Fused thiophene compounds

Abstract

The present disclosure provides compounds that modulate protein function, to restore protein homeostasis, and cell-cell adhesion. The disclosure provides methods of modulating protein-mediated diseases, such as cytokine-mediated diseases, disorders, conditions, or responses. Compositions, including in combination with other cytokine and inflammatory mediators, are provided. Methods of treatment, amelioration, or prevention of diseases, disorders, or conditions associated with a protein, are provided.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 Q 1 , Q 2 , and Q 3 , are independently CR 1 , CR 2 , or —S—; 
 wherein one of Q 1 , Q 2 , and Q 3  is —S—; one of Q 1 , Q 2 , and Q 3  is CR 1 ; and one of Q 1 , Q 2 , and Q 3  is CR 2 ; 
 each  - - -  is a carbon-carbon single bond, a carbon-carbon double bond, or a carbon-sulfur single bond; 
 R 1  is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6  alkoxy, optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, optionally substituted amino, C 1 -C 6  alkylamino, amino(C 1 -C 6  alkyl), (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, —O—(C 1 -C 6  alkoxy)C 1 -C 6  alkyl, or optionally substituted C 3 -C 8  carbocyclyl; 
 R 2  is 
 
       
         
           
           
               
               
           
         
         R 3  is H, deuterium, an optionally substituted C 1 -C 6  alkyl, 
       
       
         
           
           
               
               
           
         
         X is C═O, CHR 4A , or CR 4A R 4B ; 
         each R 4A  and R 4B  is independently H, deuterium, or C 1 -C 6  alkyl; 
         X 1  is H, deuterium, fluoro, or C 1 -C 6  alkyl; 
         each of X A , X B , and X C  is independently a bond, (CH 2 ) m , (CF 2 ) m , O, S, and NH; wherein none of X A —X B , X A —X C , or X B —X C  is a bond selected from N—N, N—O, N—S, O—N, S—N, O—O, S—S, or N═N; wherein, not more than one of X A , X B , and X C  can be a bond; and wherein any hydrogen of the (CH 2 ) m  and NH groups can be substituted by one or more R 5 ; 
         R 5  is hydrogen, deuterium, halogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         m is 1, 2, or 3; 
         n is 0, 1, or 2; 
         R 6  is C 6 -C 10  aryl, 5 to 10 membered heteroaryl, C 3  to C 8  carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, optionally substituted C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, —O—(C 1 -C 6  alkoxy)C 1 -C 6  alkyl, C 1 -C 6  alkylamino, amino(C 1 -C 6  alkyl), —C(═O)NR 16a R 16b , optionally substituted C 3 -C 7  cycloalkyl, optionally substituted C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl), optionally substituted C 6 -C 10  aryl, optionally substituted C 6 -C 10  aryl(C 1 -C 6  alkyl), optionally substituted 5 to 10 membered heteroaryl, optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6  alkyl), optionally substituted heterocyclyl, and optionally substituted heterocyclyl(C 1 -C 6  alkyl); 
         each R 16a  and R 16b  is independently H or C 1 -C 6  alkyl, or R 16a  and R 16b  together with the nitrogen atom to which they are attached form 5 or 6 membered heterocyclyl optionally substituted with one or more R 9 ; 
         each R 9  is independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, —O—(C 1 -C 6  alkoxy)C 1 -C 6  alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 9  form oxo (═O); and 
         each of R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  is independently H, an optionally substituted C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl; or R 14  and R 15  together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl. 
       
     
     
         2 . The compound of  claim 1 , having the structure of Formula (Ia), (Ib), (Ic), (Id), (Ie), or (If): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1  or  2 , wherein n is 1. 
     
     
         4 . The compound of any one of  claims 1  to  3 , wherein X is C═O. 
     
     
         5 . The compound of any one of  claims 1  to  3 , wherein X is CH 2 . 
     
     
         6 . The compound of any one of  claims 1  to  5 , wherein X 1  is H. 
     
     
         7 . The compound of any one of  claims 1  to  6 , wherein R 3  is H. 
     
