Prmt5 inhibitors and uses thereof

A compound of formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein represents a single or double bond;
• R1 is hydrogen, Rz, or —C(O)Rz, wherein Rz is optionally substituted C1-6 alkyl;
• L is —O—, —N(R)—, —C(R2)(R3)—, —O—CR2R3, —N(R)—CR2R3—, —O—CR2R3—O—, —N(R)—CR2R3—O, —N(R)—CR2R3—N(R)—, —O—CR2R3—N(R)—, —CR2R3—O—, —CR2R3—N(R)—, —O—CR2R3—CR9R10—, —N(R)—CR2R3—CR9R10—, —CR2R3—CR9R10—O—, —CR2R3—CR9R10—N(R)—, or —CR2R3—CR9R10—;
• each R is independently hydrogen or optionally substituted C1-6 aliphatic;
• R2 and R3 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 R2 and R3 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;
• Ring A is a monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R4 is -L1-Cy;
• L1 is a bond, —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO2—, —SO2N(R)—, —N(R)SO2—, —OC(O)—, —C(O)O—, or an optionally substituted, straight or branched, C1-6 aliphatic chain wherein one, two, or three methylene units of L1 are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)O—, —OC(O)N(R)—, —SO2—, —SO2N(R)—, —N(R)SO2—, —OC(O)—, or —C(O)O—;
• Cy is an optionally substituted, monocyclic, bicyclic or tricyclic, saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R5, R6, R7, and R8 are independently hydrogen, halo, or optionally substituted aliphatic;
• 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;
• each Ry is independently selected from the group consisting of halo, —CN, —NO2, optionally substituted aliphatic, 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 Rx is independently selected from the group consisting of halo, —CN, optionally substituted aliphatic, —OR′, and —N(R″)2;
• R′ is hydrogen or optionally substituted aliphatic;
• each R″ is independently hydrogen or optionally substituted aliphatic, or two R″ are taken together with their intervening atoms to form a heterocyclic ring;
• n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
• m is 0, 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits;
• and
• p is 0 or 1;
• provided that when L is —O— and Ring A is phenyl, p is 1;
• and
• provided that the compound is not one of the following: