,5-a]pyridine ring, imidazo[1,2-b]pyridazinone ring, imidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3-a]pyridine ring, a 1,2,4-triazolo[4,3-b]pyridazinone ring, 1,4-benzoxazinone ring etc. (predpochtite is) a heterocycle, where the above-mentioned 5 - or 6-membered aromatic monocyclic heterocycle is condensed with benzene ring or a heterocycle, where the same or different from each other, two of the heterocycle of the above 5 - or 6-membered aromatic monocyclic heterocycle is condensed, more preferably a heterocycle, where the above-mentioned 5 - or 6-membered aromatic monocyclic heterocycle is condensed with benzene ring, particularly preferably benzofuranol ring, benzopyrene ring, benzo[b]thiophene ring, etc. etc.

As a “non-aromatic heterocycle”, you can specify, for example, a 3-8-membered saturated or unsaturated nonaromatic a heterocycle, such as oxirane ring, azetidine ring, oxetane ring, titanoboa ring, pernovae ring, pyrolidine ring, tertrahydrofuran ring ring, Tirnovo ring, piperidine ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pieperazinove ring, 3-hexahydrotriazine[c]pyrrole ring, homopiperazine ring, homopiperazine ring, 1,2,3,6-tetrahydropyrimidine ring and so on and so on, or the non-aromatic heterocycle, where the double bond of the above aromatic monocyclic heterocycle or aromatic conden the new heterocycle is partially or fully saturated, such as dihydropyridine ring, dihydropyrimidine ring, 1,2,3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring, 3,4-dihydro-2H-1,4-benzoxazine ring, 2,3-dihydro-1-benzofuranol ring, 1,3-benzodioxane ring, chromenone ring etc., etc.

When n is an integer having a value from 2 to 5, R4and R5, respectively, can be different from each other due to the excessive n.

R1preferably represents (1) no substitution, (2) hydrogen atom, (3) C1-6alkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (4) C7-12aralkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, or (5) C1-6alkylaryl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, and more preferably (1) no substitution, (2) hydrogen atom, (3) C1-6alkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, or (4) C1-6alkylaryl, optionally containing from 1 to 5 substituents selected from the above group of substituents A.

Of the aforementioned values, preferably, when R1represents (1) OTS is a result of the substitution, (2) hydrogen atom, (3) C1-6alkyl, (4) C7-12aralkyl or (5) C1-6alkylsulphonyl, and particularly preferably - (1) no substitution, (2) hydrogen atom, (3) C1-6alkyl or (4) C1-6alkylsulphonyl.

In particular, a hydrogen atom is preferred.

As R2preferred are (1) hydrogen atom, (2) C1-6alkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (3) C3-8cycloalkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (4) C6-10aryl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (5) C1-6alkoxycarbonyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, and (6) a 5 - or 6-membered heterocyclic group, optionally containing from 1 to 5 substituents selected from the above group of substituents A, and more preferred are (1) hydrogen atom, (2) C1-6alkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (3) C3-8cycloalkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A, (4) C6-10aryl, optionally containing from 1 to 5 is of amestitelj, selected from the above group of substituents A, and (5) a 5 - or 6-membered aromatic heterocyclic group, optionally containing from 1 to 5 substituents selected from the above group of substituents A.

Of them, preferred are (1) hydrogen atom, (2) C1-6alkyl, optionally containing from 1 to 3 substituents selected from (1') hydroxy, (2') C1-6alkoxy, (3') C7-12aralkylated, (4') a mono - or di-C1-6alkylamino, (5') N-C1-6alkoxycarbonyl-N-C1-6alkylamino, (6') amino, (7') C1-6alkylcarboxylic, optionally containing 1 to 3 halogen atoms, (8') C7-12arachidonoylethanolamine and (9') C1-6alkoxycarbonyl, optionally containing 1 to 3 halogen atoms, (3) C3-8cycloalkyl, (4) C6-10aryl, optionally containing from 1 to 3 substituents selected from (1') halogen, (2') C1-6the alkyl, optionally containing 1 to 3 halogen atoms, (3') cyano, (4') C1-6alkoxycarbonyl and (5') C1-6alkylthio, (5) C1-6alkoxycarbonyl and (6) a 5 - or 6-membered heterocyclic group optionally containing a Deputy(deputies)selected from (1') hydroxy, (2') C1-6the alkyl, optionally containing C1-6alkylcarboxylic, (3') C7-19aralkyl, optionally containing C1-6alkoxy, (4') C7-12aralkylated, (5') C7-12ar is alkyloxyaryl, (6') a mono-C1-6allylcarbamate and (7') C1-6alkoxycarbonyl, and more preferred are (1) hydrogen atom, (2) C1-6alkyl, optionally containing from 1 to 3 substituents selected from (i) hydroxy, (ii) C1-6alkoxy, (iii) C7-12aralkylated, (iv) mono-C1-6alkylamino and (v) N-C1-6alkoxycarbonyl-N-C1-6alkylamino, (3) C3-8cycloalkyl, (4) C6-10aryl, optionally containing from 1 to 3 substituents selected from (i) halogen, (ii) C1-6the alkyl, optionally containing 1 to 3 halogen atoms, (iii) cyano, and (iv) C1-6alkoxycarbonyl, and (5) a 5 - or 6-membered aromatic heterocyclic group, optionally containing a Deputy(deputies), selected from (i) hydroxy, (ii) C1-6the alkyl, optionally containing C1-6alkylcarboxylic, (iii) C7-12aralkyl, optionally containing C1-6alkoxy, and (iv) C7-12aralkylated.

In particular, preferred are (1) C1-6alkyl, optionally containing a Deputy(deputies)selected from (i) C1-6alkoxy and (ii) mono-C1-6alkylamino, (2) C3-8cycloalkyl, (3) C6-10aryl, optionally containing halogen, and (4) a 5 - or 6-membered aromatic heterocyclic group, optionally containing C1-6alkyl.

R3preferably represents (1) an absence for which edenia, (2) hydrogen atom or (3) C1-6alkyl, optionally containing from 1 to 5 substituents selected from the above group of substituents A.

Of the aforementioned values, preferably, when R3represents (1) no substitution, (2) hydrogen atom or (3) C1-6alkyl.

In particular, (1) hydrogen atom or (2) C1-6alkyl are preferred.

As R4and R5preferred are hydrogen atoms.

As R6preferred are

(1) a group represented by the formula

where ring A is a cyclopentane, cyclohexane or bicyclo[2,2,2]octane;

R11represents a

(1') amino,

(2') C7-12aralkylamines,

(3') C1-6alkylcarboxylic, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl, (4”) mono - or di-C1-6alkylamino, optionally substituted hydroxy, (5”) morpholino, (6”) C1-6alkylcarboxylic, (7”) carbamoylating, (8”) 5 - or 6-membered aromatic heterocyclic group, (9”) C6-10arylamino, (10”) (5 - or 6-membered aromatic heterocyclic group)-carbylamine and

(11”) C1-6alkoxy,

(4') C2-6alkenylamine, optionally containing substituent(C is mstiteli), selected from (1”) C6-10aryl, optionally containing a Deputy(deputies)selected from halogen, C1-6of alkyl, C1-6alkoxy and halogen-(C1-6of alkyl, and (2”) 5 - or 6-membered aromatic heterocyclic group, optionally containing C1-6alkyl,

(5') C3-8cycloalkylcarbonyl,

(6') C6-10arylcarboxamide, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3”) C1-6the alkyl, optionally containing amino or C1-6alkylcarboxylic, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy, (7”) carboxy, (8”) C1-6alkoxycarbonyl, (9”) mono - or di-C1-6alkylamino, optionally containing hydroxy or C1-6alkoxy, (10) carbamoyl, (11”) halogen-C1-6alkoxy, (12”) C1-6alkylcarboxylic, (13”) aminosulfonyl, (14”) C1-6alkylsulfonyl and (15”) 5 - or 6-membered heterocyclic group or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle, which can contain a Deputy(deputies), selected from C1-6the alkyl and oxo,

(7') C7-12aralkylamines,

(8') C1-6alkoxycarbonyl,

(9') (5 - or 6-membered heterocyclic group or condensed ring group, consisting of the th of the benzene ring and 5 - or 6-membered heterocycle)-carbylamine, which can have a Deputy(deputies)selected from (1”) amino, (2”) C1-6of alkyl, (3) halogen-C1-6of alkyl, (4”) C6-10aryl, (5”) oxo and (6”) 5 - or 6-membered heterocyclic group, optionally containing C1-6alkyl,

(10') C6-10arylsulfonamides,

(11') carbamylcholine,

(12') 3-C1-6alkaluria, optionally containing a Deputy(deputies)selected from (1”) hydroxy, (2”) carboxy, (3”) C1-6alkoxy, (4”) C1-6alkoxycarbonyl, (5”) C1-6alkoxycarbonyl, (6”) amino, (7) halogen, (8) carbamoyl, (9”) C1-6alkylsulfonyl, (10”) heterocyclic group optionally substituted by oxo, and (11”) C1-6alkylcarboxylic,

(13') 3-C3-8cycloalkylation,

(14') 3-C6-10amiloride, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy, (6”) methylenedioxy, (7”) C1-6alkoxycarbonyl, (8”) of carbamoyl and (9”) 5 - or 6-membered aromatic heterocyclic group,

(15') 3-C1-6alkyl-3-C6-10amiloride,

(16') 3-C7-12aralkylated, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy,

(17') 3-C1-6alkoxyamino,

(18') 3-C6-10aresult is yureina,

(19') 3-(5 - or 6-membered heterocyclic group or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle)-ureido, which can contain 5 - or 6-membered heterocyclic group,

(20') piperidylamine, optionally containing C1-6alkylsulphonyl, or

(21') phthalimide,

(2) a group represented by the formula

where R12represents (1') hydrogen atom, (2') C6-10arylcarbamoyl, optionally containing halogen-C1-6alkyl, (3') C7-12Uralelectromed or (4') C6-10allumination; m is 0 or 1; and p is 0 or 1,

(3) a group represented by the formula

where R13represents a C6-10arylcarbamoyl,

(4) a group represented by the formula

where ring B is a pyrolidine ring or piperidine ring, each of which is optionally substituted amino; R14represents (1') hydrogen atom, (2') C7-12aralkyl, (3') C1-6alkylsulphonyl, (4') C6-10arylcarbamoyl, (5') C7-12aralkylamines, (6') C1-6alkoxycarbonyl or (7') C7-12aralkylamines,

(5) C2-6alkenylboronic, optionally containing a Deputy(deputies)selected from (1') carb is XI, (2') C1-6alkoxycarbonyl and (3') C6-10arylenecarborane,

(6) C1-6alkylsulphonyl containing a Deputy(deputies)selected from (1') amino, (2') C6-10arylcarboxamide, (3') C1-6alkoxycarbonyl and (4') 5 - or 6-membered heterocyclic group or condensed ring group consisting of a benzene ring and 5 - or 6-membered heterocycle, where each of these groups optionally substituted by oxo,

(7) 1,2,3,4-tetrahydronaphthalene,

(8) pyrrolidinyl containing C7-12aralkyl, or

(9) a group represented by the formula

where R15represents a C6-10arylcarbamoyl; r is 0 or 1; and s is 0 or 1,

and more preferred are

(1) a group represented by the formula

where ring A is a cyclopentane, cyclohexane or bicyclo[2,2,2]octane; R11represents (1') amino, (2') C7-12aralkylamines,

(3') C1-6alkylcarboxylic, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl, (4”) CI-C1-6alkylamino and (5) of morpholino, (4') C3-8cycloalkylcarbonyl, (5') C6-10arylcarboxamide, optionally containing a Deputy(deputies)selected from (1”)halogen, (2”) cyano, (3”) C1-6of alkyl, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy, (7”) carboxy, and (8”) C1-6alkoxycarbonyl, (6') C7-12aralkylamines, (7') C1-6alkoxycarbonyl, (8') (5 - or 6-membered aromatic heterocyclic group)-carbylamine, (9') piperidinecarboxylate, (10') C6-10arylsulfonyl, (11') 3-C1-6alkaluria, optionally containing a Deputy(deputies)selected from (1”) hydroxy, (2”) carboxy, (3”) C1-6alkoxy and (4”) C1-6alkoxycarbonyl, (12') 3-C3-8cycloalkylation, (13') 3-C6-10amiloride, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy and (6) of methylendioxy, (14') 3-C7-12aralkylated, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy, (15') 3-(5 - or 6-membered aromatic heterocyclic group)-ureido, (16') piperidylamine, preferably piperidinomethyl, optionally containing C1-6alkylsulphonyl, or (17') phthalimide,

(2) a group represented by the formula

where R12represents (1') hydrogen atom, (2') C6-10arylcarbamoyl, optionally containing halogen-C1-6 alkyl, or (3') C7-12Uralelectromed; m is 0 or 1; and p is 0 or 1,

(3) a group represented by the formula

where R13represents a C6-10arylcarbamoyl,

(4) a group represented by the formula

where ring B is a pyrolidine ring or piperidine ring; R14represents (1') hydrogen atom, (2') C7-12aralkyl, (3') C1-6alkylsulphonyl, (4') C6-10arylcarbamoyl, (5') C7-12aralkylamines or (6') C1-6alkoxycarbonyl,

(5) C2-6alkenylboronic, optionally containing a Deputy(deputies)selected from (1') carboxy, (2') C1-6alkoxycarbonyl and (3') C6-10arylenecarborane,

(6) C1-6alkylsulphonyl containing a Deputy(deputies)selected from (1') amino, (2') C6-10arylcarboxamide and (3') C1-6alkoxycarbonyl,

(7) 1,2,3,4-tetrahydronaphthalenes and

(8) pyrrolidinyl containing C7-12aralkyl.

Of them, especially preferred are

(1) a group represented by the formula

where ring A is a cyclohexane or bicyclo[2,2,2]octane, R11'represents (1') C1-6alkylaryl, optionally containing a Deputy(deputies), selected the from (1) halogen, (2”) hydroxy, (3”) C1-6alkoxycarbonyl and (4) of morpholino, (2') C6-10arylcarbamoyl, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano,

(3”) C1-6of alkyl, (4) halogen-C1-6of alkyl, (5”) hydroxy-C1-6of alkyl, (6”) C1-6alkoxy and

(7”) C1-6alkoxycarbonyl, (3') C7-12aralkylamines, (4') (5 - or 6-membered aromatic heterocyclic group-carbonyl, (5') C1-6alkylaminocarbonyl, optionally containing a Deputy(deputies)selected from (1”) hydroxy, (2”) C1-6alkoxy and (3”) C1-6alkoxycarbonyl, (6') C3-8cycloalkylcarbonyl, (7') C6-10allumination, optionally containing a Deputy(deputies)selected from (1”) halogen, (2”) cyano, (3) halogen-C1-6of alkyl, (4”) C1-6of alkyl, (5”) C1-6alkoxy and (6) of methylendioxy, (8') C7-12aralkylamines, optionally containing a Deputy(deputies)selected from (1”) halogen, and (2”) C1-6alkoxy, (9') (5 - or 6-membered aromatic heterocyclic group)-aminocarbonyl or (10') piperidinylcarbonyl, preferably, piperidinylcarbonyl, optionally containing C1-6alkylsulphonyl, and

(2) a group represented by the formula

where R12' represents a C6-10ar is carbonyl.

As R7preferred is a hydrogen atom.

As R8preferred are (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl, optionally containing 1 to 3 halogen atoms, (5) C6-10arylcarbamoyl, (6) C1-6alkoxy, (7) C6-10aryloxy and (8) sulfamoyl, and more preferred are (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl, optionally containing 1 to 3 halogen atoms, (5) C6-10arylcarbamoyl, (6) C1-6alkoxy and (7) C6-10aryloxy. In particular, preferred are a hydrogen atom, halogen, C1-6alkyl and C1-6alkoxy, and particularly preferred are a hydrogen atom and a halogen.

As R9preferred are (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl and (5) C1-6alkoxy. In particular, preferred are a hydrogen atom, halogen, cyano, and C1-6alkyl are preferred, and particularly preferred are a hydrogen atom and a halogen.

As R10preferred are (1) hydrogen atom, (2) halogen, (3) C1-6alkyl and (4) C1-6alkoxy. Particularly preferred are a hydrogen atom and a halogen.

As preferred values of n are 2 and 3. Particularly preferably, when n=2.

Of the compounds represented HUF who Ulai (I), especially preferred is the compound represented by the formula

where each symbol is defined above.

In particular, as preferable examples of compound (I) can be specified

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide,

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (Example 81),

N-phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea (Example 135),

2-methyl-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide (Example 201),

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamide (Example 219),

4-(1H-imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)Bentham is d (Example 281),

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(1H-pyrazole-1-yl)phenyl]urea (Example 284),

4-cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (Example 304)

etc.

Of them, especially preferred are

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (Example 81),

N-phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea (Example 135),

2-methyl-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide (Example 201),

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamide (Example 219),

4-(1H-imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (Example 281),

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(1H-pyrazole-1-yl)phenyl]urea (Example 284) and

4-cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (Example 304).

As salts of the compound (), you can specify for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic amino acids or acid type, etc. as preferred examples of metal salts is possible to specify, for example, alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like as preferable examples of salts formed with organic bases, you can specify for example, salts formed with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenziletilendiaminom, tromethamine [e.g. Tris(hydroxymethyl)methylamine], tert-butylamine and the like as preferable examples of salts formed with inorganic acids, you can specify, for example, salts formed with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. as preferred examples of salts formed with organic acids, you can specify for example, salts formed with formic acid, acetic acid triperoxonane acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like as preferable examples of salts formed with basic amino acids type, you can specify, for example, salts formed with arginine, lysine, ornithine and the like, and as preferred examples of salts formed with amino acid type, you can specify, for example, salts formed with aspartic acid, glutamic acid, etc.

Of these pharmaceutically acceptable salts are preferred. For example, when the compound contains an acidic functional group in its structure, you can specify, for example, inorganic salts such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), salts of alkaline earth metals (e.g. calcium salt, magnesium salt, barium salt etc) and the like, ammonium salts and the like, and when the compound contains a basic functional group in its structure, you can specify, for example, salts formed with inorganic acids, such as salts of hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. and salts formed with the content of inorganic fillers acids, such as salts of acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluensulfonate acid, etc.

The compound (I) may be in the form of a hydrate or in dehydrates form. As hydrate, you can specify, for example, 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, etc.

When the compound (I) may include optical isomers, the present invention essentially comprises respective optical isomers and their mixtures. If desired, these isomers can be subjected to optical separation in a known manner, or they can be obtained separately.

When the compound (I) is present in the form of spatial isomer, diastereoisomer, conformer or the like, they can be separated, if desired, known methods of separation and purification, respectively.

When the compound (I) contains a stereoisomer, such individual isomers and mixture of such isomers are also covered by the present invention.

When the compound (I) obtained as a mixture of optically active compounds (e.g. racemate), it can be distinguished in the (R) - form and (S) form, which is desirable, using well-known methods of optical separation.

The compound (I) can be marked with an isotope (for example, H,14C,35S), etc.

The prodrug of compound (I) means a compound which is converted to compound (I) under physiological conditions in vivo as a result of interaction with the enzyme, gastric acid, etc. Thus, the compound is converted into the compound (I) by enzymatic oxidation, recovery, hydrolysis or the like, or by hydrolysis caused by the action of gastric acid or the like, etc.

As a prodrug of compound (I) can be specified, for example, the compound obtained in the result of the fact that the amino group of compound (I) is subjected to acylation, alkylation or phosphorylation (e.g., the connection, which is produced by subjecting the amino group of compound (I) alzarouni, elavilelavil, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinylcarbonyl, pivaloyloxymethyl, tert-bottling plant, etc); the connection, which is produced by subjecting a hydroxy-group in the compound (I) to acylation, alkylation, phosphorylation and boronovanii (for example, a connection, which is produced by subjecting a hydroxy-group of the compound (I) acetylation, palmitoylation, propanolamine, pihlajasaari, succinylamino, funeralreview, elavilelavil, dimethylamine is carbonyliron etc.); the compound, which is obtained by exposing carboxypropyl compounds (I) esterification or amidation (e.g., a compound which is obtained by exposing carboxypropyl compounds (I) to an ethyl esterification, phenyl-esterification, carboxymethyl-esterification, dimethylaminomethyl-esterification, pivaloyloxymethyl-esterification, ethoxycarbonylmethyl-esterification, phthalidyl-esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyl-esterification, metallizirovanaya, etc) and other Such compounds can be obtained from the compound (I) in a known manner.

In addition, the prodrug of compound (I) may be a compound which is converted to compound (I) under physiological conditions as described inPharmaceutical Research and DevelopmentVol. 7 (Drug Design), pp. 163-198 (1990), published by Hirokawa Publishing Co.

Methods of obtaining the compound (I) described below. The connection specified in the diagrams include the salts, and such salts is possible to specify, for example, salts, similar to the salts of compound (I), etc.

As solvents based on aromatic amines, based solvents, halogenated hydrocarbon-based solvents aliphatic hydrocarbon-based solvents, aromatic hydrocarbon, ether solvents, amide solvents and solvent-based NITRILES on what I use in the methods of manufacturing of the present invention can be used, for example, the solvents listed below:

solvents based on aromatic amines:

solvents based on halogenated hydrocarbons: methylene chloride, dichloroethane, etc.

solvent based aliphatic hydrocarbons include pentane, hexane, heptane, etc.

solvents based on aromatic hydrocarbons: toluene, xylene, etc.

the solvents on the basis of simple ether: diethyl ether, tetrahydrofuran, etc.

solvent-based amides: N,N-dimethylformamide, N,N-dimethylacetamide, etc.

the solvents on the basis of the NITRILES include acetonitrile, propionitrile etc.

Room temperature, as a rule, means a temperature from about 10°C to about 35°C.

Scheme 1

where P represents a protective group, and other symbols are defined above.

Scheme 1 refers to the method of synthesis of compounds (Ia), where, in the compound (I) R1=H, R6=P (where P represents a protective group) and n=2 or 3, which can be synthesized in accordance with the method of R. A. Batey et al. (Chem. Commun., 1999, 651). Three components: the compound (II), the compound (III) and compound (IV) is subjected to condensation in the presence of a catalyst to obtain a mixture of stereoisomers: endo-and Exo-form. Preferably, when such interaction is carried out without solvent or in the presence of a solvent, awlays is gosia inert in this reaction. Although the solvent is not specifically limited, provided that it does not interfere with the reaction, using, for example, solvents based on aromatic amines, solvents based on halogenated hydrocarbons, solvents based on aliphatic hydrocarbons, solvents based on aromatic hydrocarbons, ether solvents, amide solvents and solvent-based NITRILES, and mixtures of two or more types of these solvents, etc. of these preferred solvents are acetonitrile, toluene and the like, the reaction Temperature is usually from -30°C to 100°C, room temperature is preferred. The reaction time is usually from 1 hour to 24 hours, preferably from 1 hour to 2 hours. As a catalyst can be used proton acid (e.g. sulfuric acid, triperoxonane acid, etc.) and Lewis acid (for example, BF3·Et2O TiCl4, AlCl3, BCl3, Dy(OTf)3, Yb(OTf)3Sc(OTf)3, La(OTf)3, Eu(OTf)3, Cu(OTf)2, Zn(OTf)2and so on and so on

As a protective group represented by P, it is possible to specify, for example, groups that are commonly used in the chemistry of peptides, etc. for Example, you can specify group, described inProtective Groups in Organic Synthesis,3rdEd. (1999), authored by Theodora W.Greene, Peter G.M.Wuts, published by Wiley-Interscience, etc. Specifically mo is but to specify tert-butoxycarbonyl group (BOC group), benzyloxycarbonyl group (Cbz group), etc.

Scheme 2

where R are identical or different from each other and each represents a C1-6alkyl (e.g. methyl, ethyl, etc.), R' represents a protective group, and other symbols are defined above.

Scheme 2 refers to the method of synthesis of compound (Ib), where in the compound (I) R1=R3=R4=R5=H, R6=P' (where P' is a protective group), the compound (V) instead of the compound (IV)indicated in figure 1, is subjected to condensation with the compound (II) and compound (III) in the presence of a catalyst for the synthesis of compound (Ib). Although the solvent is not specifically limited, provided that it does not interfere with the reaction, using, for example, solvents based on aromatic amines, solvents based on halogenated hydrocarbons, solvents based on aliphatic hydrocarbons, solvents based on aromatic hydrocarbons, ether solvents, amide solvents and solvent-based NITRILES, and mixtures of two or more types of these solvents, etc. of these preferred solvents are acetonitrile, toluene and the like, the reaction Temperature is usually from 0°C to 100°C, preferably from 50°C to 60°C. the reaction Time is usually ranges from 1 hour to 24 hours, p is edocfile from 2 hours to 3 hours.

In the above reaction as a protective group represented by P', you can specify, for example, groups similar to the above-mentioned protective group represented by P.

The mixture of stereoisomers of endo-and Exo-forms of the compounds obtained in accordance with Scheme 1 or Scheme 2 (Ia or Ib)can be isolated and purified by known methods such as distillation, crystallization, chromatography and the like

Scheme 3

where R6'represents (1) (a cyclic group, optionally containing a Deputy(deputies))-carbonyl, (2) alkenylboronic, optionally containing a Deputy(deputies), or (3) alkylsulphonyl containing a Deputy(deputies)selected from (i) cycloalkyl, optionally containing a Deputy(deputies), and (ii) amino, optionally containing a Deputy(deputies), and other symbols are defined above.

Scheme 3 refers to the removal of the protective group in the mixture of stereoisomers of endo-and Exo-forms of the compounds (Ia) or (Ib)) or isolated from this mixture of the stereoisomers. The protective group can be removed according to known methods such as the method described inProtective Groups in Organic Synthesis, 3rdEd. (1999), authored by Theodora W. Greene, Peter G. M. Wuts, published by Wiley-Interscience, etc.

The compound (Ic) can be obtained by a method that includes entries batch is e compound (VI) with compound (VII) in the presence of a suitable condensing agent and, if necessary, the base. The amount used of the compound (VII) is from about 1.0 mol to 1.5 mol, preferably from about 1.1 mol to 1.2 mol, per 1.0 mol of compound (VI). The amount of the condensing agent is from about 1.0 to 1.5 mol, preferably about 1.1 mol to 1.3 mol, per 1.0 mol of compound (VI). As the condensing agent, you can specify, for example, carbodiimide (DCC (i.e. 1,3-dicyclohexylcarbodiimide), WSC (i.e., the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DIC (i.e., the hydrochloride of 2-dimethylaminoisopropyl) etc.), derivatives of phosphoric acid (for example, diethylthiophosphate, diphenylphosphoryl, BOP-Cl (i.e. bis(2-oxo-3-oxazolidinyl)phosphorylchloride) and so on), etc. is Used, the amount of base is from about 2.0 mol to 5.0 mol, preferably about 3.0 mol to 4.0 mol on 1.0 mol of compound (VI). As the base used, for example, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like, ammonia or a mixture of two or more kinds of such grounds, etc. in Addition, compound (Ic) can also be n in order to obtain way including the interaction of the compound (VI) with a reactive derivative of compound (VII) (for example, acid halides, acid anhydrides, active esters, esters, imidazoline acid, azegami acid etc), and so on

Preferably, this reaction is carried out without solvent or in the presence of a solvent, which is inert in the reaction. Although the solvent is not specifically limited, provided that it does not interfere with the reaction, using, for example, solvents based on aromatic amines, solvents based on halogenated hydrocarbons, solvents based on aliphatic hydrocarbons, solvents based on aromatic hydrocarbons, ether solvents, amide solvents and solvent-based NITRILES, and mixtures of two or more types of these solvents, etc. of these preferred solvents are acetonitrile, N,N-dimethylformamide and the like, the reaction Temperature is usually from 0°C to 40°C, preferred is room temperature (about 10°C to about 35°C, more preferably from about 15°to about 25°C). The reaction time is usually from 0.5 hours to 24 hours, preferably 1 hour to 2 hours.

The compound (Ic) can be converted to the corresponding oxidized form by processing OK what clitellum, such as manganese dioxide, DDQ (i.e. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone), etc.

In any case, when it is also desirable that the compound (I) can be synthesized using known reactions removal protection, acylation, alkylation, hydrogenation, oxidation, reduction, lengthening the carbon chain or replacement of substituents, carrying only one of these reactions or combining two or more of them. In such reactions, for example, you can use the method described in Shinjikkenkagakukoza 14, vol.15, 1977 (Maruzen Press), etc.

The compound (I)thus obtained can be isolated and purified from the reaction mixture by known methods such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (HPLC), preparative liquid chromatography medium-pressure preparative LC medium pressure), etc.

