Pyrazolyl guanidine F1F0-ATPase inhibitors and therapeutic uses thereof

Patent metadata

Field	Value
Publication number	US-9932313-B2
Application number	US-201715421729-A
Country	US
Kind code	B2
Filing date	Feb 1, 2017
Priority date	Dec 8, 2010
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

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 method of treating ulcerative colitis in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I to treat the ulcerative colitis:

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, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 8 , —C(O)R 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 N(R 10 )(R 11 ), —C(O)N(R 10 )(R 11 ), —N(R 10 )(R 11 ), or —N(R 8 )C(O)(R 9 );
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 9 represents independently for each occurrence alkyl or cycloalkyl;
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 method 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 method of claim 1 , wherein A 2 is

4. The method of claim 2 , wherein A 2 is

5. The method of claim 3 , wherein R 1 represents independently for each occurrence halogen or haloalkyl.

6. The method of claim 4 , wherein R 1 represents independently for each occurrence halogen or haloalkyl.

7. The method of claim 3 , wherein R 1 is chloro, fluoro, or trifluoromethyl.

8. The method of claim 4 , wherein R 1 is chloro, fluoro, or trifluoromethyl.

9. The method of claim 7 , 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.

10. The method of claim 8 , 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.

11. The method of claim 8 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.

12. The method of claim 11 , wherein R 5 is hydrogen.

13. The method of claim 9 , wherein R 6 is haloalkyl.

14. The method of claim 12 , wherein R 6 is haloalkyl.

15. The method of claim 12 , wherein R 6 is trifluoromethyl.

16. The method of claim 13 , wherein R 7 is hydrogen.

17. The method of claim 15 , wherein R 7 is hydrogen.

18. The method of claim 17 , wherein n is 1 or 2.

19. The method of claim 16 , wherein the compound is administered orally to the patient.

20. The method of claim 18 , wherein the compound is administered orally to the patient.

21. A method of treating ulcerative colitis in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-A1 to treat the ulcerative colitis:

including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ;
R 3 is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or C 1 -C 6 alkylene-C 1 -C 6 alkoxy, wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano; and
R 4 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, or heteroaralkyl, 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, C 1 -C 6 alkoxy, and cyano.

22. The method of claim 21 , wherein the compound is a compound of Formula I-A1 or a stereoisomer, geometric isomer, or tautomer; or a pharmaceutically acceptable salt of any of the foregoing.

23. The method of claim 22 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.

24. The method of claim 22 , wherein R 4 is trifluoromethyl.

25. The method of claim 24 , wherein the compound is administered orally to the patient.

Assignees

• Lycera Corp

Inventors

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

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• 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

• A61P37/06

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title