Protein kinase C inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9321763-B2
Application number	US-201313857028-A
Country	US
Kind code	B2
Filing date	Apr 4, 2013
Priority date	Apr 4, 2012
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

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 (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.

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

3. The compound of claim 1 , wherein G is halogen.

4. The compound of claim 1 , wherein Ar 1 is aryl or substituted aryl.

5. The compound of claim 1 , wherein Ar 1 is heteroaryl or substituted heteroaryl.

6. The compound of claim 1 , according to the formula

wherein
H 1 and H 2 are hydrogen.

7. The compound of claim 1 , wherein the compound is a compound of formula (VII):

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;
R 20 is selected from hydrogen, alkyl, and substituted alkyl;
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.

8. The compound of claim 7 , wherein the formula is

wherein H 1 and H 2 are hydrogen with cis relative configuration.

9. The compound of claim 7 , wherein the formula is

wherein H 1 and H 2 are hydrogen with trans relative configuration.

10. The compound of claim 7 , wherein the compound is optically active.

11. The compound of claim 10 , having an enantiomeric excess of 90% or more.

12. The compound of claim 11 , wherein the enantiomeric excess is 95% or more.

13. The compound of claim 11 , wherein the enantiomeric excess is 99% or more.

14. The compound of claim 1 , wherein the compound is a compound of formula (VIII)

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;
R 20 is selected from hydrogen, alkyl, and substituted alkyl;
Y 1 and Y 2 are independently selected from hydrogen, alkyl and substituted alkyl;
Q is C or N; and
R 12 , R 13 , R 14 , R 15 , and R 16 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, hydroxyl, alkoxy, substituted alkoxy, amino, substituted amino, acylamino, aminocarbonylamin

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

• A61P43/00

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

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title