Pyrazolyl guanidine F
View Patent ↗The invention provides pyrazolyl guanidine compounds that inhibit F 1 F o -ATPase, and methods of using pyrazolyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
1. A compound represented by Formula I:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenylene;
A 2 is
R 1 represents independently for each occurrence halogen or haloalkyl;
R 2 is hydrogen or alkyl;
R 3 is aryl, aralkyl, cycloalkyl, —(C(R 8 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, —(C(R 8 ) 2 ) m -heterocycloalkyl, alkyl, haloalkyl, hydroxyalkyl, —(C(R 8 ) 2 ) m -alkoxyl, —(C(R 8 ) 2 ) m —O—(C(R 8 ) 2 ) m -alkoxyl, or —(C(R 8 ) 2 ) m —CN, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C 1 -C 6 alkoxy, cyano, and —C 1 -C 6 alkylene-CO 2 R 8 ;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl;
R 6 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl, —CO 2 R 8 , or —C(O)N(R 10 )(R 11 ), wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, hydroxyalkyl, C 1 -C 6 alkoxy, —O-aralkyl, and cyano;
R 7 is hydrogen, halogen, alkyl, or haloalkyl;
R 8 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 8 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 10 and R 11 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
n is 1, 2, or 3; and
m is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein the compound is a compound of Formula I or a stereoisomer, geometric isomer, or tautomer; or a pharmaceutically acceptable salt of any of the foregoing.
3. The compound of claim 2 , wherein A 2 is
4. The compound of claim 3 , wherein R 1 is chloro, fluoro, or trifluoromethyl.
5. The compound of claim 4 , wherein R 2 and R 4 are hydrogen.
6. The compound of claim 5 , wherein R 3 is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
7. The compound of claim 5 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
8. The compound of claim 7 , wherein R 5 is hydrogen.
9. The compound of claim 8 , wherein R 6 is alkyl, haloalkyl, cyano, or aryl, wherein said aryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, and alkyl.
10. The compound of claim 5 , wherein R 6 is haloalkyl.
11. The compound of claim 8 , wherein R 6 is haloalkyl.
12. The compound of claim 8 , wherein R 6 is trifluoromethyl.
13. The compound of claim 11 , wherein R 7 is hydrogen.
14. The compound of claim 12 , wherein R 7 is hydrogen.
15. The compound of claim 13 , wherein n is 1.
16. The compound of claim 14 , wherein n is 1.
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable carrier.
22. A method of treating inflammatory bowel disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 to treat the inflammatory bowel disease.
23. A method of treating inflammatory bowel disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 to treat the inflammatory bowel disease.
24. A method of treating inflammatory bowel disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 7 to treat the inflammatory bowel disease.
25. A method of treating inflammatory bowel disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 12 to treat the inflammatory bowel disease.
26. A method of treating inflammatory bowel disease in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 16 to treat the inflammatory bowel disease.
27. A method of treating a disorder selected from the group consisting of psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, systemic lupus erythematosus, Sjogren's syndrome, ulcerative colitis, and epidermal hyperplasia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 to treat the disorder.