Inhibitors Of Plasma Kallikrein

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, R12, R13, A, L, B, n, W, X, Y and Z are as defined herein.

What is claimed is: 
     
         1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       Wherein:
 B is 
 
       
         
           
           
               
               
           
         
         n is 0, 1 or 2; 
         W, X, Y and Z are, independently, C, C(R16)-C, C(R16)=C, C═N, N, O or S, such that the ring containing W, X, Y and Z is a six-membered aromatic heterocycle; 
         wherein, 
         R5, R6 and R7 are, independently, absent, or H, alkyl, alkoxy, halo, OH, aryl, heteroaryl, —NR8R9, CN, COOR8, CONR8R9, —NR8COR9, or CF 3 ; and 
         R16 is H, alkyl, alkoxy, halo, OH, NR8R9, aryl, heteroaryl, or CF 3 ; 
         A is aryl, heteroaryl, or a substituent group that is formula (A), (B), (C), or (D): 
       
       
         
           
           
               
               
           
         
         wherein:
 G is H, alkyl, cycloalkyl, CO-aryl, SO 2 -aryl, (CH 2 ) m -aryl, or (CH 2 ) m -heteroaryl; 
 m is 0 or 1; 
 p is 0, 1, 2 or 3; 
 R23 is aryl or heteroaryl; 
 R24 is aryl or heteroaryl; 
 
         L is a linker that is a covalent bond, —(CHR17)-, —(CH 2 ) 1-10 —, —O—(CH 2 ) 2-10 —, —(CH 2 ) 1-10 —O—(CH 2 ) 1-10 —, —(CH 2 ) 1-10 —NH—(CH 2 ) 1-10 —, —CONH—(CH 2 ) 1-10 —, —CO—, or —SO 2 —; 
         U and V are, independently, C or N such that the aromatic ring containing U and V is phenyl, pyridine or pyrazine; 
         R1 is absent when U is N; 
         R2 is absent when V is N; 
         or, when present, R1 and R2 are, independently, H, alkyl, alkoxy, CN, halo, or CF 3 ; 
         R3 is H, alkyl, alkoxy, CN, halo or CF 3 ; 
         P is H and Q is —C(R18)(R19)NH 2 , or P is —C(R18)(R19)NH 2  and Q is H; 
         R8 and R9 are, independently, H or alkyl; 
         R12 and R13 are, independently, H or alkyl, or together form a cycloalkyl ring; 
         R17 is alkyl or OH; 
         R18 and R19 are, independently, H or alkyl, or together form a cycloalkyl ring or a cyclic ether; 
         alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C 1 -C 10 ) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C 3 -C 10 ); wherein the alkyl is optionally substituted with 1 or 2 substituents that are, independently, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , COOR10, CONR10R11, fluoro, phenyl, or NR10R11; 
         cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms; 
         a cyclic ether is a monocyclic saturated hydrocarbon of between 4 and 7 carbon atoms, wherein one of the ring carbons is replaced by an oxygen atom; 
         alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C 1 -C 6 ) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C 3 -C 6 ); wherein the alkoxy is optionally substituted with 1 or 2 substituents that are, independently, OH, OCH 3 , CN, CF 3 , COOR10, CONR10R11, fluoro or NR10R11; 
         aryl is phenyl, biphenyl or naphthyl; wherein the aryl is optionally substituted with 1, 2 or 3 substituents that are, independently, alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, morpholinyl, piperidinyl, 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 ) 1-3 —NR14R15, CF 3  or —NR10R11; 
         aryl b  is phenyl, biphenyl or naphthyl, which is optionally substituted with 1, 2 or 3 substituents that are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, —COOR10, —CONR10R11, CF 3  or NR10R11; 
         heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members that are, independently, N, NR8, S or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents that are, independently, alkyl, alkoxy, OH, halo, CN, aryl, morpholinyl, piperidinyl, —(CH 2 ) 1-3 -aryl, heteroaryl b , —COOR10, —CONR10R11, CF 3  or —NR10R11; 
         heteroaryl b  is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members that are, independently, N, NR8, S or O; wherein heteroaryl b  is optionally substituted with 1, 2 or 3 substituents that are, independently, alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, aryl, —(CH 2 ) 1-3 -aryl, —COOR10, —CONR10R11, CF 3  or NR10R11; 
         R10 and R11 are, independently, H or alkyl; or R10 and R11 together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring which is saturated or unsaturated with 1 or 2 double bonds and which is optionally mono- or di-substituted with substituents that are oxo, alkyl, alkoxy, COOR8, OH, F or CF 3 ; 
         R14 and R15 are, independently, alkyl, aryl b  or heteroaryl b ; or R14 and R15 together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic ring which is saturated or unsaturated with 1 or 2 double bonds, and optionally is oxo substituted; 
         or a tautomer, isomer, stereoisomer, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 B is:   
       
         
           
           
               
               
           
         
         wherein R1, R2 and R3 are, independently, H, alkyl, alkoxy, CN, halo or CF 3 . 
       
     
     
         3 . The compound according to  claim 1 , wherein n is 1. 
     
     
         4 . The compound according to  claim 1 , wherein B is: 
       
         
           
           
               
               
           
         
         wherein 
         R1, R2 and R3 are, independently, H, alkyl or halo; 
         P is —CH 2 NH 2 . 
       
     
     
         5 . The compound according to  claim 1 , wherein L is —(CH 2 ) 1-6 — or —(CHOH)—. 
     
     
         6 . The compound according to  claim 1 , wherein, L is —CH 2 —. 
     
     
         7 . The compound according to  claim 1 , wherein W, X, Y and Z are, independently, C═N, C, C(R16)-C, C(R16)=C or N, such that the ring containing W, X, Y and Z is a six-membered aromatic heterocycle; wherein R16 is H, alkyl or OH. 
     
     
         8 . The compound according to  claim 1 , wherein W, X, Y and Z form a six-membered aromatic heterocycle that is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein A is heteroaryl substituted by phenyl wherein phenyl is optionally substituted; or A is phenyl substituted by heteroaryl, —(CH 2 ) 1-3 -heteroaryl or —(CH 2 ) 1-3 —NR14R15. 
     
     
         10 . The compound according to  claim 1 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , that is:
 N-{[4-(Aminomethyl)-2-methylphenyl]methyl}-5-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyridine-3-carboxamide;   N-{[4-(Aminomethyl)-2,6-dimethylphenyl]methyl}-5-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyridine-3-carboxamide;   N-{[4-(Aminomethyl)-2,6-dimethylphenyl]methyl}-6-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazine-2-carboxamide; or   N-{[4-(Aminomethyl)-3-fluorophenyl]methyl}-5-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyridine-3-carboxamide;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         13 . A method of treating a disease or condition in which plasma kallikrein activity is implicated, comprising administered to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  to the subject. 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . The method of  claim 14 , wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy or diabetic macular edema.