N-((HET)Arylmethyl)-Heteroaryl-Carboxamides Compounds As Kallikrein Inhibitors

Abstract

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5, R6, R7, A, B, W, X, Y and Z are as defined herein.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         B is phenyl substituted with 1 to 4 alkyl b , alkoxy, OH, halo, CN, heteroaryl, COORS, NHCOR8, CONR8R9, OCF 3 , or CF 3  substituents; 
         or B is benzothiophenyl, benzofuranyl, benzomorpholinyl or a 5 or 6 membered heterocyclic ring containing one or two N, O, or S atoms; wherein said 5 or 6 membered heterocyclic ring is aromatic or non-aromatic; and wherein said benzothiophenyl, benzofuranyl, benzomorpholinyl, or 5 or 6 membered heterocyclic ring is substituted with 1 to 3 alkyl b , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NCOR8, CONR8R9, OCF 3 , or CF 3  substituents; 
         W is C and X, Y and Z are, independently, C, N, O, or S, wherein the ring containing W, X, Y and Z is a five membered aromatic heterocycle; 
         R5 and R6 are, independently, absent, H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR8R9, CN, COOR8, CONR8R9, —NR8COR9, or CF 3 ; wherein at least one of R5 and R6 is present and is not H; 
         R7 is H; 
         A is aryl or heteroaryl; wherein aryl is substituted with 1, 2, or 3 substituents which are independently alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, —(CH 2 ) 0-3 —O-heteroaryl, aryl b , —O-aryl b , —(CH 2 ) 1-3 -aryl b , —(CH 2 ) 1-3 -heteroaryl, —COOR10, —CONR10R11, —(CH 2 ) 0-3 —NR10R11, OCF 3 , or CF 3 ; and heteroaryl is substituted with 1, 2, or 3 substituents which are independently alkyl, alkoxy, OH, OCF 3 , halo, CN, aryl, —(CH 2 ) 1-3 -aryl, —(CH 2 ) 0-3 —NR10R11, heteroaryl b , —COOR10, —CONR10R11, or CF 3 ; 
         R8 and R9 are, independently, H or alkyl; 
         alkyl is a C 1 -C 10  linear saturated hydrocarbon or a C 3 -C 10  branched saturated hydrocarbon; alkyl is optionally substituted with 1 or 2 substituents which are independently (C 1 -C 6 )alkoxy, OH, CN, CF 3 , COOR10, CONR10R11, fluoro, or NR10R11; 
         alkyl b  is a C 3 -C 6  linear saturated hydrocarbon or a C 3 -C 6  branched saturated hydrocarbon; alkyl b  is optionally substituted with 1 or 2 substituents which are independently (C 1 -C 6 )alkoxy, OH, CN, CF 3 , COOR10, CONR10R11, or fluoro; 
         cycloalkyl is a C 3 -C 6  monocyclic saturated hydrocarbon; 
         alkoxy is a C 1 -C 6  linear O-linked hydrocarbon or a C 3 -C 6  branched O-linked hydrocarbon; alkoxy is optionally substituted with 1 or 2 substituents which are independently OH, CN, CF 3 , COOR10, CONR10R11, fluoro, or NR10R11; 
         aryl is phenyl, biphenyl or naphthyl; aryl is optionally substituted with 1, 2, or 3 substituents which are independently alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, —(CH 2 ) 0-3 —O-heteroaryl, aryl b , —O-aryl b , —(CH 2 ) 1-3 -aryl b , —(CH 2 ) 1-3 -heteroaryl, —COOR10, —CONR10R11, —(CH 2 ) 0-3 —NR10R11, OCF 3 , or CF 3 ; 
         aryl b  is phenyl, biphenyl or naphthyl, which is optionally substituted with 1, 2, or 3 substituents which are independently alkyl, alkoxy, OH, halo, CN, —COOR10, —CONR10R11, CF 3 , or NR10R11; 
         heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring containing 1, 2, 3, or 4 ring members which are independently N, NR8, S, or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents which are independently alkyl, alkoxy, OH, OCF 3 , halo, CN, aryl, —(CH 2 ) 1-3 -aryl, —(CH 2 ) 0-3 —NR10R11, heteroaryl b , —COOR10, —CONR10R11, or CF 3  substituents; 
         heteroaryl b  is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring containing 1, 2, or 3 ring members which are independently N, NR8, S, or O; wherein heteroaryl b  is optionally substituted with 1, 2, or 3 substituents which are independently alkyl, alkoxy, OH, halo, CN, aryl, —(CH 2 ) 1-3 -aryl, —COOR10, —CONR10R11, CF 3 , or NR10R11; 
         R10 and R11 are, independently, H, alkyl, aryl b , or heteroaryl b  or R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional N, S, or O atom, which is saturated or unsaturated with 1 or 2 double bonds and is optionally mono- or di-substituted with oxo, alkyl, alkoxy, OH, halo, or CF 3  substituents; 
         or a tautomer, isomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein B is phenyl substituted with 1 to 4 alkyl b , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF 3 , or CF 3  substituents; or B is benzothiophenyl, benzofuranyl, or a 5 or 6 membered heterocyclic ring containing one or two N, O, or S atoms; wherein said 5 or 6 membered heterocyclic ring is aromatic or non-aromatic; and wherein said benzothiophenyl, benzofuranyl, or 5 or 6 membered heterocyclic ring is substituted with 1 to 3 alkyl b , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF 3 , or CF 3  substituents. 
     
