Degradation of cyclin-dependent kinase 8 (CDK8) by conjugation of CDK8 inhibitors with E3 ligase ligand and methods of use

A bifunctional compound of Formula X:

• wherein:
• the Targeting Ligand is of Formula TL-I:
• wherein:
• A is
• X is N or CH;
• X2 is N or CH;
• X3 is N or CH;
• X4 is N or CH;
• each R1 is independently (C1-C4) alkyl or (C1-C4) haloalkyl;
• each R2 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
• each R3 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
• each R4 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
• and
• t, n, o, and r are each independently 0, 1, 2, or 3;
• wherein the Targeting Ligand is bonded to the Linker via the next to
• the Linker is a bond or a carbon chain that serves to link the Targeting Ligand with the Degron,
• wherein,
• the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S,
• and wherein,
• one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substitutents selected from oxo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C3) alkoxy, OH, halogen, NH2, NH(C1-C3) alkyl, N(C1-C3)2, CN, (C3-C8) cycloalkyl, heterocyclyl, and phenyl;
• and
• the Degron is of Formula D1:
• 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
• or a stereoisomer or pharmaceutically acceptable salt thereof.