When the desired product is obtained in a free form by the above reaction, it can be converted into a salt in accordance with the traditional methods, or when the desired product is obtained in a salt form, it can be converted into a free form or another salt according to traditional methods. The compound (I)obtained in this about what atom, can be isolated and purified from the reaction mixture by known methods, such as phase transfer, concentration, extrace solvent fractionation, crystallization, recrystallization, chromatography and so on

The compound (I), its salt and its prodrug in accordance with the present invention (hereinafter, in some cases, abbreviated indicated as the compound of the present invention) have a strong antagonistic effect against the NK2 receptor. The compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, interactions with medications, Carcinogenicity) and is safe.

The authors of the present invention found that tricyclic compound having a partial structure represented by the formula

where n is an integer having a value of from 1 to 5; and

---represents a simple bond or double bond, and its salt have a strong antagonistic effect against the NK2 receptor, and are safe and have excellent properties in duration (for example, absorbiruyaci, metabolism, in vivo kinetics).

Connections really hard is retenu, with a strong antagonistic effect against the NK2 receptor, are useful as remedies for the prevention and/or treatment of diseases, such as inflammatory or allergic diseases (e.g., atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, chronic obstructive pulmonary disease, excessive phlegm, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, nerve pain, itching, cough and other diseases of the Central nervous system [e.g., schizophrenia, Parkinson's disease, melancholy, anxiety, fear, neurosis obsessive-compulsive disorder, panic disorder, dementia (such as Alzheimer's disease and the like) and the like], gastrointestinal diseases [for example, functional gastrointestinal disorders (e.g. irritable bowel syndrome, non-ulcer dyspepsia and the like), ulcerative colitis, Crohn's disease, disorders caused by urease-positive gram-negative helico-bacteria (e.g., Helicobacter pylori and the like) (e.g., gastritis, peptic ulcer gastritis and the like) and the like], vomiting, urination disorders (e.g., fast urination, incontinence and the like), diseases of the circulatory system (for example, stenocardia, hypertension, heart failure, thrombosis and the like), immune RA the housing, cancer, HIV infection, cardiovascular diseases, solar dermatitis, sexual disharmony, ataxia, impairment of cognitive abilities or disturbances of circadian rhythm, etc. in mammals (e.g. mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, apes, people, and so on).

Of the above compounds are useful as remedies for the prevention and/or treatment of functional gastrointestinal disorders (e.g. irritable bowel syndrome, non-ulcer dyspepsia and the like).

When the compound of the present invention is administered as pharmaceutical agents to a mammal, such as man, etc., the introduction usually includes, for example, oral administration in the form of tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, and parenteral administration in the form of injections, suppositories, pills, etc. “Parenteral” introduction includes intravenous, intramuscular, subcutaneous, blood, intranasal, intradermal, instillation, intracerebral, rectal, vaginal, intraperitoneal, intratumoral, proximal tumors introduction, etc. and direct introduction to the site of lesion.

Although the dose of a compound of the present invention varies depending on the route of administration, symptoms, etc., she sostav the em for example, from 0.01 to 1000 mg/kg body weight/day, preferably 0.01 to 100 mg/kg body weight/day, more preferably 0.5 to 100 mg/kg body weight/day, particularly preferably 0.1 to 10 mg/kg body weight/day, more preferably 1-50 mg/kg body weight/day, particularly preferably 1-25 mg/kg body weight/day, for example, oral administration to patients with a syndrome of irritated large intestine (adults weighing from 40 to 80 kg: for example, 60 kg). This number you can enter once a day or in 2 or 3 divided doses per day.

The compound of the present invention can be mixed with pharmacologically acceptable carriers and can be administered orally or parenterally in the form of solid preparations such as tablets, capsules, granules, powders and the like; or liquid preparations such as syrup, injection, etc.

As a pharmacologically acceptable carrier use various organic or inorganic carriers conventionally used as starting substances drugs, which is added in the form of excipients, lubricants, binders and baking powder for solid preparations; solvent, additives to facilitate dissolving, suspending substances, isotonicity agent, buffer and soothing remedy for liquid drugs, etc. If necessary, you can also use such supplements for drugs, ka is the preservatives, antioxidants, colorants, sweeteners, etc.

Although the pharmaceutical composition may be different depending on the dosage form, method of administration, the media, and the like, the composition can be obtained by adding compounds of the present invention, amounting, as a rule, from 0.01 to 100% (wt./wt.), preferably 0.1 to 95% (wt./wt.), from the total amount of the preparation, in accordance with the traditional method.

For example, the compound of the present invention can be used in combination with other active ingredients (hereinafter abbreviated listed as a concomitant drug).

Although the compound of the present invention shows a strong antagonistic activity against receptor NK2 when it is used as only one individual funds, its effect can be further enhanced when combined with one or more concomitant medications (joint use multiple tools).

As a companion drug, for example, you can specify the following.

(1) a Therapeutic agent for diabetes

Insulin preparations [e.g., insulin of animal origin, extracted from the pancreas of the ox or pig; preparations of human insulin synthesized modami genetic engineering using Escherichiacolior yeast; zinc insulin; Protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1 etc) and the like], agents that improve insulin resistance (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, JTT-501, MCC-555, YM-440, GI-262570, KRP-297, FK-614, CS-011, and so on), inhibitors of α-glucosidase (e.g., voglibose, acarbose, miglitol, emiglitate etc), biguanides (e.g.phenformin, Metformin, buformin and so on), the preparations on the basis of sulfonylureas (e.g. tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride and so on), and other tools that enhance insulin secretion (for example, Repaglinide, sinapinic, mitiglinide or its calcium salt (hydrate), GLP-1, nateglinide etc.)inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, PT-100, P32/98 and so on), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140 etc), agonists of amerina (for example, pramlintide etc), inhibitors phosphoribosyltransferase (for example, vanadium acid etc), inhibitors of gluconeogenesis (e.g., glycogen phosphorylase inhibitors, inhibitors of glucose-6-phosphatase, glucagon antagonists, etc.), SGLT inhibitors (i.e. co-transporters, sodium-glucose) (e.g., T-1095 etc), etc.

(2) a Therapeutic agent of diabetic complications

Inhibitors aldozoreduktaza (for example, tolrestat epalrestat, zenarestat, zopolrestat, fidarestat (SNK-860), minalrestat (ARI-509), CT-112 etc), neurotrophic factors (e.g., NGF, NT-3, etc), AGE inhibitors (e.g., ALT-945, pimagedine, paroxetin, N-phenacylthiazolium bromide (ALT-766), EXO-226, and so on), active acceptors oxygen (e.g., thioctic acid etc), cerebral vasodilators (e.g., tapered etc), etc.

(3) lipid-lowering means

Connection statin, which are inhibitors of cholesterol synthesis (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, tseriwastatina or their salts (e.g. sodium salt, etc. and so on), inhibitors stvalentines or fibrate connection with action to decrease the level of triglycerides (for example, bezafibrat, clofibrate, simfibrate, clinofibrate etc), etc.

(4) antihypertensives

Inhibitors of angiotensin-converting enzyme (for example, captopril, enalapril, delapril etc), antagonists of angiotensin II (e.g., losartan, candesartan, cilexetil etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine etc), clonidine and the like

(5) anti-obesity

Drugs against obesity, acting on the Central nervous system (for example dexfenfluramin, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, ointments the Dol, phenylpropanolamine, clobenzorex etc), inhibitors of pancreatic lipase (for example orlistat and so on), β3 agonists (e.g. CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140 etc), anorectics peptides (e.g. leptin, CNTF (Ciliary Neurotrophic Factor), and so on), cholecystokinin agonists (e.g lintitript, FPL-15849 etc), etc.

(6) Diuretics

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

(7) a Chemotherapeutic drug

Alkylating tools (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil etc), carcinostatic antibiotics (e.g., mitomycin, adriamycin etc), carcinostatic means of plant origin (for example, vincristine, vindesine, Taxol etc), cisplatin, carboplatin, etoposide and the like often the spine, derivatives of 5-fluorouracil, such as furtulon, neopentylene etc.

(8) Immunotherapy

Components isolated from microorganisms or bacteria (for example, muramyldipeptide derivatives, picibanil etc), immunoactivity polysaccharides (e.g., lentinan, sizofiran, christenings etc), genetically engineered cytokines (e.g. interferons, interleukins (IL), etc.), colony-stimulating means (e.g., granulocyte colony-stimulating factor, erythropoietin etc), etc. In particular, IL-1, IL-2, IL-12, etc.

(9) the Pharmaceutical agents, for which the effect of positive dynamics cachexia confirmed in tests on animal models or in clinical use

Derivatives of progesterone (for example, megestrol acetate) [Journal of Clinical Oncologyvol. 12, p. 213-225, (1994)], the pharmaceutical agents on the basis of metoclopramide, pharmaceutical-based tools tetrahydrocannabinol (literary sources listed above), tools, improves fat metabolism (e.g., eicosapentaenoic acid, etc.)British Journal of Cancervol. 68, p. 314-318 (1993)], growth hormone, IGF-1, antibodies against TNF-α, LIF, IL-6 and oncostatin M, which are the factors that cause cachexia, etc.

(10) Anti-inflammatories

Steroid tools (e.g., dexamethasone etc), sodium hyaluronate, ingebi the ora of cyclooxygenase (for example, indomethacin, Ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoksib etc), etc.

(11) Other funds

Inhibitors glycogenase (for example, ALT-711, etc.), stimulants nerve regeneration (e.g., Y-128, VX853, or acetyl, etc), drugs acting on the Central nervous system (e.g., antidepressants, such as desipramine, amitriptyline, imipramine, paroxetine, paroxetine, doxepin, carbamazepine, etc), anti-convulsants (e.g., lamotrigine), anti-arrhythmia (for example, meksiletin), the ligand acetylcholine receptors (e.g., ABT-594), antagonists of endothelin receptors (e.g., ABT-627), inhibitors of reuptake of monoamine (e.g., tramadol), inhibitors of reuptake of indolamine (for example, paroxetine, paroxetine), narcotic analgesics (eg, morphine), agonists of GABA receptors (e.g., gabapentin), inhibitors of GABA uptake (for example, tiagabine), agonists α2receptors (e.g., clonidine), local analgesics (e.g., capsaicin), inhibitors of protein kinase C (e.g., LY-333531), anxiolytics (e.g., benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine agonists receptor (e.g., apomorphine), anticholinergic agents, blockers α1receptor (e.g., tamsulosin), Meshech what's the ward (for example, baclofen, etc.), openers potassium channels (for example, nicorandil), calcium channel blockers (such as nifedipine), tools for prevention and/or treatment of Alzheimer's disease (e.g., donepezil, rivastigmine, galantamine), tools for treatment of Parkinson's disease (for example, L-DOPA), antithrombotic means (for example, aspirin, Cilostazol)antagonists of NK2 receptors, a treatment for HIV infection (e.g., saquinavir, zidovudine, lamivudine, nevirapine), a treatment for chronic obstructive pulmonary diseases (e.g., salmeterol, Tiotropium bromide, cilomilast), etc.

For the combined use of the compounds of the present invention and the concomitant drug during the administration of compounds of the present invention and the concomitant drug is not limited. The compound of the present invention and a concomitant drug can enter the subject, which shows this introduction, at the same time or you can enter them at different times. The dose of the concomitant drug can be determined in accordance with the clinically used dose, and it can be correctly determined depending on the subject, which impose such agent, route of administration, disease, used in combination, etc.

The method of introduction connections n the present invention and the concomitant drug is not specifically limited, and it is sufficient that the compound of the present invention and a concomitant drug unite with the introduction. Examples of this method of introduction include the following:

(1) the Compound of the present invention and a concomitant drug is administered in a dosage form simultaneously with the receipt of a single drug that is administered. (2) the Compound of the present invention and a concomitant drug is administered in the dosage form separately to obtain two kinds of preparations which are administered simultaneously by using the same route of administration. (3) the Compound of the present invention and a concomitant drug is administered in the dosage form separately to obtain two kinds of preparations which are administered using the same route of administration, only at different times. (4) the Compound of the present invention and a concomitant drug is administered in the dosage form separately to obtain two kinds of preparations which are administered simultaneously by using different routes of administration. (5) the Compound of the present invention and a concomitant drug is administered in the dosage form separately to obtain two kinds of preparations which are administered using different routes of administration, only at different times (for example, a compound present is Adamu invention and a concomitant drug is administered in this order or in reverse order), etc. Further, all such methods of administration for short listed as a joint means according to the present invention.

A joint means according to the present invention has low toxicity, and for example, the compound of the present invention or (and) the above-mentioned concomitant drug can be mixed in accordance with the known method, with a pharmacologically acceptable carrier to obtain pharmaceutical compositions, such as tablets (including tablets sugar coated tablets film-coated), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, means extended release, etc. that can be safely administered orally or parenterally (e.g., topically, rectally, intravenously, etc).

As the pharmacologically acceptable carrier that can be used to obtain the joint means of the present invention, it is possible to use the media, similar to those specified for the pharmaceutical compositions of the present invention, described above.

The ratio of the compounds of the present invention and the concomitant drug in their compounding to obtain the joint means of the present invention may be properly selected depending on the subject, the which enter the tool, route of administration, diseases, etc.

For example, the number of compounds of the present invention in the joint means of the present invention varies depending on the form of the drug, and it usually is in the range from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight, more preferably from about 0.5 to 20% by weight, based on the total weight of the preparation.

The number of concomitant medications in the joint means of the present invention varies depending on the form of the drug, and it usually is in the range from about 0.01 to less than 100 mass%, preferably from about 0.1 to 50% by weight, more preferably from about 0.5 to 20% by weight, based on the total weight of the preparation.

The amount of additives such as a carrier and the like, in a joint means according to the present invention varies depending on the form of the drug, and it usually is in the range from about 1 to 99.99% by weight, preferably from about 10 to 90% by weight, based on the total weight of the preparation.

When the compound of the present invention and a concomitant drug is administered in dosage forms separately, respectively, it is possible to apply the same amount.

The dose of the joint means of the present invention varies depending on the type of connection on this and the finding, age, body weight, condition, drug form, route of administration, duration of administration and the like, and, for example, one patient with irritable bowel syndrome (adult, body weight: about 60 kg) joint tool administered orally, usually in a dose of from about 0.01 to about 1000 mg/kg/day, preferably from about 0.01 to about 100 mg/kg/day, more preferably from about 0.1 to about 100 mg/kg/day, in particular from about 0.1 to about 50 mg/kg/day, particularly preferably from about 1.5 to about 30 mg/kg/day, based on the compound of the present invention or a concomitant drug, respectively, as a single dose or as multiple separate doses per day. Of course, since the dose indicated above, varies depending on various conditions, in some cases, will be a sufficient amount less than the above dose, and in some cases, you should enter the number in excess of these limits.

The number of concomitant medications may be any, provided that its side effects are not problematic. Daily dose per concomitant drug varies depending on the severity of the disease, age, sex, body mass, different sensitivity of the subjects, the period of introduction, interval and nature, farmacologicas the x properties type a pharmaceutical product type effective ingredient and the like, and is not specifically limited, and the quantity of a drug, for example, in the case of oral administration is usually in the range from about 0.001 to 2000 mg, preferably from about 0.01 to 500 mg, more preferably from about 0.1 to 100 mg, per 1 kg of body weight of the mammal, and it is usually injected once a day or as separate doses up to 4 times per day.

For the introduction of the joint means of the present invention, the compound of the present invention can be entered after administration of the concomitant drug or the concomitant drug can be entered after the introduction of the compounds of the present invention, although you can enter them at the same time. With the introduction of interval time interval varies depending on the input of the active ingredient, dosage form and route of administration, and, for example, when the concomitant drug is administered first, as an example of the way in which the connection of the present invention is administered with an interval of time, comprising from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour after administration of the concomitant drug. When you first enter the connection in this image is in the shadow, as an example of the way in which the concomitant drug is administered with an interval of time, comprising from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compounds of the present invention.

Examples

The present invention will be described hereinafter in more detail with the help of below the Reference Examples, Examples, Examples of the preparation of compositions and Experimental Examples, which should not be construed as limiting the present invention.

The following Reference Examples, Examples,“% ” means mass% unless otherwise specified.

Spectra1H-NMR was determined using tetramethylsilane as an internal standard, using a spectrometer Varian Gemini-200 (200 MHz)spectrometer Mercury-300 (300 MHz) spectrometer Bruker AVANCE AV300 (300 MHz). All δ values are presented in ppm (ppm).

Other used in the present description of the abbreviations mean the following:

s: singlet

d: doublet

DD: double doublet

t: triplet

kV: Quartet

m: multiplet

user.: extended

J: constant interaction

Hz: Hertz

DMF: N,N-dimethylformamide

CDCl3: deuterated chloroform

DMSO-d6: dimethylsulfoxide-d6

Boc: t is et-butoxycarbonyl

Cbz: benzyloxycarbonyl

MgSO4: magnesium sulfate

Na2SO4: sodium sulfate

WSC: hydrochloride of 1-ethyl-3- (dimethylaminopropyl)carbodiimide

HOBt: 1-hydroxy-1H-benzotriazole monohydrate

DEPC: diethylthiophosphate

Dy(OTf)3: triplet dispose

TFA: triperoxonane acid

“At room temperature”generally means in the range from about 10°C to 35°C, but not specifically limited, in the strict sense.

Reference Example 1

tert-Butyl (3aR,9bR)-2,3,3a,4,5,5a,9a,9b-octahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

Sodium (1.2 g, 50 mmol) was dissolved in methanol (15 ml)was added aniline (0.9 g, 10 mmol) at room temperature and the mixture was stirred for 10 minutes. The resulting mixture was added to a suspension of paraformaldehyde (0,42 g, 14 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The extract was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was dissolved in methanol (20 ml), was added tert-butyl 2,3-dihydro-1H-pyrrol-1-carboxylate (850 mg, 5 mmol) and the mixture was heated at the boiling point under reflux for 18 hours. The residue was subjected to column chromatography using what W silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (9:1-4:1, about./about.) obtaining specified in the title compound (180 mg, 12%) as an amorphous substance.

1H-NMR (CDCl3)δ: to 1.48 (9H, d, J=6,1 Hz), 1,76 is 2.01 (2H, m), 2,23 at 2.45 (1H, m), 3,13 is 3.57 (5H, m), 5,09 (1H, DD, J=47,2, 4.0 Hz), 6,54-6,85 (2H, m), 7,10-of 7.23 (2H, m).

LC/MS (ESI) m/z: 275 (MH+).

Reference Example 2

tert-Butyl (3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

and

tert-butyl (3aR4S,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

Benzaldehyde (2,92 g, 28 mmol), aniline (2,56 g, 28 mmol), tert-butyl 2,3-dihydro-1H-pyrrol-1-carboxylate (3.4 g, 25 mmol) and Dy(OTf)3(0,61 g, 1.38 mmol) was stirred in acetonitrile (50 ml) at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (150 g) and suirable a mixture of hexane-ethyl acetate (4:1, vol/vol.). Specified in the header connection (3aR,4R,9bR) (2.7 g, 31%) was obtained as an amorphous substance from the fraction, eluruumi first.

1H-NMR (CDCl3 )δ: 1,42-1,62 (10H, m), 2,08-of 2.28 (1H, m), 2,52 at 2.59 (1H, m), 3,32-to 3.49 (2H, m)to 3.92 (1H, m), 4,74 (1H, m), are 5.36 (1H, DD, J=42,8, 7,0 Hz), to 6.58 (1H, d, J=8.1 Hz), 6,78 (1H, m), 6,98-7,13 (1H, m), 7.23 percent-7,49 (5H, m), 7,55-7,72 (1H, m).

LC/MS (ESI) m/z: 351(MH+).

Specified in the header connection (3aR4S,9bR) (4.0 g, 46%) was obtained as an amorphous substance from the fraction, eluruumi second.

1H-NMR (CDCl3)δ: for 1.49 (9H, s), 2,03 and 2.13 (2H, m), 2,54-of 2.64 (1H, m), 3,31-3,39 (1H, m), 3,50 (1H, user. C), 4,21-4,24 (1H, m), 4,35-to 4.38 (1H, m), a 4.83 (1H, user. C)to 6.57 (1H, d, J=7,6 Hz), 6,65-6,79 (1H, m), 7,05-7,34 (6H, m), 7,49 (1H, s).

LC/MS (ESI) m/z: 351(MH+).

Reference Example 3

1-tert-Butyl 4-ethyl (3aR,4R,9bR)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1,4 -, in primary forms

and

1-tert-butyl 4-ethyl (3aR4S,9bR)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1,4 -, in primary forms

To a solution of acylglycerol (50% solution in toluene, 13,76 g of 67.4 mmol) and aniline (5.6 ml, with 61.3 mmol) in toluene (250 ml) was added magnesium sulfate (3,95 g, 32,85 mmol) and the mixture was stirred at 0°C for 30 minutes. Was added at 0°C a solution of tert-butyl 2,3-dihydro-1H-pyrrol-1-carboxylate (10,37 g, with 61.3 mmol) in toluene (50 ml) and triplet scandium (1.47 g, 3.0 mmol) and the mixture was stirred at room temperature for 16 hours. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with et is lacerata. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (4:1-2:1, about./vol.). Specified in the header connection (3aR,4R,9bR) (9,83 g, 46%) was obtained as an oil from the fractions, eluruumi first.

1H-NMR (CDCl3)δ: of 1.33 (3H, t, J=7.0 Hz), 1,73 is 2.10 (2H, m), 2,82-2,99 (1H, m), 3,22-of 3.64 (2H, m), 4,20-to 4.38 (4H, m), from 5.29 (1H, DD, J=21.2 Hz, 8.0 Hz), to 6.57 (1H, d, J=8.0 Hz), 6,72 (1H, t, J=7.8 Hz),? 7.04 baby mortality (1H, t, J=7,8 Hz), at 7.55 (1H, DD, J=36,0 Hz, 6.8 Hz).

LC/MS (ESI) m/z: 347 (MH+).

Specified in the header connection (3aR4S,9bR) (6,99 g, 33%) was obtained as an oil from the fractions, eluruumi second.

1H-NMR (CDCl3)δ: of 1.23 (3H, t, J=7.4 Hz), of 1.52 (9H, s), 2,00-2,17 (2H, m), 2,84-2,99 (1H, m), 3.25 to 3,63 (2H, m)to 3.89 (1H, s), 4,10-of 4.25 (3H, m)5,00 (1H, user. C)6,56 (1H, d, J=8.0 Hz), 6,72 (1H, t, J=7.0 Hz), 7,03 (1H, t, J=7.0 Hz), 7,54 (1H, user. C).

LC/MS (ESI) m/z: 347 (MH+).

Reference Example 4

Benzyl (3aR,4R,9bR)-4-(4-forfinal)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

4-Forbindelse (700 mg, 5.6 mmol), aniline (525 mg, 5.6 mmol), N-Cbz-4-aminobutyraldehyde diethylacetal (1.5 g, 5.6 mmol) and Dy(OTf)3(170 mg, 0,19 mmol) was stirred at 60°C for 2 hours in acetonitrile (10 ml). The reaction mixture is concentrated under reduced pressure, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (4:1, vol/about.) obtaining specified in the title compound (540 mg, 24%) as an amorphous substance.

1H-NMR (CDCl3)δ: 1,99-of 2.34 (1H, m), 2,43-2,61 (1H, m), 3,28-of 3.54 (2H, m), 3,82-of 3.94 (1H, m), 4,71 (1H, d,J=2.2 Hz), 5,09 is 5.54 (3H, m), to 6.58 (1H, d, J=7.8 Hz), 6,63-PC 6.82 (1H, m), 7,07 (3H, t, J=8.5 Hz), 7,20-7,76 (9H, m).

LC/MS (ESI) m/z: 403 (MH+).

Using various aldehydes instead of the benzaldehyde of Reference Example 2, ethylglycol Reference Example 3 and 4-forbindelse Reference Example 4, and various substituted anilines instead of aniline was synthesized replaced 2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline derivatives. The synthesized compounds are presented in Table 1

Table 1
No.PRXYZ
1Boc HHHH
2BocphenylHHH
3BocphenylFHH
4BocphenylClHH
5BocphenylMeHH
6BocphenylOMeHH
7BocphenylCNHH
8CbzphenylBu HH
9BocphenylHFH
10BocphenylHClH
11BocphenylHMeH
12BocphenylHOMeH
13BocphenylHCNH
14BocphenylHHF
15BocphenylHHCl
16BocphenylHHMe
17Cbz4-forfinalHHH
18Boc4-forfinalFHH
19bz4-chlorophenylHHH
20Cbz4-tolylHHH
21Boc4-cyanophenylHHH
22Boc4-(methylthio)phenylHHH
23 Cbz3-chlorophenylHHH
24Cbz2-chlorophenylHHH
25Cbz1-naphthylHHH
26Boc2-furylHHH
27Boc3-furylHHH
28Boc2-methyl-3-furylHHH
29Boc2-thienylHHH
30BocHHH
31Cbzpyridine-2-ylHHH
32Bocpyridine-3-ylHHH
33Cbzpyridine-4-ylHHH
34Boc1-Cbz-pyrrol-2-ylHHH
35Cbz1-Boc-pyrrol-3-ylHHH
36bz1-methylpyrrole-2-ylHHH
37Cbz1-IRP is lilacsigil-imidazol-2-yl HHH
38Cbz1-pivaloyloxymethyl-imidazol-4-ylHHH
39Boc1,3-thiazol-2-ylHHH
40Boc1,3-thiazol-5-ylHHH
41Boc1,3-oxazol-4-ylHHH
42BocethylHHH
43CbzcutHHH
44Cbzisopropyl HHH
45BoccyclopropylHHH
46CbzisobutylHHH
47CbzTert-butylHHH
48CbzbutylHHH
49CbzhexylHHH
50BocbenzoyloxymethylHHH
51Cbz(tert-butoxycarbonyl)(methyl)-amino shall util HHH
52Boc4-(N-Cbz-piperidinyl)HHH
53BocN-Cbz-aminomethylHHH
54Boc2-(N-Cbz-amino-ethyl)HHH
55Boctetrahydro-2H-Piran-4-ylHHH
56Cbz1-(4-methoxybenzyl)imidazol-2-ylHHH
57Cbz1-(4-methoxybenzyl)pyrazole-5-ylHHH
58 Cbz1-(trityl)pyrazole-5-ylHHH
59Cbz1 trityl-1H-1,2,4-triazole-5-ylHHH
60BocethoxymethylHHH
61BocetoxycarbonylHHH

Reference Example 5

tert-Butyl (3aR,4R,9bR)-4-(hydroxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

To a solution of calcium chloride (12.5 g, 113,1 mmol) in a mixture of tetrahydrofuran-ethanol (200 ml 200 ml) was added borohydride sodium (8.5 g, 226,2 mmol) at 0°C and the mixture was stirred for 30 minutes. Was added at 0°C solution of 1-tert-butyl 4-ethyl (3aR,4R,9bR)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1,4-in primary forms (14.6 g, with 46.6 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 6 hours. Was added a saturated aqueous solution of sodium bicarbonate and ethyl acetate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:9, vol/about.) obtaining specified in the title compound (326 mg, 96%) as oil.

1H-NMR (CDCl3)δ: 1,53 (9H, d, J=11.8 Hz), 1,67-2,48 (4H, m), 3,22-a 3.83 (5H, m), 4,17 (1H, user. C)to 5.21 (1H, DD, J=22,0, and 7.8 Hz), 6,53 (1H, d, J=8,2 Hz), of 6.71 (1H, t, J=7.2 Hz), 7,03 (1H, t, J=7.2 Hz), 7,55 (1H, DD, J=31,2, 7,0 Hz).

LC/MS (ESI) m/z: 305 (MH+).

Reference Example 6

tert-Butyl (3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

To a solution of the compound (a 8.34 g, a 27.4 mmol)synthesized in Reference Example 5 in tetrahydrofuran (250 ml) was added sodium hydride (60% in oil, 1,21 g is 32.8 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 30 minutes. Added methyliodide (2,04 ml, is 32.8 mmol) and the mixture was stirred at room temperature for 16 hours. Added water and the mixture was extracted with ethyl acetate, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on when likehere and suirable a mixture of hexane-ethyl acetate (1:2, about./about.) obtaining specified in the connection header (8,11 g, 93%) as a pale yellow oil.

1H-NMR (CDCl3)δ: 1,53 (9H, d, J=11,4 Hz), 1,66-of 2.09 (2H, m), 2,28-2,47 (1H, m), 3,24-3,55 (4H, m)to 3.41 (3H, s), 3,70-3,82 (1H, m), 4,10-4,22 (1H, m), a total of 5.21 (1H, DD, J=22,2, a 7.6 Hz), 6,51 (1H, d, J=8.0 Hz), of 6.71 (1H, t, J=7,4 Hz), 7,02 (1H, t, J=7.4 Hz), 7,55 (1H, DD, J=34,0 and 7.4 Hz).

