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Last Updated: December 6, 2019

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Claims for Patent: 9,474,779

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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): Lemieux; Rene M. (Newtown, CT), Popovici-Muller; Janeta (Waltham, MA), Travins; Jeremy (Southborough, MA), Cai; Zhenwei (Belle Mead, NJ), Cui; Dawei (Shanghai, CN), Zhou; Ding (Shanghai, CN)
Assignee: Agios Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:13/745,005
Patent Claims: 1. A compound of formula I or a pharmaceutically acceptable salt, tautomer, isotopologue or hydrate thereof, wherein: ##STR00451## R.sup.1 is optionally substituted C.sub.4-C.sub.6 carbocyclyl; each R.sup.2 and R.sup.3 is independently optionally substituted aryl or optionally substituted heteroaryl; R.sup.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.sup.5 groups; each R.sup.5 is independently halo; --CF.sub.3; --CN; --OR.sup.6;--N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally substituted with --OR.sup.6 or --N(R.sup.6).sub.2; --O--C.sub.1-C.sub.4 alkyl optionally substituted with halo, --OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2; --SO.sub.2(C.sub.1-C.sub.4 alkyl); --NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally substituted with one or two R.sup.6 groups; --O--(C.sub.3-C.sub.6 carbocyclyl optionally substituted with one or two R.sup.6 groups); 5-6 membered heteroaryl; --C.sub.1-C.sub.4 alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or --C(O)O--C.sub.1-C.sub.4 alkyl; or each R.sup.6 is independently H or C.sub.1-C.sub.3 alkyl.

2. The compound of claim 1, wherein: R.sup.1 is C.sub.4-C.sub.6 carbocyclyl optionally substituted with one to three R.sup.7 groups; each R.sup.2 and R.sup.3 is independently aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R.sup.7 groups; R.sup.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.sup.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.sup.5 groups; each R.sup.5 and R.sup.7 is independently halo; --CF.sub.3; --CN; --OR.sup.6;--N(R.sup.6).sub.2; --C(O)C.sub.1-C.sub.4 alkyl; C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl optionally substituted with --OR.sup.6 or --N(R.sup.6).sub.2; --O--C.sub.1-C.sub.4 alkyl optionally substituted with halo, --OR.sup.6 or --N(R.sup.6).sub.2; --SO.sub.2N(R.sup.6).sub.2; --S(O)--C.sub.1-4alkyl; --SO.sub.2(C.sub.1-C.sub.4 alkyl); --NR.sup.6SO.sub.2R.sup.6; C.sub.3-C.sub.5 carbocyclyl optionally substituted with one or two R.sup.6 groups; --O--(C.sub.3-C.sub.6 carbocyclyl optionally substituted with one or two R.sup.6 groups); 5-6 membered heteroaryl; --C.sub.1-C.sub.4 alkyl-C(O)O--C.sub.1-C.sub.4 alkyl; or --C(O)O--C.sub.1-C.sub.4 alkyl; or each R.sup.6 is independently H or C.sub.1-C.sub.4 alkyl.

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

4. The compound of claim 1 having formula II-a, ##STR00452## wherein R.sup.10 is CR.sup.11 or N; and R.sup.11 is --F, --SO.sub.2NH.sub.2, --SO.sub.2CH.sub.3, --S(O)CH.sub.3, --CN, methoxy, --OCH.sub.2OH, --CH.sub.2OH, --SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2NHCH.sub.3, --NHSO.sub.2CH.sub.3, --CH.sub.2CH.sub.2OH, --N(CH.sub.3).sub.2, t-butyl, cyclopropyl, --C(OH)(CH.sub.3).sub.2, --OCF.sub.3, --OCHF.sub.2, --O-cyclopropyl, -1-methyl-cyclopropyl, or pyrazolyl.

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

6. The compound of claim 5, wherein R.sup.1 is ##STR00453##

7. The compound of claim 5, wherein ring A is: ##STR00454## wherein ##STR00455## denotes ring A's attachment to the amide moiety of formula II-a and ##STR00456## denotes ring A's attachment to R.sup.4; and each member of ring A is optionally substituted with one or two R.sup.5 groups.

8. The compound of claim 7, wherein ring A is: ##STR00457##

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

10. The compound of claim 9, wherein R.sup.4 is: ##STR00458## wherein each member of R.sup.4 is optionally substituted with one or two R.sup.7 groups and each R.sup.7 is independently F, Cl, methyl, CF.sub.3, CN, OMe, or N(R.sup.6).sub.2.

11. The compound of claim 10, wherein R.sup.4 is: ##STR00459## wherein R.sup.100 is H, methyl, Cl, CF.sub.3, CN, OCH.sub.3, or N(R.sup.6).sub.2 and R.sup.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 .alpha.-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.

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