Bifunctional degraders of interleukin-1 receptor-associated kinases and therapeutic use thereof

A compound of Formula (I)

• or a pharmaceutically acceptable salt, isotopic form, isolated stereoisomer, or a mixture of stereoisomers thereof, wherein:
• R1 is C1-10 alkyl optionally substituted with 1-3 Ra;
• C3-10 cycloalkyl optionally substituted with 1-3 Ra;
• or 3-12 membered heterocyclyl optionally substituted with 1-3 Ra;
• L is -L1-L2-L3-L4-L5-, each L1, L2, L3, L4 and L5 being independently:
• a) C3-12 cycloalkyl optionally substituted with 1-3 Rb;
• b) C6-12 aryl optionally substituted with 1-3 Rb;
• c) 3-12 membered heterocyclyl optionally substituted with 1-3 Rb;
• d) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;
• e) direct bond;
• f) C1-12 alkylene chain optionally substituted with 1-3 Rd;
• g) C2-12 alkenylene chain optionally substituted with 1-3 Rd;
• h) C2-12 alkynylene chain optionally substituted with 1 to 3 Rd;
• i) 1-6 ethylene glycol units;
• j) 1-6 propylene glycol units;
• k) —C(O)—, —C(O)O—, —O—, —N(Rc)—, —S—, —C(S)—, —C(S)—O—, —S(O)2—, —S(O)═N—, —S(O)2NH—, —C(O)—N(Rc)—, —C═N—, —O—C(O)—N(Rc)—, -or —O—C(O)—O—;
• LHM is a ligase harness moiety;
• each Ra is independently halo, —CN, C1-3 alkyl optionally substituted with 1 to 3 Rd, C3-6 cycloalkyl optionally substituted with 1 to 3 Rd, or —ORc;
• each Rb is independently oxo, imino, sulfoximino, halo, nitro, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 3-12 membered heterocyclyl, —O—Rc, —C(O)—Rc, —C(O)O—Rc, —C(O)—N(Rc)(Rc), —N(Rc)(Rc), —N(Rc)C(O)—Rc, —N(Rc)C(O)O—Rc, —N(Rc)C(O)N(Rc)(Rc), —N(Rc)S(O)2(Rc), —NRcS(O)2N(Rc)(Rc), —N(Rc)S(O)2O(Rc), —OC(O)Rc, —OC(O)—N(Rc)(Rc), —Si(Rc)3, —S—Rc, —S(O)Rc, —S(O)(NH)Rc, —S(O)2Rc or —S(O)2N(Rc)(Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd;
• each Rc is independently hydrogen or C1-6 alkyl;
• and
• each Rd is independently halo, oxo, —CN, —OH, C1-6 alkyl optionally substituted with 1 to 3 fluoro, or C3-8 cycloalkyl, or —O—C1-6 alkyl optionally substituted with 1 to 3 fluoro.