Isoindolinone inhibitors of phosphatidylinositol 3-kinase

Patent metadata

Field	Value
Publication number	US-9676759-B2
Application number	US-201313888960-A
Country	US
Kind code	B2
Filing date	May 7, 2013
Priority date	Dec 22, 2009
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is CH or N;
R 1 is selected from a phenyl or pyridinyl ring, wherein the phenyl or pyridinyl ring is optionally substituted with 1 or 2 independent occurrences of R 1a ;
R 1a is chloro, fluoro, C 1-6 aliphatic, C 3-6 cycloaliphatic, —CN, —C(O)R 1b ,
—C(O)N(R 1b ) 2 ,
—C(O)O(R 1b ), or —OR 1b , wherein each of said aliphatic or cycloaliphatic is optionally substituted with up to 3 occurrences of J R ;
each J R is independently fluoro, oxo, —CN, —C(O)R 1b , —C(O)N(R 1b ) 2 , —C(O)O(R 1b ), —N(R 1b ) 2 , —N(R 1b )C(O)R 1b , —OR 1b , or a 5-membered heteroaryl or heterocyclyl having up to 3 atoms selected from nitrogen, oxygen, or sulfur;
each R 1b is independently selected from hydrogen, C 1-4 aliphatic, or C 3-6 cycloaliphatic;
R 2 is hydrogen, F, Cl, CF 3 , or CH 3 ;
B is N;
C is CR C , wherein R C is hydrogen, fluoro, chloro, CF 3 , —OCF 3 , or —OC 1-2 aliphatic; and
D is CR D , wherein R D is fluoro, chloro, C 1-3 aliphatic, CF 3 , —OCF 3 , or —OC 1-2 aliphatic.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 .

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a pyridinyl ring optionally substituted with 1 or 2 independent occurrences of R 1a .

5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is

R 2 is CH 3 ;
R 3 is hydrogen, C 1-2 alkyl, OH, or OCH 3 ;
R 4 is hydrogen or CH 3 ;
R C is hydrogen, F, Cl, C 1-3 aliphatic, (CH 2 ) 0-1 CF 3 , —OCF 3 , or —OC 1-8 aliphatic; and
R D is —C(O)NHC 1-8 aliphatic.

6. The compound according to claim 5 , or a pharmaceutical acceptable salt thereof, wherein R 1 is selected from

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R C and R D is —OCH 3 .

8. A compound selected from

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

10. A method of treating or lessening the severity of multiple sclerosis in a patient comprising the step of administering to said patient a compound or salt thereof according to claim 1 , or a pharmaceutical composition thereof.

11. A method of inhibiting PI3K-gamma kinase activity in a biological sample comprising contacting said biological sample with a compound according to claim 1 , or a composition comprising said compound.

Assignees

• Vertex Pharma

Inventors

• Aronov Alex
• Come Jon H
• Davies Robert J
• Pierce Albert Charles
• Collier Philip N
• Grey Ronald Lee
• O'Dowd Hardwin
• Henderson James A
• Krueger Elaine B
• Grillot Anne-Laure
• Le Tiran Arnaud
• Liao Yusheng
• Messersmith David
• Wang Jian
• Cao Jingrong
• Bandarage Upul Keerthi
• Nanthakumar Suganthini S

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title