Patent ID: 6624158
Filing Date: 2003-09-23
Classification: A61P,C07H

Abstract:
A compound of the formula or a pharmaceutically acceptable salt thereof, whereinR1 is (i) H, (ii) C1-C6alkyl optionally substituted by 1 or 2 substituents each independently selected from fluorenyl, phenyl and naphthyl, said phenyl, naphthyl and fluorenyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano, or (iii) fluorenyl; R2 is either (a) â€”CH2NHSO2â€”Aâ€”R3 wherein A is a bond or C1-C3 alkylene; and R3 is (i) H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nâ€”(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, â€”OR4, cyano, â€”COOR4, C3-C8 cycloalkyl, â€”S(O)mR5, NR4R4, â€”SO2NR4R4, â€”CONR4R4, â€”NR4COR5 or â€”NR4SO2R5, with the proviso that R3 is not H when A is a bond, or (ii) when A is C2-C3 alkylene, â€”NR8R9, â€”OR4, â€”COOR4, â€”OCOR5, â€”SO2R5, â€”CN, â€”SO2NR4R4, â€”NR4COR5 or â€”CONR4R4, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nâ€”(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, â€”OR6, R7, â€”COR6, â€”NR6R6, â€”COOR6, â€”S(O)mR7, â€”SO2NR6R6, â€”CONR6R6, â€”NR6SO2R7 or â€”NR6COR7 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nâ€”(C2-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R7, â€”COR6, â€”COOR6, â€”S(O)mR7, â€”SO2NR6R6 or â€”CONR6R6; or (b) â€”CONR10â€”A1â€”R11 wherein A1 is a bond or C1-C6 alkylene; R10 is H or C1-C6 alkyl; and R11 is (i) H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or naphthyl, said C3-C8 cycloalkyl, phenyl and naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nâ€”(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, â€”OR4, cyano, â€”COOR4, C3-C8 cycloalkyl, â€”S(O)mR5, â€”NR4R4, â€”SO2NR4R4, â€”CONR4R4, â€”NR4COR5 or â€”NR4SO2R5, with the proviso that R11 is not H when A1 is a bond, or (ii) when A1 is C2-C6 alkylene, â€”NR4R4, â€”OR4, â€”OCOR5, â€”SO2R5, â€”SO2NR4R4, â€”NR4SO2R5 or â€”NR4COR5, or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nâ€”(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, â€”OR6, R7, â€”COR6, â€”NR6R6, â€”COOR6, â€”S(O)mR7, â€”SO2NR6R6, â€”CONR6R6, â€”NR6SO2R7 or â€”NR6COR7 and optionally N-substituted by C1-C6 alkoxy-(C1-C6)-alkyl, R6R6Nâ€”(C2-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R7, â€”COR6, â€”COOR7, â€”SO2R7, â€”SO2NR6R6 or â€”CONR6R6, or (iv) when A1 is C2-C6 alkylene, N-linked azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, homopiperidinyl or tetrahydroquinolinyl, each being optionally C-substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nâ€”(C1-C6)-alkyl, halo-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, â€”OR4, cyano, â€”COOR4, C3-C8 cycloalkyl, â€”S(O)mR5, â€”NR4R4, â€”SO2NR4R4, â€”CONR4R4, â€”NR4COR5 or â€”NR4SO2R5 and said piperazinyl and homopiperazinyl being optionally substituted on the nitrogen not attached to A1 by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R4R4Nâ€”(C2-C6)-alkyl, halo-(C1-C6)-alkyl, C2-C5 alkanoyl, â€”COOR5, C3-C8 cycloalkyl, â€”SO2R5, â€”SO2NR4R4 or â€”CONR4R4, or (v) when A1 is C1-C6 alkylene, â€”COOR4, â€”CN or â€”CONR4R4; or (c) â€”Xâ€”NR12aâ€”Yâ€”NR13R14 wherein X is â€”CH2â€” or â€”CH2CH2â€”; and R12a is H or C1-C6 alkyl; or (d) â€”COâ€”NR18â€”X1â€”NR12â€”Yâ€”NR13R14 wherein (i) X1 is (1) unbranched C2-C3 alkylene optionally substituted by C1-C6 alkyl or C3-C8 cycloalkyl or (2) a group of the formula â€”(CH2)nâ€”Wâ€”(CH2)pâ€” wherein W is C5-C7 cycloalkylene, n is 0 or 1 and p is 0 or 1; R18 is H or C1-C6 alkyl; and R12 is H or C1-C6 alkyl; or (ii) X1 and R12, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl; and R18 is H or C1-C6 alkyl; or (iii) X1 and R18, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl; and R12 is H or C1-C6 alkyl; Y is CO, CS, SO2 or C&boxH;N(CN); R4 is H, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl; R5 is C1-C6 alkyl, C3-C8 cycloalkyl or phenyl; R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; R7 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, naphthyl or het; either, R8 and R9, taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperidinyl, homopiperazinyl or tetrahydroisoquinolinyl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R4R4Nâ€”(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, â€”CONR4R4, â€”COOR4 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, â€”OR4, cyano, â€”S(O)mR5, â€”NR4R4, â€”SO2NR4R4, â€”NR4COR5 or â€”NR4SO2R5, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to A or the C2-C6 alkylene group, as the case may be, by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R4R4Nâ€”(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, â€”COOR5, C3-C8 cycloalkyl, â€”SO2R5, â€”SO2NR4R4 or â€”CONR4R4, or, R8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R9 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, â€”CONR4R4, â€”COOR5, â€”COR5, â€”SO2R5 or â€”SO2NR4R4, said C1-C6 alkyl being optionally substituted by phenyl; either, R13 and R14, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C1-C6 alkyl or C3-C8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by â€”NR15R16 or â€”OR4, or, R13 is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl, said C1-C6 alkyl being optionally substituted by C3-C8 cycloalkyl, and R14 is (1) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het1, or (2) â€”(C2-C6 alkylene)-NR8R9, or (3) â€”(C1-C6 alkylene)-R17, or (4) C1-C6 alkyl or C3-C8 cycloalkyl; R15 and R16 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl; R17 is (i) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, â€”(C1-C3 alkylene)-(C1-C6 alkoxy), halo, cyano, â€”(C1-C3 alkylene)-CN, â€”CO2H, â€”(C1-C3 alkylene)-CO2H, â€”CO2(C1-C6 alkyl), â€”(C1-C3 alkylene)-CO2(C1-C6 alkyl), â€”(C1-C3 alkylene)-NR24R24, â€”CONR24R24 or â€”(C1â€”C3 alkylene)-CONR24R24, or (ii) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het1; m is 0, 1 or 2; het, used in the definitions of R6 and R7, means C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo; het1, used in the definition of R14 and R17, is a C-linked, 4- to 6-membered ring heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo; R19 is a C-linked, 5-membered aromatic heterocycle containing either (i) from 1 to 4 ring nitrogen atoms or (ii) 1 or 2 ring nitrogen atoms and 1 oxygen or 1 sulphur ring atom, said heterocycle being optionally substituted by C1-C6 alkyl, said C1-C6 alkyl being optionally substituted by phenyl, â€”OH, C1-C6 alkoxy or â€”NR20R21; R20 and R21 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl; and R24 is H or C1-C6 alkyl optionally substituted by cyclopropyl.