Therapeutically active compositions and their methods of use

1. A compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein:

R 1 is optionally substituted C 4 -C 6 carbocyclyl;

each R 2 and R 3 is independently optionally substituted aryl or optionally substituted heteroaryl;

R 4 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 R 5 groups;

each R 5 is independently halo; —CF 3 ; —CN; —OR 6 ;—N(R 6 ) 2 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; —O—C 1 -C 4 alkyl optionally substituted with halo, —OR 6 or —N(R 6 ) 2 ; —SO 2 N(R 6 ) 2 ; —SO 2 (C 1 -C 4 alkyl); —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —O—(C 3 -C 6 carbocyclyl optionally substituted with one or two R 6 groups); 5-6 membered heteroaryl; —C 1 -C 4 alkyl-C(O)O—C 1 -C 4 alkyl; or —C(O)O—C 1 -C 4 alkyl; or

each R 6 is independently H or C 1 -C 3 alkyl.

2. The compound of claim 1 , wherein:

R 1 is C 4 -C 6 carbocyclyl optionally substituted with one to three R 7 groups;

each R 2 and R 3 is independently aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R 7 groups;

R 4 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, wherein said aryl, heteroaryl, aralkyl, and heteroaralkyl are each independently optionally substituted with one to three R 7 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 R 5 groups;

each R 5 and R 7 is independently halo; —CF 3 ; —CN; —OR 6 ;—N(R 6 ) 2 ; —C(O)C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; C 1 -C 4 alkyl optionally substituted with —OR 6 or —N(R 6 ) 2 ; —O—C 1 -C 4 alkyl optionally substituted with halo, —OR 6 or —N(R 6 ) 2 ; —SO 2 N(R 6 ) 2 ; —S(O)—C 1-4 alkyl; —SO 2 (C 1 -C 4 alkyl); —NR 6 SO 2 R 6 ; C 3 -C 5 carbocyclyl optionally substituted with one or two R 6 groups; —O—(C 3 -C 6 carbocyclyl optionally substituted with one or two R 6 groups); 5-6 membered heteroaryl; —C 1 -C 4 alkyl-C(O)O—C 1 -C 4 alkyl; or —C(O)O—C 1 -C 4 alkyl; or

each R 6 is independently H or C 1 -C 4 alkyl.

3. The compound of claim 2 , wherein each R 2 and R 3 is independently aryl optionally substituted with one to three R 7 groups.

4. The compound of claim 1 having formula II-a,

wherein R 10 is CR 11 or N; and R 11 is —F, —SO 2 NH 2 , —SO 2 CH 3 , —S(O)CH 3 , —CN, methoxy, —OCH 2 OH, —CH 2 OH, —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 3 , —NHSO 2 CH 3 , —CH 2 CH 2 OH, —N(CH 3 ) 2 , t-butyl, cyclopropyl, —C(OH)(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl.

5. The compound of claim 4 , wherein R 1 is C 4 or C 6 cycloalkyl optionally substituted with one to two R 7 groups and R 7 associated with R 1 is halo.

6. The compound of claim 5 , wherein R 1 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 R 4 ; and each member of ring A is optionally substituted with one or two R 5 groups.

8. The compound of claim 7 , wherein ring A is:

9. The compound of claim 7 , wherein R 4 is aryl or heteroaryl, each aryl or heteroaryl is optionally substituted with one to three R 7 groups.

10. The compound of claim 9 , wherein R 4 is:

wherein each member of R 4 is optionally substituted with one or two R 7 groups and each R 7 is independently F, Cl, methyl, CF 3 , CN, OMe, or N(R 6 ) 2 .

11. The compound of claim 10 , wherein R 4 is:

wherein R 100 is H, methyl, Cl, CF 3 , CN, OCH 3 , or N(R 6 ) 2 and R 101 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.