Arginine methyltransferase inhibitors and uses thereof

摘要

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.;

主权项

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:
X is N, Z is NR4, and Y is CR5; or X is NR4, Z is N, and Y is CR5; or X is CR5, Z is NR4, and Y is N; or X is CR5, Z is N, and Y is NR4; R1, R2, R6, R7, and R8 are independently selected from the group consisting of hydrogen, halo, —CN, —NO2, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)2, —SRA, —C(═O)RA, —C(O)ORA, —C(O)SRA, —C(O)N(RB)2, —C(O)N(RB)N(RB)2, —OC(O)RA, —OC(O)N(RB)2, —NRBC(O)RA, —NRBC(O)N(RB)2, —NRBC(O)N(RB)N(RB)2, —NRBC(O)ORA, —SC(O)RA, —C(═NRB)RA, —C(═NNRB)RA, —C(═NORA)RA, —C(═NRB)N(RB)2, —NRBC(═NRB)RB, —C(═S)RA, —C(═S)N(RB)2, —NRBC(═S)RA, —S(O)RA, —OS(O)2RA, —SO2RA, —NRBSO2RA, and —SO2N(RB)2; each RA is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; each RB is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and a nitrogen protecting group, or two RB groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; R1 and R2 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or R1 and R6 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or R2 and R8 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; or R6 and R7 are optionally taken together to form an optionally substituted carbocyclic, optionally substituted heterocyclic, or optionally substituted aryl ring; R3 is hydrogen, C1-4alkyl, or C3-4cycloalkyl; R4 is hydrogen, optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-7cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, or optionally substituted C1-4alkyl-Cy; Cy is optionally substituted C3-7cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R5 is hydrogen, halo, —CN, optionally substituted C1-4alkyl, or optionally substituted C3-4cycloalkyl; Rx is optionally substituted C1-4alkyl or optionally substituted C3-4cycloalkyl; provided that R2 is not —CF3 or —CHF2; provided that R6 is not —CF3 or —CHF2; and provided that R1 is not —NRBC(O)RA, —NRBSO2RA, or —(CRzRz)nC(O)N(RB)2; wherein each Rz is independently hydrogen or fluoro; and n is 0, 1, 2, 3, or 4.