Enzyme 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.

What is claimed is: 
     
         1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein:
 W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N, O or N, such that the ring containing W, X, Y and Z is a 5-, or 6-membered heteroaryl; 
 R5, R6, and R7 are independently absent or independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14; 
 R16 is independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14; or 
 W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N or N, and one of R5, R6, R7 or R16 is oxo such that the ring containing W, X, Y and Z is 2-pyridone or 4-pyridone; 
 wherein the others of R5, R6, R7 and R16 are independently absent or independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14; 
 B is of Formula (II) comprising aromatic rings B′ and B″ that are linked by a bond: 
 
       
       
         
           
           
               
               
           
         
         
           
             B′ is phenyl or pyridyl; 
             B″ is pyrrole, pyrazole, triazole, or tetrazole; 
             n is 0, 1, or 2; 
             R9 and R10 are independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, or CF 3 ; 
             Each R11 is independently alkyl, cycloalkyl, alkoxy, halo, OH, —COOR13, —CONR13NR14, CN, or CF 3 ; 
           
           A is a heterocyclic ring of Formula (III) comprising an aromatic ring (A′) fused to a non-aromatic ring (A″): 
         
       
       
         
           
           
               
               
           
         
         
           
             A′1 and A′2 are independently C or N; 
             A′ is heteroaryl or phenyl, wherein phenyl optionally substituted with 1, 2, or 3 substituents that are independently alkyl, alkoxy, OH, OCF 3 , halo, CN, or CF 3 , and wherein heteroaryl is optionally substituted as stated below; 
             A″ is heterocycloalkyl;
 optionally wherein a carbon ring atom on A″ is substituted with an alkylene or a heteroalkylene such that the carbon ring atom on A″ together with the alkylene or the heteroalkylene forms a cycloalkyl or heterocycloalkyl a  that is spiro to ring A″; and/or 
 optionally wherein two ring atoms on A″ are linked by an alkylene or heteroalkylene to form a non-aromatic ring containing 5, 6, or 7 ring members; 
 
