1-PHENOXY-3-(ALKYLAMINO)-PROPAN-2-OL DERIVATIVES AS CARM1 INHIBITORS AND USES THEREOF

摘要

Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein X, R1, R2a, R2b, R2c, R2d, are as defined herein, and Ring HET is an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L1-R3, wherein L1 and R3 are as defined herein. Compounds of the present invention are useful for inhibiting CARM1 activity. Methods of using the compounds for treating CARM1-mediated disorders are also described.;

主权项

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein:
X is —O—, —S—, or —CH2—;R1 is hydrogen or optionally substituted C1-4 aliphatic;each of R2a, R2b, R2c, and R2d is independently hydrogen, halogen, —CN, —NO2, —C(═O)RA2, —C(═O)ORA2, —C(═O)N(RA2)2, —ORA2, —SRA2, —N(RA2)2, —S(═O)RA2, —S(═O)2RA2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, wherein each instance of RA2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RA2 groups attached to the same nitrogen atom are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring;Ring HET is an optionally substituted 6,5-bicyclic heteroaryl ring system comprising 2 to 5 nitrogen atoms, inclusive, wherein the point of attachment is provided on the 6-membered ring of the 6,5-bicyclic heteroaryl ring system, and wherein the 6-membered ring is further substituted with a group of formula -L1-R3;L1 is a bond, —O—, —N(RL)—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(RL)—, —C(O)N(RL)N(RL)—, —OC(O)—, —OC(O)N(RL)—, —NRLC(O)—, —NRLC(O)N(RL)—, —NRLC(O)N(RL)N(RL)—, —NRLC(O)O—, —SC(O)—, —C(═NRL)—, —C(═NNRL)—, —C(═NORL)—, —C(═NRL)N(RL)—, —NRLC(═NRL)—, —C(S)—, —C(S)N(RL)—, —NRLC(S)—, —S(O)—, —OS(O)2—, —S(O)2O—, —SO2—, —N(RL)SO2—, —SO2N(RL)—, —N(RL)SO2N(RL)—, or an optionally substituted C1-10 saturated or unsaturated hydrocarbon chain, wherein one or more moieties selected from the group consisting of —O—, —N(RL)—, —S—, —C(O)—, —C(O)O—, —C(O)S—, —C(O)N(RL)—, —C(O)N(RL)N(RL)—, —OC(O)—, —OC(O)N(RL)—, —NRLC(O)—, —NRLC(O)N(RL)—, —NRLC(O)N(RL)N(RL)—, —NRLC(O)O—, —SC(O)—, —C(═NRL)—, —C(═NNRL)—, —C(═NORL)—, —C(═NRL)N(RL)—, —NRLC(═NRL)—, —C(S)—, —C(S)N(RL)—, —NRLC(S)—, —S(O)—, —OS(O)2—, —S(O)2O—, —SO2—, —N(RL)SO2—, —SO2N(RL)—, — and —N(RL)SO2N(RL)— is optionally and independently present between two carbon atoms of the hydrocarbon chain, and optionally and independently present at one or both ends of the hydrocarbon chain;each RL is independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group, or RL and R3 taken together form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; andR3 is hydrogen, optionally substituted alkyl, optionally substit uted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided when R3 is hydrogen, then L1 is not a bond.