Prmt5 inhibitors and uses thereof

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof,
• wherein
• R1 is hydrogen, Rz, or —C(O)Rz, wherein Rz is optionally substituted C1-6 alkyl;
• Lz is a linker selected from the group consisting of —XA—C(R2A)(R3A)C(═O)N(R)—, LB, or LD wherein:
• XA is a bond, —O—, —N(R)—, —CR4AR5A—, —O—CR4AR5A, —N(R)—CR4AR5A—, —O—CR4AR5A—O—, —N(R)—CR4AR5A—O, —N(R)—CR4AR5A—N(R)—, —O—CR4AR5A—N(R)—, —CR4AR5A—O—, —CR4AR5A—N(R)—, —O—CR4AR5A—CR6AR7A—, —N(R)—CR4AR5A—CR6AR7A—, —CR6AR7A—CR4AR5A—O—, —CR6AR7A—CR4AR5A—N(R)—, or —CR6AR7A—CR4AR5A—;
• each R is independently hydrogen or optionally substituted C1-6 aliphatic;
• R2A and R3A are independently selected from the group consisting of hydrogen, halo, —CN, —NO2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, 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);
• or R2A and R3A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
• R4A and R5A are independently selected from the group consisting of hydrogen, halo, —CN, —NO2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB)7, —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;
• or R4A and R5A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
• R6A and R7A are independently selected from the group consisting of hydrogen, halo, —CN, —NO2, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —ORA, —N(RB), —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;
• or R6A and R7A are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
• each RA is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• each RB is independently selected from the group consisting of hydrogen, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RB groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
• LB is —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)O—, or —OC(O)N(R)—;
• LD is —O—, —N(R)—, —C(R2A)(R3A)—, —O—CR2AR3A, —N(R)—CR2AR3A—, —O—CR2AR3A—O—, —N(R)—CR2AR3A—O, —N(R)—CR2AR3A—N(R)—, —O—CR2AR3A—N(R)—, —CR2AR3A—O—, —CR2AR3A—N(R)—, —O—CR2AR3A—CR9R10—, —N(R)—CR2AR3A—CR9R10—, —CR2AR3A—CR9R10—, —CR2AR3A—CR9R10—N(R)—, or —CR2AR3A—CR9R10—;
• R9 and R10 are independently selected from the group consisting of hydrogen, halo, —CN, —NO2, optionally substituted aliphatic, optionally substituted carbocyclyl;
• optionally substituted phenyl, 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;
• or R9 and R10 are taken together with their intervening atoms to form an optionally substituted carbocyclic or heterocyclic ring;
• Ring Z is an optionally substituted, monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R21, R22, R23, and R24 are independently hydrogen, halo, or optionally substituted aliphatic;
• each Rx is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, and —OR′;
• R′ is hydrogen or optionally substituted aliphatic;
• and
• n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.