LC/MS (ESI) m/z: 319 (MH+).

Reference Example 7

(3aR,9bR)-2,3,3a,4,5,9b-Hexahydro-1H-pyrrolo[3,2-c]quinoline

The compound (160 mg, of 0.58 mmol)synthesized in Reference Example 1 was dissolved in ethyl acetate (5 ml)was added a 4n solution of hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred for 3 hours. The insoluble matter was separated by decantation, suspended in ethyl acetate and was added saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was dried (over anhydrous MgSO4) and the solvent evaporated. The residue was dried under reduced pressure to obtain specified in the title compound (70 mg, 69%) as an amorphous substance.

1H-NMR (CDCl3)δ: 1,57-1,72 (1H, m), 2,08-of 2.24 (1H, m), 2,36 at 2.59 (1H, m), 2,84 (1H, t, J=11,1 Hz), 2.91 in-a 3.01 (1H, m), is 3.08-3,20 (2H, m), 3,55-of 3.77 (1H, m), 3.95 to 4.09 to (2H, m), 6,56-to 6.80 (2H, m), 7,02-7,42 (2H, m).

LC/MS (ESI) m/z: 175 (MH+).

Reference Example 8

(3aS,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline of the dihydrochloride

p>

tert-Butyl (3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (2.65 g, 7.56 mmol) was dissolved in ethyl acetate (10 ml) was added a 4 n solution of hydrogen chloride in ethyl acetate (20 ml)and the mixture was stirred at room temperature for 12 hours. Precipitated crystals were collected by filtration, washed with ethyl acetate and dried under reduced pressure to obtain specified in the connection header (2,60 g, 77%).

1H-NMR (DMSO-d6)δ: 1,33-of 1.45 (1H, m), 1,88-2,04 (1H, m), 2,81 of 2.92 (1H, m), 2,96-3,11 (2H, m), 4,59 (1H, d, J=2.4 Hz), 4,98-5,46 (3H, m), 6,76 (1H, t, J=7,1 Hz)6,86 (1H, d, J=8.1 Hz), 7,12 (1H, t, J=7,1 Hz), 7,32 (2H, DD, J=17,9, 7,4 Hz), 7,38-7,49 (4H, m), 8,55 (1H, user. C)10,33 (1H, user. C).

LC/MS (ESI) m/z: 251 (MH+).

Reference Example 9

(3aS,4R,9bR)-4-(4-Forfinal)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

A mixture of benzyl (3aR,4R,9bR)-4-(4-forfinal)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (500 mg, 1,24 mmol) and 10% palladium on carbon (50% aqueous solution, 0.3 g) in ethanol (20 ml) was stirred at room temperature in a hydrogen atmosphere for 2 hours. The catalyst was filtered and the mixture was washed with ethanol. The solvent is evaporated under reduced pressure to obtain specified in the title compound (350 mg, approx. 100%) in view of the oil.

1H-NMR (CDCl3)δ: 1,34-of 1.44 (1H, m), 1,84-to 1.98 (1H, m), of 2.51-2,70 (1H, m), 2,72-2,82 (1H, m), 2,86-of 2.97 (1H, m), 3,76 (1H, s)to 4.52 (1H, d, J=8.1 Hz), to 4.62 (1H, d, J=3.2 Hz), 6,53-6,70 (1H, m), 6,78-6,84 (1H, m), 6,97-7,12 (3H, m), 7,21-7,30 (2H, m), 7,37-7,46 (2H, m).

LC/MS (ESI) m/z: 269 (MH+).

Reference Example 10

(3aS,4R,9bR)-4-(2,3,3a,4,5,9b-Hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)benzonitrile DATEFORMAT

tert-Butyl (3aR,4R,9bR)-4-(2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (670 mg, 1.78 mmol) was dissolved in chloroform (1 ml), was added triperoxonane acid (1.0 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue is suspended in chloroform and the solvent again evaporated. The residue was washed with ether and dried under reduced pressure to obtain specified in the title compound (710 mg, 79%) as colorless crystals.

1H-NMR (DMSO-d6)δ: 1,29-of 1.45 (1H, m), 1,81-2,02 (1H, m), 2,81-3,20 (3H, m), 4,69 (1H, d, J=3.2 Hz), equal to 4.97-5,13 (1H, m), of 6.29 (1H, user. C)of 6.65 (1H, user. C)of 6.71-6,94 (2H, m), 7,10-7,33 (1H, m), to 7.59-8,10 (5H, m), 8,54 (1H, user. C)to 9.70 (1H, user. C).

LC/MS (ESI) m/z: 276 (MH+).

Reference Example 11

The dihydrochloride (3aS,4R,9bR)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

To a mixture of benzyl (3aR∗/sup> ,4R,9bR)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (730 mg, about 1.75 mmol) and 10% palladium on carbon (50% aqueous solution, 0.3 g) in ethanol (10 ml) was added a solution of hydrogen chloride in methanol (1 ml) and the mixture was stirred at room temperature in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, washed with an aqueous solution of methanol, and the filtrate was concentrated. The residue was dried under reduced pressure to get crude specified in the connection header in the form of oil. (350 mg, approx. 100%)

1H-NMR (CDCl3)δ: of 1.28 to 1.48 (1H, m), 1,86-2,03 (1H, m), 2,79-of 2.93 (1H, m), 2.95 and-3,20 (2H, m), 4,18 (1H, user. C)br4.61 (1H, s), 5,02 (1H, s), from 6.22 (1H, user. C)6,76 (1H, t, J=7.4 Hz), 6,85 (1H, d, J=8.1 Hz), 7,12 (1H, t, J=7.4 Hz), 7,32 (1H, d, J=7,6 Hz), 7,38 to 7.75 (4H, m), 8,59 (1H, user. C)a 10.6 (1H, user. C).

LC/MS (ESI) m/z: 285 (MH+).

In the same manner as described in Reference Example 7 - Reference Example 11, the Cbz group and Boc group were removed from the compounds of Reference Example 6 and Table 1, respectively. The synthesized compounds are presented in Table 2.

Table 2
No.RXYZsalt
1HHHH-
2phenylHHH2HCl
3phenylFHH2HCl
4phenylClHH2HCl
5phenylMeHH2HCl
6phenylOMeHH2HCl
7phenylCNHH2HCl
8 BuHH2HCl
9phenylHFH2HCl
10phenylHClH2HCl
11phenylHMeH2HCl
12phenylHOMeH2HCl
13phenylHCNH-
14phenylHHF2HCl
15phenylH HCl2HCl
16phenylHHMe2HCl
174-forfinalHHH-
184-forfinalFHH2HCl
194-chlorophenylHHH2HCl
204-tolylHHH-
214-cyanophenylHHH2TFA
224-(methylthio)phenylHH H2HCl
233-chlorophenylHHH2HCl
242-chlorophenylHHH2HCl
251-naphthylHHH-
262-furylHHH2TFA
273-furylHHH2TFA
282-methyl-3-furylHHH2HCl
292-thienylHHH 2TFA
303-thienylHHH2TFA
31pyridine-2-ylHHH-
32pyridine-3-ylHHH3TFA
33pyridine-4-ylHHH-
341-Cbz-pyrrol-2-ylHHH2TFA
351-Boc-pyrrol-3-ylHHH-
361-methylpyrrole-2-ylHHH-
371-pivaloyloxymethyl-imidazol-2-ylHHH2HCl
381-pivaloyloxymethyl-imidazol-4-ylHHH-
391,3-thiazol-2-ylHHH2TFA
401,3-thiazol-5-ylHHH2HCl
411,3-oxazol-4-ylHHH2HCl
42ethylHHH2HCl
43cutHHH44isopropylHHH-
45cyclopropylHHH2HCl
46isobutylHHH-
47tert-butylHHH-
48butylHHH-
49hexylHHH-
50benzoyloxymethylHHH2HCl
51(tert-butoxycarbonyl)(methyl)-aminomethylHHH-
524-(N-Cbz-piperidinyl)HHH2HCl
53N-Cbz-aminomethylHHH2HCl
542-(N-Cbz-amino-ethyl)HHH2HCl
55tetrahydro-2H-Piran-4-ylHHH2HCl
561-(4-methoxybenzyl)imidazol-2-ylHHH-
571-(4-methoxybenzyl)pyrazole-5-ylHH-
581-(trityl)pyrazole-5-ylHHH-
591 trityl-1H-1,2,4-triazole-5-ylHHH-
60ethoxymethylHHH2HCl
61methoxymethylHHH2HCl

Reference Example 12

CIS-3-(Methoxycarbonyl)bicyclo[2,2,2]Oct-5-ene-2-carboxylic acid

3a,4,7,7a-Tetrahydro-4,7-ethano-2-benzofuran-1,3-dione (10.2 g, 57,2 mmol) suspended in methanol (70 ml) and the suspension was heated at the boiling point under reflux for 12 hours. The solvent is evaporated under reduced pressure to obtain specified in the title compound (11.6 g, 97%) as crystals.

1H-NMR (CDCl3)δ: 1,27-to 1.38 (2H, m), 1,47-of 1.64 (2H, m), 2,89-of 3.27 (4H, m), 3,59 (H, C), 6,26-6,41 (2H, m).

Reference Example 13

Methyl CIS-3-{[(benzyloxy)carbonyl]amino}bicyclo[2,2,2]Oct-5-ene-2-carboxylate

The compound (10.5 g, a 50.2 mmol)synthesized in Reference Example 12, was dissolved in dichloromethane (150 ml)was added at -10°C. triethylamine (5.3g, and 52.7 mmol) and ethylchloride (5.7 g, and 52.7 mmol) and the mixture was stirred at the same temperature for 20 minutes. To the mixture was added a mixture of sodium azide (6.5 g, 100 mmol), tetrabutylammonium sulfate (3.4 g, 10 mmol) and water (50 ml) and the mixture was stirred at 5°C for 3 hours. To the reaction mixture were added water and the mixture was extracted with chloroform. The extract was washed with water, dried (over anhydrous Na2SO4) and the solvent evaporated under reduced pressure to obtain methyl CIS-3-(azidocarbonyl)bicyclo[2,2,2]Oct-5-ene-2-carboxylate.

This product (50 mmol) was dissolved in 1,2-dichloroethane (150 ml), was added to hydrate p-toluensulfonate acid (catalytic amount) and the mixture was heated at the boiling point under reflux for 1.5 hours. To the reaction mixture was added benzyl alcohol (16.2 g, 150 mmol) and (atomic charges)(tributyl)stannane (175 mg, 0.5 mmol) and the mixture was heated at the boiling point under reflux for 12 hours. The solvent is evaporated under reduced pressure. The residue was subjected to kolonochnoi chromatography using silica gel (100 g) and was suirable a mixture of hexane-ethyl acetate (3:1, about./about.) obtaining specified in the title compound (7.7 g, 46%) as crystals from a fraction, eluruumi first.

1H-NMR (CDCl3)δ: 1,13-of 1.62 (6H, m), 2,69 is 2.80 (1H, m), 3.04 from (1H, d, J=9.8 Hz), of 3.45 (3H, s), 4,29-to 4.41 (1H, m), 4,96-5,13 (2H, m), 6,16 (1H, t, J=7.2 Hz), is 6.54 (1H, t, J=7.2 Hz), 7,29-7,39 (5H, m).

Reference Example 14

Methyl CIS-3-aminobutyl[2,2,2]octane-2-carboxylate

The compound (3.8 g, 11.5 mmol)synthesized in Reference Example 13, was dissolved in methanol (50 ml) and the mixture was stirred in the presence of 10% palladium on carbon (50% aqueous solution, 1.0 g) at room temperature in a hydrogen atmosphere for 12 hours. The catalyst was filtered and the residue washed with methanol. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (2.35 g, approx. 100%) as oil.

1H-NMR (CDCl3)δ: 1,23-2,03 (10H, m), 2,75-2,77 (1H, m)to 3.34 (1H, DD, J=9,6, 3.5 Hz), 3,71 (s, 3H).

Reference Example 15

Methyl CIS-3-[(tert-butoxycarbonyl)amino]-bicyclo[2,2,2]octane-2-carboxylate

Compound (2.1 g, 11.5 mmol)synthesized in Reference Example 14, suspended in dichloromethane (400 ml), was added di-tert-butyl dicarbonate (of 41.6 g of 19.1 mmol) and the mixture was stirred for 2 hours. To the reaction mixture were added water and the separated aqueous layer was extracted with chloroform. Organic with the AOI were United, was dried (over anhydrous Na2SO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) and was suirable a mixture of hexane-ethyl acetate (1:1, vol/about.) obtaining specified in the title compound (2.7 g, 83%) as an amorphous substance.

1H-NMR (CDCl3)δ: 1,35-1,92 (19H, m), 2,96 (1H, d, J=10.3 Hz), 3,66-to 3.67 (3H, m), as 4.02-4,10 (1H, m), 5,72 (1H, d, J=9,3 Hz).

Reference Example 16

CIS 3-[(tert-butoxycarbonyl)amino]-bicyclo[2,2,2]octane-2-carboxylic acid

A mixture of compound (5.7 g, a 19.5 mmol)synthesized in Reference Example 15, methanol (5 ml) and 1 N. aqueous sodium hydroxide solution (5 ml) was stirred at room temperature for 1 hour. To the reaction mixture were added 1 N. aqueous sodium hydroxide solution (5 ml) and the mixture was again stirred for 1 hour and neutralized with 1 n hydrochloric acid. The obtained crystals were collected by filtration, washed with water and dried under reduced pressure to obtain specified in the title compound (5.2 g, 94%).

1H-NMR (CDCl3)δ: 1,34-2,33 (18H, m), 2,81-is 3.08 (1H, m), 4,05-4,17 (1H, m), 5,78-to 5.85 (1H, m), 7,01-7,10 (1H, m).

Reference Example 17

tert-Butyl {(2R,3S)-3-[(3aR,4R,9bR)-(4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)Carbo is Il]bicyclo[2,2,2]Oct-2-yl}carbamate

To a mixture of compound (500 mg, 2.0 mmol)synthesized in Reference Example 8, the compound (566 mg, 2.0 mmol)synthesized in Reference Example 16, triethylamine (and 0.61 ml, 4.4 mmol), acetonitrile (10 ml) and tetrahydrofuran (10 ml) was added dropwise DEPC (359 mg, 2.2 mmol) under ice cooling and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 1 hour. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous Na2SO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (6:1-2:1, about./about.) obtaining specified in the title compound (750 mg, 75%) as an amorphous substance.

LC/MS (ESI) m/z: 502 (MH+).

Reference Example 18

Hydrochloride(2R,3S)-3-[(3aR,4R,9bR)-(4-phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-f]quinoline-1-yl)carbonyl]bicyclo[2,2,2]Octan-2-amine

The compound (730 mg, of 1.46 mmol)synthesized in Reference Example 17, was dissolved in ethyl acetate (5 ml)was added a 4 n solution of hydrogen chloride in ethyl acetate (5 ml) and the ect was stirred for 3 hours. The obtained crystals were collected by filtration, washed with ethyl acetate and dried to obtain specified in the title compound (630 mg, 92%).

LC/MS (ESI) m/z: 402 (MN+).

Reference Example 19

tert-Butyl (1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylcarbamate

and

tert-Butyl (1R,2S)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylcarbamate

To a solution of compound (13 g, 40,2 mmol)synthesized in Reference Example 8 (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (11.7 g, 48.2 mmol) in DMF (200 ml) was added drop wise addition of triethylamine (about 16.9 ml, 121 mmol) at 0°C and then a solution of DEPC (6,74 ml, with 40.2 mmol) in DMF (40 ml). The mixture was stirred at the same temperature for 30 minutes, was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (10:1-1:1, vol/vol.). tert-Butyl (1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylcarbamate (,57 g, 50%) was obtained as a colorless amorphous substance from the target fraction, eluruumi first.

LC/MS (ESI) m/z: 476 (MH+).

tert-Butyl (1R,2S)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylcarbamate (at 9.53 g, 50%) was obtained as a colorless amorphous substance from the target fraction, eluruumi second.

LC/MS (ESI) m/z: 476 (MH+).

In the same manner as in Reference Example 19 was synthesized compounds Table 3, using Table joins 2.

Table 3
No.R
1phenyl
23-thienyl
31-propyl
4cyclopropyl
5methoxymethyl
61,3-oxazol-4-yl
72-methyl-3-furyl
81,3-thiazol-5-yl
9Ethoxymethyl
101-Cbz-pyrrol-2-yl
11tetrahydro-2H-Piran-4-yl

Reference Example 20

{2-[(3aR,4R,9bR)-1-({(1S,2R)-2-[(tert-Butoxycarbonyl)amino]cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]-1H-imidazol-1-yl}Metreveli

In the same manner as in Reference Example 19 and using the dihydrochloride {2-[(3aS,4R,9bR)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]-1H-imidazol-1-yl}methylphenidate from Table 2, have been specified in the header of the connection.

LC/MS (ESI) m/z: 580 (MH+).

Reference Example 21

tert-Butyl ((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)carbamate

and

tert-butyl ((1R,2S)-2-{[(3aS,4S,9bS)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)carbamate

To a solution of compound (of 5.81 g, 10 mmol)synthesized in Reference Example 20 in methanol (150 ml) was added 25% aqueous ammonia solution (120 ml) and the mixture was stirred for 4 hours. The solvent is evaporated, the obtained residue was subjected to column chromatography using silica gel and elwira the Ali mixture of ethyl acetate-methanol (1:0-9:1, about./vol.). tert-Butyl ((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)carbamate (2.00 g, 43%) was obtained as a colorless amorphous substance from the first fraction.

LC/MS (ESI) m/z: 466 (MH+).

tert-Butyl ((1R,2S)-2-{[(3aS,4S,9bS)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)carbamate (2,11 g, 45%) was obtained as a colorless amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 466 (MH+).

Reference Example 22

{2-[(3aR,4R,9bR)-1-({(1S,2R)-2-[(tert-Butoxycarbonyl)amino]cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]-1H-imidazol-1-yl}Metreveli

and

{2-[(3aS,4S,9bS)-1-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]-1H-imidazol-1-yl}Metreveli

To a solution of compound (3aR,4R,9bR) (2,42 g, 5,19 mmol)synthesized in Reference Example 21 in DMF (50 ml) was added sodium hydride (60% in oil, 0.27 g, of 6.75 mmol) under ice cooling and the mixture was stirred at room temperature for 1 hour. Was added dropwise chlorocyphidae (0,98 ml of 6.75 mmol) under ice cooling and the mixture was stirred at room temperature for 2 hours. The solvent is evaporated and the resulting residue was diluted with ethyl acetate, about ivali water and saturated saline and dried (over anhydrous MgSO 4). After concentration under reduced pressure, the obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:1-0:1, vol/vol.). Specified in the header of the connection (of 2.51 g, 83%) was obtained as a colorless amorphous substance from the target faction.

LC/MS (ESI) m/z: 580 (MH+).

In the same way, using the compound (3aS,4S,9bS)synthesized in Reference Example 21 was synthesized {2-[(3aS,4S,9bS)-1-({(1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]-1H-imidazol-1-yl}metreweli.

LC/MS (ESI) m/z: 580 (MH+).

Reference Example 23

The dihydrochloride of (1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylamine

A mixture of tert-butyl (1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylcarbamate (2,71 g, 5.7 mmol), 4 n solution of hydrogen chloride in ethyl acetate (10 ml) and methanol (30 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was led from ethyl acetate to obtain specified in the connection header (to 2.29 g, 90%) as colorless powder.

LC/MS (ESI) m/z: 375 (MH+).

In the same manner as in Reference Example 23, using the connection, sintezirovannye in Reference Example 22, and the compounds of Table 3 were synthesized compounds Table 4 and Table 5.

Table 4
No.R
1phenyl
23-thienyl
31-pivaloyloxymethyl-2-yl
41-propyl
5Cyclopropyl
6Methoxymethyl
71,3-oxazol-4-yl
82-methyl-3-furyl
91,3-thiazol-5-yl
10ethoxymethyl
111-Cbz-pyrrol-2-yl
12tetrahydro-2H-Piran-4-yl

No.
Table 5
R
1phenyl
23-thienyl
31-pivaloyloxymethyl-2-yl
41-propyl
5Cyclopropyl
6Methoxymethyl
71,3-oxazol-4-yl
82-methyl-3-furyl
91,3-thiazol-5-yl
10Ethoxymethyl
111-Cbz-pyrrol-2-yl
12tetrahydro-2H-Piran-4-yl

Reference Example 24

tert-Butyl (3aR4S,9bR)-3a-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (indofarma)

To a mixture of benzaldehyde (425 mg, 4.0 mmol), aniline (372 mg, 4.0 mmol) and acetonitrile (8 ml) was added N-Boc-3-methyldihydro (732 mg, 4.0 mmol) and Dy(OTf)3(122 mg, 0,19 mmol) while cooling the ice and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (4:1, vol/about.) obtaining specified in the title compound (780 mg, 53%) as an amorphous substance.

1H-NMR (CDCl3) δ: 0,88 (3H, s), 1,24-of 1.36 (1H, m), 1,49-1,59 (N, m), 2,39-of 2.56 (1H, m), 3,24-to 3.58 (2H, m), 3.95 to as 4.02 (1H, m), or 4.31 is 4.35 (1H, m), to 4.87 (1H, d, J=54,0 Hz), 6,53 (1H, d, J=8,3 Hz), 6,76 (1H, t, J=7,7 Hz), 7,02-7,11 (1H, m), 7,30-7,40 (4N/ m), 7,40-of 7.48 (1H, m), of 7.48-7,79 (1H, m).

LC/MS (ESI) m/z: 365 (MN+).

Reference Example 25

tert-Butyl (3aR*,4R*,9bR*)-3A-methyl-4-(3-thienyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (indofarma)

Specified in the title compound was synthesized in the same manner as in Reference Example 24 using 3-thiophenecarbaldehyde.

1H-NMR (CDCl3)δ: 0,92 (3H, s), 1,23-to 1.38 (1H, m)of 1.53 (9H, d, J=18.3 Hz), 2,36 of $ 2.53 (1H, m), 3,23-3,59 (2H, m), 3,94-of 4.05 (1H, m), 4,47 (1H, d, J=4.4 Hz), 4,76-is 4.93 (1H, m), of 6.52 (1H, d, J=7.8 Hz), 6,76 (1H, t, J=7,6 Hz), 7,02-to 7.09 (1H, m), 7,11-7,19 (1H, m), 7,21-7,40 (2H, m), 7,60 (1H, DD, J=72,5, 7,3 Hz).

LC/MS (ESI) m/z: 371 (MH+).

Reference Example 26

The dihydrochloride (3aS4S,9bR)-3a-methyl-4-phenyl-2,3,3a,45,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

The compound (730 mg, 2.0 mmol)synthesized in Reference Example 24 was dissolved in ethyl acetate (10 ml)was added a 4 n solution of hydrogen chloride in ethyl acetate (10 ml) and the mixture was stirred for 12 hours. The obtained crystals were collected by filtration, washed with ethyl acetate and dried under reduced pressure to obtain specified in the title compound (685 mg, approx. 100%) as crystals.

LC/MS (ESI) m/z: 265 (MH+).

Reference Example 27

(3aS,4R,9bR)-3a-Methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

The compound (900 mg, 2,43 mmol)synthesized in Reference Example 25, suspended in triperoxonane acid (5 ml) and the suspension was stirred for 30 minutes. The reaction mixture was neutralized using a saturated aqueous solution of sodium bicarbonate and was extracted with chloroform. The extract was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure to obtain specified in the title compound (800 mg, approx. 100%) as crystals.

LC/MS (ESI) m/z: 271(M+H+).

Reference Example 28

Benzyl (2-oxoethyl)carbamate

Solution (30 ml) oxalicacid (1,72 ml, 20.0 mmol) in dichloromethane was added dropwise to a solution (10 ml) dimethylsulfate is Yes (2,84 ml, 40.0 mmol) in dichloromethane at -78°C and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture were added a solution (45 ml) of benzyl(2-hydroxyethyl)carbamate (1,95 g, 10.0 mmol) in dichloromethane and the mixture was again stirred for 15 minutes. Was added triethylamine (6,93 ml, 50.0 mmol) and the mixture was stirred for 5 minutes. The temperature was raised to room temperature and the reaction mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (7:3-3:2, vol/about.) obtaining specified in the title compound (930 mg, 48%) as a colourless oil.

1H-NMR (CDCl3)δ: 4,14 (2H, d, J=5,1 Hz)to 5.13 (2H, s), vs. 5.47(1H, usher.), 7,31-7,37(5H, m), for 9.64 (1H, s).

Reference Example 29

1,3-Oxazol-4-ylmethanol

To a suspension of sociallyengaged (2,69 g, to 70.9 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of ethyl 1,3 oxazol-4-carboxylate (5,00 g of 35.4 mmol) in tetrahydrofuran (50 ml) at -78°C. the Reaction mixture was stirred at the same temperature for 2 hours and the temperature was gradually raised to 0°C. After stirring for 1 hour was added water (2.7 ml), then was added 15% aqueous sodium hydroxide solution (2.7 ml) and then water (8.1 ml) and the mixture was stirred. The reaction mixture was dried over anhydrous MgSO4, the precipitate was filtered through celite and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and was suirable with ethyl acetate to obtain specified in the title compound (930 mg, 27%) as a colourless oil.

1H-NMR (CDCl3)δ: with 3.27 (1H, user. C), with 4.64 (2H, s), to 7.64 (1H, s), of 7.90 (1H, s).

Reference Example 30

1,3-Oxazol-4-carbaldehyde

To a solution of 1,3-oxazol-4-ylmethanol (1.88 g, 19 mmol) in chloroform (200 ml) was added manganese dioxide (33,0 g, 379 mmol) and the mixture was stirred over night at room temperature. Insoluble substances were filtered off and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,00 g, 54%) as a colourless oil.

1H-NMR (CDCl3) δ: 7,99 (1H, s), 8,32 (1H, s), and 10.0 (1H, s).

Reference Example 31

(2-Methyl-3-furyl)methanol

To a suspension of sociallyengaged (of 5.17 g, 136 mmol) in tetrahydrofuran (300 ml) was added dropwise a solution of ethyl 2 methyl-3-furoate (10.0 g, 64,9 mmol) in tetrahydrofuran (10 ml) at -78°C. the Reaction mixture was stirred under decree is Noah temperature for 4 hours, the temperature is gradually raised to 0°C and the mixture was again stirred for 1 hour. Added water and 15% aqueous sodium hydroxide solution and the mixture was added anhydrous MgSO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (8:2, vol/about.) obtaining specified in the header of the compound (7.98 g, approx. 100%) as a colourless oil.

1H-NMR (CDCl3)δ: to 2.29 (3H, s), 4,47 (2H, d, J=5.4 Hz), 6,36 (1H, d, J=1.5 Hz), 7,26 (1H, d, J=1.5 Hz).

Reference Example 32

2-Methyl-3-furaldehyde

To a solution of (2-methyl-3-furyl)methanol (2.00 g, 17.8 mmol) in chloroform (200 ml) was added manganese dioxide (33,0 g, 379 mmol) and the mixture was stirred at room temperature for 16 hours and then at 60°C for 3 hours. Insoluble substances were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (95:5 to 90:10, vol/about.) obtaining specified in the title compound (235 mg, 12%) as a colourless oil.

1H-NMR (CDCl3)δ: 2,59 (3H, s), of 6.68 (1H, s), 7,29 (1H, s), to 9.93 (1H, s).

Reference Example 33

(4-Formyl-1H-imidazol-1-yl)Metreveli

To a suspension of hydride soda is I (60% in oil, 1.0 g, 26 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 1H-imidazole-4-carbaldehyde (1.92 g, 20 mmol) in DMF (5 ml) at 0°C and the mixture was stirred at room temperature for 1 hour. Then added dropwise at 0°C chlorocyphidae (to 3.92 g, 26 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, was added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) and was suirable a mixture of hexane-ethyl acetate (4:1-1:2, vol/about.) obtaining specified in the header of the compound (4.11 g, 98%) as a pale yellow oil.

1H-NMR (CDCl3)δ: 1,18 (9H, s), 5,90 (2H, s), to 7.77-7,79 (2H, m), for 9.90 (1H, s).

Reference Example 34

Methyl 4-(aminocarbonyl)-3-methylbenzoate

A mixture of 4-bromo-2-methylbenzamide (1,65 g of 7.75 mmol), triethylamine (2,17 ml of 15.5 mmol), palladium acetate (0,0873 g, 0,388 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0,215 g, 0,388 mmol), methanol (5 ml) and DMF (15 ml) was stirred in an atmosphere of carbon monoxide at 70°C for 22 hours. After cooling to room temperature the reaction specieslevel with ethyl acetate, washed with water and saturated saline and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained crystals are recrystallized from ethyl acetate to obtain specified in the connection header (of 1.05 g, 70%) as a pale brown needle-shaped particles.

