Stat degraders and uses thereof

A compound having the structural formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1;
• p is 1 or 2;
• X is selected from S, SO2, —S(═O)═NH, —NR8, and —NR9;
• R1 is selected from an 8- to 10-membered fused bicyclic heteroaryl substituted with —CR1aR2aP(O)OR1bOR2b, —CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], —P(O)OR1bOR2b, —[P(O)[NHRTy][NH(AA)C(O)ORT], or —P(O)[OR1b][NH(AA)C(O)ORT];
• an 8- to 10-membered fused bicyclic heterocyclyl substituted with —CR1aR2aP(O)OR1bOR2b, —CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], —P(O)OR1bOR2b, —[P(O)[NHRTy][NH(AA)C(O)ORT], or —P(O)[OR1b][NH(AA)C(O)ORT];
• an aryl substituted with —CR1aR2aP(O)OR1bOR2b, —CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], —P(O)OR1bOR2b, —[P(O)[NHRTy][NH(AA)C(O)ORT], or —P(O)[OR1b][NH(AA)C(O)ORT], wherein said aryl may be further optionally substituted with 1 or 2 groups independently selected from cyano, (C1-C4)alkoxy, and halo;
• a —(C1-C4)alkyl(aryl) wherein said aryl portion of —(C1-C4)alkyl(aryl) is substituted with —CR1aR2aP(O)OR1bOR2b, —CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], —P(O)OR1bOR2b, —[P(O)[NHRTy][NH(AA)C(O)ORT], —[P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT], or —P(O)[OR1b][NH(AA)C(O)ORT];
• and a —(C2-C4)alkenyl(aryl) wherein said aryl portion of —(C2-C4)alkenyl(aryl) is substituted with —CR1aR2aP(O)OR1bOR2b, —CR1aR2aP(O)[OR1b][NH(AA)C(O)ORT], —P(O)OR1bOR2b, —[P(O)[NHRTy][NH(AA)C(O)ORT], or —P(O)[OR1b][NH(AA)C(O)ORT];
• R1a and R2a are each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl and fluoro;
• or R1a and R2a taken together with the carbon they are attached form oxo;
• R1b and R2b are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, —[(C1-C4)alkyl]-OC(O)—[(C1-C4)alkyl], —[(C1-C4)alkyl]-C(O)O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-O—[(C1-C20)alkyl], —[(C1-C4)alkyl]-OC(O)-[halo(C1-C4)alkyl], [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4)alky]-OC(O)-[5- to 7-membered heterocyclyl], —[(C1-C4)alkyl]-OC(O)—[(C1-C4)alkyl]-OH, —[(C1-C4)alkyl]-OC(O)—[(C1-C4)alkyl]-O—[(C1-C4)alkyl, —[(C1-C4)alkyl]-OC(O)O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-OC(O)O-[halo(C1-C4)alkyl], —[(C1-C4)alkyl]-OC(O)O—[(C1-C4)alkyl]-OH, —[(C1-C4)alkyl]-OC(O)O—[(C1-C4)alkyl]-O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-SC(O)—[(C1-C4)alkyl], —[(C1-C4)alkyl]-SC(O)-[halo(C1-C4)alkyl], —[(C1-C4)alkyl]-SC(O)—[(C1-C4)alkyl]-OH, —[(C1-C4)alkyl]-SC(O)—[(C1-C4)alkyl]-O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-OC(O)NH(C1-C4)alkyl], —[(C1-C4)alkyl]-OC(O)N[(C1-C4)alkyl]2, and aryl, wherein said 5- to 6-membered heteroaryl and aryl are each optionally and independently substituted with, as valency permits, 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl and wherein said 5- to 7-membered heterocyclyl of [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl] are each optionally and independently substituted with, as valency permits 1 to 2 groups selected from C(O)ORh;
• R2 is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl;
• R3 and R4 are each independently selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, —(C1-C4)alkylphenyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, —(C1-C4)alkyl(C1-C4)alkoxy, hydroxyl, cyano, —NRaRb, phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein said phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RS;
• R5 and R6 are each independently selected from hydrogen, phenyl, and (C1-C4)alkyl;
• R7 is selected from E, —R10AE, (C1-C4)alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RY and said phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, R11 and/or 1 to 3 groups selected from RZ;
• or
• R6 and R7 together with the nitrogen atom to which they are attached form a 4- to 14-membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which being optionally substituted with, as valency permits, R12 and/or 1 to 3 groups selected from RQ;
• R8 is selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, —(C1-C4)[5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, —(C1-C4)[5- to 10-membered heteroaryl], phenyl, —(C1-C4)alkylphenyl, —C(O)RHa, —C(O)ORHa, —C(O)NRHaRHb, —C(O)ORHa, —SORHaRHb and —SO2RHa, wherein said (C3-C6)cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 10-membered heteroaryl, phenyl, the phenyl on (C1-C4)alkylphenyl, the 5- to 7-membered heterocyclyl on —(C1-C4)[5- to 7-membered heterocyclyl], and the 5- to 6-membered heteroaryl on —(C1-C4)[5- to 6-membered heteroaryl] are each optionally substituted with, as valency permits, 1 to 3 groups selected from RU;
• R9 is selected from-R10EE and —C(O)R10E;
• R10, R10A, R10B, R10C, and R10D are each independently a chemical spacer unit;
• R11 is selected from —NHC(O)R10BE, —OR10BE, phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with-OR10BE, —NHR10BE, —[N(C1-C4)alkyl]R10BE, or R10BE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo;
• R12 is selected from —NHC(O)R10CE, —OR10CE, phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with-OR10CE, —NHR10C-E, —[N(C1-C4)alkyl]R10CE, or R10CE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo;
