Spiro-Sulfonamide Derivatives As Inhibitors Of Myeloid Cell Leukemia-1 (MCL-1) Protein

A compound of Formula I:

• or a pharmaceutically acceptable salt or solvate thereof;
• wherein
• Z is CH or N;
• Q is —O—, —S—, —S(O)—, or —S(O)2—;
• the moiety -W1-W2-W3 is —CR2R2A—CR2R2A—CR2R2A—, —O—CR2BR2C—CR2R2A—, —CR2R2A—CR2BR2C—O—, —NR2B—CR2BR2C—CR2R2A—, —CR2R2A—CR2BR2C—NR2B—, —S—CR2BR2C—CR2R2A, or —CR2R2A—CR2BR2C—S—;
• L1 is absent or is optionally substituted —C1-C6alkylene-;
• L2 is absent or is optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene;
• L3 is absent, or is —(CR4R5)p—, —(CR4R5)pO—, —O—, —S—, —S(O)—, —S(O)2—, —C(═O)—, —NR6—, —OC(═O)—, —C(═O)O—, —NR6AC(O)—, —C(═O)NR6A—, —OC(═O)N(R6A)—, —NR6AC(O)O—, —S(═O)NR6A—, —NR6AS(O)—, —S(═O)2NR6A—, or —NR6AS(O)2—;
• L4 is absent, or is —(CR4R5)pQ1(CR4R5)q—, wherein Q1 is absent, —CR4A═CR4B—, —O—, —S—, —S(O)—, —S(O)2—, —C(═O)—, —NR6—, —OC(═O)—, —C(═O)O—, —NR6AC(O)—, —C(═O)NR6A—, —NR6AC(O)R6B—, —OC(═O)N(R6A)—, —NR6AC(O)O—, —S(═O)NR6A—, —NR6AS(O)—, —S(═O)2NR6A—, or —NR6AS(O)2—;
• or is —(CR4R5)p—(CR4A═CR4B)—(CR4R5)q—O—;
• L5 is absent, or is —C1-C6 alkylene-, —C2-C6 alkenylene-, —C2-C6 alkynylene-, -arylene-, -heteroarylene-, -cycloalkenylene-, -cycloalkylene-, -heterocycloalkylene-, wherein said C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, arylene, heteroarylene, cycloalkenylene, cycloalkylene, or heterocycloalkylene groups are optionally substituted;
• L6 is absent, or is —(CR7R8)s—, —(CR7R8)sO(CR7R8)t—, —(CR7R8)sNR9(CR7R8)t—, —(CR7R8)sS(CR7R8)t—, —(CR7R8)sS(O)(CR7R8)t—, —(CR7R8)sS(O)2(CR7R8)t—, —(CR7R8)sNR9AC(O)(CR7R8)t—, —(CR7R8)sOC(O)NR9A(CR7R8)t—, —(CR7R8)sNR9AC(O)O(CR7R8)t—, —(CR7R8)sNR9AC(O)NR9B(CR7R8)t—, —(CR7R8)sNR9AS(O)(CR7R8)t—, —(CR7R8)sNR9AS(O)2(CR7R8)t—;
• —(CR7R8)s—CR4A═CR4B—(CR7R8)t—, —(CR7R8)sC(═O)(CR7R8)t—;
• —(CR7R8)sC(═O)(CR7R8)t—O—, or —(CR7R8)sC(═O)(CR7R8)t—NR6—;
• each n is independently 0-3;
• each m is independently 0-2;
• each p is independently 0-4;
• each q is independently 0-4;
• each s is independently 0-3;
• each t is independently 0-4;
• each R is independently -D, -halo, —CN, —NO2, —C1-C6alkyl, —C2-C6alkenyl, —C1-C6alkoxy, -cycloalkyl, —ORa, —SRa, —C(O)Rb, —C(O)ORa, —NRcRd, —C(O)NRcRd, or —S(O)2Ra;
• wherein said —C1-C6alkyl, —C2-C6alkenyl, —C1-C6alkoxy, or -cycloalkyl is optionally substituted;
• each R1 is independently -D, -halo, —CN, —NO2, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, —ORa, —SRa, —NRcRd, —C(O)Rb, —OC(O)Rb, —C(O)ORa, —C(O)NRcRd, —S(O)2Ra;
• -aryl, -heteroaryl, -cycloalkyl, or -heterocycloalkyl, wherein said —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, -cycloalkyl, -heterocycloalkyl, -aryl, or -heteroaryl is optionally substituted;
• each R2, R2A, or R2a is independently H, D, halo, ORa, optionally substituted C1-C6alkyl, or R2 and R2A that are attached to the same carbon atom may, together with the carbon atom to which they are both attached, form an optionally substituted cycloalkyl ring;
• each R2B and R2C is independently H, D, optionally substituted C1-C6alkyl, or R2B and R2C may, together with the carbon atom to which they are both attached, form an optionally substituted cycloalkyl ring;
• R3 is H, D, —C1-C6alkyl, —C3-C6alkenyl, —C3-C6alkynyl, cycloalkyl, heterocycloalkyl, C(O)Rb, C(O)ORa, or C(O)NRcRd;
