Macrocyclic mcl-1 inhibitors and methods of use

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

• wherein
• A2 is CR2, A3 is N, A4 is CR4a, and A6 is C;
• or
• A2 is CR2, A3 is N, A4 is O or S, and A6 is C;
• or
• A2 is CR2, A3 is C, A4 is O or S and A6 is C;
• A2 is N, A3 is C, A4 is O or S and A6 is C;
• or
• A2 is N, A3 is C, A4 is CR4a, and A6 is N;
• RA is hydrogen, CH3, halogen, CN, CH2F, CHF2, or CF3;
• X is O, or N(Rx2);
• wherein Rx2 is hydrogen, C1-C3 alkyl, or unsubstituted cyclopropyl;
• Y is (CH2)m, —CH═CH—(CH2)n—, —(CH2)p—CH═CH—, or —(CH2)q—CH═CH—(CH2)r—;
• wherein 0, 1, 2, or 3 CH2 groups are each independently replaced by O, N(Rya), C(Rya)(Ryb), C(O), NC(O)Rya, or S(O)2;
• m is 2, 3, 4, or 5;
• n is 1, 2, or 3;
• p is 1, 2, or 3;
• q is 1 or 2;
• and
• r is 1 or 2;
• wherein the sum of q and r is 2 or 3;
• Rya, at each occurrence, is independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, G1, C1-C6 alkyl, or C1-C6 haloalkyl;
• wherein the C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, and C1-C6 haloalkyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo, —N(Ryd)(Rye), G1, —ORyf, —SR9, —S(O)2N(Ryd)(Rye), and —S(O)2-G1;
• and
• Ryb is C2-C6 alkenyl, C2-C6 alkynyl, G1, C1-C6 alkyl, or C1-C6 haloalkyl;
• wherein the C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, and C1-C6 haloalkyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of oxo, —N(Ryd)(Rye), G1, —ORyf, —SRyg, —S(O)2N(Ryd)(Rye), and —S(O)2-G1;
• or
• Rya and Ryb, together with the carbon atom to which they are attached, form a C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, or a 4-7 membered monocyclic heterocycle;
• wherein the C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, and the 4-7 membered monocyclic heterocycle are each optionally substituted with 1 —ORm and 0, 1, 2, or 3 independently selected Rs groups;
• Ryd, Rye, Ryf, and Ryg, at each occurrence, are each independently hydrogen, G1, C1-C6 alkyl, or C1-C6 haloalkyl;
• wherein the C1-C6 alkyl and the C1-C6 haloalkyl are optionally substituted with one substituent selected from the group consisting of G1, —ORyh, —SRyh, —SO2Ryh, and —N(Ry)(Ryk);
• G1, at each occurrence, is piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, tetrahydropyranyl, morpholinyl, oxetanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
• wherein each G1 is optionally substituted with 1 —ORm and 0, 1, 2, or 3 substituents independently selected from the group consisting of G2, —(C1-C6 alkylenyl)-G2, and Rs;
• G2, at each occurrence, is a C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, oxetanyl, morpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
• wherein each G2 is optionally substituted with 1 —ORm and 0, 1, or 2 independently selected Rt groups;
• R2 is independently hydrogen, halogen, CH3, or CN;
• R4a, at each occurrence, is independently hydrogen, halogen, CN, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkyl, C1-C4 haloalkyl, GA, C1-C4 alkyl-GA, or C1-C4 alkyl-O-GA;
• wherein each GA is independently C6-C10 aryl, C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, or 4-7 membered heterocycle;
• wherein each GA is optionally substituted with 1, 2, or 3 Ru groups;
• R5 is independently hydrogen, halogen, G3, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• wherein the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are each optionally substituted with one G3;
• G3, at each occurrence, is independently C6-C10 aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, oxetanyl, 2-oxaspiro[3.3]heptanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, 2,3-dihydro-1,4-dioxinyl, or 1,4-dioxepanyl;
• wherein each G3 is optionally substituted with 1, 2, or 3 Rv groups;
• A7 is N or CR7;
• A8 is N or CRyg;
• A15 is N or CR15;
• R7, R12 and R16 are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, —CN, —OR7a, —SR7a, or —N(R7b)(R7c);
• R8, R13, R14, and R15, are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, —CN, —OR8a, —SR8a, —N(R8b)(R8c), or C3-C4 monocyclic cycloalkyl;
• wherein the C3-C4 monocyclic cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl;
• or
• R8 and R13 are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, —CN, —OR8a, —SR8a, —N(R8b)(R8c), or C3-C4 monocyclic cycloalkyl;
