3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH

摘要

The invention is directed to a formula (I):;;or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 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.

主权项

1. A compound according to formula (I)wherein:
R1 is hydrogen, methyl or ethyl; R2a is hydrogen, methyl or C1-3 haloalkyl; R2b is OH, halo, C1-6 alkoxy, C1-3 haloalkyl, NH2, NH(CH3) or N(CH3)2; R3 and R4 are each independently hydrogen, methyl or ethyl or R3 and R4 are joined together forming cyclopropyl, cyclobutyl or oxetanyl; R5 and R6 are each independently hydrogen, deuterium, halo, —C(O)OCH3, C1-3 alkyl or C1-3 haloalkyl; R7 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 R8 is independently hydrogen, halo, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy;n is 1 or 2;R9 is hydrogen, halo, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted 5 or 6 membered heterocyclic, optionally substituted heteroaryl, —OR9a, —SO2R9a, —C(O)NHR9a, CH2R9b or CHCH3R9b, provided that when X is N, R9 is hydrogen, C1-3 haloalkyl, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —SO2R9a or —C(O)NHR9a, wherein:
said C1-6 alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of: OH, phenyl and phenoxy, andsaid C3-6 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, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;R9a is optionally substituted C1-6 alkyl, C1-6 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, or optionally substituted heterocyclic, wherein:
said C1-6 alkyl is optionally substituted with one C3-6 cycloalkyl,said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, cyano, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, andsaid phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, —NRR, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;R9b is optionally substituted C3-6 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclic,
said C3-6 cycloalkyl and heterocyclic are each optionally substituted with one to four substituents each independently selected from the group consisting of: hydroxyl, CH2OH, —NRR, —NRC(O)CH3, 4 to 6 membered heterocyclic, cyano, halo, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy, andsaid phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; andeach R is independently selected from the group consisting of H, C1-3 alkyl and C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.