Compounds for targeting degradation of irak4 proteins

A compound of Formula (A):

• IRAK-L-DSM (A)
• or a pharmaceutically acceptable salt thereof, wherein:
• DSM is a degradation signaling moiety that is covalently attached to the linker L,
• L is a linker that covalently attaches IRAK to DSM;
• and
• IRAK is an IRAK4 binding moiety represented by Formula (I) that is covalently attached to linker L;
• wherein:
• A1 is selected from N, CH and CR3, and A2 is selected from N, CH and CR4, provided only one of A1 or A2 may be N;
• one of B1 and B2 is N, and the other is C;
• R1 is selected from:
• i. phenyl optionally substituted with 1 to 3 R5,
• ii. a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl is optionally substituted with 1 to 3 R5,
• iii. a 5 or 6 membered partially or fully saturated heterocycle having 1 to 2 heteroatoms independently selected from oxygen and nitrogen, said heterocycle may be optionally substituted with 1 to 3 R5,
• iv. a partially or fully saturated C3-6 cycloalkyl which may be optionally substituted with 1 to 3 R5,
• v. a 7 to 10 membered fused heterobicyclic ring system having 1, 2 or 3 heteroatoms independently selected from nitrogen and oxygen, said heterobicylic ring system is optionally substituted with 1 to 3 R5, and
• vi. a 7 to 10 membered fused carbobicyclic ring system, said carbobicyclic ring system is optionally substituted with 1 to 3 R5;
• R2 is hydrogen, C1-4 alkyl or halogen;
• R3 and R4 are each independently selected from halogen, C1-4alkyl, nitrile and —OR6, wherein the C1-4alkyl is optionally substituted with C1-4alkoxy or at least one halogen;
• R5 for each occurrence, is independently selected from CN, hydroxyl, C1-4 alkyl, oxo, halogen, —NR8R9, C1-4 alkoxy, —O—C1-4 alkyl, C3-6cycloalkyl, —C1-4alkyl-C3-6cycloalkyl, C(O)NR10R11, a C4-7 heterocycle, and a 5 or 6 membered heteroaryl having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, said C1-4 alkyl is optionally substituted with one or more substituents independently selected from CN, halo, C1-4alkoxy, and hydroxyl, said C3-6cycloalkyl and heteroaryl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C1-4 alkyl, hydroxyl and halogen;
• or two R5 groups together with the intervening atoms can form a ring selected from phenyl, C4-6 carbocycle, C4-6 heterocycle, or a 7-membered bridged ring system optionally having 1 heteroatom selected from nitrogen and oxygen, wherein said phenyl, C4-6 carbocycle and C4-6 heterocycle are each optionally substituted with 1 to 2 C1-4 alkyl, halogen or C1-4 haloalkyl;
• R6 is hydrogen, C1-5alkyl, C3-6cycloalkyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, a 5 to 10 membered spiro carbocyclic ring and a 4 to 10 membered heterocycle having 1 to 2 heteroatoms independently selected from nitrogen and oxygen;
• wherein the C1-5alkyl represented by R6 is optionally substituted with 1 to 3 substituents R6a independently selected from halogen, hydroxyl, C1-5alkyl, C1-4alkoxy, C1-4 haloalkoxy, C3-6cycloalkyl, phenyl, a 4 to 7 membered partially or fully saturated heterocycle containing 1 or 2 heteroatoms selected from nitrogen and oxygen, and a fully saturated 5 to 8 membered bridged-heterocyclic ring system having 1 to 2 heteroatoms independently selected from nitrogen and oxygen;
• wherein the C3-6cycloalkyl represented by R6 is optionally substituted with 1 to 3 substituents R6b independently selected from halogen, C1-4alky, C1-4 haloalkyl, and C1-4alkoxy;
• wherein the 4 to 7 membered partially or fully saturated heterocycle, the 5 to 10 membered spiro carbocyclic ring and 5 to 10 membered spiro heterobicyclic ring system represented by R6 is optionally substituted with 1 to 3 substituents R6, independently selected from C1-4alky and oxo;
• and wherein said C3-6cycloalkyl, phenyl, 4 to 7 membered partially or fully saturated heterocycle represented by R6a are optionally substituted with 1 to 3 R7;
• each R7 is independently selected from oxo, halogen, C1-4 haloalkyl and C1-4 alkyl;
• R8 and R9 are each independently selected from hydrogen, —C(O)C1-4 alkyl and C1-4 alkyl;
• or R8 and R9 may combine to form a 4 to 6 membered saturated ring optionally containing one additional heteroatom selected from nitrogen or oxygen wherein said additional nitrogen may be optionally substituted with C1-4 alkyl;
• R10 and R11 are each independently selected from hydrogen and C1-4 alkyl;
• and
• —* represents a bond to the linker L.