Claims for Patent: 9,474,779

Summary for Patent: 9,474,779

Title:	Therapeutically active compositions and their methods of use
Abstract:	Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
Inventor(s):	Rene M. Lemieux, Janeta Popovici-Muller, Jeremy Travins, Zhenwei Cai, DaWei Cui, Ding Zhou
Assignee:	PHARMARESOURCES (SHANGHAI) CO Ltd, Servier Pharmaceuticals LLC
Application Number:	US13/745,005
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,474,779
Patent Claims:	1. A compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein: R1 is optionally substituted C4-C6 carbocyclyl; each R2 and R3 is independently optionally substituted aryl or optionally substituted heteroaryl; R4 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms N, O or S, wherein ring A is optionally substituted with one or two R5 groups; each R5 is independently halo; —CF3; —CN; —OR6;—N(R6)2; —C(O)C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkyl optionally substituted with —OR6 or —N(R6)2; —O—C1-C4 alkyl optionally substituted with halo, —OR6 or —N(R6)2; —SO2N(R6)2; —SO2(C1-C4 alkyl); —NR6SO2R6; C3-C5 carbocyclyl optionally substituted with one or two R6 groups; —O—(C3-C6 carbocyclyl optionally substituted with one or two R6 groups); 5-6 membered heteroaryl; —C1-C4 alkyl-C(O)O—C1-C4 alkyl; or —C(O)O—C1-C4 alkyl; or each R6 is independently H or C1-C3 alkyl. 2. The compound of claim 1, wherein: R1 is C4-C6 carbocyclyl optionally substituted with one to three R7 groups; each R2 and R3 is independently aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R7 groups; R4 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R7 groups; ring A is 4-6 membered non-aromatic ring having 0-1 additional heteroatoms N, O or S, wherein ring A is optionally substituted with one or two R5 groups; each R5 and R7 is independently halo; —CF3; —CN; —OR6;—N(R6)2; —C(O)C1-C4 alkyl; C1-C4 haloalkyl; C1-C4 alkyl optionally substituted with —OR6 or —N(R6)2; —O—C1-C4 alkyl optionally substituted with halo, —OR6 or —N(R6)2; —SO2N(R6)2; —S(O)—C1-4alkyl; —SO2(C1-C4 alkyl); —NR6SO2R6; C3-C5 carbocyclyl optionally substituted with one or two R6 groups; —O—(C3-C6 carbocyclyl optionally substituted with one or two R6 groups); 5-6 membered heteroaryl; —C1-C4 alkyl-C(O)O—C1-C4 alkyl; or —C(O)O—C1-C4 alkyl; or each R6 is independently H or C1-C4 alkyl. 3. The compound of claim 2, wherein each R2 and R3 is independently aryl optionally substituted with one to three R7 groups. 4. The compound of claim 1 having formula II-a, wherein R10 is CR11 or N; and R11 is —F, —SO2NH2, —SO2CH3, —S(O)CH3, —CN, methoxy, —OCH2OH, —CH2OH, —SO2N(CH3)2, —SO2NHCH3, —NHSO2CH3, —CH2CH2OH, —N(CH3)2, t-butyl, cyclopropyl, —C(OH)(CH3)2, —OCF3, —OCHF2, —O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl. 5. The compound of claim 4, wherein R1 is C4 or C6 cycloalkyl optionally substituted with one to two R7 groups and R7 associated with R1 is halo. 6. The compound of claim 5, wherein R1 is 7. The compound of claim 5, wherein ring A is: wherein denotes ring A's attachment to the amide moiety of formula II-a and denotes ring A's attachment to R4; and each member of ring A is optionally substituted with one or two R5 groups. 8. The compound of claim 7, wherein ring A is: 9. The compound of claim 7, wherein R4 is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R7 groups. 10. The compound of claim 9, wherein R4 is: wherein each member of R4 is optionally substituted with one or two R7 groups and each R7 is independently F, Cl, methyl, CF3, CN, OMe, or N(R6)2. 11. The compound of claim 10, wherein R4 is: wherein R100 is H, methyl, Cl, CF3, CN, OCH3, or N(R6)2 and R101 is H, F or methyl. 12. The compound of claim 1 which is any one of the compounds from Table 1. 13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12; and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition of claim 13, further comprising a second therapeutic agent useful or treating a cancer. 15. A method of treating a cancer characterized by an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate in a patient, comprising administering to the patient in need thereof the pharmaceutical composition of claim 13. 16. The method of claim 15, wherein the IDH1 mutation is an IDH1 R132H or R132C mutation. 17. The method of claim 15, wherein the cancer is glioma (glioblastoma), acute myelogenous leukemia, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), or colon cancer. 18. The method of claim 17, further comprising administering to the patient a second therapeutic agent useful or treating cancer.