           
           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 ); alkyl is optionally substituted with 1 or 2 substituents that are independently (C 1 -C 6 )alkoxy, OH, —NR13R14, —COOR13, —CONR13R14, CN, CF 3 , or halo; 
           alkyl b  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 ); alkyl b  is optionally substituted with 1 or 2 substituents that are independently (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           alkylene is a bivalent linear saturated hydrocarbon having 1 to 5 carbon atoms (C 1 -C 5 ); alkylene is optionally substituted with 1 or 2 substituents that are independently alkyl, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           aryl is phenyl, biphenyl or naphthyl; aryl is optionally substituted with 1, 2 or 3 substituents that are independently alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl a , —(CH 2 ) 0-3 —O-heteroaryl a , aryl b , —O-aryl b , —(CH 2 ) 1-3 -aryl b , —(CH 2 ) 1-3 -heteroaryl a , —COOR13, —CONR13R14, —(CH 2 ) 0-3 —NR13R14, OCF 3  or CF 3 ; 
           aryl b  is phenyl, biphenyl or naphthyl; aryl b  is optionally substituted with 1, 2 or 3 substituents that are independently alkyl b , alkoxy, OH, halo, CN, or CF 3 ; 
           heteroalkylene is a bivalent linear saturated hydrocarbon having 2 to 5 carbon atoms (C 2 -C 5 ), wherein at least one of the 2 to 5 carbon atoms is replaced with NR8, S, or O; heteroalkylene is optionally substituted with 1 or 2 substituents that are independently alkyl (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           cycloalkyl is a monocyclic saturated hydrocarbon ring of between 3 and 6 carbon atoms (C 3 -C 6 ); cycloalkyl is optionally substituted with 1 or 2 substituents that are independently alkyl, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           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 ); alkoxy is optionally substituted with 1 or 2 substituents that are independently OH, CN, CF 3 , or fluoro; 
           halo is F, Cl, Br, or I; 
           heteroaryl is a 5- or 6-membered carbon-containing aromatic ring containing one, two or three ring members that are N, NR8, S, or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents that are independently alkyl, alkoxy, OH, OCF 3 , halo, CN, or CF 3 ; 
           heteroaryl a  is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2, 3 or 4 ring members are independently N, NR12, S or O; heteroaryl a  is optionally substituted with 1, 2 or 3 substituents that are independently alkyl, alkoxy, OH, OCF 3 , halo, CN, aryl b , —(CH 2 ) 1-3 -aryl b , —(CH 2 ) 0-3 —NR13R14, heteroaryl b , —COOR13, —CONR13R14 or CF 3 ; 
           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, NR12, S or O; wherein heteroaryl b  is optionally substituted with 1, 2 or 3 substituents that are independently alkyl b , alkoxy, OH, halo, CN, aryl b , —(CH 2 ) 1-3 -aryl b , or CF 3 ; 
           heterocycloalkyl is a non-aromatic carbon-containing monocyclic ring containing 5, 6, or 7 ring members, wherein one or two ring members are independently N, NR8, S, SO, SO 2 , or O; wherein heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents that are independently alkyl, alkoxy, OH, OCF 3 , halo, oxo or CN; 
           heterocycloalkyl a  is a non-aromatic carbon-containing monocyclic ring containing 3, 4, 5, or 6, ring members, wherein at least one ring member is independently NR8, S, SO, SO 2 , or O; heterocycloalkyl a  is optionally substituted with 1 or 2 substituents that are independently alkyl (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           R8 is independently H, alkyl, cycloalkyl, or heterocycloalkyl b ; 
           heterocycloalkyl b  is a non-aromatic carbon-containing monocyclic ring containing 3, 4, 5, or 6, ring members, wherein at least one ring member is independently N, NR12, S, or O; heterocycloalkyl b  is optionally substituted with 1 or 2 substituents that are independently alkyl, (C 1 -C 6 )alkoxy, OH, CN, CF 3 , or halo; 
           R12 is independently H, alkyl b , or cycloalkyl; 
           R13 and R14 are independently H, alkyl b , aryl b  or heteroaryl b  or R13 and R14 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 heteroatom that is N, NR12, S, SO, SO 2 , or O, which is optionally saturated or unsaturated with 1 or 2 double bonds and which is optionally mono- or di-substituted with substituents that are oxo, alkyl b , alkoxy, OH, halo or CF 3 ; 
         
         or a tautomer, isomer, deuterated isotope, or a pharmaceutically acceptable salt and/or solvate thereof. 
       
     
     
         2 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or a pharmaceutically acceptable salt and/or solvate thereof,
 wherein W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N or N, such that the ring containing W, X, Y and Z is a 5-, or 6-membered heteroaryl;   R5, R6, and R7 are independently absent, H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14;   R16 is independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14; or   W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N or N, and one of R5, R6, R7 or R16 is oxo such that the ring containing W, X, Y and Z is 2-pyridone or 4-pyridone;   wherein the others of R5, R6, R7 and R16 are independently absent, H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, CF 3 , aryl, heteroaryl a , N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, —NR13R14, —COOR13, —CONR13R14, or —NR13COR14.   
     
     
         3 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein W, X, Y and Z is independently C, C(R16)-C, C(R16)=C, C═N or N, such that the ring containing W, X, Y and Z is a 5-, or 6-membered heteroaryl;   R5, R6, and R7 are independently absent, H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, or CF 3 ;   R16 is independently H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, or CF 3 ; or   W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N or N, and one of R5, R6, R7 or R16 is oxo such that the ring containing W, X, Y and Z is 2-pyridone or 4-pyridone;   wherein the others of R5, R6, R7 and R16 are independently absent, H, alkyl, cycloalkyl, alkoxy, halo, OH, CN, or CF 3 .   
     
     
         4 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or a pharmaceutically acceptable salt and/or solvate thereof,
 wherein W, X, Y and Z are independently C, C(R16)-C, C(R16)=C, C═N or N, such that the ring containing W, X, Y and Z is a 5-, or 6-membered heteroaryl.   
     
     
         5 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or a pharmaceutically acceptable salt and/or solvate thereof,
 wherein W, X, Y and Z are independently C or N, such that the ring containing W, X, Y and Z is a 5-membered heteroaryl.   
     
     
         6 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein W, X, Y and Z are independently C or N, such that the ring containing W, X, Y and Z is pyrazole.   
     
     
         7 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein at least one of R5, R6, or R7 is present and is not H.   
     
     
         8 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein R7 is H.   
     
     
         9 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein one of R5 or R6 is absent and one of R5 or R6 is alkyl substituted with optionally substituted alkoxy.   
     
     
         10 . The compound of formula (I) according to  claim 9 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein one of R5 or R6 is absent and one of R5 or R6 is —CH 2 OMe.   
     
     
         11 . The compound of formula (I) according to  claim 1 , or a tautomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B′ is optionally substituted phenyl.   
     
     
         12 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein R9 is halo and R10 is alkoxy.   
     
     
         13 . The compound of formula (I) according to  claim 12 , or a tautomer, isomer, a deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein R9 is F and R10 is —OMe.   
     
     
         14 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B″ pyrrole, pyrazole, or triazole.   
     
     
         15 . The compound of formula (I) according to  claim 14 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B″ is pyrazole, or triazole.   
     
     
         16 . The compound of formula (I) according to  claim 15 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B″ is optionally substituted pyrazole.   
     
     
         17 . The compound of formula (I) according to  claim 15 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B″ is optionally substituted 1, 2, 3-triazole.   
     
     
         18 . The compound of formula (I) according to  claim 15 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein B″ is optionally substituted 1, 2, 4-triazole.   
     
     
         19 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein n is 1, and R11 is alkyl, cyclopropyl, CN, or CF 3 .   
     
     
         20 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is optionally substituted phenyl.   
     
     
         21 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is optionally substituted heteroaryl.   
     
     
         22 . The compound of formula (I) according to  claim 21 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is an optionally substituted 5-membered heteroaryl.   
     
     
         23 . The compound of formula (I) according to  claim 22  or a tautomer, isomer, deuterated isotope, or a pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is optionally substituted pyrrole or imidazole. 
 
     
     
         24 . The compound of formula (I) according to  claim 21 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is a optionally substituted 6-membered heteroaryl.   
     
     
         25 . The compound of formula (I) according to  claim 24 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A′ is optionally substituted pyridine.   
     
     
         26 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is an optionally substituted non-aromatic carbon-containing monocyclic ring containing 5 ring members, wherein one or two ring members are independently N, NR8, S, or O.   
     
     
         27 . The compound of formula (I) according to  claim 26 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is optionally substituted pyrrolidine.   
     
     
         28 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is an optionally substituted non-aromatic carbon-containing monocyclic ring containing 6 ring members, wherein one or two ring members are independently N, NR8, S, or O.   
     
     
         29 . The compound of formula (I) according to  claim 28 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is optionally substituted piperidine.   
     
     
         30 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is an optionally substituted non-aromatic carbon-containing monocyclic ring containing 7 ring members, wherein one or two ring members are independently N, NR8, S, or O.   
     
     
         31 . The compound of formula (I) according to  claim 30 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein A″ is optionally substituted azepane.   
     
     
         32 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein a carbon ring atom on A″ is substituted with an alkylene such that the carbon ring atom on A″ together with the alkylene forms an optionally substituted cycloalkyl that is spiro to ring A″.   
     
     
         33 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein a carbon ring atom on A″ is substituted with an alkylene such that the carbon ring atom on A″ together with the alkylene forms an optionally substituted cyclopropane that is spiro to ring A″.   
     
