US 9,957,274 B2 · Indane inhibitors of EED and methods of their use

Abstract

Compounds having a structure of Formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein A1, A2, A3, A4, A5, n, and m are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various EED-related conditions or diseases, including cancer, by administration of such compounds are also provided.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof,

wherein
A1 and A2 are each independently C1-C2 alkyl;
A3 is selected from the group consisting of aryl, heterocyclyl, and heteroaryl, wherein the A3 aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of R1, OR1, SR1, S(O)R1, SO2R1, C(O)R1, CO(O)R1, OC(O)R1, OC(O)OR1, NH2, NHR1, N(R1)2, NHC(O)R1, NR1C(O)R1, NHS(O)2R1, NR1S(O)2R1, NHC(O)OR1, NR1C(O)OR1, NHC(O)NH2, NHC(O)NHR1, NHC(O)N(R1)2, NR1C(O)NHR1, NR1C(O)N(R1)2, C(O)NH2, C(O)NHR1, C(O)N(R1)2, C(O)NHOH, C(O)NHOR1, C(O)NHSO2R1, C(O)NR1SO2R1, SO2NH2, SO2NHR1, SO2N(R1)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR1, C(N)N(R1)2, CNOH, CNOCH3, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
A4, at each occurrence, is a substituent on a substitutable position of the benzene ring of the indane independently selected from the group consisting of C1-C6 alkyl, OH, F, Cl, Br and I;
A5 is a substituent on a substitutable position of the cyclopentane ring of the indane independently selected from the group consisting of C1-C6 alkyl, OH, F, Cl, Br and I;
R1, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R1 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R2, OR2, SR2, S(O)R2, SO2R2, C(O)R2, CO(O)R2, OC(O)R2, OC(O)OR2, NH2, NHR2, N(R2)2, NHC(O)R2, NR2C(O)R2, NHS(O)2R2, NR2S(O)2R2, NHC(O)OR2, NR2C(O)OR2, NHC(O)NH2, NHC(O)NHR2, NHC(O)N(R2)2, NR2C(O)NHR2, NR2C(O)N(R2)2, C(O)NH2, C(O)NHR2, C(O)N(R2)2, C(O)NHOH, C(O)NHOR2, C(O)NHSO2R2, C(O)NR2SO2R2, SO2NH2, SO2NHR2, SO2N(R2)2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
wherein each R1 aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R3, OR3, SR3, S(O)R3, SO2R3, C(O)R3, CO(O)R3, OC(O)R3, OC(O)OR3, NH2, NHR3, N(R3)2, NHC(O)R3, NR3C(O)R3, NHS(O)2R3, NR3S(O)2R3, NHC(O)OR3, NR3C(O)OR3, NHC(O)NH2, NHC(O)NHR3, NHC(O)N(R3)2, NR3C(O)NHR3, NR3C(O)N(R3)2, C(O)NH2, C(O)NHR3, C(O)N(R3)2, C(O)NHOH, C(O)NHOR3, C(O)NHSO2R3, C(O)NR3SO2R3, SO2NH2, SO2NHR3, SO2N(R3)2, C(O)H, C(O)OH, C(O)C(O)NH2, C(O)C(O)NHR3, C(O)C(O)N(R3)2, C(N)NH2, C(N)NHR3, C(N)N(R3)2, CNOH, CNOCH3, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
R2, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R2 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
wherein each R2 aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
R3, at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R3 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R4, OR4, SR4, S(O)R4, SO2R4, C(O)R4, CO(O)R4, OC(O)R4, OC(O)OR4, NH2, NHR4, N(R4)2, NHC(O)R4, NR4C(O)R4, NHS(O)2R4, NR4S(O)2R4, NHC(O)OR4, NR4C(O)OR4, NHC(O)NH2, NHC(O)NHR4, NHC(O)N(R4)2, NR4C(O)NHR4, NR4C(O)N(R4)2, C(O)NH2, C(O)NHR4, C(O)N(R4)2, C(O)NHOH, C(O)NHOR4, C(O)NHSO2R4, C(O)NR4SO2R4, SO2NH2, SO2NHR4, SO2N(R4)2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
wherein each R3 aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, C(O)H, C(O)OH, C(N)NH2, C(N)NHR5, C(N)N(R5)2, CNOH, CNOCH3, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
R4 is at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R4 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
wherein each R4 aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
R5 is at each occurrence, is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
wherein each R5 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
wherein each R5 aryl, heteroaryl, heterocyclyl, cycloalkyl, and cycloalkenyl is optionally substituted with one or more substituents independently selected from the group consisting of NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, OH, (O), CN, NO2, CF3, CF2CF3, OCF3, OCF2CF3, F, Cl, Br and I;
n is 0, 1, or 2;
and
m is 0 or 1.

20 more elements

Indane inhibitors of EED and methods of their use

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Indane inhibitors of EED and methods of their use

Life of this patent

Abstract

Claims9