• wherein the C3-C4 monocyclic cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-C3 alkyl, and C1-C3 haloalkyl;
• and
• R14 and R15, together with the carbon atoms to which they are attached, form a monocyclic ring selected from the group consisting of benzene, cyclobutane, cyclopentane, and pyridine;
• wherein the monocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, —CN, —OR8a, —SR8a, and —N(R8b)(R8c);
• R9 is —OH, —O—C1-C4 alkyl, —O—CH2—OC(O)(C1-C6 alkyl), —NHOH,
• or —N(H)S(O)2—(C1-C6 alkyl);
• R10A and R10B, are each independently hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
• or R10A and R10B, together with the carbon atom to which they are attached, form a cyclopropyl;
• wherein the cyclopropyl is optionally substituted with one or two substituents independently selected from the group consisting of halogen and CH3;
• W is —CH═CH—, C1-C4 alkyl, —O—CHF—, -L1-CH2—, or —CH2-L1-;
• wherein L1 at each occurrence, is independently O, S, S(O), S(O)2, S(O)2N(H), N(H), or N(C1-C3 alkyl);
• R11 is a C6-C10 aryl or a 5-11 membered heteroaryl;
• wherein each R11 is optionally substituted with 1, 2, or 3 independently selected Rw groups;
• Rw, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, NO2, —OR11a, —SR11b, —S(O)2R11b, —S(O)2N(R11c)2, —C(O)R11a, —C(O)N(R11c)2, —N(R11c)2, —N(R11c)C(O)R11b, —N(R11c)S(O)2R11b—N(R11c)C(O)O(R11b), —N(R11c)C(O)N(R11c)2, G4, —(C1-C6 alkylenyl)-OR11a —(C1-C6 alkylenyl)-OC(O)N(R11c)2, —(C1-C6 alkylenyl)-SR11a, —(C1-C6 alkylenyl)-S(O)2R11b —(C1-C6 alkylenyl)-S(O)2N(R11c)2—(C1-C6 alkylenyl)-C(O)R11a —(C1-C6 alkylenyl)-C(O)N(R11c)2, —(C1-C6 alkylenyl)-N(R11c)2, —(C1-C6 alkylenyl)-N(R11c)C(O)R11b —(C1-C6 alkylenyl)-N(R11c)S(O)2R11b —(C1-C6 alkylenyl)-N(R11c)C(O)O(R11b), —(C1-C6 alkylenyl)-N(R11c)C(O)N(R11c)2, —(C1-C6 alkylenyl)-CN, or —(C1-C6 alkylenyl)-G4;
• R11a and R11c, at each occurrence, are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, G4, —(C2-C6 alkylenyl)-OR11d, —(C2-C6 alkylenyl)-N(R11c)2, or —(C2-C6 alkylenyl)-G4;
• R11b, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, G4, —(C2-C6 alkylenyl)-OR11d —(C2-C6 alkylenyl)-N(R11e)2, or —(C2-C6 alkylenyl)-G4;
• G4, at each occurrence, is independently phenyl, monocyclic heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,6-dioxa-9-azaspiro[4.5]decanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl, dihydropyrrolyl, pyrrolidinyl, 2,3-dihydrodioxinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
• wherein each G4 is optionally substituted with 1 —ORm and 0, 1, 2, or 3 substituents independently selected from the group consisting of G5, Ry, —(C1-C6 alkylenyl)-G5, —(C1-C6 alkylenyl)-L2-(C1-C6 alkylenyl)-G5, and -L2-(C1-C6 alkylenyl)s-G5;
• L2 is O, C(O), N(H), N(C1-C6 alkyl), NHC(O), C(O)O, S, S(O), or S(O)2;
• s is 0 or 1;
• G5, at each occurrence, is independently phenyl, monocyclic heteroaryl, C3-C7 monocyclic cycloalkyl, C4-C7 monocyclic cycloalkenyl, piperazine, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
• wherein each G5 is optionally substituted with 1 independently selected —ORm or 0, 1, 2, or 3 Rz groups;
• Rs, Rt, Ru, Rv, Ry, and Rz, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, oxo, NO2, P(O)(Rk)2, —OC(O)Rk, —OC(O)N(Rj)2, —SRj, —S(O)2Rk, —S(O)2N(Rj)2, —C(O)Rj, —C(O)N(Rj)2, —N(Rj)2, —N(Rj)C(O)Rk, —N(Rj)S(O)2Rk, —N(Rj)C(O)O(Rk), —N(Rj)C(O)N(Rj)2, —(C1-C6 alkylenyl)-ORj, (C1-C6 alkylenyl)-OC(O)N(Rj)2, —(C1-C6 alkylenyl)-SRj, —(C1-C6 alkylenyl)-S(O)2Rk, —(C1-C6 alkylenyl)-S(O)2N(Rj)2, —(C1-C6 alkylenyl)-C(O)Rj, —(C1-C6 alkylenyl)-C(O)N(Rj)2, —(C1-C6 alkylenyl)-N(Rj)2, —(C1-C6 alkylenyl)-N(Rj)C(O)Rk, —(C1-C6 alkylenyl)-N(Rj)S(O)2Rk, —(C1-C6 alkylenyl)-N(Rj)C(O)O(Rk), —(C1-C6 alkylenyl)-N(Rj)C(O)N(Rj)2, or —(C1-C6 alkylenyl)-CN;
• Rm is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C2-C6 alkylenyl)-ORj, or —(C2-C6 alkylenyl)-N(Rj)2;
• Ryh, Ry, Ryk, Rya, R7b, R7c, R8a, R8b, R8c, R11d, R11c, and Rj, at each occurrence, are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• and
• Rk, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl;
• wherein at least one of G1, G2, G3, G4, and G5 is 2,2-dimethyl-1,3-dioxolanyl, 2,3-dihydro-1,4-dioxinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl.