Protein kinase C inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9682976-B2
Application number	US-201615056535-A
Country	US
Kind code	B2
Filing date	Feb 29, 2016
Priority date	Apr 4, 2012
Publication date	Jun 20, 2017
Grant date	Jun 20, 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 according to the formula (XII):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 1 and R 2 together form an oxo group; or R 3 and R 4 together form an oxo group; or R 5 and R 6 together form an oxo group;
R 7 , R 8 , R 9 , and R 10 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 7 and R 8 together form an oxo group; or R 9 and R 10 together form an oxo group;
Z 1 is OR 17 , —NR 17 R 18 or X;
Z 2 is H, or Z 1 and Z 2 together form an oxo, ═NR 19 or ═NNR 20 R 21 ;
R 17 is H, alkyl, substituted alkyl, acyl, acylamino, —SO 2 -alkyl or —SO 2 -aryl;
R 18 is H, alkyl, substituted alkyl, acyl, acylamino, —SO 2 -alkyl, —SO 2 -aryl, aryl or heteroaryl;
X is halo or azido;
R 19 , R 20 , and R 21 each independently are selected from alkyl, substituted alkyl, aryl substituted aryl, heteroaryl and substituted heteroaryl; and
the compound is optically active.

2. A method of inhibiting a protein kinase C (PKC) activity comprising contacting a PKC with a compound of formula (VI):

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 1 and R 2 together form an oxo group; or R 3 and R 4 together form an oxo group; or R 5 and R 6 together form an oxo group;
R 7 , R 8 , R 9 , and R 10 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 7 and R 8 together form an oxo group; or R 9 and R 10 together form an oxo group;
R 11 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halogen, thiol, thioalkoxy, substituted thioalkoxy, acyl, aminoacyl, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl;
R 20 is selected from hydrogen, alkyl, and substituted alkyl;
G is halogen or —NY 2 Ar 1 ;
Y 1 and Y 2 are independently selected from hydrogen, alkyl and substituted alkyl; and
Ar 1 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
or a salt or stereoisomer thereof.

3. The method of claim 2 , wherein the inhibition of PKC results in treatment of a disease or disorder that is mediated or sustained through the activity of a PKC activity.

4. The method of claim 3 , wherein the disease or disorder is associated with activation of T cells.

5. The method of claim 4 , wherein the disease or disorder is an inflammatory disease.

6. The method of claim 4 , wherein the disease or disorder is selected from inflammatory bowel disease, Crohn's disease and ulcerative colitis.

7. A method of studying a biological sample known to comprise PKC, the method comprising:
(a) contacting the biological sample with a compound of formula (VI) according to claim 2 ; and
(b) determining the PKC activity inhibiting effects caused by the compound on the biologic sample.

8. The method of claim 7 , wherein the determination step is performed using an assay of inhibition of PKC activity.

9. A method for making a compound according to the formula

wherein
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 1 and R 2 together form an oxo group; or R 3 and R 4 together form an oxo group; or R 5 and R 6 together form an oxo group;
R 7 , R 8 , R 9 , and R 10 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl and —SO 2 -heteroaryl; or R 7 and R 8 together form an oxo group; or R 9 and R 10 together form an oxo group;
R 11 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 substituted alkyl; and
Ar 1 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
the method comprising contacting a compound of the formula

wherein X 1 is a halogen;
with a compound of the formula HNY 2 Ar 1 .

10. The method of claim 2 , wherein G is —NY 2 Ar 1 .

11. The method of claim 2 , wherein G is halogen.

12. The method of claim 2 , wherein Ar 1 is aryl or substituted aryl.

13. The method of claim 2 , wherein Ar 1 is heteroaryl or substituted heteroaryl.

14. The method of claim 2 , wherein the compound is a compound accordin

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Singh Rajinder
• Duncton Matthew
• Zhang Jing
• Alvarez Salvador
• Tso Kin
• Holland Sacha
• Yen Rose
• Kolluri Rao
• Heckrodt Thilo
• Chen Yan
• Masuda Esteban
• Li Hui
• Payan Donald G
• Kelley Ryan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/04

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