ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF

摘要

Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention 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:
each of X, Y, Z, and V is independently O, S, N(RN)m, or CRC as valence permits; m is 0 or 1; each instance of RN is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —C(═O)RA, —C(═O)ORA, —C(═O)SRA, —C(═O)N(RB)2, —C(═NRB)RA, —C(═NNRB)RA, —C(═NORA)RA, —C(═NRB)N(RB)2, —C(═S)RA, —C(═S)N(RB)2, —S(═O)RA, —SO2RA, —SO2N(RB)2, and a nitrogen protecting group; each instance of RC 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, optionally substituted alkyl-Cy, —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 instance of RA is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; each instance of RB is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, and a nitrogen protecting group, or two RB groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; each instance of Cy is independently optionally substituted C3-7 cycloalkyl, optionally substituted 4- to 7-membered heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; R3 is hydrogen, C1-4 alkyl, or C3-4 carbocylyl; Rx is optionally substituted C1-4 alkyl, or optionally substituted C3-4 carbocylyl; provided that at least one of X, Y, Z, and V is O, S, or N(RN)m; and provided that when:
V is CRC, X is N, Z is NRN, and Y is CRC; orV is CRC, X is NRN, Z is N, Y is CRC; orV is CRC, X is CRC, Z is NRN, Y is N; orV is CRC, X is CRC, Z is N, Y is NRN;then each instance of RN is optionally substituted aryl or optionally substituted heteroaryl; andeach instance of RC 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, optionally substituted alkyl-Cy, —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;oreach instance of RC is independently selected from the group consisting of optionally substituted C5-8 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted C5-8 cycloalkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted alkyl-Cy, —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; andeach instance of RN is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl-Cy, —C(═O)RA, —C(═O)ORA, —C(═O)SRA, —C(═O)N(RB)2, —C(═NRB)RA, —C(═NNRB)RA, —C(═NORA)RA, —C(═NRB)N(RB)2, —C(═S)RA, —C(═S)N(RB)2, —S(—O)RA, —SO2RA, —SO2N(RB)2, and a nitrogen protecting group.