Irak degraders and uses thereof

A compound of formula I-xxx-1:

• or a pharmaceutically acceptable salt thereof, wherein:
• (a)
• X and X′ are each independently CR8, N or —N+—O−;
• Y is independently N,-N+-O− or CR8′;
• provided that at least one of X, X′ or Y is neither N nor —N+—O− and that no more than one of X, X′ or Y is —N+—O−;
• R1 is C1-C6alkyl;
• C2-C6alkenyl;
• C2-C6alkynyl;
• —(CR3aR3b)m-(3- to 7-membered cycloalkyl);
• —(CR3aR3b)m-(3- to 7-membered heterocycloalkyl) having one to three heteroatoms;
• —(CR3aR3b)m-(5- to 10-membered heteroaryl), having one to three heteroatoms;
• or —(CR3aR3b)m-C6-C12aryl;
• wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five halogen, deuterium, —OR5, —SR5, —NR11aR11, cyano, C1-C6alkyl, C3-C6cycloalkyl or —C1-C6alkoxy;
• R2 is —(CR3aR3b)m-(3- to 10-membered cycloalkyl);
• —(CR3aR3b)m-(3- to 10-membered heterocycloalkyl) having one to three heteroatoms;
• —(CR3aR3b)m-(5- to 10 membered heteroaryl) having one to three heteroatoms;
• or —(CR3aR3b)m-C6-C12aryl;
• wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five R4;
• and wherein, if the heteroatom on said heterocycloalkyl and heteroaryl is N, said N is
• optionally substituted with R4′;
• or R2 is C1-C6alkyl, wherein said alkyl is optionally substituted with NH2, OH or cyano;
• R3a and R3b for each occurrence are independently hydrogen or C1-C3alkyl;
• R4 for each occurrence is independently a bond, deuterium halogen, cyano, C1-C6alkyl, C2-C6alkenyl, oxo, —OR5, —SR5, —S(O)R9, —S(O)2R9, —NR11aR11b, —C(O)R10—(CR3aR3b)n-(3- to 7-membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl), having one to three heteroatoms, —(CR3aR3b)n-(5- to 10 membered heteroaryl), having one to three heteroatoms, or —(CR3aR3b)n—C6-C12 aryl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each optionally and independently substituted with one to five deuterium, halogen, OR5, —SR5, —NR11aR11, cyano, C1-C6alkyl, C3-C6cycloalkyl or -C1-C6alkoxy;
• or two R4 taken together with the respective carbons to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NR11aR11b, cyano or C1-C6alkyl or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, —SR5, —NR11aR11b, or cyano;
• and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R4′;
• R4′ is independently C1-C6alkyl, C2-C6alkenyl, —C(O)R10, —S(O)2R9, —(CR3aR3b)n-(3- to 7-membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl) or C(O)(CH2)tCN;
• wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C1-C6alkoxy;
• or R4 and R4′ taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NR11aR11b, cyano, C1-C6alkyl or C1-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, —SR5, —NR11aR11b, or cyano;
• R5 is independently hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with halogen, deuterium, C1-C6alkoxy, C1-C6alkylthiolyl, —NR11aR11b, cyano, C1-C6alkyl or C3-C6cycloalkyl;
• or two R taken together with the oxygen atoms to which they are bonded form a 5- or 6-membered heterocycloalkyl;
• R6 is —C(O)NHR7, CO2R7 or cyano;
• R7 is hydrogen or C1-C6alkyl;
• each R8 is independently hydrogen, halogen, cyano, —OR5, —SR5, —NR11aR11b, C6alkyl, C3-C6cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogen, —NR11aR11b, OR5, —SR5, cyano, C1-C3 alkyl, —C(O)R10 or oxo;
• R8′ is hydrogen, deuterium, halogen, cyano, —OR5, —SR5 or NR11aR11b;
• R9 is —(CR3aR3b)p-(C1-C3alkyl), —(CR3aR3b)p-(4- to 6-membered cycloalkyl), —(CR3aR3b)p-(4- to 6-membered heterocycloalkyl) or —(CR3aR3b)p-(C5-C9aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fluoro or C1-C3alkyl;
• R10 is C1-C6alkyl, wherein said alkyl is optionally substituted with deuterium, halogen, OH, C1-C6alkoxy or cyano;
• R11a and R11b are each independently hydrogen or C1-C6alkyl, wherein said alkyl is optionally substituted with deuterium, C1-C6alkoxy or cyano;
• and if C2-C6alkyl, said alkyl is optionally substituted with deuterium, C1-C6alkoxy, cyano, halogen or OH;
• m is independently 0, 1, 2 or 3;
• n is independently 0, 1, 2 or 3;
• p is independently 0 or 1;
• and
• t is 1,2 or 3;
• (b)
• 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—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,
• wherein:
• 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 4-7 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 4-7 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
• and
• each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 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;
• and
• (c)
• LBM is
• 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 ring selected from 6-membered aryl containing 0-1 nitrogen atoms;
• and
• m is 0, 1, 2, 3 or 4.