IRAK degraders and uses thereof

A method of treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I-a-5:

• or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein:
• each Rx is independently hydrogen, Rz, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CFR2, —CF2R, —CF3, —CR2(OR), —CR2 (NR2), —C(O)R, —C(O)OR, —C(O) NR2, —C(S)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O) NR2, —N(R)S(O)2R, —N+(O−)R2, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, —P(O)R2, —SiR3, —Si(OR)R2, or
• or
• two Rx groups are optionally taken together to form an optionally substituted 5-6 membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
• two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the carbon or nitrogen, independently selected from nitrogen, oxygen, and sulfur;
• each Ry is independently hydrogen, Rz, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, —CF2R, —CF3, —CR2 (OR), —CR2 (NR2), —C(O)R, —C(O) OR, —C(O) NR2, —C(S)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)NR2, —OP(O)(NR2)2, —SiR3, —SF5, or
• each Rz is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• Ring T is selected from phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups;
• x is 0, 1, 2, or 3;
• y is 0, 1, 2, 3 or 4;
• L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —Si(R)2—, —Si(OH)(R)—, —Si(OH)2—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR2)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —N(R)S(O)2—, —S(O)2N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—
• each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-12 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-12 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• and
• LBM is an IMiD-based cereblon E3 ubiquitin ligase binding moiety selected from:
• (i)
• or a pharmaceutically acceptable salt thereof, wherein:
• Y is a bond;
• X1-X2is C(H)═N or C(C1-C4 alkyl)═N;
• each R1 is independently hydrogen, halogen, —NH2, —OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• R3 is hydrogen;
• two R4, together with the carbon atom to which they are attached, form C(O);
• R5 is hydrogen or C1-C3 alkyl;
• t is 1;
• m is 0, 1, 2 or 3;
• and
• n is 0;
• and
• (ii)
• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is —C(O)—;
• X2 is —C(O)—;
• X3 is —CH2— or —C(O)—;
• R1 is hydrogen or C1-4 aliphatic;
• each of R2 is independently hydrogen, halogen, C1-4 aliphatic or —OC1-4 aliphatic;
• Ring A is a fused 6-membered aryl containing 0-1 nitrogen atoms;
• and
• m is 0, 1, 2, or 3,
• wherein the IRAK4-mediated disorder, disease or condition is lymphoma, leukemia, myeloma, or a MyD88 driven disorder.