• R13 is selected from —NHC(O)R10DE, —OR10DE, phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl each of said phenyl, (C3-C6)cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl being substituted with —OR10DE, —NHR10DE, —[N(C1-C4)alkyl]R10DE, or R10DE, and wherein said 4- to 6-membered heterocyclyl is optionally substituted further with oxo;
• E is a chemical moiety that binds to E3 ligase;
• RHa is selected from (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl, wherein said (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl are each optionally substituted with, as valency permits, 1 to 2 groups selected from RO and wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4- to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, cyano, and 4- to 6-membered heterocyclyl optionally substituted with C1-C4alkyl;
• RO is selected from halo, (C1-C4)alkoxy, OH, phenyl, NH2, —NH(C1-C10)alkyl, —N[(C1-C10)alkyl], (C3-6cycloalkyl), 4- to 10-membered monocyclic or fused bicyclic heterocyclyl and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said 5- to 10-membered monocyclic or bicyclic heteroaryl and said 4- to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with, as valency permits, 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, and cyano;
• RHb is hydrogen or (C1-C4)alkyl;
• AA is the residue of an alpha or beta natural or non-natural amino acid;
• RT and RTy are each independently selected from (C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with 1 or 2 groups selected from halo, (C1-C4)alkyl, and halo(C1-C4)alkyl;
• RQ and RU are each independently selected from halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, —ORe, —C(O)Rg, —C(O)ORe, —NRcC(O)Re, —C(O)NReRd, —NRaRb, —S(O)ReRf, —S(O)2Rf, —S(O)—NH(C1-C4)alkyl, —S(O)NReRf, and —S(O)2NReRf, wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RM, and wherein said phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently substituted with, as valency permits, 1 to 3 groups selected from RF;
• RY is selected from halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, —C(O)Rg, —C(O)ORc, —NHC(O)Re, —NRaRb, —S(O)ReRf, —S(O)2Rf, —S(O)NReRf, —S(O)═NH(C1-C4)alkyl, —S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX;
• RM and RJ are each independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, —C(O)Rg, —C(O)ORe, —NHC(O)Re, —C(O)NReRd, —NRaRb, —S(O)ReRf, —S(O)2Rf, —S(O)NReRf, —S(O)═NH(C1-C4)alkyl, —S(O)2NReRf, hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally substituted with, as valency permits, 1 to 3 groups selected from RX;
• RF, RS, and RX are each independently selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, —(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, —(C1-C4)alkylphenyl, —(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, —ORe, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, —S(O)ReRf, —S(O)2Rf, —S(O)═NH(C1-C4)alkyl, —S(O)NReRf, and —S(O)2NReRf, —C(O)ORe, —NRcC(O)Re, —(C1-C4alkyl)C(O)Rg, —C(O)Rg, —(C1-C4alkyl)C(O)NReRd, —C(O)NRcRd, —NO2, and —NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for —(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alknyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5- to 10-membered monocyclic or bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclyl each of said 5- to 10-membered monocyclic and bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo,
• RZ is selected from halo, cyano, (C1-C4)alkyl, (C3-C6cycloalkyl), halo(C1-C4)alkyl, —(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, —(C1-C4)alkylphenyl, —(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, —OR, oxo, imino, phenyl, 4- to 6-membered heterocyclyl, —S(O)ReRf, —S(O)2Rf, —S(O)═NH(C1-C4)alkyl, —S(O)NReRf, and —S(O)2NReRf, —C(O)ORe, —NRcC(O)Re, —(C1-C4alkyl)C(O)Rg, —C(O)Rg, —(C1-C4alkyl)C(O)NRcRd, —C(O)NRcRd, —NO2, and —NRaRb, wherein the (C1-C4)alkyl is optionally substituted with cyano, wherein said phenyl, said 4- to 6-membered heterocyclyl, and said phenyl for —(C1-C4)alkylphenyl are each optionally and independently substituted with, as valency permits R13 and/or 1 to 3 groups selected from halo, cyano, oxo, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, and halo(C1-C10)alkoxy, wherein said (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)alkynyl are each optionally substituted with, as valency permits a 5- to 10-membered monocyclic or bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclyl each of said 5- to 10-membered monocyclic and bicyclic heteroaryl or a 4- to 10-membered monocyclic or bicyclic heterocyclyl being optionally substituted with oxo or a 5- to 7-membered heterocyclyl that is optionally substituted with 1 to 2 oxo;
• Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are each independently selected from, as valency permits, hydrogen, (C1-C4)alkyl, (C2-C4)alkynyl, —(C1-C4)alkylphenyl, phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, wherein said (C1-C4)alkyl is optionally substituted with, as valency permits, 1 to 3 groups selected from RJ, and said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with, as valency permits, 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxyl, phenyl, and benzyl.