3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH

Patent metadata

Field	Value
Publication number	US-9434719-B2
Application number	US-201414408418-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 14, 2013
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

Abstract

The invention is directed to a formula (I):

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b and R 3 -R 7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

First claim

What is claimed is:

1. A compound according to formula (V):

or a pharmaceutically acceptable salt thereof, wherein:
R 2a is methyl or C 1-3 haloalkyl;
R 5 and R 6 are each independently hydrogen, deuterium, halo, —C(O)OCH 3 , C 1-3 alkyl or C 1-3 haloalkyl;
R 7 is

wherein:
ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms;
ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
X is N or CH;
each R 8 is independently hydrogen, halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy;
n is 1 or 2;
R 9 is hydrogen, halo, C 1-3 haloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR 9a , —SO 2 R 9a , —C(O)NHR 9a , CH 2 R 9b or CHCH 3 R 9b , provided that when X is N, R 9 is hydrogen, C 1-3 haloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO 2 R 9a or —C(O)NHR 9a , wherein:
said C 1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, and
said C 3-6 cycloalkyl, 5 or 6 membered heterocyclic, aryl and heteroaryl are each optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;

R 9a is optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic, wherein:
said C 1-6 alkyl is optionally substituted with one C 3-6 cycloalkyl,
said C 3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH 2 OH, —NRR, cyano, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkoxy, and
said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy;

R 9b is optionally substituted C 3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
said C 3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH 2 OH, —NRR, —NRC(O)CH 3 ; 4 to 6 membered heterocyclic, cyano, halo, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkoxy, and
said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy; and

each R is independently selected from the group consisting of H, C 1-3 alkyl and C 3-6 cycloalkyl.

2. The compound according to claim 1 wherein:
R 5 is hydrogen or halo; and
R 6 is hydrogen, halo, methyl, CH 2 F, CHF 2 , or CF 3 ; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

4. The compound according claim 2 wherein R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R 2a is methyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 7 is:

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 9 is hydrogen, halo, C 1-3 haloalkyl, optionally substituted C 1-6 alkyl or optionally substituted C 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 9 is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: fluoro, chloro, bromo, cyano, methoxy, C 1-4 alkyl, C 1-4 haloalkyl and C 1-3 haloalkoxy; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 9 is pyrazolyl, pyridinyl, indolyl or isoquinolinyl each of which is optionally substituted; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R 9 is CH 2 R 9b wherein R 9b is piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, halo, —NRR, cyano, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkoxy.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from:
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl) oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-2-methyl-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl) oxazolidin-2-one;
(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(2,5-difluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(2-(2-(trifluoromethyl)pyridin-4-yl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-(difluoromethyl)-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-(difluoromethyl)phenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chloro-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(5-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-chlorophenyl)-1H-pyrazol-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(3,5-difluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-fluoroethyl)oxazolidin-2-one;
(R)-3-(2-(((S)-1-(1-(4-(difluoromethyl)-3-fluorophenyl)-1H-imidazol-4-yl)ethyl)amino)pyrimidin-

Assignees

• Caferro Thomas Raymond
• Chen Zhuoliang
• Cho Young Shin
• Costales Abran Q
• Levell Julian Roy
• Liu Gang
• Manning James R
• Sendzik Martin
• Shafer Cynthia
• Shultz Michael David
• Sutton James
• Wang Yaping
• Zhao Qian
• Novartis Ag

Inventors

• Caferro Thomas Raymond
• Chen Zhuoliang
• Cho Young Shin
• Costales Abran Q
• Levell Julian Roy
• Liu Gang
• Manning James R
• Sendzik Martin
• Shafer Cynthia
• Shultz Michael David
• Sutton James
• Wang Yaping
• Zhao Qian

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title