1H-NMR (CDCl3)δ: 2,53 (3H, s), 3,39 (3H, s), 5,73-5,96 (2H, m)to 7.50 (1H, d, J=7.5 Hz), the 7.85-7,94 (2H, m).

Reference Example 35

4-(Aminocarbonyl)-3-methylbenzoic acid

To a solution of compound (0,759 g, 3,39 mmol)synthesized in Reference Example 34, in methanol (20 ml) was added dropwise 1 N. aqueous sodium hydroxide solution (7.9 ml, 7.9 mmol) and the mixture was stirred at 60°C for 2.5 hours. After cooling to room temperature the reaction mixture was concentrated to about half volume under reduced pressure. Added water and the mixture is washed with diethyl ether. The organic layer was extracted with water and the combined aqueous layers were added dropwise at 0°C 6 n hydrochloric acid (1.5 ml). The precipitated colorless powder was collected by filtration and washed with water to obtain specified in the connection header (0,643 g, 91%).

1H-NMR (DMSO-d6)δ: 2,40 (3H, s), 7,44 (1H, d, J=7.8 Hz), 7,52 (1H, user. C)7,75-7,89 (3H, m).

Reference Example 36

Ethyl (2E)-3-(1-trityl-1H-imidazol-2-yl)acrylic Jerusalem.

To a suspension of sodium hydride (60% in oil, 0,811 g, 20.3 mmol) in tetrahydrofuran (60 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (4,33 ml, and 21.8 mmol) and the mixture was stirred for 30 minutes. Was added dropwise a solution of 2-formyl-1-tritylimidazole (5,28 g, 15.6 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 8 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (9:1-1:1, vol/vol.). Specified in the title compound(3.28 g, 52%) was obtained as colorless powder from the target faction.

1H-NMR (CDCl3)δ: of 1.13 (3H, t, J=7.2 Hz), 4,00 (2H, d, J=7,2 Hz), 6,51 (1H, d, J=15.3 Hz), of 6.68 (1H, d, J=15.3 Hz), 6,86 (1H, d, J=1.2 Hz), 7,08-7,16 (7H, m), 7,28-to 7.35 (9H, m).

Reference Example 37

(2E)-3-(1-Trityl-1H-imidazol-2-yl)acrylic acid

In the same manner as in Reference Example 35 using the compound obtained in Reference Example 36 was synthesized specified in the header of the connection.

1H-NMR (DMSO-d6)δ: 6,28 (1H, d, J=15,0 Hz), 6,55 (1H, d, J=15,0 Hz), PC 6.82 (1H, d, J=1.2 Hz), 7,00-was 7.08 (6H, m), 7,10 (1H, d, J=1.2 Hz), 7,33 was 7.45 (9H, m), 12,1 (1H, user. C).

Silo the hydrated Example 38

(2E)-3-(1-Methyl-1H-imidazol-2-yl)acrylic acid

In the same manner as in Reference Example 36 and Reference Example 35, using 2-formyl-1-Mei instead of 2-formyl-1-tritylimidazole Reference Example 36 was synthesized specified in the header of the connection.

1H-NMR (DMSO-d6)δ: 3,76 (3H, s), 6,53 (1H, d, J=15,5 Hz), 7,05 (1H, s), 7,33 (1H, s), 7,46 (1H, d, J=15.3 Hz).

Reference Example 39

Benzyl (3aR,4R,9bR)-5-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

Sodium hydride (60% in oil, 120 mg, 3.0 mmol) suspended in DMF (12 ml), was added benzyl (3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (960 mg, 2.5 mmol) and the mixture was stirred at room temperature for 10 minutes. To the mixture was added methyliodide (426 mg, 3.0 mmol) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous Na2SO4) and the solvent evaporated. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (5:1, vol/about.) obtaining specified in the title compound (330 mg, 33%) and Ortega substances.

1H-NMR (CDCl3)δ: 1,51 is 1.58 (1H, m), 1,87-of 2.16 (1H, m), 2,39-2,62 (1H, m), is 2.74 (3H, d, J=2.0 Hz), 3.25 to of 3.48 (2H, m), 4,49 (1H, DD, J=6,2, 3.8 Hz), 5,15-5,43 (3H, m), 6,64-6,85 (2H, m), 7,11-of 7.23 (1H, m), 7.24 to to 7.59 (11H, m).

LC/MS (ESI) m/z: 399 (MH+).

Reference Example 40

(3aR,4R,9bR)-5-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

The compound (300 mg, 0.75 mmol)synthesized in Reference Example 39 was dissolved in ethanol (10 ml) and the hydrogenation reaction was carried out in the presence of 10% palladium on carbon (50% aqueous solution, 0.15 g) at room temperature for 2 hours. The catalyst was filtered and washed with ethanol. The filtrate and washing liquid were combined and concentrated under reduced pressure to obtain specified in the title compound as an oil (150 mg, 65%). This product is not subjected to further purification and was used for the next reaction.

1H-NMR (CDCl3)δ: 1,59-of 1.73 (2H, m), 1,87-2,02 (1H, m), 2,40-of 2.56 (1H, m), 2,59-2,69 (1H, m), 2,70-of 2.86 (4H, m), 4,24-4,32 (1H, m)to 4.41 (1H, d, J=4.6 Hz), 6,76-6,83 (2H, m), 7,16-7,39 (7H, m).

LC/MS (ESI) m/z: 265 (MH+).

Reference Example 41

Ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]benzoate

To a solution of {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (2.00 g, 11.5 mmol) in dichloromethane (50 ml) was added ethyl 4-aminobenzoate (1.90 g, 11.5 mmol) and the mixture paramashiva and at room temperature for 1 hour. Added triacetoxyborohydride sodium (3,41 g, 16,1 mmol) and the mixture was stirred over night. To the reaction mixture was added under ice cooling a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the connection header (3,52 g, 95%) as a colourless oil.

1H-NMR (CDCl3)δ: 0,00 (6H, s), or 0.83 (9H, s)of 1.29 (3H, t, J=6.9 Hz), 3,21 (2H, t, J=5,1 Hz in), 3.75 (2H, t, J=5,1 Hz), 4,24 (2H, q, J=6.9 Hz), 6,50 (2H, d, J=8.1 Hz), 7,80 (2H, d, J=8,1 Hz).

Reference Example 42

Ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}-ethyl)(methyl)amino]benzoate

To a solution of ethyl 4-[(2-{[tert-butyl(dimethyl)-silyl]oxy}ethyl)amino]benzoate (2,52 g, 7,79 mmol) in dichloromethane (32 ml) was added 37% aqueous formaldehyde solution (2,08 ml of 25.7 mmol) and triacetoxyborohydride sodium (6,93 g, to 32.7 mmol) and the mixture was heated at the boiling point under reflux overnight. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was subjected to column address chronic is ecografia on silica gel and was suirable a mixture of hexane-ethyl acetate (1:0-7:3, about./about.) obtaining specified in the connection header (2,33 g, 89%) as a colourless oil.

1H-NMR (CDCl3)δ: 0,00 (6H, s)of 0.87 (9H, s)of 1.36 (3H, t, J=7,1 Hz), 3,05 (3H, s), 3,53 (2H, t, J=5,9 Hz), of 3.78 (2H, t, J=5,9 Hz), or 4.31 (2H, q, J=7,1 Hz), only 6.64 (2H, d, J=7,2 Hz), 7,88 (2H, d, J=7,2 Hz).

Reference Example 43

Ethyl 4-[(2-hydroxyethyl)(methyl)amino]benzoate

To a solution (30 ml) of ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)(methyl)amino]benzoate (2,33 g of 6.90 mmol) in tetrahydrofuran was added tetrabutylammonium fluoride (a 1.0 M solution in toluene, 10.4 ml, 10.4 mmol) at room temperature and the mixture was stirred over night. After concentrating the reaction mixture under reduced pressure, the residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (3:2-1:4, vol/about.) obtaining specified in the connection header (1,11 g, 72%) as a colourless oil.

1H-NMR (CDCl3)δ: of 1.36 (3H, t, J=7,1 Hz), of 3.07 (3H, s), of 3.57 (2H, t, J=5.4 Hz), a-3.84 (2H, t, J=5.4 Hz), or 4.31 (2H, q, J=7,1 Hz), 6,70 (2H, d, J=8.0 Hz), 7,89 (2H, d, J=8.0 Hz).

Reference Example 44

4-[(2-Hydroxyethyl)(methyl)amino]benzoic acid

To a solution (10 ml) of ethyl 4-[(2-hydroxyethyl)(methyl)amino]benzoate (500 mg, 2,24 mmol) in methanol was added 1M aqueous sodium hydroxide solution (10 ml) and the mixture was stirred at room temperature for 3 hours. To actionnow mixture was added water and the mixture is washed with diethyl ether. Solution was added 1M hydrochloric acid (10 ml) and the mixture was extracted with dichloromethane and concentrated under reduced pressure to obtain specified in the title compound (119 mg, 27%) as a white solid.

1H-NMR (CDCl3)δ: of 3.07 (3H, s), of 3.56 (2H, t, J=6.0 Hz), of 3.78 (2H, t, J=6.0 Hz), 3,84 (1H, s)6,70 (2H, d, J=8,9 Hz), of 7.90 (2H, d, J=8,9 Hz).

Reference Example 45

Methyl 4-(4-methyl-1H-imidazol-1-yl)benzoate

A mixture of methyl 4-perbenzoate (1,00 g of 6.49 mmol), 4-methylimidazole (559 mg, for 6.81 mmol), potassium carbonate (941 mg, for 6.81 mmol) and DMF (30 ml) was stirred at 110°C for 24 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was subjected to column chromatography using basic silica gel, and was suirable a mixture of ethyl acetate-methanol (1:0-1:1, vol/about.) obtaining specified in the title compound (137 mg, 10%) as a colourless oil.

1H-NMR (CDCl3)δ: 2,31 (3H, s), of 3.95 (3H, s), 7,07 (1H, s), 7,41-7,44 (2H, m), a 7.85 (1H, s), 8,11-8,19 (2H, m).

Reference Example 46

4-(4-Methyl-1H-imidazol-1-yl)benzoic acid

To a solution (5 ml) of methyl 4-(4-methyl-1H-imidazol-1-yl)benzoate (137 mg, 0,635 mmol) in methanol was added 1M sodium hydroxide solution (5 ml) and the mixture was stirred PR the room temperature for 3 hours. To the reaction mixture solution was added 1M hydrochloric acid (5 ml) and the solvent evaporated under reduced pressure. The residue was used for next reaction without purification.

1H-NMR (CDCl3)δ: 2,50 (3H, s), to 7.68 (1H, s), to 7.77 (2H, d, J=8,3 Hz), by 8.22 (2H, d, J=8,3 Hz), made up 9.77 (1H, s).

Reference Example 47

Ethyl 4-[(2-methoxyethyl)(methyl)amino]benzoate

To a solution of ethyl 4-[(2-hydroxyethyl)(methyl)-amino]benzoate (611 mg, is 2.74 mmol) in DMF (10 ml) was added sodium hydride (60% in oil, 143 mg of 3.56 mmol) and methyliodide (0,222 ml of 3.56 mmol) and the mixture was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:0-7:3, vol/about.) obtaining specified in the header of the compound (467 mg, 72%) as a colourless oil.

1H-NMR (CDCl3)δ: of 1.36 (3H, t, J=7.2 Hz), 3,06 (3H, s)to 3.35 (3H, s), 3,56-to 3.58 (4H, m), or 4.31 (2H, q, J=7.2 Hz), of 6.66 (2H, d, J=7,2 Hz), of 7.90 (2H, d, J=7,2 Hz).

Reference Example 48

4-[(2-Methoxyethyl)(methyl)amino]benzoic acid

To a solution (10 ml) of ethyl 4-[(2-methoxyethyl)(methyl)amino]benzoate (467 mg, 1.97 mmol) in methanol was added 1M aqueous solution g is droxia sodium (10 ml) and the mixture was stirred at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added water and diethyl ether. The organic layer was separated. The aqueous layer was neutralized using 1M hydrochloric acid (10 ml) and was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and concentrated under reduced pressure to obtain specified in the title compound (340 mg, 82%) as a white solid.

Reference Example 49

Methyl 4-(methyl bromide)-3-methoxybenzoate

A mixture of methyl 3-methoxy-4-methylbenzoate (10.0 g, of 55.5 mmol), N-bromosuccinimide (10.7 g, 60,9 mmol), 2,2'-azobis(isobutyronitrile)(1.6 mg) and ethyl acetate (200 ml) was heated at the boiling point under reflux overnight. The solvent is evaporated under reduced pressure and to the residue was added hexane. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (9:1 to 7:3, vol/about.) obtaining specified in the title compound (12.8 g, 92%) as a colourless oil.

1H-NMR (CDCl3)δ: to 3.92 (3H, s), of 3.95 (3H, s)4,55 (2H, s), 7,38 (1H, d, J=8.1 Hz), 7,53 (1H, d, J=1.5 Hz), 7,60 (1H, DD, J=1.5 and 8.1 Hz).

Reference Example 50

Methyl 4-formyl-3-methoxybenzoate

To a solution of methyl 4-(Bromma who yl)-3-methoxybenzoate (3.00 g, 11.6 mmol) in dimethyl sulfoxide (16 ml) was added sodium bicarbonate (1,00 g of 13.6 mmol) and the mixture was stirred at 50°C for 3 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:0-7:3, vol/about.) obtaining specified in the title compound (870 mg, 39%) as a colourless oil.

1H-NMR (CDCl3)δ: of 3.96 (3H, s)to 3.99 (3H, s), to 7.67 (1H, s), to 7.68 (1H, d, J=8,9 Hz), 7,88 (1H, d, J=8,9 Hz), 10,51 (1H, s).

Reference Example 51

Methyl 4-cyano-3-methoxybenzoate

To a solution (20 ml) of methyl 4-formyl-3-methoxybenzoate (870 mg, 4,48 mmol) in formic acid was added hydroxylamine hydrochloride (405 mg, of 5.82 mmol) and the mixture was stirred at room temperature for 1 hour. The temperature was raised to 50°C and the mixture was again stirred for 24 hours. To the reaction mixture was added water, the mixture is neutralized using a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:0-7:3, about the./about.) obtaining specified in the title compound (780 mg, 91%) as a colourless oil.

1H-NMR (CDCl3)δ: of 3.96 (3H, s)to 3.99 (3H, s), 7,62-of 7.69 (3H, m).

Reference Example 52

4-Cyano-3-methoxybenzoic acid

To the solution (37 ml) of methyl 4-cyano-3-methoxybenzoate (700 mg, 3,66 mmol) in methanol was added 1M aqueous sodium hydroxide solution (37 ml) and the mixture was stirred over night at room temperature. The solvent is evaporated under reduced pressure, the residue was dissolved in water and the mixture is washed with diethyl ether. The aqueous layer was neutralized using 1M hydrochloric acid and was extracted with dichloromethane. The extract was dried over anhydrous MgSO4and concentrated under reduced pressure to obtain specified in the title compound (690 mg, approx. 100%) as a white solid.

Reference Example 53

Methyl 6-morpholine-4-incomenet

A mixture of methyl 6-chloronicotinate (1,02 g, to 5.93 mmol), research (or 0.57 ml, of 6.52 mmol), potassium carbonate (1.06 g, 7,71 mmol) and DMF (20 ml) was stirred at 100°C for 6 hours. The reaction mixture was cooled to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and concentrated under reduced pressure. The obtained solid substance was collected, filtrowanie the m and washed with diisopropyl ether to obtain specified in the connection header (0,93 g, 71%) as colorless powder.

1H-NMR (CDCl3)δ: 3,64-3,70 (4H, m), 3,78-of 3.85 (4H, m), 3,88 (3H, s), to 6.57 (1H, DD, J=9,0, 0.6 Hz), with 8.05 (1H, DD, J=9,0, 2.4 Hz), 8,81 (1H, DD, J=2,4, 0.6 Hz).

Reference Example 54

Methyl 6-(1H-pyrazole-1-yl)nicotinate

To a suspension of pyrrole (0,356 g, 5,23 mmol) in DMF (20 ml) was added sodium hydride (60% in oil, 0,233 g of 5.81 mmol). After stirring for 5 hours was added methyl 6-chloronicotinate (1,00 g of 5.81 mmol) and the mixture was again stirred for 27 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solids were collected by filtration and washed with hexane to obtain specified in the connection header (0,683 g, 64%) as a colorless powder.

1H-NMR (CDCl3)δ: of 3.97 (3H, s), 6,51 (1H, DD, J=4.2, and the 2.4 Hz), 7,75-7,81 (1H, m), with 8.05 (1H, DD, J=12,6, 0.9 Hz), 8,40 (1H, DD, J=12,6, and 3.3 Hz), to 8.62 (1H, DD, J=4.2, and 1.2 Hz), 9,03 (1H, DD, J=3.3, which is 0.9 Hz).

Reference Example 55

Methyl 6-(2-methyl-1H-imidazol-1-yl)nicotinate

In the same manner as in Reference Example 54 using 2-Mei, synthesized specified in the header of the connection.

1H-NMR (CDCl3)δ: to 2.67 (3H, s)to 3.99 (3H, s), 7,05 (1H, d, J=1.5 Hz), 7,35-the 7.43 (2H, m), 8,40-of 8.47 (1H, m), 9,14-9,17 (1H, m).

the following compounds of Reference Example 56 - Reference Example 58 hydrolyzed at room temperature in the same manner as in Reference Example 35.

Reference Example 56

6-Morpholine-4-indicatinga acid

1H-NMR (DMSO-d6)δ: 3,56-3,62 (4H, m), 3,65-3,71 (4H, m)6,86 (1H, d, J=9.0 Hz), 7,95 (1H, DD, J=9,0, 2.4 Hz), 8,64 (1H, d, J=2,4 Hz).

Reference Example 57

6-(1H-Pyrazole-1-yl)nicotinic acid

1H-NMR (DMSO-d6)δ: of 6.65 (1H, DD, J=2.7, and 1.5 Hz), 7,92 (1H, DD, J=1.5 and 0.6 Hz), of 8.04 (1H, DD, J=8,7, and 0.9 Hz), 8,44 (1H, DD, J=8,7, and 2.1 Hz), to 8.70 (1H, DD, J=2.7, and 0.6 Hz), 8,96 (1H, DD, J=2.1 a, and 0.9 Hz).

Reference Example 58

6-(2-Methyl-1H-imidazol-1-yl)nicotinic acid

1H-NMR (CD3OD)δ: 2,05 (3H, s), of 6.52 (1H, d, J=2.7 Hz), 7,01-7,05 (2H, m), 7,89 (1H, DD, J=9,6, and 3.3 Hz), 8,48 (1H, DD, J=3.3V, 1.2 Hz).

Reference Example 59

Ethyl 1-[(benzoylamine)methyl]cyclohexanecarboxylate

A solution of ethyl 1-cyanocyclohexane (10.0 g, with 55.1 mmol) in ethanol (200 ml) was stirred at 40°C for 12 hours in the presence of Raney Nickel (10 g) in hydrogen atmosphere (4 ATM). The catalyst was filtered and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate (300 ml) and 10% aqueous sodium carbonate solution (150 ml)was added dropwise at 0°C. benzoyl chloride (6,34 ml, 55,1 ml) and the mixture was stirred at room t is mperature within 6 hours. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous MgSO4. After concentration under reduced pressure the residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (3:1-1:1, vol/about.) obtaining specified in the title compound (10.2 g, 63%) as a colourless oil.

1H-NMR (CDCl3)δ: of 1.29 (3H, t, J=7.0 Hz), 1,40-1,70 (8H, m), 2,04 (2H, t, J=8.0 Hz), 3,61 (2H, d, J=6.0 Hz), is 4.21 (2H, q, J=7.4 Hz), 6,60 (1H, user. C), 7,26-7,53 (3H, m), 7,73 for 7.78 (2H, m).

Reference Example 60

1-[(Benzoylamine)methyl]cyclohexanecarbonyl acid

To a solution of ethyl 1-[(benzoylamine)methyl]-cyclohexanecarboxylate (10.2 g, and 35.1 mmol) in ethanol (50 ml) was added 50% aqueous potassium hydroxide solution (4 ml) and the mixture was heated at the boiling point under reflux for 6 hours. Was added water (400 ml) and the reaction mixture is washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5 n hydrochloric acid, the precipitate was collected by filtration, washed with water and dried at 50°C under reduced pressure. Recrystallization from ethanol-toluene gave specified in the header connection (6,83 g, 74%) as colorless crystals.

1H-NMR (CDCl3)δ: 1,05-to 1.63 (8H, m), 1.85 to 2,03 (2H, usher.), to 3.38 (2H, d, J=6.2 Hz), 7,39-7,58 (MN, m), 7,75-,88 (2H, m), 8,30 (1H, user. C), 12,21 (1H, s).

Reference Example 61

Ethyl-(1-hydroxycyclohexyl)acetate

To a solution of cyclohexanone (9,52 g, 97,0 mmol), zinc powder (7.6 g, 116,4 mmol) and small amount of iodine in THF (100 ml) was added dropwise ethylbromoacetate (11.8 ml, 106,7 mmol) under nitrogen atmosphere and the mixture was heated at the boiling point under reflux for 5 hours. Was carefully added under ice cooling a 10% solution of sulfuric acid (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4and concentrated under reduced pressure to obtain specified in the connection header (17,2 g, 94%) as a colourless oil.

1H-NMR (CDCl3) δ: of 1.27 (3H, t, J=7.0 Hz), 1,35-1,71 (10H, m), 2,46 (2H, s), 3,43 (1H, s), 4,17 (2H, kb, J=7,4 Hz).

Reference Example 62

[1-(Benzoylamine)cyclohexyl]acetic acid

To a mixture of ethyl (1-hydroxycyclohexyl)acetate (17.1 g, to 92.1 mmol) and benzonitrile in 9.5 ml of 92.1 mmol) was added concentrated sulfuric acid (50 ml) at 0°C and the mixture was stirred at room temperature for 12 hours. To the reaction mixture were added water (200 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and the eating saturated saline and dried over anhydrous MgSO 4. After concentration under reduced pressure, ethanol (50 ml) and to the residue was added 50% aqueous potassium hydroxide solution (10 ml) and the mixture was heated at the boiling point under reflux for 6 hours. To the reaction mixture were added water (400 ml) and the mixture washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5 n hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous Na2SO4and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol-toluene obtaining specified in the connection header (18,1 g, 75%) as colorless crystals.

1H-NMR (CDCl3)δ: 1,14-of 1.62 (8H, m), 2,25 is 2.43 (2H, m), is 2.74 (2H, s), 3,32 (1H, s), of 7.36-EUR 7.57 (3H, m), 7,73-7,80 (2H, m), 11,93 (1H, s).

LC/MS (ESI) m/z: 262 (MH+).

Reference Example 63

Ethyl (4-hydroxycitrate-2H-Piran-4-yl)acetate

To a solution of tetrahydro-4H-Piran-4-one (5.5 g, 51.6 mmol), zinc powder (of 4.05 g of 61.9 mmol) and small amount of iodine in tetrahydrofuran (60 ml) was added dropwise ethylbromoacetate (6,28 ml of 56.7 mmol) under nitrogen atmosphere. After heating at the boiling point under reflux for 6 hours was carefully added 10% solution of sulfuric acid (50 ml) under cooling with ice and MES were extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4and concentrated under reduced pressure to obtain specified in the connection header (of 6.73 g, 69%) as a colourless oil.

1H-NMR (CDCl3)δ: of 1.29 (3H, t, J=7.0 Hz), 1,62 by 1.68 (4H, m), 2,48 (2H, s), 3,67-4,00 (5H, m), 4,19 (2H, q, J=6,8 Hz).

Reference Example 64

[4-(Benzoylamine)tetrahydro-2H-Piran-4-yl]acetic acid

To a mixture of ethyl (4-hydroxycitrate-2H-Piran-4-yl)acetate (6.73 x g, 35.8 mmol) and benzonitrile (of 4.05 ml, or 39.3 mmol) was added concentrated sulfuric acid (25 ml) under cooling with ice. After stirring at room temperature for 16 hours the reaction mixture was added to water (100 ml) under ice cooling and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, then with saturated saline and dried over anhydrous MgSO4. After concentration under reduced pressure, to the obtained residue were added ethanol (50 ml) and 50% aqueous potassium hydroxide solution (10 ml) and the mixture was heated at the boiling point under reflux for 6 hours. To the reaction mixture were added water (200 ml) and the mixture washed with diethyl ether. The aqueous layer was acidified (pH 2) with 5 n hydrochloric acid solution, the extras who were garofali a mixture of ethyl acetate-tetrahydrofuran (2:1, about./vol.). The extract was washed with saturated saline, dried over anhydrous Na2SO4and concentrated under reduced pressure. The obtained solid substance was collected by filtration and washed with diisopropyl ether to obtain specified in the title compound (1.64 g, 17%) as colorless crystals.

1H-NMR (DMSO-d6)δ: 1,59-of 1.75 (2H, m), 2,23-to 2.42 (2H, m), 2,80 (2H, s), 3,50-to 3.67 (4H, m), 7,38-rate of 7.54 (3H, m), 7,76-7,87 (3H, m).

LC/MS (ESI) m/z: 264 (MH+).

Reference Example 65

(1S,2S)-2-(Benzoylamine)cyclohexanecarbonyl acid

A mixture of (1R,2S)-2-(benzoylamine)cyclohexanecarboxylic acid (2,47 g, 10 mmol), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (2.30 g, 12 mmol), acetonitrile (25 ml) and tetrahydrofuran (25 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, was added methanol (25 ml) and the mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure, was added diluted hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, then saturated saline solution and dried (over anhydrous MgSO4). The solvent is evaporated under reduced pressure. To the residue was added a 28% solution of methoxide n the sodium in methanol (1,93 g, 10 mmol) and methanol (30 ml) and the mixture was heated at the boiling point under reflux for 5 hours. Was added under ice cooling 1 N. hydrochloric acid solution (11 ml) and the methanol evaporated under reduced pressure. To the obtained residue was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The obtained solid substance was collected by filtration and washed with diisopropyl ether to obtain methyl (1S,2S)-2-(benzoylamine)cyclohexanecarboxylate (1,33 g, 51%) as a colorless powder.

1H-NMR (CDCl3)δ: 1,15-of 1.85 (6H, m), 1,94-2,05 (1H, m), 2,15-of 2.27 (1H, m), 2,42 (1H, dt, J=3,4, 11.3 Hz), the 3.65 (3H, s), 4,10-4,24 (1H, m), the 6.06 (1H, d, J=8.1 Hz), 7,38-7,52 (3H, m), 7,69 to 7.75 (2H, m).

To a solution of compound (1.23 g, 4,69 mmol), obtained as above, was added methanol (30 ml) and 1 N. aqueous sodium hydroxide solution (10 ml) and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure and added with ice cooling 1 N. hydrochloric acid solution (11 ml). Precipitated solids were collected by filtration, washed with water and dried under reduced pressure to obtain specified in the connection header (1,14 g, 98%) as a colourless powder is A.

1H-NMR (CDCl3)δ: 1,16-1,90 (6H, m), 1,97-of 2.08 (1H, m), 2.13 and amounts to 2.24 (1H, m), of 2.38 (1H, dt, J=11,3, 3.5 Hz), 4,18 (1H, dt, J=11,0, 4,1 Hz), 7,38-7,52 (3H, m), 7,71-to 7.77 (2H, m).

Reference Example 66

tert-Butyl (4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-carboxylate

and

tert-butyl (4aS,5R,10bS)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-carboxylate

Benzaldehyde (531 mg, 5 mmol) was dissolved in acetonitrile (15 ml)was added aniline (466 mg, 5 mmol) at 0°C and the mixture was stirred at the same temperature for 1 hour. Added tert-butyl 3,4-dihydropyridines-1(2H)-carboxylate (917 mg, 5 mmol) and Dy(OTf)3(153 mg, 0.25 mmol) at 0°C and the mixture was again stirred for 1.5 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) and was suirable a mixture of hexane-ethyl acetate (19:1 to 6:1, about./vol.). Specified in the header connection (4aR,5R,10bR) (109 mg, 6%) was obtained as a colorless amorphous substance from the fraction, eluruumi first.

1 H-NMR (CDCl3)δ: 1,20-1,70 (13H, m), 1,98-2,12 (1H, m), 2,45-2,60 (1H, m), 3,80-4,12 (2H, m), 4,80 (1H, user. C)5,63-to 5.85 (1H, m), 6,57-6,63 (1H, m), of 6.73 (1H, t, J=7,6 Hz), 6,93-to 7.18 (2H, m), 7,27-of 7.48 (5H, m).