• wherein said C1-C6alkyl, —C3-C6alkenyl, —C3-C6alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted;
• or R3 is —C1-C6alkyl substituted at the C1 carbon atom with —OR3A wherein R3A is C1-C6alkyl, —PO3H, —C(O)OR2C, or —C(O)NR3AR3B wherein R3A and R3B are each independently H, D, optionally substituted C1-C6alkyl;
• each R4 or R7 is independently H, D, halo, —OH, —CN, —NO2, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Ra, —C(O)ORa, —C(O)NRcRd, —S(O)Rb, or —S(O)2Rb, wherein said C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, or heterocycloalkyl is optionally substituted;
• each R4A or R4B is independently H, D, -Me, —CF3 or —F;
• each R5 or R8 is independently H, D, fluoro, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, —C(O)Rb, —C(O)ORa, —C(O)NRcRd, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted;
• or R4 and R5 together with the C atom to which they are attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted;
• or an R4 and an R5 attached to adjacent carbon atoms, together with the C atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted;
• or R7 and R8 together with the C atom to which they are both attached form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted, each optionally substituted;
• or an R7 and an R8 attached to adjacent carbon atoms, together with the C atoms to which they are attached, form a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, each optionally substituted;
• each R6 or R9 is independently H, D, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, —OC1-C6alkyl, —C(O)Rb, —C(O)ORa, —C(O)NRcRd, —S(O)Rb or —S(O)2Rb, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, wherein said C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, —OC1-C6alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring, is optionally substituted;
• or R9 together with either an R7 or an R8 forms an optionally substituted heterocyclic alkylene;
• each R6A, R6B, R9A, or R9B is independently H, D, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted;
• or R6A and R6B together with the N atoms to which they are attached form an optionally substituted heterocycloalkyl or heterocycloalkenyl ring;
• or R9A and R9B together with the N atoms to which they are attached form an optionally substituted heterocycloalkyl or heterocycloalkenyl ring;
• each Ra is independently H, D, —C(O)Rb, —C(O)ORc, —C(O)NRcRd, —P(ORc)2, —P(O)RcRb, —P(O)ORcORb, —S(O)Rb, —S(O)NRcRd, —S(O)2Rb, —S(O)2NRcRd, —B(ORc)(ORb), SiRb3, —C1-C10alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl wherein said C1—C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted;
• each Rb, is independently H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl wherein said —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkeneyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted;
• each Rc or Rd is independently H, D, —C1-C10 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, wherein said C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —OC1-C6alkyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl are each optionally substituted;
• or Rc and Rd, together with the N atom to which they are both attached, form an optionally substituted monocyclic or multicyclic heterocycloalkyl, or optionally substituted monocyclic or multicyclic heterocycloalkenyl group.