     
         3 . The compound according to  claim 1 , wherein B is phenyl, thiophenyl, benzothiophenyl, or and pyridyl, each substituted with 1 to 3 alkyl b , alkoxy, halo, CN, COOR8, CONR8R9, OCF 3 , or CF 3  substituents. 
     
     
         4 . The compound according to  claim 1 , wherein B is phenyl or pyridyl, each substituted with 1 to 3 alkyl b , alkoxy, CF 3 , or halo substituents. 
     
     
         5 . The compound according to  claim 1 , wherein W is C and X, Y and Z are, independently, C or N, wherein the ring containing W, X, Y and Z is a five membered aromatic heterocycle. 
     
     
         6 . The compound according to  claim 1 , wherein W is C, X is N, and Y and Z are C or N. 
     
     
         7 . The compound according to  claim 1 , wherein R5 and R6 are, independently, absent, H, CH 2 OCH 3 , cycloalkyl, —NR8R9, —NR8COR9, CN, or CF 3 ; wherein at least one of R5 and R6 is present and is not H. 
     
     
         8 . The compound according to  claim 1 , wherein A is phenyl substituted with —(CH 2 ) 1-3 -heteroaryl or —(CH 2 ) 1-3 —NR10R11 and, optionally, 1 or 2 additional substituents which are independently alkyl, halo, or CF 3 . 
     
     
         9 . The compound according to  claim 1 , wherein A is pyridyl substituted with heteroaryl b  or —NR10R11 and, optionally, 1 or 2 additional substituents which are independently alkyl, halo, or CF 3 . 
     
     
         10 . The compound according to  claim 1 , that is:
 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide;   N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;   3-cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-(dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-acetamido-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(3-chloro-2,6-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methy]phenyl}methyl)pyrazole-4-carboxamide;   N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[3-(difluoromethoxy)-2-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2-fluoro-6-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-amino-N-[(2-fluoro-3-hydroxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(3-ethyl-2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}ethyl)pyrazole-4-carboxamide;   N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl-2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;   N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;   N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-2-(trifluoromethyl)imidazole-4-carboxamide;   3-amino-N-[(7-chloro-4-methyl-2,3-dihydro-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;   3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide   
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         12 . A method of treating a disease or condition in which plasma kallikrein activity is implicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the disease or condition in which plasma kallikrein activity is implicated is impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery, or bleeding from post operative surgery. 
     
     
         14 . The method of  claim 12 , wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy or diabetic macular edema. 
     
     
         15 . The method of  claim 12 , wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema. 
     
     
         16 . The method of  claim 12 , wherein the disease or condition in which plasma kallikrein activity is implicated is hereditary angioedema. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 10  and a pharmaceutically acceptable carrier, diluent or excipient.