LC/MS (ESI) m/z: 365 (MH+).

Specified in the header connection (4aS,5R,10bS) (1.26 g, 69%) was obtained as a colorless amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 365 (MH+).

Reference Example 67

tert-Butyl ((1R,2S)-2-{[(4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-yl]carbonyl}cyclohexyl)carbamate

TFA (1 ml) was added to tert-butyl (4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-carboxylate (195 mg, 0.54 mmol) and the mixture was stirred at room temperature for 3 minutes. To the reaction mixture was added ice water, podslushivaet 8 N. aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4), and the solvent evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml)was added (1S,2R)-2-[(tert-butoxycarbonyl)amino]-cyclohexanecarbonyl acid (131 mg, 0.54 mmol) and triethylamine (109 mg, 1.1 mmol)was added at 0°C DEPC (88 mg, 0.54 mmol) and the mixture was stirred over night at room temperature. The reactions which authorized the mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4), and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (9:1-4:1, vol/about.) obtaining specified in the title compound (69 mg, 26%) as a colorless amorphous substance.

LC/MS (ESI) m/z: 490 (MH+).

Reference Example 68

{1-[(Anilinoacrolein)amino]cyclohexyl}acetic acid

To a solution of (1-aminocyclohexane)acetic acid (0,232 mg, 1.48 mmol) in a mixture of 1,4-dioxane (9 ml) and water (3 ml) was added 30% aqueous solution of sodium hydroxide to achieve a pH=9. Was added dropwise at 35°C phenylisocyanate (of 0.24 ml, 2.22 mmol) was added 30% aqueous sodium hydroxide solution to bring the solution to pH 9. The reaction mixture was stirred at 40°C for 1.5 hours and concentrated under reduced pressure. Added 5 n hydrochloric acid for acidification of the solution (pH 3) and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solids were collected by filtration and washed with diisopropyl ether to obtain the specified in the connection header (0,228 g) as colorless powder with impurities.

1H-NMR (DMSO-d6)δ: 1,12-of 1.30 (2H, m), 1,35-to 1.60 (6H, m), 2,04-2,17 (2H, m), 3,32 (2H, s), 6,80-of 6.90 (1H, m), 7,16-7,24 (2H, m), 7,29-7,40 (2H, m).

Reference Example 69

tert-Butyl (2R)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}piperidine-1-carboxylate (low polarity)

and

tert-butyl (2R)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}piperidine-1-carboxylate (high polarity)

In the same manner as in Reference Example 19 using N-Boc-D-gamopolis instead of (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid, synthesized specified in the header of the connection.

(3aR,4R,9bR)-form:1H-NMR (CDCl3)δ: the 1.44 (9H, s), 1,54-1,89 (7H, m), 2,25-of 2.64 (2H, m), 3,44-of 3.78 (3H, m), 3,84-was 4.02 (2H, m), 4,66-4,82 (2H, m), USD 5.76-by 5.87 (1H, m), to 6.58 (1H, d, J=8,1, 1.2 Hz), 6,69-6,77 (1H, m), 7,02-7,10 (1H, m), 7,27-7,53 (6H, m).

(3aS,4S,9bS)-form:1H-NMR (CDCl3)δ: 1,26-is 1.51 (9H, m), 1,54 is 2.10 (7H, m), 2,18-of 2.38 (1H, m), 2,42-of 2.56 (1H, m), 3,20-of 3.46 (2H, m), 3,49-of 3.60 (1H, m), of 3.77-4.09 to (2H, m), 4,60-4,94 (2H, m), 5,74-to 5.85 (1H, m), to 6.57 (1H, DD, J=8,1, 1.2 Hz), 6,67-6,76 (1H, m), 7,00-to 7.09 (1H, m), 7,28-of 7.60 (6H, m).

Reference Example 70

The dihydrochloride(3aS,4S,9bS)-4-phenyl-1-[(2R)-piperidine-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

In the same manner as in Reference Example 23, using tert-butyl (2R)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]x is the nolin-1-yl]carbonyl}piperidine-1-carboxylate (high polarity), synthesized specified in the header of the connection.

1H-NMR (CD3OD)δ: 1,60-2,00 (9H, m), 2,18 to 2.35 (2H, m), 2,67-and 2.79 (1H, m), 3,02-3,14 (1H, m), 3,34-3,44 (1H, m), 3,47-to 3.73 (2H, m), a 4.03-of 4.12 (1H, m), 5,69 (1H, d, J=7,2 Hz), 6,82-of 6.90 (2H, m), 7,10-to 7.18 (1H, m), 7,31-7,46 (3H, m), 7,50-EUR 7.57 (2H, m), 7,60-to 7.67 (1H, m).

Reference Example 71

tert-Butyl 4-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate

A mixture of tert-butyl (3aR4S,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (20.5 g, 58.6 mmol), manganese dioxide (50,9 g, 586 mmol) and toluene (400 ml) was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered through celite and the residue was washed with ethyl acetate. The filtrate and washing liquid were combined and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using basic silica gel, and was suirable a mixture of hexane-ethyl acetate (10:1-8:1, vol/vol.). Concentrated target fraction was recrystallized mixture sexan-ethyl acetate to obtain specified in the title compound (11.7 g, 58%) as colorless needle crystals.

1H-NMR (CDCl3)δ: 1.57 in (9H, s), and 3.31 (2H, t, J=8.1 Hz), 4,28 (2H, t, J=8.1 Hz), 7,40-rate of 7.54 (4H, m), to 7.61-to 7.68 (1H, m), 7,78-to 7.84 (2H, m), 8,10-8,17 (2H, m).

Reference Example 72

4-Phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline/p>

To a solution of compound (11.7 g, 33.8 mmol)synthesized in Reference Example 71, in methanol (100 ml) was added dropwise 4 n solution of hydrogen chloride in ethyl acetate (100 ml) and the mixture was stirred at 60°C for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting powder was collected by filtration and washed with ethyl acetate to obtain specified in the title compound as hydrochloride (9,14 g, 96%).

The above hydrochloride was added water (2 ml) (0,206 mg, 0,728 mmol) and the mixture was then podlachian (pH=11) by adding dropwise 1 N. aqueous sodium hydroxide solution. The reaction mixture was extracted twice with dichloromethane and the combined extract was dried (over anhydrous MgSO4) and concentrated under reduced pressure to obtain specified in the connection header (0,185 g, approx. 100%) as colorless crystals.

1H-NMR (CDCl3)δ: 3,39 (2H, t, J=9.0 Hz), a-3.84 (2H, t, J=9.0 Hz), 4,80 (1H, user. C), 7,32-rate of 7.54 (4H, m), 7,56-the 7.65 (2H, m), 7,80-7,89 (2H, m), 8,01-8,10 (1H, m).

Reference Example 73

The dihydrochloride (3aR,4R,9bR)-4-phenyl-1-[(2R)-piperidine-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

In the same manner as in Reference Example 23, using tert-butyl (2R)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}Piperi the Jn-1-carboxylate (low polarity), synthesized specified in the header of the connection.

1H-NMR (CD3OD)δ: 1,61 is 2.00 (8H, m), 2,10-to 2.18 (1H, m), 2,20-is 2.37 (1H, m), 2,58-2,69 (1H, m), 3,02-3,13 (1H, m), 3,21-3,68 (4H, m), 4,08-4,16 (1H, m), 5,79 (1H, d, J=7.5 Hz), of 6.71-PC 6.82 (2H, m), 7,05-7,16 (1H, m), 7,30-7,45 (4H, m), 7,49-7,56 (2H, m).

Reference Example 74

tert-Butyl (4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]-carbonyl}benzyl)carbamate

In the same manner as in Reference Example 19, using 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid dihydrochloride and (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}of cyclohexanamine, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 577 (MH+).

Example 1

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

To a mixture of (3aR4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (620 mg, 2,47 mmol), (1S,2R)-2-(benzoylamine)cyclohexanecarboxylic acid (671 mg, 2.7 mmol), triethylamine (to 0.72 ml, 5.2 mmol), acetonitrile (17 ml) and tetrahydrofuran (17 ml) was added dropwise DEPC (440 mg, 2.7 mmol) under ice cooling and the mixture was stirred for 10 minutes. The mixture was again given to warm to room temperature is s and the mixture was stirred for 1 hour. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4) and the solvent evaporated. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (9:1 to 7:3, vol/about.) obtaining specified in the title compound (735 mg, 62%) as an amorphous substance.

LC/MS (ESI) m/z: 480 (MH+).

The following compounds of Example 2 of Example 49 was synthesized using the compound of Reference Example 7 - Reference Example 9 and Table 2, in the same manner as in Example 1.

Example 2

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 3

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Chloro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 4

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 5

N-((1R,2S)-2-{[(3aR,4R,9bR )-8-Methoxy-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 510 (MH+).

Example 6

N-((1R,2S)-2-{[(3aR,4R,9bR)-7-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 7

N-((1R,2S)-2-{[(3aR,4R,9bR)-7-Chloro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 8

N-((1R,2S)-2-{[(3aR,4R,9bR)-6-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 9

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(4-Forfinal)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 10

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Fluoro-4-(4-forfinal)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 516 (MH+).

Example 11

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(2-Chlorophenyl)-2,3,3a,4,5,9-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 12

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(4-Cyanophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 505 (MH+).

Example 13

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 14

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(2-Chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 15

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(2-Furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 470 (MH+).

Example 16

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

Example 17

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(2-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

IHMS (ESI) m/z: 486 (MH +).

Example 18

N-((1R,2S)-2-{[(3aS4S,9bS)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

Example 19

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Pyridin-2-yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 481 (MH+).

Example 20

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Pyridin-3-yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 481 (MH+).

Example 21

Benzyl 2-((3aR,4R,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-pyrrole-1-carboxylate

LC/MS (ESI) m/z: 603 (MH+).

Example 22

tert-Butyl 3-((3aR,4R,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-pyrrole-1-carboxylate

LC/MS (ESI) m/z: 569 (MH+).

Example 23

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1-Methyl-1H-pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 483 (MH+).

Example 24

[2-((3aR,4R,9bR)-1-{[(1S,2R)-2-(Benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]Metreveli

LC/MS (ESI) m/z: 584 (MH+).

Example 25

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1,3-Thiazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 487 (MH+).

Example 26

N-{(1R,2S)-2-[((3aR,4R,9bR)-4-Ethyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

LC/MS (ESI) m/z: 432 (MH+).

Example 27

N-((1R,2S)-2-{[(3aR4S,9bR)-4-Propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 446 (MH+).

Example 28

N-((1R,2S)-2-[(3aR4S,9bR)-4-Isopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl)cyclohexyl)benzamide

LC/MS (ESI) m/z: 446 (MH+).

Example 29

N-((1R,2S)-2-{[(3aR4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 444(MH +).

Example 30

N-{(1R,2S)-2-[((3aR4S,9bR)-4-tert-Butyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

LC/MS (ESI) m/z: 460 (MH+).

Example 31

N-{(1R,2S)-2-[((3aR4S,9bR)-4-Butyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

LC/MS (ESI) m/z: 460 (MH+).

Example 32

N-[(1R,2S)-2-({(3aR4S,9bR)-4-[(Benzyloxy)methyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

LC/MS (ESI) m/z: 524 (MH+).

Example 33

tert-Butyl [((3aR,4R,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)methyl]methylcarbamate

LC/MS (ESI) m/z: 547 (MH+).

Example 34

N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[1-(4-Methoxybenzyl)-1H-imidazol-2-yl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

LC/MS (ESI) m/z: 560 (MH+).

Example 35

N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[1-(4-Methoxybenzyl)-1H-pyrazole-5-yl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

LC/MS (ESI) m/z: 590 (MH+).

Example 36

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1-Trityl-1H-pyrazole-5-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 712 (MH+).

Example 37

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1-Trityl-1H-1,2,4-triazole-5-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 713 (MH+).

Example 38

N-{(1R,2S)-2-[(3aR,9bR)-2,3,3a,4,5,9b-Hexahydro-1H-pyrrolo[3,2-c]quinoline-1-ylcarbonyl]cyclohexyl}-benzamide

LC/MS (ESI) m/z: 404 (MH+).

Example 39

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(4-Were)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 40

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1-Naphthyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 530 (MH+).

Example 41

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Pyridin-4-yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 481 (MH+).

Example 42

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Butyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 536 (MH+).

Example 43

N-{(1R,2S)-2-[((3aR,4R,9bR)-4-Hexyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

LC/MS (ESI) m/z: 488 (MH+).

Example 44

N-((1R,2S)-2-{[(3aR,4R,9bR)-7-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 45

N-((1R,2S)-2-{[(3aR,4R,9bR)-7-Cyano-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 505 (MH+).

Example 46

N-((1R,2S)-2-{[(3aR,4R,9bR)-6-Chloro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 47

N-((1R,2S)-2-{[(3aR,4R,9bR)-6-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 48

N-((1R,2S)-2-{[(3a,4R,9bR)-7-Methoxy-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 510 (MH+).

Example 49

[4-((3aR,4R,9bR)-1-{[(1S,2R)-2-(Benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]pivalate

LC/MS (ESI) m/z: 584 (MH+).

Example 50

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Hydroxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The compound (850 mg, of 1.62 mmol)synthesized in Example 32 was dissolved in ethanol (25 ml) and the hydrogenation reaction was carried out in the presence of 10% palladium on carbon (50% aqueous solution, 500 mg) at room temperature for 12 hours. The reaction mixture was filtered and washed with ethanol. The filtrate and washing liquid were combined and concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the title compound (130 mg, 19%) as an amorphous substance.

LC/MS (ESI) m/z: 434 (MH+).

Example 51

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexage the ro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

Sodium hydride (60% in oil, 14 mg, 0.1 mmol) suspended in tetrahydrofuran (1 ml)was added the compound (35 mg, 0.08 mmol)synthesized in Example 50, with ice cooling, and the suspension was stirred for 1 hour. To the mixture was added methyliodide (14 mg, 0.1 mmol) and the mixture was stirred under ice cooling for 30 minutes and then at room temperature for 2 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and suirable a mixture of hexane-ethyl acetate (4:1, vol/about.) obtaining specified in the title compound (30 mg, 84%) as an amorphous substance.

LC/MS (ESI) m/z: 448 (MH+).

Example 52

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Pyrrol-3-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The compound (537 mg, of 0.94 mmol)synthesized in Example 22 was dissolved in dichloromethane (3 ml), was added TFA (1 ml) at 0°C and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added ice water, podslushivaet 8 N. aqueous solution of Ki is rockside sodium and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the title compound (71 mg, 16%) as a colorless amorphous substance.

LC/MS (ESI) m/z: 469 (MH+).

Example 53

N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[(Methylamino)methyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide the dihydrochloride

Compound (130 mg, 0,238 mmol)synthesized in Example 33 was dissolved in ethyl acetate (5 ml), was added a solution of 4 N. hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred for 3 hours. Precipitated crystals were collected by filtration, washed with ethyl acetate and dried under reduced pressure to obtain specified in the title compound (110 mg, 89%).

LC/MS (ESI) m/z: 447 (MH+).

Example 54

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The compound (200 mg, 0.34 mmol)synthesized in Example 24 was dissolved in methanol (4 ml) was added 28% aqueous ammonia (6 ml) and room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with ethanol. The residue was subjected to column chromatography using basic silica gel (30 g), and suirable a mixture of ethyl acetate-methanol (1:0-11:1, vol/about.) obtaining specified in the title compound (152 mg, 95%) as a colorless powder.

LC/MS (ESI) m/z: 470 (MH+).

Example 55

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-4-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

In the same way as in Example 54, using the compound synthesized in Example 49 was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 470 (MH+).

Example 56

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Pyrazole-5-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The compound (126 mg, 0.18 mmol)synthesized in Example 36 was dissolved in dichloromethane (3 ml), was added monohydrate p-toluensulfonate acid (37 mg, 0.23 mmol) at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution hydrocarb the Nata sodium and saturated saline solution, was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using basic silica gel (30 g), and suirable a mixture of ethyl acetate-methanol (1:0-19:1, vol/about.) obtaining specified in the title compound (65 mg, 79%) as colorless powder.

LC/MS (ESI) m/z: 470 (MH+).

Example 57

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-1,2,4-Triazole-5-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

In the same manner as in Example 56, using the compound of Example 37 was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 471 (MH+).

Example 58

N-{(1R,2S)-2-[((3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

and

N-{(1R,2S)-2-[((3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

Connection (1,38 g is 2.88 mmol)synthesized in Example 1 was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (3:1, vol/about.) obtaining specified in the connection header (3aR,4R,9bR) (486 mg, 35%) as an amorphous substance from the fraction, eluruumi first.

LC/MS (ESI) m/z: 480 (MH+).

Specified in the header of the connection is of (3aS,4S,9bS) (678 mg, 49%) was obtained as an amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 480 (MH+).

The following compounds of Example 59 Example 63 was isolated by column chromatography in the same manner as in Example 58.

Example 59

N-((1R,2S)-2-[(3aR,4S,9bR)-(4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl)benzamide

LC/MS (ESI) m/z: 444 (MH+).

Example 60

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

and

N-((1R,2S)-2-{[(3aS,4S,9bS)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

Example 61

N-((1R,2S)-2-{[(3aR,4R,9bR)-8-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 499 (MH+).

and

N-((1R,2S)-2-{[(3aS,4S,9bS)-8-fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 499 (MH+).

Example 62

N-{(1R,2S)-2-[(3aR,4S,9bR)-(4-Propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]-cyclohexyl}benzamide

LC/MS (ESI) m/z: 446 (MH+)./p>

and

N-{(1R,2S)-2-[(3aS,4S,9bS)-(4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

LC/MS (ESI) m/z: 446 (MH+).

Example 63

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

and

N-((1R,2S)-2-{[(3aS,4S,9bS)-4-(3-furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 486 (MH+).

Example 64

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

and

N-((1R,2S)-2-{[(3aS,4S,9bS)-4-(1H-pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

Benzyl 2-((3aR,4R,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-pyrrole-1-carboxylate (407 mg, 0.67 mmol) was dissolved in methanol (3 ml), was added 10% palladium on carbon (50% aqueous solution of 240 mg) and the mixture was stirred in an atmosphere of hydrogen for 2 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography with ispolzovaniya (30 g) and suirable a mixture of hexane-ethyl acetate (9:1-4:1, about./vol.). Specified in the header connection(3aR,4R,9bR) (64 mg, 20%) was obtained as a colorless amorphous substance from the fraction, eluruumi first.

LC/MS (ESI) m/z: 469 (MH+).

Specified in the header of the compound (3aS,4S,9bS) (78 mg, 25%) was obtained as a colorless amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 469 (MH+).

Example 65

N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[4-(Methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

and

N-[(1R,2S)-2-({(3aS,4S,9bS)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

To a suspension of (3aS,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (1.10 g, 3.0 mmol) and (1S,2R)-2-(benzoylamine)cyclohexanecarboxylic acid (0.74 g, 3.0 mmol) in DMF (20 ml) was added under cooling with ice, triethylamine (0,91 g, 9.0 mmol) and then a solution of DEPC (0,49 g, 3.0 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous MgSO4and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (2:-1:1, about./about.) obtaining N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]-benzamide (0.45 g, 29%) from the faction, eluruumi first.

LC/MS (ESI) m/z: 526 (MH+).

N-[(1R,2S)-2-({(3aS,4S,9bS)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide (0,42 g, 27%) was obtained from fraction, eluruumi second.

LC/MS (ESI) m/z: 526 (MH+).

The following compounds of Example 66 Example 68 was synthesized using the compounds of Table 2, in the same manner as in Reference Example 65.

Example 66

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Isobutyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 460 (MH+).

and

N-((1R,2S)-2-{[(3aS,4R,9bS)-4-isobutyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

After purification on a column of silica gel crystallization from a mixture of ethyl acetate-isopropyl ether gave colorless crystals having the melting point to 173.3-173,4°C.

LC/MS (ESI) m/z: 460 (MH+).

Example 67

Benzyl 4-((3aR,4S,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)piperidine-1-carboxylate

LC/MS (ESI) m/z: 621 (MH+).

Example 68

Benzyl 2-((3aR,4S,9bR)-1{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)eticaret

LC/MS (ESI) m/z: 581 (MH+).

Example 69

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-piperidine-4-yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

A suspension of compound (0,41 g, 0.66 mmol)synthesized in Example 67, and 10% palladium on carbon (50% aqueous solution, 0.04 g) in methanol (50 ml) was stirred at room temperature in an atmosphere of hydrogen for 48 hours. The catalyst was filtered and washed with methanol and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using basic silica gel (30 g), and suirable a mixture of ethyl acetate-methanol (3:1, vol/vol.). Recrystallization from methanol-simple ether gave specified in the title compound (0.16 g, 50%) as white crystals.

LC/MS (ESI) m/z: 487 (MH+).

Example 70

4-((3aR,4S,9bR)-1-{[(1S,2R)-2-(Benzoylamine)-cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-N-ethylpiperidine-1-carboxamide

A mixture of the compound (0.20 g, 0.41 mmol)synthesized in Example 69, triethylamine (0.17 g, of 1.64 mmol), utilizationof (0,058 g, 0.82 mmol) and tetrahydrofuran (20 ml) was stirred at room temperature for 60 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed n is sasenum salt solution, was dried (over anhydrous

Na2SO4) and the solvent evaporated under reduced pressure. The residue was recrystallized from a mixture of hexane-ethyl acetate to obtain specified in the title compound (0.20 g, 87%) as white crystals.

LC/MS (ESI) m/z: 558 (MH+).

Example 71

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-(2-amino-ethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

In the same way as in Example 69, and using the compound synthesized in Example 68 was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 447 (MH+).

Example 72

Benzyl ((3aR,4R,9bR)-1-{[1S,2R]-2-(benzoylamine)cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]methylcarbamate

To the solution (14 ml) of tert-butyl (3aR,4R,9bR)-4-({[benzyloxy]carbonyl}amino)methyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (1.29 g, with 2.93 mmol) in methanol was added dropwise 4 n solution of hydrogen chloride in ethyl acetate (1,94 ml, to 7.77 mmol) under cooling with ice. The reaction mixture was stirred over night at room temperature and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 ml), was added under cooling with ice, triethylamine (0,868 ml, 6.21 mmol), (1S,3R)-2-(benzoylamine)cyclohexane the oil acid (563 mg, 2.28 mmol) and DEPC (0,310 ml, 2,07 mmol) and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (9:1-1:1, vol/about.) obtaining specified in the connection header (69,6 mg, 6%) as an amorphous substance from the fraction, eluruumi first. Benzyl ((3aR,4R,9bR)-1-{[1S,2R]-2-(benzoylamine)cyclohexyl}-carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]methylcarbamate (480 mg, 41%) was obtained from fraction, eluruumi second.

LC/MS (ESI) m/z: 567 (MH+).

Example 73

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Aminomethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

A solution of benzyl ((3aR,4R,9bR)-1-{[1S,2R]-2-(benzoylamine)cyclohexyl}carbonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl]methylcarbamate (480 mg, 0,847 mmol)obtained in Example 72, in methanol (8 ml) was stirred in the presence of 10% palladium on carbon (50% aqueous solution, 100 mg) in hydrogen atmosphere for 4 days. The catalyst was filtered and the filtrate was concentrated under reduced Yes the tion. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (1:0-1:1, vol/about.) obtaining specified in the title compound (283 mg, 77%) as an amorphous substance.

LC/MS (ESI) m/z: 433 (MH+).

Example 74

N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[(Acetylamino)methyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl]benzamide

To a solution of compound (163 mg, 0,377 mmol)synthesized in Example 73, in tetrahydrofuran (3 ml) was added acetic anhydride (0,179 ml, 1.88 mmol) under ice cooling and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography using basic silica gel, and was suirable a mixture of hexane-ethyl acetate (8:2-0:1, vol/about.) obtaining specified in the title compound (117 mg, 60%) as an amorphous substance.

LC/MS (ESI) m/z: 475 (MH+).

Example 75

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(2-Methyl-3-furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

To a suspension of the hydrochloride of (1R,2S)-2-{[(3aR,4R,9bR)-4-(2-methyl-3-furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}of cyclohexanamine (201 mg, 0,445 mmol) in dichloromethane (5 ml) was added triethylamine (0,203 ml, 147 mmol) and benzoyl chloride (0,0568 ml, 0,490 mmol) under cooling with ice. The reaction mixture was stirred over night at room temperature, was added water and was extracted with dichloromethane. The extract was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (4:1-3:2, vol/about.) obtaining specified in the title compound (176 mg, 82%) as an amorphous substance.

LC/MS (ESI) m/z: 484 (MH+).

The following compounds of Example 76 Example 80 was synthesized using the compounds shown in Table 3, in the same manner as in Example 75.

Example 76

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1,3-Oxazol-4-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 471 (MH+).

Example 77

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Ethoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 462 (MH+).

Example 78

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1,3-Thiazol-5-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 487 (MH+).

Example 79

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Tetrahydro-2H-Piran-4-yl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cycle is hexyl)benzamide

LC/MS (ESI) m/z: 488 (MH+).

Example 80

[2-((3aR,4R,9bR)-1-{[(1S,2R)-2-(Benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-)-1H-imidazol-1-yl]Metreveli

The dihydrochloride [2-((3aR,4R,9bR)-1-{[(1S,2R)-2-aminocyclohexanol]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]methylphenidate (1.28 g, 2,31 mmol) was dissolved in ethyl acetate (30 ml) was added under cooling with ice and 10% aqueous sodium carbonate solution (15 ml) and benzoyl chloride (0,303 ml, is 0.260 mmol). The reaction mixture was stirred at room temperature for 1 hour and separated organic layer was washed with saturated saline and dried over anhydrous MgSO4. The solvent is evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (3:2-1:9, vol/about.) obtaining specified in the title compound (1.25 g, 93%) as an amorphous substance.

LC/MS (ESI) m/z: 584 (MH+).

Example 81

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The compound (1.25 g, 2.14 mmol), sintezirovannye in Example 80 was dissolved in methanol (50 ml)was added 25% aqueous ammonia solution (25 ml) and the mixture was stirred for 4 cha is impressive. The solvent is evaporated and the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-9:1, vol/vol.). Specified in the header connection (0,929 g, 92%) was obtained as a colorless amorphous substance from the target faction.

1H-NMR (CDCl3)δ: 1,35-2,23 (12H, m), 2,35-of 2.50 (1H, m), 2,55 of 2.68 (1H, m), 2,82-2,95 (1H, m), 3,38-3,44 (2H, m), 4,25 was 4.42 (2H, m), of 4.77 (1H, d, J=2.7 Hz), the 5.65 (1H, d, J=6.9 Hz), 6,51 (1H, DD, J=8,1, 0.9 Hz), 6,69-6,76 (1H, m), 6,93-7,05 (1H, m), 7,20-7,28 (3H, m), 7,34-7,51 (4H, m), 7,72-a 7.85 (2H, m).

LC/MS (ESI) m/z: 470 (MH+).

Example 82

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1-Methyl-1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

To a solution of compound (119 mg, 0,252 mmol)synthesized in Example 81, in DMF (1 ml) was added sodium hydride (60% in oil, 12,1 mg, 0.30 mmol) under ice cooling and the mixture was stirred for 1 hour. Was added dropwise methyliodide (0,0187 ml, 0.30 mmol) and the mixture was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (5:95, about./about.) obtaining specified in the header soy is inane (76,5 mg, 63%) as an amorphous substance.

LC/MS (ESI) m/z: 484 (MH+).

Example 83

N-((1R,2S)-2-{[(3aR,4S,9bR)-3a-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

and

N-((1R,2S)-2-{[(3aS,4R,9bS)-3a-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

Hydrochloride (3aR4S,9bR)-3a-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (210 mg, of 0.62 mmol) suspended in acetonitrile (3 ml)and tetrahydrofuran (3 ml), was added triethylamine (263 mg, 2.6 mmol) and the suspension was stirred at room temperature for 15 minutes. To the resulting suspension was added (1S,2R)-2-(benzoylamine)cyclohexanecarbonyl acid (170 mg, of 0.68 mmol) was added under ice cooling DEPC (110 mg, of 0.68 mmol) and the mixture was stirred for 10 minutes. The reaction mixture was again given to warm to room temperature and was stirred for 1 hour. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and suirable a mixture of hexane-ethyl acetate (9:1-1:1, vol/about.) obtaining a mixture of diastereoisomers (170 mg, 6%) as an amorphous substance.

The resulting mixture of diastereomers (150 mg) was subjected to column chromatography using silica gel (10 g) and suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the connection header (3aR,4S,9bR) (40 mg, 27%) as an amorphous substance from the fraction, eluruumi first.

LC/MS (ESI) m/z: 494 (MH+).

Specified in the header of the compound (3aS,4R,9bS) (20 mg, 13%) was obtained as an amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 494 (MH+).

