Protein kinase C inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9732070-B2
Application number	US-201615261294-A
Country	US
Kind code	B2
Filing date	Sep 9, 2016
Priority date	Dec 1, 2009
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

This disclosure concerns compounds which are useful as inhibitors of protein kinase C (PKC) and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC. This disclosure also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

First claim

What is claimed is:

1. A compound of formula (V):

wherein
R 5 is selected from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;
Y 1 and Y 2 are independently selected from hydrogen, alkyl, and acyl;
R 1 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, acyl, and oxy radical;
R a and R b are independently selected from hydrogen and alkyl;
R c and R d are independently selected from hydrogen and alkyl;
Q is selected from N and CR 7b ;
R 6a , R 7b and R 8 are independently selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonyloxy, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxycarbonylamino, aminocarbonylamino, acyl, carboxyl, carboxyl ester, aminoacyl, sulfonyl, sulfonylamino, aminosulfonyl, and —O-alk-A;
alk is a bond, alkylene or substituted alkylene;
A is selected from aryl, cycloalkyl, heteroaryl, and heterocyclyl;
wherein the A ring can be substituted or unsubstituted; and
R 7y is selected from hydrogen, alkyl, and substituted alkyl;
or a salt or stereoisomer thereof.

2. The compound of claim 1 , wherein R 5 is cyano or halogen.

3. The compound of claim 1 , wherein R 5 is halogen.

4. The compound of claim 1 , wherein R 5 is fluoro.

5. The compound of claim 1 , wherein R 5 is cyano.

6. The compound of claim 1 , wherein R 8 is selected from hydrogen, alkyl, substituted alkyl, halogen, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl.

7. The compound of claim 1 , wherein R 8 is selected from alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl.

8. The compound of claim 1 , wherein R 8 is cycloalkyl or substituted cycloalkyl.

9. The compound of claim 1 , wherein R 8 is cyclopropyl.

10. The compound of claim 1 , wherein Y 1 and Y 2 are each hydrogen.

11. The compound of claim 1 , wherein R 1 is hydrogen.

12. The compound of claim 1 , wherein R 1 is alkyl.

13. The compound of claim 1 , wherein R a , R b , R c and R d are each alkyl.

14. The compound of claim 1 , wherein R 6a is selected from hydrogen, alkyl, substituted alkyl, and halogen.

15. The compound of claim 1 , wherein R 6a is hydrogen.

16. The compound of claim 1 , wherein Q is CR 7b , and R 7b is selected from hydrogen, alkyl, and substituted alkyl.

17. The compound of claim 16 , wherein R 7b is hydrogen.

18. The compound of claim 1 , wherein R 7y is alkyl.

19. The compound of claim 1 , wherein the compound is 1-(2-cyclopropyl-4-fluoro-5-(5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyrimidin-2-ylamino)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (Compound I-14).

20. The compound of claim 1 , wherein the compound is 1-{2-Cyclopropyl-4-fluoro-5-[5-fluoro-4-(1,2,2,6,6-pentamethyl-piperidin-4-ylamino)-pyrimidin-2-ylamino]-phenyl}-4-methyl-1,4-dihydro-tetrazol-5-one (Compound (I-16).

21. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

22. A method of inhibiting a protein kinase C (PKC) activity, wherein the method comprises:
contacting a PKC with a compound of claim 1 , wherein the contacting results in inhibition of the PKC activity.

23. The method of claim 22 , wherein the contacting comprises administering a therapeutically effective amount of the compound of formula (V) to a subject in need of treatment of a disease or disorder that is mediated or sustained through the PKC activity, and wherein the administering results in treatment of the disease or disorder that is mediated or sustained through the PKC activity.

24. The method of claim 23 , wherein the disease or disorder is associated with activation of T cells.

25. The method of claim 23 , wherein the disease or disorder is an inflammatory disease.

26. The method of claim 23 , wherein the disease or disorder is an autoimmune disease.

27. The method of claim 23 , wherein the disease or disorder is an ocular disease or disorder involving inflammatory and/or neovascular events.

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Singh Rajinder
• Tso Kin
• Zhang Jing
• Duncton Matthew
• Alvarez Salvador
• Kolluri Rao
• Ramphal John
• Holland Sacha

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

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