     
         34 . The compound of formula (I) according to  claim 1 , or a tautomer, isomer, deuterated isotope, or pharmaceutically acceptable salt and/or solvate thereof,
 wherein two ring atoms on A″ are linked by an alkylene or heteroalkylene to form a non-aromatic ring containing 5, 6, or 7 ring members.   
     
     
         35 . The compound of formula (I) according to  claim 1 , wherein the isomer is a stereoisomer. 
     
     
         36 . The compound of formula (I) of  claim 35 , wherein the stereoisomer is an enantiomer, diastereomer, or a racemic or scalemic mixture thereof. 
     
     
         37 . A compound that is:
 N-({6-[4-(difluoromethyl)-1,2,3-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(3-methyl-1,2,4-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-{[6-(3-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[6-(3-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[6-(3-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[6-(4-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({6-[4-(difluoromethyl)-1,2,3-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]pyrazole-4-carboxamide;   N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]pyrazole-4-carboxamide;   N-{[6-(3-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[6-(3-cyanopyrazol-1-yl)-2-fluoro-3-methoxyphenyl]methyl}-1-[(2-isopropyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-({6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-2-fluoro-3-methoxyphenyl}methyl)-1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   1-[(2-ethyl-3,4-dihydro-1H-isoquinolin-6-yl)methyl]-N-({2-fluoro-3-methoxy-6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-[(2-methyl-1,3-dihydroisoindol-5-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(2-isopropyl-1,3-dihydroisoindol-5-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   1-[(6-fluoro-2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{[2-( 2 H 3 )methyl-3,4-dihydro-1H-isoquinolin-7-yl]methyl}pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(3-isopropyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-{2′-methyl-1′,3′-dihydrospiro[cyclopropane-1,4′-isoquinoline]-7′-ylmethyl}pyrazole-4-carboxamide;   1-{2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-ylmethyl}-N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;   3-(difluoromethyl)-N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-({5-methyl-4H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}methyl)pyrazole-4-carboxamide;   3-(difluoromethyl)-N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(7-methyl-6,8-dihydro-5H-1,7-naphthyridin-3-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-1,2,3-triazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(2-isopropyl-1,3-dihydroisoindol-5-yl)methyl]-1,2,3-triazole-4-carboxamide;   N-({2-chloro-6-[3-(difluoromethyl)-1,2,4-triazol-1-yl]-3-methoxyphenyl}methyl)-3-(methoxymethyl)-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyrazole-4-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-1-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]-6-oxopyridine-3-carboxamide;   N-{[2-fluoro-3-methoxy-6-(4-methyl-1,2,3-triazol-1-yl)phenyl]methyl}-5-[(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)methyl]pyridine-3-carboxamide;   
       or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         38 . The compound of formula (I) according to  claim 1  that is a pharmaceutically acceptable salt thereof. 
     
     
         39 . The compound of formula (I) according to  claim 1  that is a pharmaceutically acceptable solvate thereof. 
     
     
         40 . The compound of formula (I) according to  claim 1  that is a pharmaceutically acceptable solvate of a salt thereof. 
     
     
         41 . A pharmaceutical composition comprising:
 (i) a compound of formula (I) according to  claim 1 , a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable solvate of a salt thereof; and   (ii) a pharmaceutically acceptable carrier, diluent or excipient.   
     
     
         42 . A method of treatment of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         43 . The method of  claim 42 , wherein the disease or condition in which plasma kallikrein activity is implicated is a bradykinin-mediated angioedema. 
     
     
         44 . The method of  claim 43 , wherein the bradykinin-mediated angioedema is hereditary angioedema. 
     
     
         45 . The method of  claim 43 , wherein the bradykinin-mediated angioedema is non hereditary. 
     
     
         46 . The method of  claim 43 , wherein the bradykinin-mediated angioedema is hereditary angioedema or an acute non-hereditary bradykinin-mediated angioedema. 
     
     
         47 . The method of  claim 42 , wherein the disease or condition in which plasma kallikrein activity is implicated is impaired visual acuity, diabetic retinopathy, diabetic macular edema, 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.