Degradation of tripartite motif-containing protein 24 (TRIM24) by conjugation of TRIM24 inhibitors with E3 ligase ligand and methods of use

A bifunctional compound of Formula X:

• wherein:
• the Targeting Ligand is capable of binding to TRIM24;
• the Linker is a group that covalently binds to the Targeting Ligand and the Degron;
• and
• the Degron is capable of binding to a ubiquitin ligase,
• wherein the Targeting Ligand is of Formula TL-I:
• or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
• A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R5;
• G is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R6;
• X is S(O)t;
• Y is O or NR4;
• R1 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
• R2 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
• R3 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
• R4 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
• each R5 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, OH, or NH2, wherein the alkyl or alkoxy is optionally substituted with one or more substituents selected from NR7R8, phenyl, and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S;
• each R6 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, halogen, OH, or NH2, wherein the alkyl or alkoxy is optionally substituted with one or more substituents selected from NR7R8, phenyl, and 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S;
• each R7 and R8 is independently H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
• and
• t is 0, 1, or 2,
• wherein the Targeting Ligand is bonded to the Linker via attachment to A or G;
• wherein the Linker is of Formula L0:
• or an enantiomer, diastereomer, or 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, or 0 when Q is Q1-(O)0-1-Q2;
• each W is independently absent, CH2, O, S, NH, or NR19;
• Z1 is absent, OCH2C(O)NH, OCH2C(O)NR19, C(O)NH, C(O)NR19, NHC(O), NR19C(O), C(O), CH2, O, NH, or NR19;
• each R19 is independently C1-C3 alkyl;
• and
• Q is absent, NHC(O)CH2, O(CH2)0-2, or Q1-(O)0-1-Q2;
• Q1 and Q2 are each independently absent, C1-C4 alkylenyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or 5- or 6-membered heterocyclyl containing 1 or 2 N,
• wherein the Linker is covalently bonded to the Degron via the
• next to Q, and covalently bonded to the Targeting Ligand via the
• next to Z1:
• wherein the Degron is of Formula D1, D2, or D3:
• or an enantiomer, diastereomer, or stereoisomer thereof, wherein:
• Y1 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;
• v is 0, 1, 2, or 3;
• each R17 is independently C1-C3 alkyl;
• q′ is 0, 1, 2, 3 or 4;
• R18 is H or C1-C3 alkyl;
• R20 is t-butyl or i-propyl;
• R21 is
• and bonded to the carbon atom marked with * with the nitrogen atom, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S;
• and
• R22 is H or C1-C3 alkyl,
• wherein the Degron is covalently bonded to the Linker via