Claims for Patent: 11,198,691

Summary for Patent: 11,198,691

Title:	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.
Inventor(s):	Rebecca Louise Davie, Hannah Joy Edwards, David Michael Evans, Simon Teanby Hodgson
Assignee:	Kalvista Pharmaceuticals Ltd
Application Number:	US16/804,872
Patent Claims:	1. A method of treating a subject in need thereof having a disease or condition in which plasma kallikrein activity is implicated comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein: B is phenyl substituted with 1 to 4 of alkylb, alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3, or CF3; or B is benzothiophenyl, benzofuranyl, benzomorpholinyl or a 5 or 6 membered heterocyclic ring containing one or two heteroatoms that are N, O or S; wherein said 5 or 6 membered heterocyclic ring is aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 of alkylb, alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 or CF3; W is C and (i) X is N, Y is N, and Z is C or (ii) X is N, Y is C, and Z is N, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle; R5 and R6 are independently absent or independently 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 CF3; wherein at least one of R5 and R6 is present and is not H; R7 is H; A is aryl or a 6- or 10- membered nitrogen containing heteroaryl; wherein aryl is independently substituted with 1, 2 or 3 of alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, —(CH2)0-3-O-heteroaryl, arylb, —O-arylb, —(CH2)1-3-arylb, —(CH2)1-3-heteroaryl, —COOR10, —CONR10R11, —(CH2)0-3—NR10R11, OCF3 or CF3; and heteroaryl is independently substituted with 1, 2 or 3 of alkyl, alkoxy, OH, OCF3, halo, CN, aryl, —(CH2)1-3-aryl, —(CH2)0-3—NR10R11, heteroarylb, —COOR10, —CONR10R11 or CF3; R8 and R9 are independently H or alkyl; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10); wherein the alkyl is unsubstituted or independently substituted with 1 or 2 of (C1-C6)alkoxy, OH, CN, CF3, COOR10, CONR10R11, fluoro or NR10R11; alkylb is a linear saturated hydrocarbon having up to 6 carbon atoms or a branched saturated hydrocarbon of between 3 and 6 carbon atoms (C3-6); wherein the alkylb is unsubstituted or independently substituted with 1 or 2 of (C1-C6)alkoxy, OH, CN, CF3, COOR10, CONR10R11 or fluoro; cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched 0-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); wherein the alkoxy is unsubstituted or independently substituted with 1 or 2 of OH, CN, CF3, COOR10, CONR10R11, fluoro or NR10R11; aryl is phenyl, biphenyl or naphthyl; wherein the aryl is unsubstituted or independently substituted with 1, 2 or 3 of alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, —(CH2)0-3—O-heteroaryl, arylb, —O-arylb, —(CH2)1-3-arylb, —(CH2)1-3-heteroaryl, —COOR10, —CONR10 R11, —(CH2)0-3—NR10R11, OCF3 or CF3; arylb is phenyl, biphenyl or naphthyl, which is unsubstituted or independently substituted with 1, 2 or 3 of alkyl, alkoxy, OH, halo, CN, —COOR10, —CONR10R11, CF3 or NR10R11; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2, 3 or 4 ring members that are, independently, N, NRB, S or O; wherein the heteroaryl is unsubstituted or independently substituted with 1, 2 or 3 of alkyl, alkoxy, OH, OCF3, halo, CN, aryl, —(CH2)1-3-aryl, —(CH2)0-3-NR10R11, heteroarylb, —COOR10, —CONR10R11 or CF3; heteroarylb 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, NRB, S or O; wherein heteroarylb is unsubstituted or independently substituted with 1, 2 or 3 of alkyl, alkoxy, OH, halo, CN, aryl, —(CH2)1-3-aryl, —COOR10, —CONR10R11, CF3 or NR10R11; R10 and R11 are independently H, alkyl, arylb or heteroarylb 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 heteroatom that is N, S or O, which is saturated or unsaturated with 1 or 2 double bonds and is unsubstituted or mono- or di-substituted with oxo, alkyl, alkoxy, OH, halo or CF3; or a tautomer, isomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof. 2. The method of claim 1, 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. 3. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy or diabetic macular edema. 4. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is hereditary angioedema. 5. The method of claim 1, wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema. 6. The method of claim 1, wherein B is phenyl substituted with 1 to 4 of alkylb, alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3, or CF3; or B is benzothiophenyl, benzofuranyl, or a 5 or 6 membered heterocyclic ring containing one or two heteroatoms that are N, O or S; wherein said 5 or 6 membered heterocyclic ring is aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5 or 6 membered heterocyclic ring is substituted with 1 to 3 of alkylb, alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 or CF3. 7. The method of claim 1, wherein B is phenyl, thiophenyl, benzothiophenyl or pyridyl, each substituted with 1 to 3 of alkylb, alkoxy, halo, CN, COOR8, CONR8R9, OCF3 or CF3. 8. The method of claim 1, wherein B is phenyl or pyridyl, each substituted with 1 to 3 of alkylb, alkoxy, CF3 or halo. 9. The method of claim 1, wherein B is pyridyl substituted with 1 to 3 of alkylb, alkoxy, CF3 or halo. 10. The method of claim 1, wherein W is C and X, Y and Z are independently C or N, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle. 11. The method of claim 1, wherein W is C, X is N and Y and Z are C or N. 12. The method of claim 1, wherein R5 and R6 are independently absent, or independently H, CH2OCH3, cycloalkyl, —NR8R9, —NR8COR9, CN or CF3; wherein at least one of R5 and R6 is present and is not H. 13. The method of claim 1, wherein R5 is CH2OCH3. 14. The method of claim 1, wherein (i) A is phenyl substituted with —(CH2)1-3-heteroaryl or —(CH2)1-3-NR10R11, or (ii) A is phenyl substituted with —(CH2)1-3-heteroaryl or —(CH2)1-3-NR10R11 independently substituted with 1 or 2 of alkyl, halo or CF3. 15. The method of claim 1, wherein (i) A is pyridyl substituted with heteroarylb or —NR10R11, or (ii) A is pyridyl substituted with heteroarylb or —NR10R11 independently substituted with 1 or 2 of alkyl, halo or CF3. 16. The method of claim 1, wherein R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered carbon containing heterocyclic ring, containing an additional N atom, which is saturated or unsaturated with 1 or 2 double bonds, and unsubstituted or mono- or di-substituted with oxo, methyl, Cl or F. 17. The method of claim 1, wherein A is: 18. The method of claim 1, wherein A is: 19. The method of claim 1, wherein the compound 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-methyl pyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methyl pyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methyl phenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)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-methyl phenyl)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)methyl]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-methyl phenyl)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}methyl)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 salts and solvates thereof. 20. A method of treating a subject in need thereof having a disease or condition in which plasma kallikrein activity is implicated comprising administering to the subject therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof 21. The method of claim 20, 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. 22. The method of claim 20, wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema. 23. The method of claim 20, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy or diabetic macular edema. 24. The method of claim 1, wherein the stereoisomer thereof is an enantiomer, a diastereoisomer, a racemic mixture, or a scalemic mixture thereof.