Prmt5 inhibitors and methods of use

A compound of Formula (I), a pharmaceutical salt thereof, an ester thereof, a prodrug thereof, a stereoisomer thereof or isotopic derivative thereof:

• wherein, W is C;
• wherein, X3 is N or CRX3;
• X4 is N or CRX4;
• X5 is N or CRX5;
• X6 is N or CRX6;
• wherein, when X3 is CRX3, RX3 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, —ORa, —SRa, —P(O)RaRb, —CN, —S(O)2Ra, —S(O)Ra, —SF5, —NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, hydroxy(C1-C6 alkyl) or C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each ring of C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl is optionally substituted with 0-4 deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, when X4 is CRX4, RX4 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, —ORa, —SRa, —P(O)RaRb, —CN, —S(O)2Ra, —S(O)Ra, —SF5, —NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, hydroxy(C1-C6 alkyl) or C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each ring of C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl is optionally substituted with 0-4 deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, when X5 is CRX5, RX5 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, —ORa, —SRa, —P(O)RaRb, —CN, —S(O)2Ra, —S(O)Ra, —SF5, —NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, hydroxy(C1-C6 alkyl) or C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each ring of C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl is optionally substituted with 0-4 deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, when X6 is CRX6, RX6 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, —ORa, —SRa, —P(O)RaRb, —CN, —S(O)2Ra, —S(O)Ra, —SF5, —NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, hydroxy(C1-C6 alkyl) or C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, or 5-10 membered heteroaryl, wherein each ring of C3-C10 cycloalkyl, C6-C10 cycloalkenyl, 4-10 membered heterocyclyl, 6-10 membered heterocycloalkenyl, C6-C10 aryl, and 5-10 membered heteroaryl is optionally substituted with 0-4 deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, a ring A is optionally fuse at a chemical bond between X3 and X4 with a 5-6 membered saturated or unsaturated ring, wherein the 5-6 membered saturated or unsaturated ring contains 0-3 heteroatoms selected from O, N, and S;
• wherein, the ring A is optionally fuse at a chemical bond between X4 and X5 with the 5-6 membered saturated or unsaturated ring, wherein the 5-6 membered saturated or unsaturated ring contains 0-3 heteroatoms selected from O, N, and S;
• wherein, the ring A is optionally fuse at a chemical bond between X5 and X6 with the 5-6 membered saturated or unsaturated ring, wherein the 5-6 membered saturated or unsaturated ring contains 0-3 heteroatoms selected from O, N, and S;
• wherein, the ring A is further optionally substituted with 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, —ORa, —SRa, —P(O)RaRb, —CN, —S(O)2Ra, —S(O)Ra, —SF5, —NRaRb, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy(C1-C6) alkyl, or substituted groups optionally substituted with 0-4 substituted groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxy (C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, R′ is C1-C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl, which are independently optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated monocyclic heterocyclyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —S(O)2Ra, —S(O)Ra, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, R′ is —CHR2R3 or -CDR2R3;
• wherein, R2 and R3 are independently hydrogen, deuterium, —ORa, halogen, —CN, —C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), —C3-C10 cycloalkyl or 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl, the 4-10 membered heterocyclyl, the C6-C10 aryl, and the 5-10 membered heteroaryl are optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, oxo, hydroxyl(C1-C6 alkyl), NRaRb, —CN, C1-C6 haloalkyl, C1-C6 haloalkoxy, —SO3Ra, —SRa, —S(O)2Ra, —S(O)Ra, —SF5, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —OC(O)NRaRb, —NRaCORb, or —CONRaRb;
• wherein, M1 is CRaRb, NRa, O, S, or Se;
• wherein, RL and RL′ are independently hydrogen, deuterium, or C1-C6 alkyl, or RL and RL′ are taken together with atoms to which they are attached to form a C3-C6 carbocyclyl or heterocyclyl;
• wherein, n and o are independently 0, 1, or 2;
• wherein, X1 is N or CRX1;
• wherein, X2 is N or CRX2;
• wherein, Y1 is CRY1RY1′, NRY1, O, S, or Se;
• wherein, Y2 is CRY2RY2′, NRY2, O, S, or Se;
• wherein, Y3 is CRY3RY3′, NRY3, O, S, or Se;
• wherein, RX1 and RX2 are independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy(C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynl, —ORa, —SRa, —S(O)2Ra, —S(O)Ra, —CN, —OC(O)Ra, —OCONRaRb, halogen, —OSO3Ra, —NRaRb, or —SF5;
• wherein, RY1, RY1′, RY2, RY2′, RY3, and RY3′ are independently absent, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl(C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —ORa, —SRa, —S(O)2Ra, —S(O)Ra, —CN, —OC(O)Ra, —OCONRaRb, halogen, —OSO3Ra, —NRaRb, or —SF5;
• wherein, is a single bond or a double bond;
• wherein, Ra and Rb are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cyclopropyl, or C1-C6 haloalkyl, or Ra and Rb are taken together with atoms to which they are attached to form a 3-14 membered saturated or unsaturated cycle, wherein the 3-14 membered saturated or unsaturated cycle optionally contains 0-2 heteroatoms selected from O, S, and N.