Example 84

N-((1R,2S)-2-{[(3aR,4R,9bR)-3a-Methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

and

N-((1R,2S)-2-{[(3aS,4S,9bS)-3a-methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

To a mixture of (3aS,4R,9bR)-3a-methyl-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (750 mg, 2.77 mmol), (1S,2R)-2-(benzoylamine)cyclohexanecarboxylic acid (685 mg, 2.77 mmol), triethylamine (606 mg, 6,10 mmol), acetonitrile (14 ml) and tetrahydrofuran (14 ml) was added DEPC (500 mg, of 3.05 mmol) under ice cooling and the mixture was stirred for 10 minutes. The mixture was again given to warm to room temperature and was stirred for 12 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture is extra is Aravali with ethyl acetate. The extract was dried (over anhydrous Na2SO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (100 g) and was suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the connection header (3aR,4R,9bR) (110 mg, 8%) as an amorphous substance from the fraction, eluruumi first.

LC/MS (ESI) m/z: 500 (MH+).

Specified in the header of the compound (3aS,4S,9bS) (150 mg, 10%) was obtained as an amorphous substance from the fraction, eluruumi second.

LC/MS (ESI) m/z: 500 (MH+).

Example 85

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)ndimethylacetamide

To a mixture of compound (is 0.135 g, 0.3 mmol)synthesized in Reference Example 23, 10% aqueous sodium carbonate solution (5 ml) and ethyl acetate (10 ml) was added acetylchloride (to 0.032 ml, 0.45 mmol) at room temperature and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (3:2-0:1, vol/about.) obtaining from the target fraction specified in the title compound (0.124 g,99%) as an amorphous substance.

LC/MS (ESI) m/z: 418 (MH+).

The following compounds of Example 86 Example 117 was synthesized using the corresponding acid anhydrides, in the same manner as in Example 85.

Example 86

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 432 (MH+).

Example 87

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(trifluoromethyl)benzamid

LC/MS (ESI) m/z: 548 (MH+).

Example 88

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)for 3,5-bis(trifluoromethyl)benzamid

LC/MS (ESI) m/z: 616 (MH+).

Example 89

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)thiophene-2-carboxamide

LC/MS (ESI) m/z: 486 (MH+).

Example 90

4-Methoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 510 (MH+).

Example 91

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)isonicotinamide

W is/MS (ESI) m/z: 481 (MH +).

Example 92

4-Fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 93

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide

LC/MS (ESI) m/z: 474 (MH+).

Example 94

2-Methoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 510 (MH+).

Example 95

3-Methoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 510 (MH+).

Example 96

3-Fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 498 (MH+).

Example 97

2-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 98

3-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494(MH +).

Example 99

4-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

Example 100

Methyl 4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoate

LC/MS (ESI) m/z: 538 (MH+).

Example 101

(2E)-3-Phenyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

LC/MS (ESI) m/z: 506 (MH+).

Example 102

4-Cyano-N-((1R,2S)-2-([(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl)cyclohexyl)benzamide

LC/MS (ESI) m/z: 505 (MH+).

Example 103

3-Phenyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 508 (MH+).

Example 104

3,4-Dimethoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 540 (MH+).

Example 105

(2E)-3-(4-Methoxyphenyl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

img src="https://img.russianpatents.com/1049/10490799-s.jpg" height="33" width="47" />

LC/MS (ESI) m/z: 536 (MH+).

Example 106

(2E)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-[4-(trifluoromethyl)phenyl]acrylamide

LC/MS (ESI) m/z: 574 (MH+).

Example 107

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2-naptime

LC/MS (ESI) m/z: 530 (MH+).

Example 108

Ethyl 4-oxo-4-[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]butanoate

LC/MS (ESI) m/z: 504 (MH+).

Example 109

6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide

LC/MS (ESI) m/z: 554, 555 (MH+).

Example 110

2-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 446 (MH+).

Example 111

2,2-Dimethyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 460 (MH+).

Example 112

2-Phenyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cycle is hexyl)ndimethylacetamide

LC/MS (ESI) m/z: 494 (MH+).

Example 113

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)cyclohexanecarboxylic

LC/MS (ESI) m/z: 486 (MH+).

Example 114

4-Chloro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 115

Ethyl 3-oxo-3-[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]propanoate

LC/MS (ESI) m/z: 490 (MH+).

Example 116

Methyl 6-oxo-6-[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]hexanoate

LC/MS (ESI) m/z: 518 (MH+).

Example 117

6-Morpholine-4-yl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide

6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide (166 mg, 0.30 mmol), morpholine (28 μl, 0,331 mmol) and potassium carbonate (207 mg, 1.5 mmol) was heated at the boiling point under reflux for 6 hours in acetonitrile (3 ml). To the reaction the mixture was added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography on basic silica gel and was suirable with ethyl acetate to obtain specified in the title compound (153 mg, 91%) as a white solid.

LC/MS (ESI) m/z: 559 (MH+).

Example 118

6-[(2-Hydroxyethyl)amino]-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide

6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide (150 mg, 0.27 mmol) was stirred in 2-aminoethanol (3 ml) at 60°C for 6 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography on basic silica gel and was suirable a mixture of ethyl acetate-methanol (5:1, vol/about.) obtaining specified in the title compound (106 mg, 73%) as a white solid.

LC/MS (ESI) m/z: 533 (MH+).

Example 119

6-Hydroxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)hexanamide

The mixture of calcium chloride (88 mg,0.8 mmol), of sodium borohydride (60 mg, 1.6 mmol), tetrahydrofuran (2.5 ml) and ethanol (2.5 ml) was stirred in nitrogen atmosphere under ice cooling for 30 minutes. To the mixture was added methyl 6-oxo-6-[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]hexanoate (106 mg, 0.20 mmol) under ice cooling and the mixture was stirred at room temperature for 16 hours. Added water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography using basic silica gel, and was suirable with ethyl acetate to obtain specified in the title compound (89 mg, 92%) as a white solid.

LC/MS (ESI) m/z: 490 (MH+).

Example 120

4-(Hydroxymethyl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

In the same manner as in Example 119, using methyl 4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoate was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 510 (MH+).

Example 121

4-Hydroxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]Carboni is}cyclohexyl)butanamide

In the same manner as in Example 119, using ethyl 4-oxo-4-(((1R,2S)-2-(((3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl)cyclohexyl)amino)butanoate, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 462 (MH+).

Example 122

4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoic acid

To a solution of methyl 4-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoate (77 mg, 0.14 mmol) in tetrahydrofuran (4 ml) and methanol (1 ml) was added 2 N. aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at 60°C for 16 hours. The reaction mixture was neutralized (pH 7) by adding 3 n hydrochloric acid under ice cooling. The mixture was concentrated under reduced pressure and extracted with a mixture solvent ethyl acetate-tetrahydrofuran (2:1, vol/vol.). The extract was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure. The obtained solid was washed with isopropyl ether-hexane (1:2, vol/about.) obtaining specified in the title compound (51 mg, 68%) as a white solid.

LC/MS (ESI) m/z: 524 (MH+).

Primer

2-{[((1R,2's)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}benzoic acid

The compound (135 mg, 0.30 mmol)synthesized in Reference Example 23, phthalic anhydride (53 mg, 0.36 mmol) and triethylamine (91,5 μl, 0.66 mmol) was heated at the boiling point under reflux in chloroform (4 ml) for 20 hours. The solvent is evaporated under reduced pressure, was added water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4and the solvent evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain specified in the title compound (136 mg, 87%) as a white solid.

LC/MS (ESI) m/z: 524 (MH+).

Example 124

2-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-isoindole-1,3(2H)-dione

To a solution of the compound (70 mg, 0.13 mmol) of Example 123 and triethylamine (20,9 ml, 0.15 mmol) in DMF (5 ml) was added DEPC (24.5 ml, 0.15 mmol) under ice cooling and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography on silicagel the e and suirable a mixture of hexane-ethyl acetate (3:1-1:1, about./about.) obtaining specified in the title compound (54 mg, 71%) as a white solid.

LC/MS (ESI) m/z: 506 (MH+).

Example 125

(4-(Dimethylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)butanamide

To a mixture of compound (135 mg, 0.30 mmol)synthesized in Reference Example 23, 4-(dimethylamino)butane acid (60 mg, 0.36 mmol) and triethylamine (0,167 ml, 1.2 mmol) in DMF (3 ml) was added DEPC (to 0.060 ml, 0.36 mmol) under cooling with ice. The reaction mixture was stirred at room temperature for 12 hours, was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography on basic silica gel. Specified in the title compound (129 mg, 88%) was obtained as a white solid from fraction elution which was carried out by using a mixture of ethyl acetate-methanol (1:0-9:1, vol/vol.).

LC/MS (ESI) m/z: 489 (MH+).

The following compound of Example 126 Example 133 was synthesized using the appropriate carboxylic acid in the same manner as in Reference Example 125.

Example 126

4-orfelin-4-yl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)butanamide

LC/MS (ESI) m/z: 531 (MH+).

Example 127

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)pyrazin-2-carboxamide

LC/MS (ESI) m/z: 482 (MH+).

Example 128

(2E)-3-(1H-Imidazol-4-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

LC/MS (ESI) m/z: 496 (MH+).

Example 129

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-imidazol-2-carboxamid

LC/MS (ESI) m/z: 470 (MH+).

Example 130

(2E)-3-(1-Methyl-1H-imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

LC/MS (ESI) m/z: 510 (MH+).

Example 131

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-imidazol-5-carboxamid

LC/MS (ESI) m/z: 470 (MH+).

Example 132

1-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-imidazol-2-carboxamid

LC/MS (ESI) m/z: 484 (MH+).

Example 133

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-FeNi the -2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 520 (MH+).

Example 134

(2E)-3-(1H-Imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

To a mixture of compound (0,319 g, 0,712 mmol)synthesized in Reference Example 23, (2E)-3-(1-trityl-1H-imidazol-2-yl)acrylic acid (0,298 g, 0,783 mmol) and DMF (10 ml) was added triethylamine (0.3 ml, 2.14 mmol) and then was added DEPC (to 0.127 ml, 0,783 mmol) at 0°C. the Mixture was stirred at the same temperature for 30 minutes, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (4:1-3:7, Rev./vol.). (2E)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-(1-trityl-1H-imidazol-2-yl)acrylamide (0,457 g, 87%) was obtained as a colorless amorphous substance from the target faction. The compound obtained was dissolved in tetrahydrofuran (5 ml)was added dropwise 6 N. hydrochloric acid solution (0,206 ml of 1.24 mmol) and the mixture was heated at the boiling point under reflux for 30 minutes. Was added dropwise at 0°C8 N. an aqueous solution of sodium hydroxide (0.2 ml) and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous MgSO4and after concentration under reduced pressure, the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-7:3, vol/vol.). Specified in the header connection (0,228 g, 74%) was obtained as a colorless amorphous substance from the target faction.

LC/MS (ESI) m/z: 496 (MH+).

Example 135

N-Phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

To a mixture of compound (is 0.135 g, 0.3 mmol)synthesized in Reference Example 23, ethyl acetate (10 ml) and 10% aqueous sodium carbonate solution (5 ml) was added phenylisocyanate (0,039 ml, 0.36 mmol) at room temperature and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution and dried (over anhydrous MgSO4). The solvent is evaporated under reduced pressure and the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (9:1-4:6, vol/vol.). Specified in the header of the connection (is 0.135 g, 91%) was obtained as an amorphous substance from the target faction.

1H-NMR (CDCl3)δ: 1,3-2,00 (7H, m), 2,15-2,48 (3H, m), 2,83-of 2.97 (1H, m), 3,40-of 3.60 (3H, m), 3,80-4,18 (2H, m), 4,58 (1H, d, J=2.1 Hz), 5,67 (1H, d, J=7,2 Hz), 5,90-6,01 (1H, m), 6,50-6,60 (1H, m), 6,62-6,70 (1H, m), 6.89 in (1H, user. C)6,94-7,07 (2H, m), 7,18 is 7.50 (10H, m).

LC/MS (ESI) m/z: 495 (MH+).

Example 136

N-(4-Chlorophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

The compound (0.172 g, 0.384 mmol)synthesized in Reference Example 23, triethylamine (0,163 ml, 1.15 mmol) and 4-chloronicotinate (0,0709 g, 0,461 mmol) was stirred for 4.5 hours in tetrahydrofuran (10 ml). To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (19:1-1:4, vol/vol.). Specified in the header connection (0,210 g, approx. 100%) was obtained as an amorphous substance from the target faction.

LC/MS (ESI) m/z: 529 (MH+).

The following compounds of Example 137 - Example 155 and Example 159 was synthesized using the appropriate isocyanate, in the same manner as in Example 135 or Example 136.

Example 137

N-(4-Methoxyphenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-feast of the olo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 525 (MH+).

Example 138

N-(4-Were)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 509 (MH+).

Example 139

N-(4-Forfinal)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 513 (MH+).

Example 140

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(trifluoromethyl)phenyl]urea

LC/MS (ESI) m/z: 563 (MH+).

Example 141

N-(3-Chlorophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 529 (MH+).

Example 142

N-(2-Chlorophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 529 (MH+).

Example 143

N-Benzyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 509 (MH+).

Example 144

N-(4-Methoxybenzyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,59b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 539 (MH+).

Example 145

N-(4-Terbisil)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 527 (MH+).

Example 146

N-(2-Phenylethyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 523 (MH+).

Example 147

N-(4-Cyanophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 520 (MH+).

Example 148

N-1,3-Benzodioxol-5-yl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 539 (MH+).

Example 149

N-Cyclohexyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 501 (MH+).

Example 150

N-(4-Isopropylphenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 537 (MH+).

Example 151

N-Ethyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-is hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 447 (MH+).

Example 152

N-Isopropyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 461 (MH+).

Example 153

N-Butyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 475 (MH+).

Example 154

N-Hexyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 503 (MH+).

Example 155

Ethyl N-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}-beta-alaninate

LC/MS (ESI) m/z: 519 (MH+).

Example 156

N-(3-Hydroxypropyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

In the same manner as in Example 120 and using the compound synthesized in Example 155, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 477 (MH+).

Example 157

N-{[((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbon is l}-beta-alanine

Connection (0,211 g, 0,407 mmol)synthesized in Example 155, and 1 N. aqueous sodium hydroxide solution (0,814 ml, 0,814 mmol) was stirred in methanol (10 ml) at 60°C for 2 hours. After the mixture was allowed to cool to room temperature, the reaction mixture was diluted with water and added 1 n solution of hydrochloric acid (0,814 ml). The mixture was extracted twice with dichloromethane and the combined extract was dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of ethyl acetate-methanol (1:0-4:1, vol/about.) obtaining specified in the connection header (0,171 g, 86%) as an amorphous substance from the target faction.

LC/MS (ESI) m/z: 491 (MH+).

Example 158

N3-[((1R,2S)-2-{[(3R,4R,9bR)-4-Phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}-beta-alaninate

Connection (0,171 g, 0,348 mmol)synthesized in Example 157, ammonium chloride (0,0261 g, 0,488 mmol), triethylamine (0,0685 ml, 0,488 mmol) and diethylthiophosphate (0,07 ml, 0,418 mmol) was stirred in DMF (5 ml) under cooling with ice for 1 hour and at room temperature for 1 hour. To the reaction mixture were added saturated aqueous solution of bicarbonate soda is I and water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using basic silica gel (30 g) and suirable a mixture of ethyl acetate-methanol (1:0-4:1, vol/about.) obtaining from the target fraction specified in the connection header (0,117 g, 69%) as an amorphous substance.

LC/MS (ESI) m/z: 490 (MN+).

Example 159

Ethyl 4-({[((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo [3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}amino)benzoate

LC/MS (ESI) m/z: 567 (MH+).

Example 160

4-({[((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}amino)benzamide

In the same way as in Example 157 and Example 158, using the compound synthesized in Example 159, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 538 (MH+).

Example 161

N-(3-Methoxypropyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

Connection (0,209 g, 0,467 mmol)synthesized in Reference Example 23, 1,1-carbonyldiimidazole (0,151 g, 0,934 mmol) and triethylamine (0.21 in ml, for 1.49 mmol) was stirred in DMF (5 ml) at ohla the Denia ice for 1 hour. Was added at the same temperature 3-methoxypropylamine (0,143 ml, 1.4 mmol) and triethylamine (0,196 ml, 1.4 mmol) and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of ethyl acetate-methanol (1:0-4:1, vol/about.) obtaining from the target fraction specified in the connection header (0,226 g, 99%) as an amorphous substance.

LC/MS (ESI) m/z: 491 (MH+).

The following compounds of Example 162 Example 174 was synthesized using the appropriate amines, in the same manner as in Example 161.

Example 162

N-(2-Ethoxyethyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 491 (MH+).

Example 163

N-[2-(Methylsulphonyl)ethyl]-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 525 (MH+).

Example 164

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-(2-pyridin-2-ilat the l)urea

LC/MS (ESI) m/z: 524 (MH+).

Example 165

N-[2-({[((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]carbonyl}amino)ethyl]ndimethylacetamide

LC/MS (ESI) m/z: 504 (MH+).

Example 166

N-(3-Methylbutyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 489 (MH+).

Example 167

N-(3-Morpholine-4-ylpropyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 546 (MH+).

Example 168

N-[3-(2-Oxopyrrolidin-1-yl)propyl]-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 544 (MH+).

Example 169

N-[3-(1H-Imidazol-1-yl)propyl]-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 527 (MH+).

Example 170

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-pyridine-2-rocephine

LC/MS (ESI) m/z: 496 (MH+).

Example 171

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-pyridine-3-rocephine

LC/MS (ESI) m/z: 496 (MH+).

Example 172

4-Phenyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)piperidine-1-carboxamide

LC/MS (ESI) m/z: 563 (MH+).

Example 173

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-(2,2,2-triptorelin)urea

LC/MS (ESI) m/z: 501 (MH+).

Example 174

N-Methoxy-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 449 (MH+).

Example 175

N-(1-Acetylpiperidine-4-yl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

N-Acetylethanolamine acid (0,343 g, a 2.01 mmol), triethylamine (0,282 ml, a 2.01 mmol) and diphenylphosphoryl (0,432 ml, a 2.01 mmol) was stirred in toluene (10 ml) at 80°C for 2 hours. This reaction mixture was allowed to cool to room temperature, was added dropwise to a suspension of compound (0.18 g, 0,402 mmol)synthesized in Reference Example 23, and triethylamine (0,169 m is, to 1.21 mmol) in tetrahydrofuran (5 ml) and the mixture was stirred for 21 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of ethyl acetate-methanol (1:0-7:3, vol/about.) obtaining from the target fraction specified in the connection header (0,192 g, 88%) as an amorphous substance.

LC/MS (ESI) m/z: 544 (MH+).

Example 176

N-Methyl-N-phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

Connection (0,134 g, 0,299 mmol)synthesized in Reference Example 23, triethylamine (is 0.135 ml, 0,963 mmol) and N-methyl-N-phenylcarbamoyloxy (0,056 g, 0.33 mmol) was stirred in dichloromethane (5 ml) for 24 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (7:3-1:4, vol/about.) to receive the drug from the target fraction specified in the connection header (0,139 g, 91%) as an amorphous substance.

LC/MS (ESI) m/z: 509 (MH+).

Example 177

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)piperidine-1-carboxamide

To a mixture of compound (is 0.135 g, 0.3 mmol)synthesized in Reference Example 23, ethyl acetate (10 ml) and 10% aqueous sodium carbonate solution (5 ml) was added piperidine-1-carbonylchloride (0,089 g, 0.6 mmol) at room temperature and the mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate and the extract was washed with saturated saline solution and dried (over anhydrous MgSO4). The solvent is evaporated under reduced pressure and the obtained residue was dissolved in tetrahydrofuran (5 ml). Was added at room temperature triethylamine (0,084 ml, 0.6 mmol) and piperidine-1-carbonylchloride (0,044 g, 0.3 mmol) and the mixture was stirred for 3 days. The reaction mixture was concentrated under reduced pressure and added a 10% aqueous solution of sodium carbonate. The mixture was extracted with ethyl acetate and the extract was washed with saturated saline solution and dried (over anhydrous MgSO4). The solvent is evaporated under reduced pressure and the residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (7:3-0:1, vol/about.) with receipt from target fracc is specified in the title compound (0.125 g, 86%) as an amorphous substance.

LC/MS (ESI) m/z: 487 (MH+).

Example 178

N-((2R,3S)-3-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}bicyclo[2,2,2]Oct-2-yl)benzamid

and

N-((2S,3R)-3-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}bicyclo[2,2,2]Oct-2-yl)benzamid

and

N-((2R,3S)-3-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}bicyclo[2,2,2]Oct-2-yl)benzamid

and

N-((2S,3R)-3-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}bicyclo[2,2,2]Oct-2-yl)benzamid

To a solution of the compound (200 mg, 0.42 mmol)synthesized in Reference Example 23, and benzoyl chloride (65 mg, 0.47 mmol) in dichloromethane (4 ml) was added drop wise addition of triethylamine (140 mg, 1.4 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and the mixture was extracted with chloroform. The extract was dried (over anhydrous Na2SO4) and the solvent evaporated. The residue was subjected to column chromatography using basic silica gel (5 g), and suirable a mixture of hexane-ethyl acetate (6:1-1:1, vol/about.) with the mixture specified in the title compound (170 mg, 80%) in amorphous form. The mixture was subjected to high performance liquid is based chromatography, using an optically active column, the compound (2R,3S,3aR,4R,9bR) (61 mg) was obtained as an amorphous substance from the fraction, eluruumi first, the compound (2S,3R,3aS,4S,9bS) (62 mg) was obtained as an amorphous substance from the fraction, eluruumi second, the compound (2R,3S,3aS,4S,9bS) (12 mg) was obtained as an amorphous substance from the fraction, eluruumi third, the compound (2S,3R,3aR,4R,9bR) (10 mg) was obtained as an amorphous substance from the fraction, eluruumi fourth.

Example 179

N-{(1R,2S)-2-[(3aR,4R,9bR)-(5-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

A mixture of 5-methyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (130 mg, 0.48 mmol), (1S,2R)-2-(benzoylamine)cyclohexanecarboxylic acid (131 mg, of 0.53 mmol), WSC (116 mg, 0.61 mmol), HOBt (97 mg, 0,63 mmol), acetonitrile (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 12 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous Na2SO4) and the solvent evaporated. The residue was subjected to column chromatography using silica gel (150 g) and suirable a mixture of hexane-ethyl acetate (4:1-1:1, vol/about.) obtaining specified in the connection header (200 is g, 84%) as an amorphous substance.

LC/MS (ESI) m/z: 494 (MH+).

The following compounds were synthesized using the compounds shown in Table 3, the carboxylic acid synthesized in Reference Examples, etc. in the same way as in Example 179, unless otherwise noted.

Example 180

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-methoxybenzamide

LC/MS (ESI) m/z: 474 (MH+).

Example 181

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-phenylpropanamide

LC/MS (ESI) m/z: 472 (MH+).

Example 182

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-perbenzoic

LC/MS (ESI) m/z: 462 (MH+).

Example 183

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-prilocaine

LC/MS (ESI) m/z: 459 (MH+).

Example 184

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-Cyclopropyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-(4-methoxyphenyl)urea

LC/MS (ESI) m/z: 489 (MH+).

Example 185

N-((1R,2S)-2-{[(3aR,4S,9bR)-4-CEC is propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-atilmotin

LC/MS (ESI) m/z: 411 (MH+).

Example 186

N-Phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 501 (MH+).

Example 187

N-Ethyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 453 (MH+).

Example 188

N-Butyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 481 (MH+).

Example 189

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamid

LC/MS (ESI) m/z: 527 (MH+).

Example 190

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-LC/MS (ESI) m/z: 529 (MH+).

Example 191

2-Methyl-N4-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)terephthalamide

LC/MS (ESI) m/z: 543 (MN+).

Example 192

2-Methyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 540 (MN+).

Example 193

N-((1R,2S)-2-{[(3aR,4R,9bR)-3A-Methyl-4-(3-thienyl)2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 500 (MH+).

Example 194

4-Methoxy-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 476 (MH+).

Example 195

N-Phenyl-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 461 (MH+).

Example 196

N-(4-Methoxyphenyl)-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 491 (MH+).

Example 197

N-(4-Forfinal)-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 479 (MH+).

Example 198

N-Ethyl-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 413 (MH+).

Example 199

N-Butyl-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]Hino is Jn-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 441 (MH+).

Example 200

N-1,3-Benzodioxol-5-yl-N'-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 505 (MH+).

Example 201

2-Methyl-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide

To a suspension of the hydrochloride of (1R,2S)-2-{[(3aR,4R,9bR)-4-(propyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}of cyclohexanamine (203 mg, 0,490 mmol) in DMF (4 ml) was added 2-methyl-1H-benzimidazole-5-carboxylic acid (86,2 mg, 0,490 mmol), triethylamine (0,206 ml of 1.47 mmol) and DEPC (0,0812 ml, 0,490 mmol) under ice cooling and the mixture was stirred at room temperature for 15 hours. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-9:1) to obtain the specified title compound (115 mg, 47%) as an amorphous substance.

1H-NMR (CDCl3) δ: of 0.94 (3H, t, J=6.6 Hz), 1,20-2,11 (14N, m), 2,25-is 2.37 (1H, m), 2,47-2,66 (1 is, m), 2,62 (3H, s), 2.95 and totaling 3.04 (1H, m), 3,38-to 3.67 (3H, m), or 4.31-of 3.42 (1H, m), to 5.57 (1H, d, J=6.9 Hz), 6,47 (1H, DD, J=8,l, and 0.9 Hz), 6,63-6,70 (1H, m), 6,98? 7.04 baby mortality (1H, m), 7,40-7,72 (3H, m), of 8.06 (1H, user. C).

LC/MS (ESI) m/z: 500 (MN+).

Example 202

4-Cyano-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 471 (MN+).

Example 203

N-((1R)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 448 (MH+).

Example 204

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-prilocaine

LC/MS (ESI) m/z: 463 (MH+).

Example 205

N-(4-Forfinal)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 481 (MH+).

Example 206

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-(4-methoxyphenyl)urea

LC/MS (ESI) m/z: 493 (MH+).

Example 207

N-Ethyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 415 (MH+).

Example 208

N-1,3-Benzodioxol-5-yl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 507 (MH+).

Example 209

(2E)-N-((1R,2S)-2-{(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl}carbonyl)cyclohexyl)-3-[4-(trifluoromethyl)phenyl]acrylamide

LC/MS (ESI) m/z: 542 (MH+).

Example 210

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(trifluoromethyl)benzamid

LC/MS (ESI) m/z: 516 (MH+).

Example 211

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-6-nicotine amide

LC/MS (ESI) m/z: 463 (MH+).

Example 212

3,4-Debtor-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 463 (MH+).

Example 213

4-(Dimethylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 491 (MH+).

Example 214

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(IU shall oxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)terephthalamide

LC/MS (ESI) m/z: 491 (MH+).

Example 215

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(triptoreline)benzamid

LC/MS (ESI) m/z: 532 (MH+).

Example 216

4-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 473 (MH+).

Example 217

N-(Cyanophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 488 (MH+).

Example 218

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-indol-5-carboxamid

LC/MS (ESI) m/z: 487 (MH+).

Example 219

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamid

To a solution (5 ml) hydrochloride (1R,23)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}of cyclohexanamine (200 mg, to 0.480 mmol) in THF was added triethylamine (0,199 ml, 1.44 mmol), 1H-1,2,3-benzotriazol-5-carboxylic acid (to 78.3 mg, to 0.480 mmol who) and DEPC (0,079 ml, 0,528 mmol) under ice cooling and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane:ethyl acetate (1:1-1:9) to obtain the specified title compound (187 mg, 80%) as an amorphous substance.

1H-NMR (CDCl3) δ: 0,86-0,88 (1H, m)of 1.26 (1H, m), USD 1.43-1,96 (10H, m), 2,08-of 2.21 (2H, m), is 2.41 (1H, m), 2,95 (1H, m), 3,37-of 3.48 (3H, m), to 3.58 is 3.76 (3H, m), of 4.57 (1H, m), to 5.66 (1H, d, J=6.9 Hz), 6,53 (1H, d, J=7,3 Hz), 6,69 (1H, DD, J=7,6, 7,7 Hz), 7,03 (1H, DD, J=7,3, 7,6 Hz), 7,31-7,34 (1H, m), of 7.48 (1H, d, J=7,2 Hz), 7,66 (1H, d, J=7,7 Hz), 8,17 (1H, s).

LC/MS (ESI) m/z: 489 (MN+).

Example 220

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)academic

LC/MS (ESI) m/z: 415 (MH+).

Example 221

3-Hydroxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 416 (MH+).

LC/MS (ESI) m/z: 416 (MH+).

Example 222

2 Ethoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)ndimethylacetamide

<>

LC/MS (ESI) m/z: 430 (MH+).

Example 223

N2-Acetyl-N1-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)glycinamide

LC/MS (ESI) m/z: 443 (MN+).

Example 224

N2(Aminocarbonyl)-Nl-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)glycinamide

LC/MS (ESI) m/z: 444 (MH+).

Example 225

3-Hydroxy-2,2-dimethyl-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)propanamide

LC/MS (ESI) m/z: 444 (MH+).

Example 226

(2E)-3-(1H-Imidazol-4-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

LC/MS (ESI) m/z: 464 (MH+).

Example 227

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2-(1H-tetrazol-1-yl)ndimethylacetamide

LC/MS (ESI) m/z: 454 (MH+).

Example 228

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-oxo-4H-Piran-2-carboxamide

LC/MS ESI) m/z: 466 (MH +).

Example 229

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4H-indol-2-carboxamide

LC/MS (ESI) m/z: 487 (MH+).

Example 230

4-(Acetylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 505 (MH+).

Example 231

N-{2-[((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)amino]-2-oxoethyl}-2-furamide

LC/MS (ESI) m/z: 495 (MH+).

Example 232

2-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 473 (MH+).

Example 233

3-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 473 (MH+).

Example 234

4-(Deformedarse)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 235

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-carboxamid

LC/MS (ESI) m/z: 481 (M).

Example 236

3-Amino-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,4-triazole-5-carboxamide

LC/MS (ESI) m/z: 454 (MH+).

Example 237

N-((1R,2S)-2-{[(3R,4R,9bR)-4-(Methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-f]quinoline-1-yl]carbonyl}cyclohexyl)-

1H-benzimidazole-2-carboxamide

LC/MS (ESI) m/z: 488 (MH+).

Example 238

N1-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N2-phenylglycinate

LC/MS (ESI) m/z: 477 (MN+).

Example 239

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(methylamino)benzamide

LC/MS (ESI) m/z: 477 (MH+).

Example 240

2-(Dimethylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 491 (MH+).

Example 241

3-(Dimethylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 491 (MH+).

<> Example 242

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-pyrazole-4-carboxamide

LC/MS (ESI) m/z: 438 (MH+).

Example 243

4-(Acetylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)butanamide

LC/MS (ESI) m/z: 471 (MH+).

Example 244

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-indol-3-carboxamide

LC/MS (ESI) m/z: 487 (MH+).

Example 245

4-(Aminosulfonyl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 527 (MH+).

Example 246

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)cinoxacin-6-carboxamide

LC/MS (ESI) m/z: 500 (MH+).

Example 247

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)quinoline-2-carboxamide

LC/MS (ESI) m/z: 499 (MH+).

Example 248

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,-c]quinoline-1-yl]carbonyl}cyclohexyl)-2,3-dihydro-1-benzofuran-5-carboxamide

LC/MS (ESI) m/z: 490 (MH+).

Example 249

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)of-2.1-benzisoxazol-3-carboxamide

LC/MS (ESI) m/z: 489 (MH+).

Example 250

4-(1H-Imidazol-1-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 514 (MH+).

Example 251

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide

LC/MS (ESI) m/z: 502 (MH+).

Example 252

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-yl)benzamid

LC/MS (ESI) m/z: 544 (MH+).

Example 253

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1,3-benzothiazol-6-carboxamide

LC/MS (ESI) m/z: 505 (MH+).

Example 254

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-6-piperidine-1-iniatiated

LC/MS (ESI) m/z: 532 (MH+).

Example 255

4-Cyano-2-fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 490 (MH+).

Example 256

4-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-methylbenzamide

LC/MS (ESI) m/z: 487 (MH+).

Example 257

4-Cyano-3-fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 491 (MH+).

Example 258

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(1H-pyrrol-1-yl)benzamid

LC/MS (ESI) m/z: 513 (MH+).

Example 259

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 488 (MH+).

Example 260

N-1H-1,2,3-Benzotriazol-6-yl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 504 (MH+).

Example 261

N-((1R,2S)-2-{[(3aR,4R,9bR)--(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(2-methyl-1,3-thiazol-4-yl)benzamid

LC/MS (ESI) m/z: 545 (MH+).

Example 262

The dihydrochloride 4-(aminomethyl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 477 (MH+).

Example 263

4-[(Acetylamino)methyl]-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 519 (MH+).

Example 264

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(1H-pyrazole-1-yl)benzamid

LC/MS (ESI) m/z: 514 (MH+).

Example 265

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(1H-1,2,4-triazole-1-yl)benzamid

LC/MS (ESI) m/z: 515 (MH+).

Example 266

4-[(2-Hydroxyethyl)amino]-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 507 (MH+).

Example 267

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(4-methylpiperazin-1-yl)benzamid

The x/MS (ESI) m/z: 546 (MH +).

Example 268

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-morpholine-4-benzamide

LC/MS (ESI) m/z: 533 (MH+).

Example 269

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-carboxamid

LC/MS (ESI) m/z: 519 (MH+).

Example 270

4-[(2-Hydroxyethyl)(methyl)amino]-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 521 (MH+).

Example 271

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(2-methyl-1H-imidazol-1-yl)benzamid

LC/MS (ESI) m/z: 528 (MH+).

Example 272

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(4-methyl-1H-imidazol-1-yl)benzamid

LC/MS (ESI) m/z: 528 (MH+).

Example 273

4-[(2-Methoxyethyl)(methyl)amino]-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 535 (MH+).

Example 274

4-Cyano-3-methoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 503 (MH+).

Example 275

3-Cyano-4-methoxy-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 503 (MH+).

Example 276

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1,2-dimethyl-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 516 (MH+).

Example 277

N-[4-(1H-Imidazol-1-yl)phenyl]-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 529 (MH+).

Example 278

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(methylsulphonyl)benzamid

LC/MS (ESI) m/z: 526 (MH+).

Example 279

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2-methyl-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 502 (MH+).

Example 280

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(is ethoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-2-phenyl-1H-imidazol-4-carboxamid

LC/MS (ESI) m/z: 514 (MH+).

Example 281

4-(1H-Imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

To a solution of hydrochloride (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}of cyclohexanamine (200 mg, to 0.480 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0,199 ml, 1.44 mmol), 4-(1H-imidazol-2-yl)benzoic acid (99,0 mg, 0,529 mmol) and DEPC (0,079 ml, 0,529 mmol) under ice cooling and the mixture was stirred at room temperature for 1 hour. To the reaction solution were added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-4:1) to obtain the specified title compound (150 mg, 61%) as an amorphous substance.

1H-NMR (CDCl3) δ: 1,25-2,50 (11N, m), 2,96-to 2.99 (1H, m), 3,34-of 3.42 (5H, m), 3,54 is 3.57 (2H, m), 3,70-and 3.72 (1H, m), 4,17 (1H, m), 4,30 (1H, m), 5,64 (1H, d, J=6.6 Hz), of 6.52 (1H, d, J=7.5 Hz), of 6.68 (1H, DD, J=7,5, 7.5 Hz), 7,02 (1H, DD, J=7,5, 7.5 Hz), 7,15-7,20 (2H, m), of 7.36 (1H, d, J=7.5 Hz), 7,42 (1H, d, J=7.5 Hz), 7,83-to 7.93 (4H, m).

LC/MS (ESI) m/z: 514 (MN+).

Example 282

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3A,4,5,9b-g is kagero-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-2-(trifluoromethyl)-1H-benzimidazole-5-carboxamide

LC/MS (ESI) m/z: 556 (MN+).

Example 283

T-(4-Cyano-3-were)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2 - c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 502 (MH+).

Example 284

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(1H-pyrazole-1-yl)phenyl]urea

To a suspension of 4-(1H-pyrazole-1-yl)benzoic acid (271 mg, 1.44 mmol) in toluene (5 ml) was added at room temperature triethylamine (0,200 ml, 1.44 mmol) and diphenylphosphoryl (0,310 ml, 1.44 mmol) and the mixture was stirred at 80°C for 2 hours. This reaction mixture was allowed to cool to room temperature and added dropwise to a solution of dihydrochloride of (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}-cyclohexanamine (200 mg, to 0.480 mmol) and triethylamine (0,200 ml, 1.44 mmol) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 3 hours, was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate, dried over anhydrous MgSO4and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using the receiving of silica gel and was suirable a mixture of hexane-ethyl acetate (5:5-0:1) to obtain the specified title compound (194 mg, 76%) as an amorphous substance.

1H-NMR (CDCl3) δ: 0,86-2,14 (7H, m), 2,28 of-2.32 (2H, m), with 2.93 (1H, m), 3,32 is 3.40 (5H, m), 3,52-the 3.65 (3H, m), 3,81-3,93 (2H, m), 4,11-4,19 (2H, m), to 5.57 (1H, d, J=6, 9 Hz), 6,07 (1H, d, J=6.0 Hz), 6,41-6,44 (1H, m), 6,50 (1H, d, J=7.8 Hz), only 6.64 (1H, DD, J=7,4,-7,4 Hz), 7,01 (1H, DD, J=7,8, and 7.8 Hz), 7,15-7,16 (1H, m), 7,39 (2H, d, J=8,9 Hz), 7,51 (2H, d, J=8,9 Hz), of 7.70 (1H, s), 7,79 (1H, s).

LC/MS (ESI) m/z: 529 (MH+).

Example 285

N-(3-Cyano-4-methoxyphenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 518 (MN+).

Example 286

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)--6-morpholine-4-iniatiated

LC/MS (ESI) m/z: 534 (MH+).

Example 287

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-6-(2-methyl-1H-imidazol-1-yl)nicotinamide

LC/MS (ESI) m/z: 529 (MH+).

Example 288

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-6-(1H-pyrazole-1-yl)nicotinamide

LC/MS (ESI) m/z: 515 (MH+).

Example 289

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-(6-morpholine-4-espiridion-yl)urea

LC/MS (ESI) m/z: 549 (MH+).

Example 209

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(1,3-oxazol-5-yl)benzamid

LC/MS (ESI) m/z: 515 (MH+).

Example 291

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-thiomorpholine-4-ylbenzene

LC/MS (ESI) m/z: 549 (MH+).

Example 292

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(Methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(1-oxidatively-4-yl)benzamid

To a solution of compound (398 mg, 0,725 mmol) of Example 291 in tetrahydrofuran (7 ml) was added an aqueous solution (7 ml) peroxymonosulfate potassium (267 mg, 0,435 mmol) at 0°C and the mixture was stirred at the same temperature for 1 hour. Was added a saturated aqueous sodium thiosulfate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate (7:3-0:1) to obtain the specified title compound (191 mg, 47%) as a colourless oil.

LC/MS (ESI) m/z: 565 (MH +).

The following compounds of Example 293 Sample 310 synthesized by converting them into amido - or urea-derivatives using [2-((3aR,4R,9bR)-1-{[(1S,2R)-2-aminocyclohexanol]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]Metreveli and then removing pivaloyloxymethyl group in the same manner as in Example 81.

Example 293

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-N'-prilocaine

LC/MS (ESI) m/z: 485 (MH+).

Example 294

(2E)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-[4-(trifluoromethyl)phenyl]acrylamide

LC/MS (ESI) m/z: 564 (MH+).

Example 295

N-Ethyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 437 (MH+).

Example 296

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-4-(trifluoromethyl)benzamid

LC/MS (ESI) m/z: 538 (MH+).

Example 297

(2E)-3-(4-Forfinal)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)acrylamide

LC/MS (ESI) m/z: 514 (MH+).

Example 298

N-(4-Forfinal)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 503 (MH+).

Example 299

N-Butyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 465 (MH+).

Example 300

(2E)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-Tien-2-ylacrylic

LC/MS (ESI) m/z: 502 (MH+).

Example 301

3-Chloro-4-fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 522 (MH+).

Example 302

2-Fluoro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 488 (MH+).

Example 303

4-Chloro-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 504 (MH+).

Example 304

4-Cyano-N-((1R,2S)-2-{[(3aR,4R9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

The dihydrochloride [2-((3aR,4R,9bR)-1-{[(1S,2R)-2-aminocyclohexanol]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]methylphenidate (7,16 g, 13,0 mmol) was dissolved in ethyl acetate (170 ml) was added under cooling with ice and 10% aqueous sodium carbonate solution (140 ml) and 4-cyanobenzoate (2,59 g, 15.6 mmol). The reaction mixture was stirred at room temperature for 2 hours and the separated aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-10:1, vol/about.) obtaining an amorphous substance. This substance was dissolved in methanol (200 ml)was added dropwise to 28% aqueous ammonia (100 ml) and the mixture was stirred for 5 hours. The solvent is evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel and was suirable a mixture of ethyl acetate-methanol (1:0-5:1, vol/about.) obtaining specified in the connection header (6,06 g, 94%) as an amorphous substance.

1H-NMR (CDCl3)δ: 1,34-to 2.06 (9H, m), 2,11-to 2.29 (1H, m), 2,44-of 2.56 (1H, m), 2,62-to 2.74 (1H, m), 2,89-of 2.97 (1H, m), 3.43 points-of 3.60 (2H, m), 4,20-4,32 (2H, m), 4,88 (1H, d, J=3.0 Hz), 5,70 (1H, d, J=7.5 Hz), 6,54-of 6.61 (1H, m), 6,74-PC 6.82 (1H, m), 7,00-7,10 (3H, m), 7,40-7,49 (2H, m), 7,69 for 7.78 (2H, m), 7,88-to 7.99 (2H, m), and 9.6 (1H, user. C).

LC/MS (ESI) m/z: 495 (MH+).

Example 305

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-(trifluoromethyl)benzamid

LC/MS (ESI) m/z: 538 (MH+).

Example 306

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)- 2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)terephthalamide

LC/MS (ESI) m/z: 513 (MH+).

Example 307

N-(4-Cyanophenyl)-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

LC/MS (ESI) m/z: 510 (MH+).

Example 308

3-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 495 (MH+).

Example 309

4-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-3-methylbenzamide

LC/MS (ESI) m/z: 509 (MH+).

Example 310

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamid

LC/MS (ESI) m/z: 511 (MH+).

Example 311

(1R,2S ∗,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl)cyclohexanecarboxylic

and

(1SThat 2R)-N-phenyl-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexanecarboxylic (racemate)

To a mixture of compound (242 mg, 0.75 mmol)synthesized in Reference Example 8, (1SThat 2R)-2-(anilinoacrolein)cyclohexanecarboxylic acid (222 mg, 0.90 mmol) and triethylamine (0,313 ml, 2.25 mmol) in DMF (7.5 ml) was added DEPC (0,151 ml, 0.90 mmol) at 0°C and the mixture was stirred at room temperature for 1 hour. Was added a saturated aqueous solution of sodium bicarbonate and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous Na2SO4. The solvent is evaporated under reduced pressure, the obtained residue was subjected to column chromatography on silica gel and was suirable a mixture of hexane-ethyl acetate (2:1, vol/vol.). Specified in the header of the compound (1R,2S,3aR,4R,9bR) (163 mg, 45%) was obtained as white solids from the faction, eluruumi first.

LC/MS (ESI) m/z: 480 (MH+).

Specified in the title compound (1SThat 2R,3aR,4R,9b) (76 mg, 21%) was obtained as white solids from the faction, eluruumi second.

LC/MS (ESI) m/z: 480 (MH+).

Example 312

N-(1-{2-Oxo-2-[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]ethyl}cyclohexyl)benzamide

Specified in the title compound was synthesized in the same manner as in Example 1, using [1-(benzoylamine)cyclohexyl]acetic acid.

LC/MS (ESI) m/z: 494 (MH+).

Example 313

N-[(1-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)methyl]benzamide

Specified in the title compound was synthesized in the same manner as in Example 1, using 1-[(benzoylamine)methyl]cyclohexanecarbonyl acid.

LC/MS (ESI) m/z: 494 (MH+).

Example 314

N-(4-{2-Oxo-2-[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]ethyl}tetrahydro-2H-Piran-4-yl)benzamid

Specified in the title compound was synthesized in the same manner as in Example 1, using [4-(benzoylamine)tetrahydro-2H-Piran-4-yl]acetic acid.

LC/MS (ESI) m/z: 496 (MH+).

Example 315

N-((1S,2S)-2-{[(3aR,4R,9bR)-4-Phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-yl]carbonyl}-cyclohexyl)benzamide

Specified in the title compound was synthesized in the same manner as in Example 1 using (1S,2S)-2-(benzoylamine)cyclohexanecarbonyl acid.

LC/MS (ESI) m/z: 480 (MH+).

Example 316

N-{(1R,2S)-2-[(3aR,4R,9bR)-(5-Acetyl-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}benzamide

Compound (130 mg, 0.27 mmol) of Example 1 and triethylamine (69 mg, 0.30 mmol) was dissolved in chloroform (2 ml), was added under cooling with ice acetylchloride (99 mg, 0.33 mmol) and the mixture was stirred at room temperature for 1 hour and at 60°C for 2 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated. The residue was subjected to column chromatography using silica gel (150 g) and suirable a mixture of hexane-ethyl acetate (3:1-0:1, vol/about.) obtaining specified in the title compound (65 mg, 46%) as an amorphous substance.

LC/MS (ESI) m/z: 522 (MH+).

Example 317

N-((1R,2S)-2-{[(4aR,5R,10bR)-5-Phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-yl]carbonyl}cyclohexyl)benzamide

To tert-butyl ((1R,2S)-2-{[(4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydrobenzo[h]-1,6-naphthiridine-1(2H)-yl]carbonyl}cyclohexyl)carbamate (69 mg, 0.14 mmol) was added TFA (1 ml) and the mixture was stirred at room temperature for 3 minutes. To the reaction solution was added ice and the mixture was podslushivaet 8 N. aqueous sodium hydroxide solution and was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The obtained residue was dissolved in dimethylacetamide (2 ml)was added at 0°C. benzoyl chloride (28 mg, 0,17 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and suirable a mixture of hexane-ethyl acetate (7:1-3:1, vol/about.) obtaining specified in the title compound (45 mg, 65%) as a colorless amorphous substance.

LC/MS (ESI) m/z: 494 (MH+).

Example 318

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclopentyl)benzamide

To tert-butyl (3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]hee the Olin-1-carboxylate (178 mg, 0.5 mmol) was added TFA (1 ml) and the mixture was stirred at room temperature for 3 minutes. To the reaction solution was added ice and the mixture was podslushivaet 8 N. aqueous sodium hydroxide solution and was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml) was added (1S,2R)-2-(benzoylamine)cyclopentanecarbonyl acid (117 mg, 0.5 mmol) and triethylamine (101 mg, 1.0 mmol). Was added at 0°C DEPC (82 mg, 0.5 mmol) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (5:1-2:1, about./about.) obtaining specified in the title compound (104 mg, 44%) as a colorless powder.

LC/MS (ESI) m/z: 472 (MH+).

Example 319

N-Phenyl-N'-((1R,2S)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea

In the same way as When the ore 135, using dihydrochloride of (1R,2S)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexylamine, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 495 (MH+).

Example 320

N-(1-{2-Oxo-2-[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]ethyl}cyclohexyl)-N'-prilocaine

LC/MS (ESI) m/z: 509 (MH+).

Example 321

N-((1R,2S)-2-{[(3aS,4S,9bS)-4-(1H-Imidazol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

Specified in the title compound was synthesized in the same manner as in Examples 80 and 81, using the dihydrochloride [2-((3aS,4S,9bS)-1-{[(1S,2R)-2-aminocyclohexanol]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]methylphenidate.

LC/MS (ESI) m/z: 470 (MH+).

The compound of Example 322 and Example 323 synthesized by amidation using benzyl 2-((3aR,4R,9bR)-1-{[(1S,2R)-2-aminocyclohexanol]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-pyrrole-1-carboxylate, with the subsequent removal of the Cbz group in the same manner as in Example 64.

Example 322

4-Cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

LC/MS (ESI) m/z: 494 (MH+).

<> Example 323

N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-Pyrrol-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)terephthalamide

LC/MS (ESI) m/z: 512 (MH+).

Example 324

(3aS,4S,9bS)-1-{[(2R)-1-Benzoylpiperidine-2-yl]carbonyl}-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline

Specified in the title compound was synthesized in the same manner as in Example 75, using the dihydrochloride (3aS,4S,9bS)-4-phenyl-1-[(2R)-piperidine-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline.

LC/MS (ESI) m/z: 466 (MH+).

Example 325

N-((1R,2S)-2-{[4-(3-Thienyl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

A mixture of N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide and N-((1R,2S)-2-{[(3aS,4R,9bS)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide (422 mg, 0.87 mmol) was dissolved in toluene (30 ml)was added manganese dioxide (7.6 g, 87 mmol) and the mixture was subjected to boiling under reflux overnight. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica compound is El (30 g) and suirable a mixture of hexane-ethyl acetate (9:1-2:1, about./vol.). Crystallization from diisopropyl ether gave specified in the title compound (70 mg, 17%) as pale-brown crystals.

LC/MS (ESI) m/z: 482 (MH+).

Example 326

N-Phenyl-N'-{(1R,2S)-2-[(4-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)carbonyl]cyclohexyl}urea

In the same way as in Example 325, using N-phenyl-N'-((1R,2S)-2-{[(3aS,4S,9bS)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)urea was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 491 (MH+).

Example 327

Ethyl 1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-4-carboxylate

In the same way as in Example 325, using ethyl 1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-carboxylate was synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 472 (MH+).

Example 328

N-((1R,2S)-2-{[4-(1H-Imidazol-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}cyclohexyl)benzamide

In the same way as in Example 325, [2-((3aR,4R,9bR)-1-{[(1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]Metreveli was subjected to oxidation reaction for the synthesis of [2-(1-{[1S,2R)-2-(benzoylamine)cyclohexyl]carbonyl}-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-4-yl)-1H-imidazol-1-yl]methylphenidate, and then specified in the title compound was synthesized in the same manner as in Example 81 by deleting pivaloyloxymethyl group.

LC/MS (ESI) m/z: 466 (MH+).

Example 329

N-{1-[2-Oxo-2-(4-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline-1-yl)ethyl]cyclohexyl}benzamide

To a mixture of {1-[(anilinoacrolein)amino]cyclohexyl}acetic acid (0,551 g, 2,11 mmol) and DMF (0,016 ml) in dichloromethane (20 ml) was added dropwise oxalicacid (0,275 ml, 3,17 mmol). After stirring for 1 hour the solvent is evaporated to obtain the corresponding chlorhydric acid in powder form. To a solution of 4-phenyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (0,346 g of 1.41 mmol) in toluene (10 ml) was added sodium hydride (60% in oil, 0,0676 g, 1,69 mmol) and the mixture was stirred for 30 minutes. Solution was added the above chlorhydric acid in dichloromethane (10 ml), the mixture was stirred at room temperature for 1 hour and at 60°C for 16 hours. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate and the separated organic layer was washed with saturated saline solution and dried (over anhydrous MgSO4). After concentration under reduced pressure, the obtained residue was subjected to column chromatography using silica gel and was suirable a mixture of hexane-ethyl acetate(9:1-2:3, about/about) obtaining from the target fraction specified in the title compound (0.17 g, 25%) as a colorless amorphous substance.

LC/MS (ESI) m/z: 490 (MH+).

Example 330

(2R)-N-(2-Phenylethyl)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}piperidine-1-carboxamide

In the same manner as in Example 135 using the dihydrochloride (3aS,4S,9bS)-4-phenyl-1-[(2R)-piperidine-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline and geneticization, synthesized specified in the header of the connection.

LC/MS (ESI) m/z: 509 (MH+).

Example 331

N-(2-{[(3aR,4R,9bR)-4-(3-Thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-yl]carbonyl}phenyl)benzamide

To tert-butyl (3aR,4R,9bR)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (219 mg, 0.61 mmol) was added TFA (1 ml) and the mixture was stirred at room temperature for 3 minutes. To the reaction solution was added ice and the mixture was podslushivaet 8 N. aqueous sodium hydroxide solution and was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml) was added 2-(benzoylamine)benzoic KIS the GTC (162 mg, 0.67 mmol) and triethylamine (124 mg, 1.2 mmol). Was added at 0°C DEPC (99 mg, 0.61 mmol) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed 6% aqueous solution of sodium bicarbonate and saturated saline solution, dried (over anhydrous MgSO4) and the solvent evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g) and suirable a mixture of hexane-ethyl acetate (9:1-3:1, vol/about.) obtaining specified in the title compound (126 mg, 43%) as colorless crystals.

LC/MS (ESI) m/z: 480 (MH+).

Example of formulation composition 1

(1) Connection Example 110.0 g
(2) Lactose70,0
(3) Corn starch50.0 g
(4) Soluble starch7.0 g
(5) magnesium Stearate3.0 g

The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) was granulated with an aqueous solution of soluble starch (70 ml, 7.0 g per soluble starch), sushi and mixed with lactose (70,0) and corn starch (50.0 g) (lactose, corn starch, soluble starch and magnesium stearate - all products that can be found in the Japanese Pharmacopoeia 14th ed.). The mixture was extruded to obtain pellets.

Experimental Example 1

Effect on inhibition of binding of the radioactive ligand to the receptor in the membrane fraction of CHO cells expressing the receptor hNK2

Expressing hNK2 receptor CHO cells (obtained from EUROSCREEN) were cultured in medium HAM-F12 containing 400 μg/ml Geneticin, 100 U/ml penicillin, 100 μg/ml of streptomycin and 10% inactivated serum. The medium was removed and fused cells were washed using PBS was added in PBS containing 5 mm EDTA to extract the cells from the flask. The cells were recovered by centrifugation, suspended in suspendium buffer A (15 mm Tris-HCl (pH 7.5), 2 mm MgCl2, 0.3 mm EDTA, 1 mm EGTA), were separated using a homogenizer transmitter station (manufactured by KINEMATICA) and centrifuged at 800×g for 10 minutes. The supernatant was removed and centrifuged at 100000×g for 25 minutes. Settled solids suspended in suspendium buffer B (7.5 mm Tris-HCl (pH 7.5), 12.5 mm MgCl2, 0.3 mm EDTA, 1 mm EDTA, 250 mm sucrose) and subjected to cryopreservation (-80°C) as the sample receptor.

Buffer for analysis (50 μl, 50 mm Tris-HCl (pH of 7.4), 0.02% of bovine serum albumin, 2 mg/ml hemostasia, 40 μg/ml bacitracin, 40 μg/ml APMSF, 3 mm MnCl 2) were added to 96-well analytical microplate. To the mixture was added to the sample membranes 20 μg/ml, suspended in buffer for analysis (50 μl). Buffer for analysis (50 μl)containing 2% dimethyl sulfoxide was added for analysis of total binding, a solution of 4 ám its NKA (manufactured by Peptide Institute, Inc.) (50 μl)diluted with buffer for analysis containing 2% dimethyl sulfoxide was added for analysis of nonspecific binding, and the test compound, diluted with buffer for analysis (50 µl, containing 2% dimethyl sulfoxide)was added to analyze the activity of the test compounds on the inhibition of binding. In addition, to each well was added a solution (50 μl) 400 µm [125I]-NKA (manufactured by Amersham Biosciences).

The reaction was carried out at 25°C for 30 minutes, then stopped using rapid filtration on a filter plate (GF/C) (manufactured by PerkinElmer)using the device to collect cells (manufactured by PerkinElmer), and the cells were washed 5 times with buffer 50 mm Tris-HCl (pH 7,4)containing 0.02% of bovine serum albumin (250 μl). The filter plate GF/C was dried and added 20 μl Scinti-O (manufactured by PerkinElmer) and radioactivity was measured using a Topcount (manufactured by PerkinElmer). Used filter plate GF/C, which before it was immersed for one day in 0.3% polyethylenimine.

Specific binding is represented by a value obtained by subtracting nonspecific binding from total binding. The activity of the test compounds on the inhibition of binding is represented by the ratio of the magnitude obtained by subtracting the value obtained by adding the test compounds from the total binding to the magnitude of the specific binding.

The results are presented in Table 6.

td align="center"> 99
Table 6
Example No.Activity by inhibition of binding of hNK2 receptor, IR50(nm)
1<10
6<10
7<10
8<10
9<10
15<10
16<1
17<10
18<1
19<10
20<10
23<10
25<10
27<10
28<10
29<10
51<10
52<10
53<10
54<1
56<10
58<10
59<10
60<1
61<10
62<1
63<1
64<1
66<10
6875<10
76<10
78<10
79<10
81<1
82<10
83<10
85<10
86<10
87<10
89<10
90<1
91<10
92<10
93<10
94<10
95<10
96<10
97<10
98<1
<10
100<10
101<1
102<10
103<1
104<1
105<1
106<10
107<1
108<10
109<10
114<10
116<10
117<10
119<10
120<10
127<10
128<10
129<10
132<10
133 <1
134<1
135<1
136<10
137<1
138<1
139<1
140<10
141<10
143<10
144<10
145<10
146<10
147<10
148<1
149<10
150<10
151<10
152<10
153<1
154 <1
155<10
156<10
159<10
160<1
161<10
162<10
164<1
166<1
168<10
170<10
171<10
172<10
173<10
175<10
178<10
180<1
181<1
182<1
183<1
184<1
185<10
186<1
187<1
188<1
189<1
190<1
191<1
192<1
193<1
194<1
195<1
196<1
197<1
198<10
199<10
200<1
201<1
202<1
204<1
205<1
206<1
208<1
209<1
210<1
211<10
212<1
213<1
215<1
216<10
217<1
218<1
219<1
229<1
232<10
233<10
234<1
237<1
238<10
239<1
241<10
244 <10
245<10
246<10
247<10
248<1
249<10
250<1
252<1
253<10
254<1
256<1
258<1
259<10
261<1
263<10
264<1
265<1
266<10
267<10
268<10
269<1
270<10
271<10
272<1
273<1
274<10
275<1
276<10
277<1
278<10
279<1
280<1
281<1
282<10
283<1
284<1
285<1
286<10
287<10
288<1
289<10
290<1
291<1
293<1
294<1
295<10
296<1
297<1
298<1
299<1
300<1
301<1
302<1
303<1
304<1
305<1
306<10
307<1
308<1
309<1
310<1
312 <10
321<10
322<1
323<1
326<10

Experimental Example 2

Evaluation of antagonistic activity, determined by intracellular calcium concentration using the test connection, Neirokinina A and CHO cells expressing the receptor hNK2

The CHO cells expressing the receptor hNK2, were sown in 96-well plates at a density of 3×104cells/well and were cultured for 24 hours. Then the medium was removed by aspiration and add 20 mm HEPES buffer (pH 7,4)-HBSS (50 μl). To the mixture was added to the prepared buffer 1×Reagent (50 ál, FLIPR Calcium Assay Kit, Molecular Devices Corporation, Japan) and the mixture was allowed to react at 37°C for 1 hour. The test compound diluted in 20 mm HEPES buffer (pH 7,4)-HBSS (50 μl containing 0.4% DMSO)was added to study the antagonistic activity of the test compounds. Then added a 20 nm solution Neirokinina And (50 μl) and changes in intracellular calcium concentration was measured using FLIPR (Molecular Devices Corporation, Japan). In the result it was found that the test compound inhibited the increase Nutrilite the Noy concentration of calcium, caused by Neirokinina A. the Results are presented in Table 7.

Table 7
Analysis of antagonistic activity
Test connectionThe rate of inhibition (%)
10 µm1 micron
Connection Example 19745

Industrial applicability

Since the compound (I) of the present invention, its salt and its prodrug possess antagonistic activity against receptor NK2 and have low toxicity, they are particularly useful as a means for the prevention and/or treatment of functional gastrointestinal disorders (e.g. irritable bowel syndrome, non-ulcer dyspepsia, etc.

This application is based on patent application No. 2004-134705 filed in Japan, the contents of which are fully incorporated into the present application by reference.

1. The compound represented by formula (I)

where R1means
(1) no substitution
(2) a hydrogen atom,
(3) (C1-6lkyl or
(4)1-6alkyl-carbonyl;
R2means
(1) a hydrogen atom,
(2) C1-6alkyl, optionally contains 1-3 substituent selected from (1') hydroxy, (2') C1-6alkoxy, (3') C7-12aralkylated, (4') a mono - or di-C1-6alkylamino, (5') N-C1-6alkoxy-carbonyl-N-C1-6alkylamino, (6') amino, (7') C1-6alkyl-carbylamine, optionally containing 1-3 halogen atoms, (8') C7-12Arakelov-carbylamine and (9') C1-6alkoxycarbonyl, optionally containing 1-3 atoms of halogen;
(3) (C3-8cycloalkyl,
(4)6-10aryl, optionally contains 1-3 substituent selected from (1') halogen, (2') C1-6the alkyl, optionally containing 1-3 atoms of halogen, (3') cyano, (4') C1-6alkoxycarbonyl and (5') C1-6alkylthio;
(5) C1-6alkoxy-carbonyl, or
(6) a 5-6-membered heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, optionally containing a Deputy(deputies)selected from (1') hydroxy, (2')1-6the alkyl, optional with C1-6alkylcarboxylic, (3') C7-19aralkyl, optional with C1-6alkoxy, (4')7-12aralkylated, (5') C7-12Arakelov-carbonyl, (6') a mono-C1-6alkyl-carbarnoyl and (7') C1-6alkoxy-carbonyl;
R3means
(1) the absence of samase the Oia,
(2) a hydrogen atom, or
(3) C1-6alkyl;
R4means a hydrogen atom;
R5means a hydrogen atom;
R6means
(1) a group represented by the formula

where ring a is a cyclopentane, cyclohexane or bicyclo[2.2.2]octane;
R11means
(1')1-6alkyl-carbylamine, optionally containing substituent(s) selected from (1") halogen, (2") hydroxy, (3") C1-6alkoxy-carbonyl, (4") mono - or di-C1-6alkylamino, optionally substituted hydroxy, (5") morpholino, (6") C1-6alkylcarboxylic, (7") carbamoylating, (8") a 5-6-membered aromatic heterocyclic group having from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, (9")6-10arylamino, (10") (5-6-membered aromatic heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom), carbylamine and (11") C1-6alkoxy;
(2')2-6alkenyl-carbylamine, optionally containing substituent(s)selected from (1")6-10aryl, optionally having substituent(s)selected from halogen, C1-6of alkyl, C1-6alkoxy and halogen-C1-6of alkyl and (2") a 5-6-membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from a nitrogen atom, atom CI is the oxygen and sulfur atom, optional with C1-6alkyl;
(3')3-8cycloalkyl-carbylamine,
(4')6-10aryl-carbylamine, optionally having substituent(s)selected from (1") halogen, (2") cyano, (3") C1-6the alkyl, optionally having the amino or C1-6alkylcarboxylic, (4) halogen-C1-6of alkyl, (5") hydroxy-C1-6of alkyl, (6")1-6alkoxy, (7") carboxy, (8") C1-6alkoxy-carbonyl, (9") mono - or di-C1-6alkylamino, optionally substituted by hydroxy or C1-6alkoxy, (10") carbarnoyl, (11") halogen-From1-6alkoxy, (12")1-6alkylcarboxylic, (13") aminosulfonyl, (14") C1-6alkylsulfonyl, and (15") 5-6-membered heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or a condensed group of benzene and 5-6-membered heterocyclic group having 1 to 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom which may have a substituent(s)selected from C1-6the alkyl and oxo;
(5')7-12aralkyl-carbylamine,
(6') C1-6alkoxy-carbylamine,
(7') (5-6-membered heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or a condensed ring group of the benzene with a 5-6-membered heterocyclic group having from 1 to 3 heteroa the Ohm selected from a nitrogen atom, oxygen atom and sulfur atom), carbylamine, which may have a substituent(s)selected from (1") amino, (2") C1-6of alkyl, (3) halogen-C1-6of alkyl, (4")6-10aryl, (5") oxo and (6") 5 - or 6-membered heterocyclic group having 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, with optional C1-6alkyl,
(8') carbamylcholine,
(9') 3-C1-6alkyl-ureido, optionally having substituent(s)selected from (1") hydroxy, (2") carboxy, (3") C1-6alkoxy, (4") C1-6alkoxy-carbonyl, (5") C1-6alkoxy-carbylamine, (6") amino, (7) halogen, (8) carbamoyl, (9") C1-6alkylsulfonyl, (10") a 5-6-membered heterocyclic group having 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, optionally substituted by oxo and (11") C1-6alkyl-carbylamine;
(10') 3-C3-8cycloalkyl-ureido,
(1G) 3-C6-10aryl-ureido, optionally having substituent(s)selected from (1") halogen, (2") cyano, (3) halogen-C1-6of alkyl, (4") C1-6of alkyl, (5")1-6alkoxy, (6") methylenedioxy, (7") C1-6alkoxy-carbonyl, (8") of carbamoyl and (9") 5-6-membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom;
(12') 3-C1-6alkyl-3-C6-10aryl-ureido,
(13') 3-is 7-12aralkyl-ureido, optionally having substituent(s)selected from (1") halogen, and (2) With1-6alkoxy,
(14') 3-C1-6alkoxy-ureido,
(15') 3-(5-6-membered heterocyclic group having 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or a condensed ring group of a benzene ring with a 5-6-membered heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom), ureido, which may have a 5-6-membered heterocyclic group having 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom;
(16') piperidylamine, optional with C1-6alkyl-carbonyl, or
(17') phthalimido,
(2) a group represented by the formula:

where R12means
(1')6-10aryl-carbonyl, optionally having halogen-C1-6alkyl, or
(2')6-10aryl-aminocarbonyl; m is 0 or 1; and p is 0 or 1;
(3) a group represented by the formula

where R13means6-10aryl-carbonyl,
(4) a group represented by the formula

where the ring is piperidine ring, optionally substituted amino; R14means (1')6-10aryl-carbonyl or (2') C7-12aralkyl-carbarnoyl, or
(5) group, before the purposes of the formula

where R15means6-10aryl-carbonyl; r is 0 or 1; and s is 0 or 1;
R7represents a hydrogen atom;
R8represents (1) hydrogen atom, (2) halogen, (3) C1-6alkyl, optionally having 1 to 3 halogen atoms, or (4) C1-6alkoxy;
R9represents (1) hydrogen atom, (2) halogen, (3) cyano, (4) C1-6alkyl or (5) C1-6alkoxy;
R10represents (1) hydrogen atom, (2) halogen, or (3) C1-6alkyl; and
n is 2 or 3,
--- is the lack of a replacement or a simple bond; and
represents a simple bond or a double bond, or its salt.

2. The compound according to claim 1,
where R1means
(1) no substitution
(2) a hydrogen atom,
(3) C1-6alkyl or
(4)1-6alkyl-carbonyl;
R2means
(1) a hydrogen atom,
(2) C1-6alkyl, optionally contains 1-3 substituent selected from (1') hydroxy, (2')1-6alkoxy, (3')7-12aralkylated, (4') a mono - or di-C1-6alkylamino and (5') N-C1-6alkoxy-carbonyl-N-C1-6alkylamino;
(3) (C3-8cycloalkyl,
(4)6-10aryl, optionally contains 1-3 substituent selected from (1') halogen, (2') C1-6the alkyl, optionally containing 1-3 atoms of halogen, (3') cyano and (4') C1-6alkoxycarbonyl or
(5) 56-membered aromatic heterocyclic group, having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, optionally containing a Deputy(deputies)selected from (1') hydroxy, (2')
C1-6the alkyl, optional with C1-6alkylcarboxylic, (3') C7-19aralkyl, optional with C1-6alkoxy and (4')7-12aralkylated;
R3means
(1) no substitution
(2) a hydrogen atom, or
(3) C1-6alkyl;
R4represents a hydrogen atom;
R5represents a hydrogen atom;
R6means
(1) a group represented by the formula

where ring a is a cyclopentane, cyclohexane or bicyclo[2.2.2]octane;
R11means
(1') C1-6alkyl-carbylamine, optionally containing substituent(s)selected from (1") halogen, (2") hydroxy, (3")1-6alkoxy-carbonyl, (4") CI-C1-6alkylamino and (5) of morpholino;
(2')3-8cycloalkyl-carbylamine,
(3')6-10aryl-carbylamine, optionally having substituent(s)selected from (1") halogen, (2") cyano, (3")1-6of alkyl, (4) halogen-C1-6of alkyl, (5") hydroxy-C1-6of alkyl, (6") C1-6alkoxy, (7") carboxy, (8") C1-6alkoxy-carbonyl and (9) halogen-C1-6alkoxy;
(4')7-12aralkyl-carbylamine,
(5') C1-6alkoxy-carbonylation is,
(6') (5-6-membered aromatic heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom), carbylamine,
(7') piperidinecarboxylate,
(8') 3-C1-6alkyl-ureido, optionally having substituent(s)selected from (1") hydroxy, (2") carboxy, (3") C1-6alkoxy and (4") C1-6alkoxy-carbonyl;
(9') 3-C3-8cycloalkyl-ureido,
(10') 3-C6-10aryl-ureido, optionally having substituent(s)selected from (1") halogen, (2") cyano, (3) halogen-C1-6of alkyl, (4") C1-6of alkyl, (5") C1-6alkoxy and (6) of methylendioxy;
(11') 3-C7-12aralkyl-ureido, optionally having substituent(s)selected from (1") halogen, and (2") C1-6alkoxy,
(12') 3-(5-6-membered aromatic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom), ureido;
(13') piperidinium, optional with C1-6alkyl-carbonyl, or
(14') phthalimido,
(2) a group represented by the formula:

where R12means
(1')6-10aryl-carbonyl, optionally having halogen-C1-6alkyl; m is 0 or 1; and p is 0 or 1;
(3) a group represented by the formula

where R13means6-10aryl-carbonyl, or
(4) a group represented by the formula

where the ring is piperidine ring; R14means (1')6-10aryl-carbonyl or (2')7-12aralkyl-carbonyl,
R7represents a hydrogen atom;
R8represents (1) hydrogen atom, (2) halogen, (3) C1-6alkyl, optionally having 1 to 3 halogen atoms, or (4)1-6alkoxy;
R9represents (1) hydrogen atom, (2) halogen, (3) cyano, (4)1-6alkyl or (5) C1-6alkoxy;
R10represents (1) hydrogen atom, (2) halogen, or (3) C1-6alkyl; and n is 2 or 3.

3. The compound according to claim 1,
where R1means a hydrogen atom.

4. The compound according to claim 1,
where R2means
(1) C1-6alkyl, optionally containing substituents selected from (1')1-6alkoxy and (2') a mono-C1-6alkylamino,
(2)3-8cycloalkyl, or
(3) (C6-10aryl, optionally containing substituted with halogen, or
(4) a 5 - or 6-membered aromatic heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom, optionally containing a Deputy(deputies)selected from (1') C1-6the alkyl.

5. The compound according to claim 1, where R3means (1) hydrogen atom or (2) C1-6alkyl.

6. The compound according to claim 1, where R6means
(1) a group represented by the formula

where ring A' means cyclohexane or bicyclo[2.2.2]octane,
R11'means
(1')1-6alkylaryl, optionally containing a Deputy (deputies)selected from (1") halogen, (2") hydroxy, (3") C1-6alkoxycarbonyl and (4) of morpholino,
(2')6-10arylcarbamoyl, optionally containing a Deputy (deputies)selected from (1") halogen, (2") cyano, (3") C1-6of alkyl, (4) halogen-C1-6of alkyl, (5") hydroxy-C1-6of alkyl, (6") C1-6alkoxy and (7") C1-6alkoxycarbonyl,
(3')7-12aralkylamines,
(4') (5 - or 6-membered aromatic heterocyclic group having from 1 to 3 heteroatoms selected from nitrogen atoms, oxygen or sulfur)-carbonyl,
(5') C1-6alkylaminocarbonyl, optionally containing a Deputy(deputies)selected from (1") hydroxy, (2") C1-6alkoxy and
(3") C1-6alkoxycarbonyl,
(6')3-8cycloalkylcarbonyl,
(7')6-10allumination, optionally containing a Deputy (deputies)selected from (1") halogen, (2") cyano, (3) halogen-C1-6of alkyl, (4") C1-6of alkyl, (5") C1-6alkoxy and (6) of methylendioxy,
(8')7-12aralkylamines, optionally containing a Deputy (deputies)selected from (1") halogen, and (2") C1-6alkoxy,
(9') (5 - or 6-membered aromatic heterocyclics the group, having 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom or sulfur atom)-aminocarbonyl or
(10') piperidinylcarbonyl, optional contains1-6alkylsulphonyl, or
(2) a group represented by the formula

where R12'means6-10arylcarbamoyl.

7. The compound according to claim 1, where R means a hydrogen atom or a halogen.

8. The compound according to claim 1, where R9means a hydrogen atom or a halogen.

9. The compound according to claim 1, where R10means a hydrogen atom or a halogen.

10. The compound according to claim 1, where n has a value of 2.

11. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl} cyclohexyl)benzamide, or its salt.

12. The compound according to claim 1 N-phenyl-N'-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl} cyclohexyl)urea, or its salt.

13. The compound according to claim 1 2-methyl-N-((1R,2S)-2-{[(3aR,4S,9bR)-4-propyl-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-1H-benzimidazole-5-carboxamide, or its salt.

14. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-1H-1,2,3-benzotriazol-5-carboxamide, or its salt.

15. The compound according to claim 1 4-(1H-imidazol-2-yl)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-and the]carbonyl}cyclohexyl)benzamide, or its salt.

16. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-N'-[4-(1H-pyrazole-1-yl)phenyl]urea or its salt.

17. The compound according to claim 1 4-cyano-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(1H-imidazol-2-yl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)benzamide or its salt.

18. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-4-(trifluoromethyl)benzamide or its salt.

19. The compound according to claim 1 4-(dimethylamino)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)benzamide or its salt.

20. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-4-(triptoreline)benzamide or its salt.

21. The compound according to claim 1 4-(deformedarse)-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)benzamide or its salt.

22. The compound according to claim 1 N-((1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3A,4,5,9b-hexahydro-1H-pyrrolo[3,2-C]quinoline-1-yl]carbonyl}cyclohexyl)-4-(methylamino)benzamide or its salt.

23. The method of obtaining the compound represented by formula (Ic)

where each symbol has the value disclosed in claim 1 or its salt, br/> (1) the reaction of condensation of the compound represented by formula (II)

where each character defined in claim 1, or its salt,
compounds represented by formula (III)

where R2defined in claim 1, or its salt, and
compounds represented by formula (IV)

where R denotes a protective group, and other symbols defined in claim 1, or its salt to obtain the compound represented by formula (Ia)

where each symbol is defined above, or its salt with subsequent removal of the protective group R, or
(2) the reaction of condensation of the compound represented by formula (II)

where each symbol is defined above, or its salt,
compounds represented by formula (III)

where R2defined above, or its salt, and
compounds represented by formula (V)

where all R are the same or different from each other and each means C1-6alkyl, P' is a protective group, and n are defined in claim 1, or its salt to obtain the compound represented by formula (Ib)

where each symbol is defined above, or its salt with subsequent removal of the protective group P', and
the interaction of the compound, presented the military formula (VI)

where each symbol is defined above, or its salt obtained above in [1] or [2], with the compound represented by formula (VII)

where R6'defined above, or its salt.

24. The NK2 receptor antagonist comprising the compound according to claim 1.

25. The pharmaceutical agent having an antagonistic effect against the NK2 receptor, comprising a compound according to claim 1.

26. Pharmaceutical product A.25, which means the agent for the prevention or treatment of functional gastrointestinal diseases.

27. Pharmaceutical product A.25, which means the agent for the prophylaxis or treatment of irritable bowel syndrome or non-ulcer dyspepsia.

28. How anthonyjasony NK2 receptor, which includes the introduction of an effective amount of a compound according to claim 1 to a mammal.

29. The method of prevention or treatment of functional gastrointestinal diseases, which includes the introduction of an effective amount of a compound according to claim 1 to a mammal.

30. The use of compounds according to claim 1 to obtain a NK2 receptor antagonist.

31. The use of compounds according to claim 1 to obtain funds for the prevention or treatment of functional gastrointestinal diseases.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of photoactivation of a photocatalyst by irradiating a composition containing the said catalyst. The method of using a photolatent catalyst (a) in which a composition containing said catalyst is irradiated before subsequent treatment is characterised by that, the photolatent catalyst is: (a1) a compound selected from a group consisting of a photolatent acid, an aromatic iodonium salt or oxime-based photolatent acid; (a2) a photolatent base compound. Also described is a substrate on which a coating made from the composition is deposited in accordance with the above described method. Also described is a method of using photolatent catalyst (a), in which a composition containing said catalyst is irradiated before subsequent treatment, characterised by that subsequent treatment is preparation of foam material and the composition contains polyol and isocyanate components and photolatent base (a2) as photolatent catalyst.

EFFECT: provision for solidification of the system.

13 cl, 10 tbl, 16 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a dynamic nuclear polarisation method of a compound which contains one or more carboxyl groups, distinguished by that, the radical of formula (I) , where M is one equivalent cation of an alkali metal; and R1, which are identical or different, each represents a C1-C6-alkyl group with a straight or branched chain or a -(CH2)n-X-R2 group, where n equals 1, 2 or 3; X is O; and R2 is a C1-C4alkyl group with a straight or branched chain, which are used a paramagnetic agent in the said dynamic nuclear polarisation process. The invention also relates to new radicals, to their use as paramagnetic agents.

EFFECT: obtaining new radicals of formula (I), which are used as paramagnetic agents in dynamic nuclear polarisation processes.

17 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a liquid composition which contains hyperpolarised 13C-pyruvate, involving: a) formation of a liquid mixture containing a radical of formula (I) , where M is hydrogen or one equivalent cation; and R1, which are identical or different, each represents hydroxylated and/or alkoxolated C1-C4-hydrocarbon group with a straight or branched chain, 13C-pyroracemic acid and/or 13C-pyruvate, and freezing this mixture; b) increasing polarisation of 13C nuclei of pyroracemic acid and/or pyruvate in this mixture through dynamic nuclear polarisation c) addition of a physiologically transferable buffer, which provides for pH in the range from 7 to 8, and a base to the frozen mixture for its dissolution and for converting 13C-pyroracemic acid to 13C-pyruvate, obtaining a liquid composition or, when at stage (a) only 13C-pyruvate is used, addition of a buffer to the frozen mixture for its dissolution, obtaining a liquid composition; and d) possible removal of the radical and/or its reaction products from the liquid composition. The invention also relates to use of such a composition and to a radical of formula (I).

EFFECT: obtaining a composition for use as MP of a visualising agent.

22 cl, 2 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new photochromic monomers and new polymers based on such monomers, intended for use in making two-photon photochromic recording media for three dimensional optical memory and photoswitches of optical signals. Description is given of monomers

Q=; ; ;

Alk=CH3-C10H21 X=Cl, Br, I, F, NH2, CH2OH, CH2Cl, CH2Br, CHO, CO2H and X=CH2, O, S, NAlk; Y=O, S, NAlk; n=0-6; Q=; ; ; ; ;

Alk=CH3-C10H21, methods of obtaining them, photochromic polymers based on them, method of obtaining photochromic monomers and their application. The proposed materials exhibit thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

EFFECT: obtaining materials with thermal irreversibility of photochromic transformations and properties, making it possible to use photochromic polymers in two-photon random access optical memory.

15 cl, 46 dwg, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

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

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

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

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

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

54 cl

Organic compounds // 2379309

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (I) in free or salt form, where Q is a bond, R1 and R2 independently represent H or C1-C8alkyl, or R3 is C1-C8alkyl, R4 and R5 independently represent halogen, C1-C8alkyl, C1-C8haloalkyl, C3-C15carbocyclic group, nitro group, cyano-group, C1-C8alkylsulphonyl group, R6 is H or C1-C8alkyl; W is a group of formula (Wa1) or (Wa2), where A independently represents C or N, or W represents a group of formula (Wb); where Y independently represents C or N; and Z represents N, O or S, or W represents a group of formula (Wc), where Y independently represents C or N; and Z represents O or S; X represents -SO2-, -CH2-, -CH(C1-C8alkyl)- or a bond; m and n each independently represents an integer from 0 to 3; and p is 1, to a pharmaceutical composition with CRTh2 antagonist activity, as well as to use thereof as a medicinal agent and production method thereof.

EFFECT: new compounds which can be used in medicine are obtained and described.

10 cl, 153 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula I or to their pharmaceutically acceptable salts, where X1 - CH; X2 - N or CH; Q1 represents ,

where X11 - CH or C-halogen; X12 - CH, C-halogen or C-CF3; X13 - CH; X14 - C-E11, and E11 represents C0-10alkyl or C0-10alkoxy; X15 - CH or N; X16 - N or N+ -0; G1 - phenyl or 5-6-members unsaturated ring containing one heteroatom N or S; R1 - C0-10alkyl, cycloC3-10alkyl or piperidinyl, any of which is optionally substituted with 1-2 independent substitutes G11, or R1 represents phenyl; G11 is chosen from: OR21 where R21 represents C0-10alkyl; -oxo; -cycloC3-8alkyl; -C0-10alkyl optionally substituted with group N(C0-10alkyl)(C0-10alkyl) wherein C0-10alkyl is optionally substituted with group N(C0-10alkyl)C(O)C0-10alkyl; group OR2221, where R2221 - C0-10alkyl; group N(C0-10alkyl)C(O)C0-10alkyl; group N(C0-10alkyl)SO2(C0-10alkyl); group -N(C0-10alkyl)C(O)N(C0-10alkyl)(C0-10alkyl); group -N(C0-10alkyl)C(=O)R3331, where R3331 - C1-10alkoxy C1-10alkyl or tetrahydrofuranyl; -N(R21)R31 where R21 and R31 independently represent C0-10alkyl optionally substituted with thiophenyl, morphlinyl, furanyl; cycloC3-8alkyl; C1-10alkoxyC1-10alkyl; tetrahydropyranyl; piperidylC0-10alkyl; or piperidyl optionally substituted with C0-10alkyl; or R21 and R31 optionally taken together with nitrogen atom whereto attached, form 3-10-members saturated ring optionally substituted with one or more independent substitutes G1111, and optionally including one or more heteroatoms different from nitrogen whereto R21 and R31 are attached; where G1111 - C0-10alkyl optionally substituted with group OR77 where R77 - C0-10alkyl, or G1111 represents C1-10alkoxyC1-10alkyl, pirimidinyl, pyrazinyl, imidazolylmethyl; C(O)N(R21)R31 where R21 and R31 independently represent C0-10alkyl; -C(O)O(C0-10alkyl); -C(O) C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or halogen; -heterocyclylC0-10alkyl where heterocyclyl represents 4-6-members saturated ring containing 1 or 2 heteroatoms, independently chosen from N, O or S optionally substituted with a substitute chosen from: 1) OR2221, where R2221 - pyrimidinyl or C0-10lkyl; 2) C(O)OR2221, where R2221 - C0-10alkyl or phenyl-C0-10alkyl; 3) C(O)C0-10alkyl optionally substituted with N(C0-10alkyl)(C0-10alkyl) or C1-10alkoxy C1-10alkyl; 4) C(O)N(C0-10alkyl)(C0-10alkyl); 5) S(O)2C0-10alkyl; 6) SO2N(C0-10alkyl)(C0-10alkyl); 7) -NR2221R3331, where R2221 and R3331 taken together with nitrogen atom whereto attached, form pyrrolidinyl; or G11 represents C, which taken together with carbon whereto attached, forms C=C double bond substituted with R5 and G111 where R5 and G111 are hydrogens. The invention also specifically concerns cys-3-[8-amino-1-(2-phenylquinoline-7-yl)-imidazo[1,5-α]pyrazine-3-yl]-1-methl-cyclobutanole or its pharmaceutically acceptable salt. The specified compounds and their pharmaceutically acceptable salts are applicable in treatment of conditions mediated by activity IGF-1R proteinkinase, particularly angiogenesis, vascular permeability, immune response, cell apoptosis, tumour growth or inflammation. The invention also concerns a pharmaceutical composition.

EFFECT: improved efficiency of the composition and method of treatment.

14 cl, 3 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: described is compound representing 2,5-disubstituted 3-mercaptopentanic acid of formula (I) or its pharmaceutically acceptable salt, where R' represents phenyl, possibly substituted, naphtyl, pyridinyl, 1,2,3,4-tetrahydropyrimidine-2,4-dion-yl, substituted with C1-4alkyl, or tetrahydrothienyl; R2 represents aminopyridinyl, aminothiazolyl or 3-azabicyclo[3.2.1]octyl; R3 represents C1-4alkoxy, possibly substituted with phenyl (substituted with halogen) or pyridinyl; NR5R6 or N-bonded 5- or 6-member heterocyclic ring representing pyrrolidinyl, piperidinyl or piperazinyl ring, non-substituted or monosubstituted, or condensed with benzene ring, which is possibly substituted with C1-4alkoxy; R4 represents N-bonded pyrrolidinyl ring, monosubstituted with C1-4alkyl, which is substituted with NHphenyl; R5 and R6 independently represent hydrogen, C1-4alkyl, possibly substituted, or C2-4alkenyl; and method of obtaining it.

EFFECT: obtaining compounds inhibiting carboxypeptidase and which can be used in prevention and treatment of diseases in which inhibiting carboxypeptidase is useful.

7 cl, 1 tbl, 53 ex

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