THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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.
1 . A compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 1 is optionally substituted C 4 -C 6 carbocyclyl;
each R 2 and R 3 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;
R 4 is saturated heterocyclyl, —CH(R 5 )N(R 5 )-heteroaryl, —CH(R 5 )N(R 5 )-aryl, —CH(R 5 )N(R 5 )-heterocyclyl, —CH(R 5 )N(R 5 )-carbocyclyl, heteroaralkyl, —CH 2 -heterocyclyl, 1H-indol-2-yl, indolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, imidazo[1,2-a]pyridine-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl, —(CR 5 R 6 ) 1-4 N(R 5 )C(O)O(C 1 -C 6 alkyl), or —(CR 5 R 6 ) 1-4 N(R 5 )SO 2 (C 1 -C 6 alkyl), wherein each saturated heterocyclyl, heteroaryl, aryl, heterocyclyl, or carbocyclyl is independently optionally substituted;
each R 5 is independently selected from hydrogen and methyl; and
each R 6 is independently selected from hydrogen, methyl, CH 2 OH, CH(CH 3 )OH, CH 2 NH 2 , or CH(CH 3 )NH 2 ; and provided that:
(i) R 4 is other than thien-2-ylmethyl, 1H-benizimidazol-1-ylmethyl, 1H-indol-3-ylmethyl, or 1H-benzotriazol-1-ylmethyl; and (ii) the compound is not N-[2-[[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]phenylamino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester or N-[2-[(2-benzoylphenyl)[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]amino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester.
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 selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently optionally substituted with one to three R 7 groups or acrylamido;
R 4 is saturated heterocyclyl, —CH(R 5 )N(R 5 )-heteroaryl, —CH(R 5 )N(R 5 )-aryl, —CH(R 5 )N(R 5 )-heterocyclyl, —CH(R 5 )N(R 5 )-carbocyclyl, heteroaralkyl, —CH 2 -heterocyclyl, 1H-indol-2-yl, indolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, imidazo[1,2-a]pyridine-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl, —(CR 5 R 6 ) 1-4 N(R 5 )C(O)O(C 1 -C 6 alkyl), or —(CR 5 R 6 ) 1-4 N(R 5 )SO 2 (C 1 -C 6 alkyl), wherein each saturated heterocyclyl, heteroaryl, aryl, heterocyclyl, or carbocyclyl is independently optionally substituted with one to three R 7 groups;
each R 5 is independently selected from hydrogen and methyl;
each R 6 is independently selected from hydrogen, methyl, CH 2 OH, CH(CH 3 )OH, CH 2 NH 2 , or CH(CH 3 )NH 2 ;
each R 7 is independently halo, —CF 3 , —CN, —OR 8 , —N(R 8 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —SO 2 (C 1 -C 3 alkyl), —C(O)N(R 8 ) 2 , —O(CH 2 ) 2 —OR 8 , SO 2 N(R 8 ) 2 , heteroaryl, —C 1 -C 3 haloalkyl, C 1 -C 3 alkyl optionally substituted with —OR 8 or —N(R 8 ) 2 ; and
each R 8 is independently H or C 1 -C 3 alkyl; and provided that:
(i) R 4 is other than thien-2-ylmethyl, 1H-benizimidazol-1-ylmethyl, 1H-indol-3-ylmethyl, or 1H-benzotriazol-1-ylmethyl; and (ii) the compound is not N-[2-[[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]phenylamino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester or N-[2-[(2-benzoylphenyl)[2-(cyclohexylamino)-1-(3-hydroxyphenyl)-2-oxoethyl]amino]-2-oxoethyl]-carbamic acid 1,1-dimethylethyl ester.
3 . The compound of claim 1 , wherein R 1 is C 4 -C 6 cycloalkyl optionally substituted with one to two R 7 groups.
4 . The compound of claim 3 , wherein R 1 is
5 . The compound of claim 3 , wherein each R 2 and R 3 is independently aryl optionally substituted with one to three R 7 groups.
6 . The compound of claim 5 , wherein R 2 is phenyl optionally substituted with one to two R 7 groups and each R 7 is independently F, Cl or methyl.
7 . The compound of claim 5 , wherein R 3 is phenyl optionally substituted with one to two R 7 groups wherein each R 7 is independently F, CN, —SO 2 NH 2 , —SO 2 NH(CH 3 ), acrylamido or oxadiazolyl.
8 . The compound of claim 5 , wherein R 4 is 4-6 membered saturated heterocyclyl, —CH 2 -heteroaryl, —CH 2 -heterocyclyl, —CH(R 5 )N(R 5 )-heteroaryl, 1H-indol-2-yl, indolin-2-yl, 1,2,3,4-tetrahydroquinolin-2-yl, imidazo[1,2-a]pyridine-5-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl, —(CR 5 R 6 ) 1-4 N(R 5 )C(O)O(C 1 -C 6 alkyl), or —(CR 5 R 6 ) 1-4 N(R 5 )SO 2 (C 1 -C 6 alkyl), wherein each said saturated heterocyclyl, heteroaryl, or heterocyclyl is independently optionally substituted with one to three R 7 groups.
9 . The compound of claim 8 , wherein R 4 is:
wherein X is CH(R 7″ ), O, NH, or NC(O)CH 3 ; R 7′ is H, —C(O)CH 3 , —C(O)OCH 3 , —SO 2 (C 1 -C 3 alkyl), —C(O)N(R 8 ) 2 , pyrimidinyl, pyridyl; and R 7″ is H, —O(CH 2 ) 2 —OCH 3 , —O(CH 2 ) 2 —OCH, OH, OCH 3 , NH 2 , or F.
10 . The compound of claim 8 , wherein R 4 is —CH 2 —NH(heteroaryl) or —CH(CH 2 OH)—NH(heteroaryl), wherein heteroaryl is pyridinyl or pyrimidinyl each optionally substituted with one R 7 .
11 . The compound of claim 8 , wherein R 4 is —CH 2 -heteroaryl wherein heteroaryl is imidazolyl, triazolyl, pyridinyl or tetrazole, each of imidazolyl, triazolyl, pyridinyl or tetrazole, optionally substituted with one to two R 7 groups.
12 . The compound of claim 8 , wherein R 4 is —(CR 5 R 6 )N(R 5 )C(O)O(C 1 -C 4 alkyl) wherein each R 5 is independently H or methyl and R 6 is methyl or CH 2 OH.
13 . The compound of claim 8 , wherein R 4 is 1,2,3,4-tetrahydroquinolin-2-yl, or 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-yl.
14 . The compound is selected from any one of compounds from Table 1.
15 . A pharmaceutical composition comprising the compound of claim 1 ; and a pharmaceutically acceptable carrier.
16 . The composition of claim 15 , further comprising a second therapeutic agent useful in the treatment of cancer.
17 . A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 15 .
18 . The method of claim 17 , wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.
19 . The method of claim 17 , wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, melanoma, non-small cell lung cancer (NSCLC), cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer in a patient.
20 . The method of claim 19 , further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of cancer.