Compounds that inhibit MCL-1 protein

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• a, b, and c, each represented by the symbol , is a single or double chemical bond which may be cis or trans, wherein one of a, b, c, d and e is a double bond, or each of a, b, c, d and e is a single bond, or a and c are double bonds and b, d, and e are single bonds;
• A is CR9A or N;
• wherein when A is CR9A, R9 and R9A together may form ═CH2;
• Q is selected from C or S;
• wherein R5 and R5A may both be absent if Q is S;
• or R5 and R5A together may form ═O when Q is C or S;
• or R5 and R5A together may form ═CH2 or ═N when Q is C;
• T is CH, CR1 or N;
• V is selected from C, O, or N;
• wherein if V is O, then R7 and R7A are absent;
• further wherein if V is N, then R7A is absent;
• and further wherein if V is C, then R7 and R7A together may form a ═O;
• W is selected from C, O, or N;
• wherein if W is O, then R8 and R8A are absent;
• and further wherein if W is N, then R8A is absent;
• Z is selected from C, O, or N;
• wherein if Z is O, then R6 and R6A are absent;
• and further wherein if Z is N, then R6A is absent;
• a and b are single bonds if Z is O or N;
• a is a single bond if Q is S;
• R5 and R6A are absent when a is a double bond;
• R6A and R7A are absent when b is a double bond;
• R7A and R8A are absent when c is a double bond;
• R8A and R10A are absent when d is a double bond;
• R10A and R9A are absent when e is a double bond;
• R5 is H, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, or —Y—R11;
• Y is independently O, or NR14;
• R5A is H;
• p is 0 or 1;
• q is 0, 1, or 2;
• wherein if q is 0, then d and e represent the same bond;
• v is 0, 1, or 2;
• w is 0, 1, or 2;
• z is 0 or 1;
• wherein z is 0 only if q is 0;
• wherein if z is 0 and q is 0, then c and e represent the same bond;
• each of R1 and R3 is independently selected from halo, C1-6alkylhalo, C1-6alkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, or —C(═O)NRaRb;
• each of R2, R4, R6, R7, R8, R9, and R10 is independently selected from H, halo, C1-6haloalkyl, C1-6alkyl, O—C1-6alkyl, C1-6alkenyl, C1-6alkenylene, —C1-6alkyl-O—C1-6alkyl, —(CH2CH2O)nRa, —SO2Ra, —CN, —C(═O)Ra, —C(═O)ORa, —OC(═O)Ra, —C(═O)NRaRb, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• R11 is independently selected from H, C1-6haloalkyl, C1-6alkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —C1-6alkyl-O—C1-6alkyl, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• each of R2A, R5A, R6A, R7A, R8A, R9A and R10A is independently H, OH, halo, —C1-6alkyl;
• alternatively R6 and R7 together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• alternatively R6 and R9 together may form a 5- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• alternatively R6 and R10 together may form a 5- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• alternatively R8 and R9 together may form a 4- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• alternatively R8 and R10 together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• alternatively R9 and R10 together may form a 3- to 8-membered ring, optionally containing a heteroatom selected from N, O or S atom, which may contain a double bond;
• and
• the ring optionally may be substituted by R14;
