Claims for Patent: 11,001,578

Summary for Patent: 11,001,578

Title:	N-((HET)arylmethyl)-heteroaryl-carboxamides compounds as plasma 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:	US16/438,061
Patent Claims:	1. A compound of formula (I): wherein: B is phenyl substituted with 1 to 4 substituents that are alkylb alkoxy, OH, halo, CN, heteroaryl, COO(alkyl), 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 substituents that are alkylb alkoxy, OH, oxo, halo, CN, heteroaryl, COO(alkyl), NHCOR8, CONR8R9, OCF3 or CF3; 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, —NR8R9, CN, —NR8COR9, or CF3; 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 that are, independently, 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 substituted with 1, 2 or 3 substituents that are, independently, 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; wherein: 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); alkyl is optionally substituted with 1 or 2 substituents that are, independently, (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); alkylb is optionally substituted with 1 or 2 substituents that are, independently, (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 O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy is optionally substituted with 1 or 2 substituents that are, independently, OH, CN, CF3, CONR10R11, fluoro, or NR10R11; 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, —(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; arylb is phenyl, biphenyl, or naphthyl, which is optionally substituted with 1, 2 or 3 substituents that are, independently, 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, NR8, S, or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents that are, independently, 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, NR8, S, or O; heteroarylb is optionally substituted with 1, 2 or 3 substituents that are, independently, 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 which is optionally mono- or di-substituted with substituents that are oxo, alkyl, alkoxy, OH, halo, or CF3; or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof. 2. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is phenyl, thiophenyl, benzothiophenyl, or pyridyl, each substituted with 1 to 3 substituents that are alkylb, alkoxy, halo, CN, COORS, CONR8R9, OCF3, or CF3. 3. The compound of claim 2, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is phenyl or pyridyl, each substituted with 1 to 3 substituents that are alkylb, alkoxy, CF3, or halo. 4. The compound of claim 3, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is pyridyl substituted with 1 to 3 substituents that are alkylb, alkoxy, CF3, or halo. 5. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is phenyl substituted with 1 to 3 substituents that are alkylb, alkoxy, CF3, or halo. 6. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, 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. 7. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein W is C, X is N and Y and Z are C or N. 8. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein R5 and R6 are, independently, absent, H, CH2OCH3, cycloalkyl, —NR8R9, —NR8COR9, CN, or CF3; and wherein at least one of R5 and R6 is present and is not H. 9. The compound of claim 8, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein R5 is CH2OCH3. 10. The compound of claim 1 or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein A is phenyl substituted with —(CH2)1-3-heteroaryl or —(CH2)1-3—NR10R11 and, optionally, 1 or 2 additional substituents that are, independently, alkyl, halo, or CF3. 11. The compound of claim 10, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof wherein R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered carbon containing heterocyclic ring, optionally containing an additional N atom, which is saturated or unsaturated with 1 or 2 double bonds, and optionally mono- or di-substituted with substituents that are oxo, methyl, Cl, or F. 12. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein A is pyridyl substituted with heteroarylb or —NR10R11 and, optionally, 1 or 2 additional substituents that are, independently, alkyl, halo, or CF3. 13. The compound of claim 12, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered carbon containing heterocyclic ring, optionally containing an additional N atom, which is saturated or unsaturated with 1 or 2 double bonds, and optionally mono- or di-substituted with substituents that are oxo, methyl, Cl, or F. 14. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein A is: 15. The compound of claim 14 or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein A is: 16. The compound of claim 14, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein A is: 17. The compound of 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-[(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-(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-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}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; 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. 18. The compound of claim 1, wherein the stereoisomer is an enantiomer, diastereoisomer, a racemic mixture thereof, or a scalemic mixture thereof. 19. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof: wherein: A is 20. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof: wherein: A is 21. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof: wherein: A is 22. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof: wherein: A is 23. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof: wherein: A is 24. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is phenyl substituted with F and —OMe. 25. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is pyridyl substituted with F and —OMe. 26. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein B is pyridyl substituted with CF3. 27. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein the ring containing W, X, Y and Z is pyrazole. 28. The compound of claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein the ring containing W, X, Y and Z is imidazole. 29. A pharmaceutical composition comprising: (i) a compound of Formula (I): wherein: B is phenyl substituted with 1 to 4 substituents that are 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 substituents that are alkylb alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 or CF3; 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, —NR8R9, CN, —NR8COR9, or CF3; 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 that are, independently, 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 substituted with 1, 2 or 3 substituents that are, independently, 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; wherein: 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); alkyl is optionally substituted with 1 or 2 substituents that are, independently, (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); alkylb is optionally substituted with 1 or 2 substituents that are, independently, (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 O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy is optionally substituted with 1 or 2 substituents that are, independently, OH, CN, CF3, CONR10R11, fluoro, or NR10R11; 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, —(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; arylb is phenyl, biphenyl, or naphthyl, which is optionally substituted with 1, 2 or 3 substituents that are, independently, 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, NR8, S, or O; heteroaryl is optionally substituted with 1, 2 or 3 substituents that are, independently, 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, NR8, S, or O; heteroarylb is optionally substituted with 1, 2 or 3 substituents that are, independently, 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 which is optionally mono- or di-substituted with substituents that are oxo, alkyl, alkoxy, OH, halo, or CF3; or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof; and (ii) a pharmaceutically acceptable carrier, diluent, or excipient. 30. A pharmaceutical composition comprising (i) a compound of claim 17, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.