Pyrazolyl guanidine F1F0-ATPase inhibitors and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-9580388-B2
Application number	US-201514800969-A
Country	US
Kind code	B2
Filing date	Jul 16, 2015
Priority date	Dec 8, 2010
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Lycera Corp

Inventors

• Glick Gary D
• Hurd Alexander R
• Taylor Clarke B
• Vanhuis Chad A

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title