Compositions and methods for treating heart failure
Certain substituted benzamide derivatives of Formula I: selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.
1. A compound represented by Formula I:
wherein:
R 1 is phenyl, pyridinyl, or phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, beuzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
R 2 is fluoro, ethoxycarbonyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl, wherein said oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl is optionally substituted with lower alkoxy or oxo; and
R 3 is aryl or heteroaryl each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
wherein said heteroaryl group is a 5-, 6- or 7-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S; a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S; or a tricyclic 12- to 14-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S,
or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 where R 1 is 3-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 3-methylphenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
3. The compound of claim 2 where R 1 is 4-fluorophenyl, pyridin-2-yl or pyridin-3-yl.
4. The compound of claim 1 where R 3 is phenyl, optionally substituted with lower alkoxy, lower alkyl, halo, hydroxy, hydroxy-lower alkyl or nitro.
5. The compound of claim 1 where R 3 is benzodioxolyl, furanyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or thienyl, optionally substituted with lower alkyl, lower alkoxy, or halo.
6. The compound of claim 3 where R 3 is:
phenyl, optionally substituted with lower alkoxy, lower alkyl, halo, hydroxy, hydroxy-lower alkyl or nitro; or
benzodioxolyl, furanyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or thienyl, optionally substituted with lower alkyl, lower alkoxy, or halo.
7. The compound of claim 1 or 3 where R 3 is 3-hydroxyphenyl, 4-hydroxyphenyl, 4-fluorophenyl, isoxazol-5-yl, pyridin-3-yl, pyridin-4-yl, thien-2-yl, or 5-methyl-thien-2-yl.
8. The compound of claim 1 where R 1 is heteroaryl and R 2 is fluoro.
9. The compound of claim 8 where R 1 is pyridin-3-yl.
10. The compound of claim 1 that is:
3-(4-fluoro-benzoylamino)-5-(pyridin-3-yloxy)-benzoic acid ethyl ester;
4-fluoro-N-[3-pyridin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
4-fluoro-N-[3-pyrazin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-3-hydroxy-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-4-hydroxy-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-nicotinamide; or
isoxazole-5-carboxylic acid [3-fluoro-5-(pyridin-3-yloxy)-phenyl)-amide.
11. A compound represented by Formula I:
wherein:
R 1 is alkyl, aryl, or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
R 2 is nitro; and
R 3 is aryl, or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
wherein said heteroaryl group is a 5-, 6- or 7-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S; a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S; or a tricyclic 12- to 14-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S,
provided that:
when R 1 is pyridin-3-yl, R 3 is not 3-bromophenyl, 3-fluorophenyl, 4-fluorophenyl, furan-2-yl, 4-methoxyphenyl or 1-methyl-1H-pyrazol-3-yl;
when R 1 is 4-bydroxyophenyl, R 3 is not furan-2-yl;
when R 1 is 4-fluorophenyl, R 3 is not furan-2-yl or pyridin-4-yl; and
when R 3 is pyridin-4-yl, R 1 is not phenyl, 3-chlorophenyl, 4-hydroxyphenyl or 3-methylphenyl;
or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 where R 1 is aryl or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy.
13. The compound of claim 12 where R 1 is phenyl, pyridinyl, or phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy.
14. The compound of claim 13 where R 1 is 3-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 3-methylphenyl, pyridin-2-yl or pyridin-3-yl.
15. The compound of claim 14 where R 1 is 4-fluorophenyl, pyridin-2-yl or pyridin-3-yl.
16. The compound of claim 11 , 14 or 15 where R 3 is aril or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy.
17. The compound of claim 16 where R 3 is phenyl, 4-fluorophenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-methylphenyl, isoxazol-5-yl, thiophene-2-yl, or 5-methyl-thiophene-2-yl.
18. The compound of claim 11 that is:
thiophene-2-carboxylic acid [3-(4-fluoro-phenoxy)-5-nitro-phenyl-amide;
isoxazole-5-carboxylic acid [3-(4-fluoro-phenoxy)-5-nitro-phenyl-amide;
5-methyl-thiophene-2-carboxylic acid [3-nitro-5-(pyridin-3-yloxy)phenyl]-amide; or
4-fluoro-N-[3-nitro-5-(pyridin-2-yloxy)-phenyl]-benzamide.
19. A method of treatment for heart failure, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by Formula I:
wherein:
R 1 is, phenyl, pyridinyl, or phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
R 2 is fluoro, ethoxycarbonyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl, wherein said oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl is optionally substituted with lower alkoxy or oxo; and
R 3 is aryl, or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
wherein said heteroaryl group is a 5-, 6- or 7-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S; a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S; or a tricyclic 12- to 14-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S,
or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 where R 1 is 3-chlorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 3-methylphenyl, pyridin-2-yl or pyridin-3-yl.
21. The method of claim 19 , or 20 where R 3 is:
phenyl, optionally substituted with lower alkoxy, lower alkyl, halo (particularly bromo, chloro or fluoro), hydroxy, hydroxy-lower alkyl or nitro; or
benzodioxolyl, furanyl, indolyl, isoxazolyl, pyrazolyl, pyridinyl or thiophenyl, optionally substituted with lower alkyl, lower alkoxy, or halo.
22. The method of claim 21 where R 3 is 3-hydroxyphenyl, 4-hydroxyphenyl, 4-fluorophenyl, isoxazol-5-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl or 5-methyl-thiophen-2-yl.
23. The method of claim 19 where R 1 is phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy and R 2 is nitro.
24. The method of claim 23 where where R 1 is 4-fluorophenyl.
25. The method of claim 19 where R 1 is heteroaryl and R 2 is fluoro.
26. The method of claim 25 where where R 1 is pyridin-3-yl.
27. The method of claim 19 where R 1 is heteroaryl.
28. The method of claim 27 where where R 1 is pyridin-3-yl.
29. The method of claim 28 where R 3 is phenyl, 4-fluorophenyl, 4-cyanophenyl, 4-methoxyphenyl or 4-methylphenyl.
30. The method of claim 19 comprising a method of treating a heart disease that is associated with systolic dysfunction.
31. The method of claim 19 where the compound is:
4-fluoro-N-[3-(pyridin-3-yloxy)-5-trifluoromethyl-phenyl]-benzamide;
5-methyl-thiophene-2-carboxylic acid [3-nitro-5-(pyridin-3-yloxy)phenyl]-amide;
4-fluoro-N-[3-pyridin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
4-fluoro-N-[3-pyrazin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
4-fluoro-N-[3-nitro-5-(pyridin-2-yloxy)-phenyl]-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-3-hydroxy-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-4-hydroxy-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-nicotinamide; or
isoxazole-5-carboxylic acid [3-fluoro-5-(pyridin-3-yloxy)-phenyl)-amide.
32. A pharmaceutical formulation comprising a pharmaceutically accepted excipient and a therapeutically effective amount of a compound represented by Formula I:
wherein:
R 1 is phenyl, pyridinyl, or phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
R 2 is fluoro, ethoxycarbonyl, oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl, wherein said oxazolyl, pyrazinyl, pyridinyl, pyrimidinyl, tetrazolyl or thiazolyl is optionally substituted with lower alkoxy or oxo; and
R 3 is aryl, or heteroaryl, each of which is optionally substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy;
wherein said heteroaryl group is a 5-, 6- or 7-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N or S; a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S; or a tricyclic 12- to 14-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N or S,
or a single stereoisomer, or mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.
33. The pharmaceutical formulation of claim 32 where R 1 is phenyl substituted with alkyl, halogen, hydroxy, alkoxy, alkylenedioxy, fluoroalkyl, carboxy, carboalkoxy, carboxyalkyl, carboxamido, sulfonamidoalkyl, sulfonamidyoaryl, aminocarbonyl, benzyloxycarbonylamino, cyano, carbonyl, nitro, dialkylamino, alkylamino, amino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, arylthio, arylsulfinyl, arylsulfonyl, amidino, phenyl, benzyl, heteroaryl, heterocyclyl, phenoxy, benzyloxy, or heteroaryloxy and R 2 is nitro.
34. The pharmaceutical formulation of claim 33 where where R 1 is 4-fluorophenyl.
35. The pharmaceutical formulation of claim 32 where R 1 is heteroaryl and R 2 is fluoro.
36. The pharmaceutical formulation of claim 35 where where R 1 is pyridin-3-yl.
37. The pharmaceutical formulation of claim 32 where R 1 is heteroaryl.
38. The pharmaceutical formulation of claim 37 where where R 1 is pyridin-3-yl.
39. The pharmaceutical formulation of claim 38 where R 3 is phenyl, 4-fluorophenyl, 4-cyanophenyl, 4-methoxyphenyl or 4-methylphenyl.
40. The pharmaceutical formulation of claim 32 where the compound is:
N-[3-cyano-5-(pyridin-3-yloxy)-phenyl]]-4-fluoro-benzamine;
4-fluoro-N-[3-(pyridin-3-yloxy)-5-trifluoromethyl-phenyl]-benzamide;
5-methyl-thiophene-2-carboxylic acid [3-nitro-5-(pyridin-3-yloxy)phenyl]-amide;
4-fluoro-N-[3-pyridin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
4-fluoro-N-[3-pyrazin-2-yl-5-(pyridin-3-yloxy)-phenyl]-benzamide;
4-fluoro-N-[3-nitro-5-(pyridin-2-yloxy)-phenyl]-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-3-hydroxy-benzamide;
N-[3-fluoro-5-(pyridin-3-yloxy)-phenyl]-4-hydroxy-benzamide;
N-[3-fluoro-5-pyridin-3-yloxy)-phenyl]-nicotinamide; or
isoxazole-5-carboxylic acid [3-fluoro-5-(pyridin-3-yloxy)-phenyl)-amide.
41. The compound of claim 1 wherein R 2 is oxazol-2-yl, pyrazin-2-yl, pyridin-1-yl, pyridin-2-yl, pyrimidin-2-yl, tetrazol-2-yl, or thiazol-2-yl.
42. The compound of claim 41 wherein R 2 is 3-methoxy-2-oxo-2H-pyridin-1-yl.
43. The compound of claim 41 wherein R 2 is 1-methoxymethoxy-1H-tetrazol-5-yl, or 2-methoxymethoxy-2H-tetrazol-5-yl.