• wherein the C1-6alkyl of any of the R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R2A, R6A, R7A, R8A, R9A and R10A substituents is substituted by 0, 1, 2 or 3 R12 substituents independently selected from OH, —OC1-6alkyl, —C1-6alkyl-O—C1-6alkyl, halo, —O-haloC1-6alkyl, —CN, —NRaRb, —(NRaRbRc)+, —SO2Ra, —(CH2CH2O)nCH3, —C(═O)Ra, —OC(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —O— (3- to 10-membered heterocycloakyl), a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl or spiroheterocycloalkyl group of any of the R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, and R12 substituents can be unsubstituted or substituted with from 1 to 4 R13 substituents independently selected from OH, halo, —NRcRd, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-O—C1-6alkyl, C1-6haloalkyl, —O-haloC1-6alkyl, —SO2Rc, —CN, —C(═O)NRcRd, —C(═O)Rc, —OC(═O)Ra, —C(═O)ORc, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• wherein each Ra, Rb, Rc, and Rd is independently hydrogen, OH, —C1-6alkyl, —C1-6alkyl-NR14R14, NR14R14, —SO2R14, —(CH2CH2O)nCH3, —C(═O)R14, —OC(═O)R14, —C(═O)OR14, —C(═O)NR14R14, —CN, C1-6haloalkyl, —O-haloC1-6alkyl, —C1-6alkyl-O—C1-6alkyl, benzyl, phenyl, a —C1-6alky 1-heterocycloalkyl, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl, heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocycloalkyl, or the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• and
• the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, heterocycloalkyl or the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl group of Ra, Rb, Rc, and Rd can be unsubstituted or substituted with from 1 to 4 R14 substituents independently selected from H, OH, halo, —C1-6alkyl, —OC1-6alkyl, —CN, C1-6haloalkyl, —O-haloC1-6alkyl, phenyl, tolyl, —C(O)C1-6alkyl, —C(O)OCH3 and —SO2—N(CH3)2;
• wherein n is independently in each instance an integer from 1 to 4;
• and
• wherein at least one of the following is true:
• a) A is N;
• or
• b) Z is O or N;
• or
• c) Q is S;
• or
• d) V is O or N;
• or
• e) W is O or N;
• or
• f) at least one of R2 and R2A is independently OH, halo, —C1-6alkyl;
• or
• g) v is 1 or 2;
• or
• h) w is 0;
• or
• i) w is 2;
• or
• j) w is 1 and R3 is C1-6haloalkyl, C1-6alkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, or —C(═O)NRaRb;
• or
• k) R4 is C1-6alkyl;
• or
• l) R8 is independently selected from halo, C1-6haloalkyl, C1-6alkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• or
• m) R8A is independently selected from OH or halo;
• or
• n) z is 0;
• or
• o) q is 0;
• or
• p) q is 2;
• or
• q) when q is 1, R10 is independently selected from halo, C1-6alkyl-OH, C1-6haloalkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-membered cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• or
• r) when q is 1, R10A is independently selected from OH or halo;
• or
• s) when A is C, R9A is independently selected from OH or halo;
• or
• t) R9 is independently selected from halo, C1-6alkyl-OH, C1-6haloalkyl, C1-6alkenylene, —(CH2CH2O)nRa, —SO2Ra, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, a 5- to 10-membered aryl or heteroaryl, a 5- to 10-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 10-cycloalkenyl, monocyclic or bicyclic cycloalkyl, or monocyclic or bicyclic heterocycloalkyl group, where the heteroaryl, spiroheterocycloalkyl or heterocycloalkyl group can have from 1 to 4 heteroatoms independently selected from O, N or S, and the spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group may include a C═O group, and the spiroheterocycloalkyl, or heterocycloalkyl may include a S═O or SO2;
• or
• u) a is a double bond;
• or
• v) c is a double bond;
• or
• w) d is a double bond;
• or
• x) e is a double bond;
• or
• y) a and c are each double bonds;
• or
• z) R7 and R7A together represent ═O;
• or
• aa) when Y is O, then R11 is not H, C1-6alkyl, or —(CH2CH2O)nCH3;
• or
• bb) Q is S;
• or
• cc) when A is CR9A, R9 and R9A together form ═CH2 or R7 and R7A together form a ═O;
• or
• dd) each R5 and R5A is H;
• or
• ee) when R11 is H, unsubstituted C1-6alkyl, or —(CH2CH2O)nCH3, at least one of R8, R9, R10, R2, R2A, R6A, R7A, R8A, R9A and R10A is not H, C1-6alkyl, 3-6-membered cycloalkyl, or (CH2)n-3-6-membered cycloalkyl.