Smarca degraders and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

1 - 26 . (canceled) 
     
     
         27 . A method of degrading one or more of SMARCA2, SMARCA4, and PB1 protein in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of formula I-a-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutical composition thereof, wherein: 
         Ring W is 
       
       
         
           
           
               
               
           
         
         Ring Y is a fused-ring selected from 6-membered aryl, 5 to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4 to 9-membered saturated or partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur: 
         each of R x  and R y  is independently hydrogen, R halogen, —CN, —NO 2 , —OR—SR, —NR 2 , —SiR 3 , —S(O) 2 R—S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R; or
 two R x  groups or two R y  groups are optionally taken together to form an optionally substituted 5-7 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         each R is independently hydrogen, or an optionally substituted group selected from C 1-6  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, or:
 two R groups on the same atom are 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 atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; 
 
         each R z  is independently an optionally substituted group selected from C 1-6  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; 
         x is 0, 1, 2, 3, 4, or 5; 
         y is 0, 1, 2, 4, or 5; 
         L 1  is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50  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)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(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 5-11 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 5-11 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; 
         r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
         DIM is a degradation inducing moiety selected from a ligase binding moiety (LBM), wherein the LBM is a cereblon E3 ligase binding moiety of formula I-aa: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is a bivalent moiety selected from a covalent bond, —CH 2 —, —CHCF 3 —, —SO 2 —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR 2 —, —C(O)—, —C(S)—, and 
       
       
         
           
           
               
               
           
         
         X 2  is a carbon atom or silicon atom; 
         X 3  is a bivalent moiety selected from —CR 2 —, —NR—, —O—, —S—, and —Si(R 2 )—; 
         R1 is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O)R, —N(R) 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)(R) 2 , —Si(R) 3 , or an optionally substituted C 1-4  aliphatic; 
         each R 2  is independently hydrogen, R, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R; 
         Ring A is a bicyclic or tricyclic ring selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 
         R 3  is selected from hydrogen, halogen, —OR, —N(R) 2 , and —SR; 
         each R 4  is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R; 
         R 5  is hydrogen, C 1-4  aliphatic, or —CN; 
         each R 6  is independently an optionally substituted group selected from C 1-6  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; 
         L 1  is a covalent bond or a C 1-3  bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CF(R)—, —C(F) 2 —, —N(R)—, —S—, —S(O) 2 — or —(C)═CH—; and 
         m is 0, 1, 2, 3 or 4. 
       
     
     
         28 . A method of treating one or more SMARCA2-mediated, SMARCA4-mediated, or PB1-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I-a-3: 
       
         
           
           
               
               
           
         
         or a pharmaceutical composition thereof, wherein: 
         Ring W is 
       
       
         
           
           
               
               
           
         
         Ring Y is a fused-ring selected from 6-membered aryl, 5 to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 4 to 9-membered saturated or partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; 
         each of R x  and R y  is independently hydrogen, R halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O) 2 R—S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)NR 2 , —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R; or
 two R x  groups or two R y  groups are optionally taken together to form an optionally substituted 5-7 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         each R is independently hydrogen, or an optionally substituted group selected from C 1-6  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, or:
 two R groups on the same atom are 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 atom to which they are attached, independently selected from nitrogen, oxygen, and sulfur; 
 
         each R z  is independently an optionally substituted group selected from C 1-6  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; 
         x is 0, 1, 2, 3, 4, or 5; 
         y is 0, 1, 2, 4, or 5; 
         L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50  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)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(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 5-11 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 5-11 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; 
         r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and 
         DIM is a degradation inducing moiety selected from a ligase binding moiety (LBM), wherein the LBM is a cereblon E3 ligase binding moiety of formula I-aa: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X 1  is a bivalent moiety selected from a covalent bond, —CH 2 —, —CHCF 3 —, —SO 2 —, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR 2 —, —C(O)—, —C(S)—, and 
       
       
         
           
           
               
               
           
         
         X 2  is a carbon atom or silicon atom; 
         X 3  is a bivalent moiety selected from —CR 2 —, —NR—, —O—, —S—, and —Si(R 2 )—; 
         R 1  is hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O) 2 R, —N(R) 2 , —P(O)(OR) 2 , —P(O)(NR 2 )OR, —P(O)(NR 2 ) 2 , —Si(OH) 2 R, —Si(OH)(R) 2 , —Si(R) 3 , or an optionally substituted C 1-4  aliphatic; 
         each R 2  is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —Si(R) 3 , —S(O) 2 R—S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)(NR 2 ), —OP(O)(NR 2 ) 2 —, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —NP(O)R 2 , —N(R)P(O)(OR) 2 , —N(R)P(O)(OR)(NR 2 ), —N(R)P(O)(NR 2 ) 2 , or —N(R)S(O) 2 R; 
         Ring A is a bicyclic or tricyclic ring selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 
         R 3  is selected from hydrogen, halogen, —OR, —N(R) 2 , and —SR; 
         each R 4  is independently hydrogen, R 6 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R; 
         R 5  is hydrogen, C 1-4  aliphatic, or —CN; 
         each R 6  is independently an optionally substituted group selected from C 1-6  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; 
         L 1  is a covalent bond or a C 1-3  bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R) 2 —, —CF(R)—, —C(F) 2 —, —N(R)—, —S—, —S(O) 2 — or —(C)═CH—; and 
         m is 0, 1, 2, 3 or 4. 
       
     
     
         29 . The method of  claim 28 , further comprising administration of an additional therapeutic agent. 
     
     
         30 . The method of  claim 28 , wherein the one or more SMARCA2-mediated, SMARCA4-mediated, or PB1-mediated disorder, disease or condition is selected from a cancer, a neurodegenerative disease, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, a pathologic immune condition involving T cell activation, a cardiovascular disorder, and a CNS disorder. 
     
     
         31 . The method of  claim 30 , wherein the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer, glioma, breast cancer, pancreatic cancer, colorectal cancer, bladder cancer, endometrial cancer, penile cancer, esophagogastric cancer, hepatobiliary cancer soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carsinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendiceal cancer, small bowel cancer, non-melanoma skin cancer, melanoma, leukemia, and malignant rhabdoid tumors (MRT). 
     
     
         32 . The method of  claim 28 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         33 . The method of  claim 28 , wherein Ring Y is a fused 4 to 9-membered saturated or partially unsaturated monocyclic, bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. 
     
     
         34 . The method of  claim 28 , wherein each R x  and R y  are independently hydrogen, R z , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, or —N(R)S(O) 2 R. 
     
     
         35 . The method of  claim 28 , wherein X 1  is a bivalent moiety selected from —CH 2 — or —C(O)—. 
     
     
         36 . The method of  claim 28 , wherein X 2  is a carbon atom. 
     
     
         37 . The method of  claim 28 , wherein X 3  is a bivalent moiety selected from —CR 2 —. 
     
     
         38 . The method of  claim 28 , wherein R 1  is hydrogen or C 1-4  aliphatic. 
     
     
         39 . The method of  claim 28 , wherein each R 2  is independently hydrogen, R, halogen, —CN, —NO 2 , —OR, —SR, —N(R) 2 , —S(O) 2 R, —S(O) 2 N(R) 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —C(R) 2 N(R)C(O)R, —C(R) 2 N(R)C(O)N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R) 2 , or —N(R)S(O) 2 R. 
     
     
         40 . The method of  claim 28 , wherein Ring A is a bicyclic ring selected from 
       
         
           
           
               
               
           
         
       
     
     
         41 . The method of  claim 28 , wherein Ring B is a fused ring selected from 6-membered aryl and 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         42 . The method of  claim 28 , wherein the LBM is a cereblon E3 ligase binding moiety selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 28 , wherein L is a bivalent, saturated or unsaturated, straight or branched C 1-20  hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by —Cy—, —O—, —N(R)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, or —N(R)C(O)O—. 
     
     
         44 . The method of  claim 28 , wherein each —Cy— is independently selected from phenylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 5-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 
     
     
         45 . The method of  claim 28 , wherein L is selected from: