Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
Disclosed are beta and gamma-amino isoquinoline amide compounds and substituted benzamide compounds. In particular, the invention provides compounds that affect the function of kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. The compounds of the invention are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, and diseases characterized by abnormal growth, such as cancers. The invention further provides compositions containing the beta or gamma-amino isoquinoline amide compounds or substituted benzamide compounds.
1. A compound of formula (I):
or any optical isomer, diastereomer, enantiomer, tautomer, or physiologically acceptable salt thereof;
wherein R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 carbonyl, or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms;
wherein one of R 3 and R 4 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkenyl, and the other of R 3 and R 4 is hydrogen or C 1 -C 4 alkyl; and
wherein X 1 and X 2 are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, amino, nitro, or cyano.
2. The compound according to claim 1 , wherein one of R 3 and R 4 is aryl or heteroaryl.
3. The compound according to claim 2 , wherein R 1 and R 2 are, independently, hydrogen or methyl.
4. The compound according to claim 1 , wherein X 1 and X 2 are, independently, hydrogen, hydroxy, chloro or fluoro.
5. The compound according to claim 1 , wherein one of R 3 and R 4 is aryl or heteroaryl; wherein R 1 and R 2 are, independently, hydrogen or methyl; and wherein X 1 and X 2 are, independently, hydrogen, hydroxyl, chloro or fluoro.
6. The compound according to claim 5 , wherein the other of R 3 and R 4 is hydrogen.
7. The compound according to claim 1 , wherein one of R 3 and R 4 is aryl or heteroaryl.
8. The compound according to claim 2 , wherein one of R 3 and R 4 is thienyl.
9. The compound according to claim 2 , wherein one of R 3 and R 4 is monosubstituted phenyl or monosubstituted thienyl.
10. The compound according to claim 9 , wherein the substituent is fluoro, chloro or cyano.
11. The compound according to claim 2 , wherein one of R 3 and R 4 is unsubstituted phenyl or unsubstituted thienyl.
12. The compound according to claim 1 , wherein X 1 is hydroxy and X 2 is hydrogen.
13. The compound according to claim 1 , wherein a hydroxy is at the 1-position.
14. The compound according to claim 1 , wherein a hydrogen is at the 1-position.
15. The compound according to claim 1 , wherein R 1 and R 2 are, independently, hydrogen or methyl; R 3 is hydrogen, R 4 is phenyl; X 1 and X 2 are hydrogen.
16. A compound of formula (II):
or any optical isomer, diastereomer, enantiomer, tautomer, or physiologically acceptable salt thereof;
wherein R 1 and R 2 are, independently, hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 carbonyl, or C 1 -C 4 carboxyl; or R 1 and R 2 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms, or R 1 and R 3 combine to form a heterocycloalkyl ring of at least 5 and at most 8 member atoms;
wherein one of R 3 , R 4 , and R 5 is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C 1 -C 8 alkyl, or C 2 -C 8 alkenyl, and the other two of R 3 , R 4 , and R 5 is hydrogen or C 1 -C 4 alkyl; and
wherein X 1 and X 2 are, independently, hydrogen, hydroxyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, amino, nitro, or cyano.
17. The compound according to claim 16 , wherein one of R 3 , R 4 and R 5 is aryl or heteroaryl.
18. The compound according to claim 17 , wherein R 1 and R 2 are, independently, hydrogen or methyl.
19. The compound according to claim 16 , wherein X 1 and X 2 are, independently, hydrogen, hydroxy, chloro or fluoro.
20. The compound according to claim 16 , wherein one of R 3 , R 4 and R 5 is aryl or heteroaryl; wherein R 1 and R 2 are, independently, hydrogen or methyl; and wherein X 1 and X 2 are, independently, hydrogen, hydroxyl, chloro or fluoro.
21. The compound according to claim 20 , wherein the other of R 3 , R 4 and R 5 are hydrogen.
22. The compound according to claim 16 , wherein one of R 3 , R 4 and R 5 is aryl or heteroaryl.
23. The compound according to claim 22 , wherein one of R 3 , R 4 and R 5 is thienyl.
24. The compound according to claim 22 , wherein one of R 3 , R 4 and R 5 is monosubstituted phenyl or monosubstituted thienyl.
25. The compound according to claim 24 , wherein the substituent is fluoro, chloro or cyano.
26. The compound according to claim 24 , wherein one of R 3 , R 4 and R 5 is unsubstituted phenyl or unsubstituted thienyl.
27. The compound according to claim 16 , wherein X 1 is hydroxy and X 2 is hydrogen.
28. The compound according to claim 16 , wherein a hydroxy is at the 1-position.
29. The compound according to claim 16 , wherein a hydrogen is at the 1-position.
30. The compound according to claim 16 , wherein R 1 and R 2 are, independently, hydrogen or methyl; R 3 and R 4 are hydrogen, R 5 is phenyl; X 1 and X 2 are hydrogen.
31. A composition comprising a compound according to claim 1 and a carrier.
32. The composition of claim 31 , wherein the carrier is saline buffered to a pH of about 5.5 to about 6.5.
33. A composition comprising a compound according to claim 16 and a carrier.
34. The composition of claim 33 , wherein the carrier is saline buffered to a pH of about 5.5 to about 6.5.
35. A method of treating a disease in a subject comprising:
administering to a subject an effective amount of a compound according to claim 1 ;
wherein the disease comprises eye disease.
36. The method of claim 35 , wherein the eye disease comprises glaucoma or a neurodegenerative eye disease.