Degradation of cyclin-dependent kinase 4/6 (CDK4/6) by conjugation of CDK4/6 inhibitors with E3 ligase ligand and methods of use

A bifunctional compound of Formula X:

• wherein:
• the Targeting Ligand is capable of binding to CDK4 and/or CDK6, and is of Formula TL-I:
• or a stereoisomer or pharmaceutically acceptable salt thereof,
• wherein:
• A is absent or C(R4)2;
• A′ is NR5 or O;
• B is
• X is N or CH;
• X2 is N or CR5;
• each R1 is independently (C1-C4) alkyl or (C1-C4) haloalkyl;
• R2 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, OH, or NH2;
• R3 is (C6-C10) aryl or a monocyclic or bicyclic heteroaryl comprising one to four heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R7;
• or
• R2 and R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more R8;
• or R2 and R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R9;
• each R4 is independently H or (C1-C4) alkyl;
• R5 is H or (C1-C4) alkyl;
• each R6 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
• each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
• or
• each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl, or two R8 together with the carbon to which they are attached form C(O);
• each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl;
• and
• n and t are independently 0, 1, 2, or 3,
• wherein the Targeting Ligand is bonded to the Linker via the
• next to
• the Linker is a group that covalently binds to the Targeting Ligand and the Degron, and is of Formula L0:
• or a stereoisomer thereof, wherein:
• p1 is an integer selected from 0 to 12;
• p2 is an integer selected from 0 to 12;
• p3 is an integer selected from 1 to 6;
• each W is independently absent, CH2, O, S, NH, or NR19;
• Z1 is absent, C(O), CH2C(O)NH, CH2, O, NH, or NR19;
• each R19 is independently (C1-C3) alkyl;
• and
• Q is absent or NHC(O)CH2,
• wherein the Linker is covalently bonded to a Degron via the
• next to Q, and covalently bonded to a Targeting Ligand via the
• next to Z1;
• and
• the Degron is capable of binding to a ubiquitin ligase, and is of Formula D1:
• or a stereoisomer thereof, wherein:
• Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR11, (CH2)0-6—NR11C(O), (CH2)0-6—NH, or (CH2)0-6—NR12;
• Z is C(O) or C(R13)2;
• R11 is H or (C1-C6) alkyl;
• R12 is (C1-C6) alkyl or C(O)—(C1-C6) alkyl;
• each R13 is independently H or (C1-C3) alkyl;
• each R14 is independently (C1-C3) alkyl;
• R15 is H, deuterium, (C1-C3) alkyl, F or Cl;
• each R16 is independently halogen, OH, (C1-C6) alkyl, or (C1-C6) alkoxy;
• q is 0, 1, or 2;
• and
• v is 0, 1, 2, or 3,
• wherein the Degron is covalently bonded to the Linker via the