Therapeutic compounds and compositions
Provided are aryl sulfonamide diarylurea derivative compounds that are inhibitors of mutant isocitrate dehydrogenase 1/2 (IDH 1/2), useful for treating cancer. Also provided are methods of treating cancer comprising administering to a subject in need thereof a compound described herein. Cancers that are treatable by the compounds of the invention are glioblastoma, myelodysplastic syndrome, myeloproliferative neoplasm, acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, and non-Hodgkin's lymphoma (NHL).
1. A compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
A 1 is C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl;
each R 2 is independently halo, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 thioalkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl-OH, aryl, aralkyl, aryloxy, —NO 2 , —C(O)—O—C 1-6 alkyl, —S(O) 2 —NH-aryl, —S(O) 2 —C 1-6 alkyl or —S(O)—C 1-6 alkyl, wherein each said aryl moiety may be substituted with 0-3 occurrences of R 6 ;
R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocyclyl, each of which may be substituted with 0-3 occurrences of R 6 ;
R 4 is C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 thioalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —N(R 5 )—C 1-6 alkyl or —N(R 5 )-aryl, wherein each C 1-6 alkyl, C 2-6 alkynyl, C 1-6 thioalkyl, aryl, heteroaryl, heterocyclyl, —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —N(R 5 )—C 1-6 alkyl or N(R 5 )-aryl is independently substituted with 0-3 occurrences of R 7 ;
each R 5 is independently hydrogen or C 1-6 alkyl;
each R 6 is independently halo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, cyano, NO 2 , —CO 2 H, —C(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O—S(O) 2 —C 1-6 alkyl, —O—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkyl-C(O)—O—C 1-6 alkyl, —N(R 5 )—C(O)—C 1-6 alkyl, —N(R 5 )—C 1-6 alkyl-C(O)—O—C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; or adjacent R 6 moieties, taken together with the atoms to which they are attached form a heterocyclyl;
each R 7 is independently C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, hydroxyl, halo, —NHC(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; and
n is 0, 1, 2, 3 or 4;
provided that:
(1) when A 1 is phenyl, X is CH, and R 4 1-piperidinyl, 1-pyrrolidinyl, N-morpholinyl, or N-azepanyl, then R 3 is not phenyl optionally substituted with 0-3 occurrences of R 6 ; and
(2) the compound is not
N-(2,5-dichlorophenyl)-4-(diethylamino)-3-[[[(4-nitrophenyl)amino]carbonyl]amino]-benzenesulfonamide.
2. A compound of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein:
L 1 is a bond;
A 1 is C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl;
L 2 is —NR 5 —;
each R 2 is independently halo, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 thioalkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl-OH, aryl, aralkyl, aryloxy, —NO 2 , —C(O)—O—C 1-6 alkyl, —S(O) 2 —NH-aryl, —S(O) 2 —C 1-6 alkyl or —S(O)—C 1-6 alkyl, wherein each said aryl moiety may be substituted with 0-3 occurrences of R 6 ;
R 3 is C 2-6 alkenyl, C 3-8 cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocyclyl, each of which may be substituted with 0-3 occurrences of R 6 ;
R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 thioalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, aryl, heteroaryl, —S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —N(R 5 )—C 1-6 alkyl or —N(R 5 )-aryl, wherein each C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 thioalkyl, aryl, heteroaryl, S(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —N(R 5 )—C 1-6 alkyl or —N(R 5 )-aryl is independently substituted with 0-3 occurrences of R 7 ;
each R 5 is independently hydrogen or C 1-6 alkyl;
each R 6 is independently hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, cyano, NO 2 , —CO 2 H, —C(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —O—S(O) 2 —C 1-6 alkyl, —O—C 1-6 alkyl-C(O)OH, —O—C 1-6 alkyl-C(O)—O—C 1-6 alkyl, —N(R 5 )—C(O)—C 1-6 alkyl, —N(R 5 )—C 1-6 alkyl-C(O)—O—C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; or adjacent R 6 moieties, taken together with the atoms to which they are attached form a heterocyclyl;
each R 7 is independently C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, hydroxyl, halo, —NHC(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; and
n is 1, 2, 3 or 4;
provided that:
when R 5 is H, and R 4 is methyl, then R 3 is not methyl.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
5. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The composition of claim 5 , comprising an additional cancer therapeutic agent.
7. A compound of or pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa), wherein:
A 1 is aryl;
each R 2 is independently C 1-6 haloalkyl or C 1-6 haloalkoxy;
R 3 is C 1-6 alkyl, C 3-8 cycloalkyl, or heterocyclyl, each of which may be substituted with 0-3 occurrences of R 6 ;
R 4 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, aryl, heteroaryl, heterocyclyl, or —S(O) 2 —C 1-6 alkyl, wherein each C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, aryl, heteroaryl, or —S(O) 2 —C 1-6 alkyl is independently substituted with 0-3 occurrences of R 7 ;
each R 6 is independently C 1-6 alkyl, C 1-6 haloalkyl, cyano, or heterocyclyl; or adjacent R 6 moieties, taken together with the atoms to which they are attached form a heterocyclyl;
each R 7 is independently C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, hydroxyl, halo, —NHC(O)—C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; and
n is 0, 1, 2, 3 or 4;
provided that:
(1) when R 4 is methyl, then R 3 is not methyl;
(2 ) when R 4 is methoxy, then R 3 is not cyclopropyl.
8. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
9. The compound of claim 2 or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
10. A pharmaceutical composition comprising a compound of claim 2 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , comprising an additional cancer therapeutic agent.