     
         8 . The compound of any one of  claims 1  to  7 , wherein
 R 2  is 
 
       
         
           
           
               
               
           
         
         X B  is a bond, O, S, or NR 5E ; 
         each of R 5A , R 5B , R 5C , R 5D , and R 5E  is independently hydrogen, deuterium, halogen, C 1  to C 6  alkyl, or C 1 -C 6  haloalkyl; and 
         each m1 and m2 is independently 1, 2, or 3. 
       
     
     
         9 . The compound of  claim 8 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       and wherein each m1 and m2 is independently 1 or 2. 
     
     
         10 . The compound of  claim 9 , wherein X B  is a bond, O, or NR 5E . 
     
     
         11 . The compound of  claim 8 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       and wherein m1 is 1 or 2. 
     
     
         12 . The compound of  claim 11 , wherein X B  is O or NR 5E . 
     
     
         13 . The compound of  claim 8 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
       and wherein m2 is 1 or 2. 
     
     
         14 . The compound of  claim 13 , wherein X B  is O or NR 5E . 
     
     
         15 . The compound of any one of  claims 9  to  14 , wherein each of R 5A , R 5B , R 5C , R 5D  is hydrogen. 
     
     
         16 . The compound of any one of  claims 9  to  14 , wherein at least one of R 5A , R 5B , R 5C , R 5D  is halogen or C 1 -C 6  alkyl. 
     
     
         17 . The compound of any one of  claims 9  to  16 , wherein each R 5E  is independently hydrogen or methyl. 
     
     
         18 . The compound of any one of  claims 1  to  17 , wherein R 1  is H. 
     
     
         19 . The compound of any one of  claims 1  to  18 , wherein R 6  is C 6 -C 10  aryl, 5 to 10 membered heteroaryl, C 3  to C 8  carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, optionally substituted C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, (C 1 -C 6  alkoxy)C 1 -C 6  alkyl, —O—(C 1 -C 6  alkoxy)C 1 -C 6  alkyl, C 1 -C 6  alkylamino, amino(C 1 -C 6  alkyl), —C(═O)NR 16a R 16b , C 3 -C 7  cycloalkyl optionally substituted with one or more R 9 , C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 , C 6 -C 10  aryl optionally substituted with one or more R 9 , C 6 -C 10  aryl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 , 5 or 6 membered heteroaryl optionally substituted with one or more R 9 , 5 or 6 membered heteroaryl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 , heterocyclyl optionally substituted with one or more R 9 , and heterocyclyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 . 
     
     
         20 . The compound of  claim 19 , wherein R 6  is a phenyl substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkylamino, amino(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl optionally substituted with one or more R 9 , C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 , 5 or 6 membered heterocyclyl optionally substituted with one or more R 9 , and 5 or 6 membered heterocyclyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 . 
     
     
         21 . The compound of  claim 19  or  20 , wherein R 6  is a phenyl substituted with 
       
         
           
           
               
               
           
         
       
       each optionally substituted with one or more R 9 . 
     
     
         22 . The compound of  claim 19  or  20 , wherein R 6  is a phenyl substituted with 
       
         
           
           
               
               
           
         
       
       each optionally substituted with one or more R 9 . 
     
     
         23 . The compound of any one of  claims 20  to  22 , wherein R 9  is halogen, C 1 -C 6  alkyl, or C 1 -C 6 haloalkyl. 
     
     
         24 . The compound of  claim 19  or  20 , wherein R 6  is a phenyl substituted with —NH(C 1 -C 4  alkyl) or —N(C 1 -C 4  alkyl) 2 . 
     
     
         25 . The compound of  claim 19  or  20 , wherein R 6  is a phenyl substituted with —(CH 2 ) 1-3 —NH(C 1 -C 4  alkyl) or —(CH 2 ) 1-3 —N(C 1 -C 4  alkyl) 2 . 
     
     
         26 . The compound of  claim 19  or  20 , wherein R 6  is a phenyl substituted with one, two, or three substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, —NH(Me), —NH(Et), —N(Me) 2 , —N(Et) 2 , 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 19 , wherein R 6  is a pyridyl substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  alkylamino, amino(C 1 -C 6  alkyl), C 3 -C 7  cycloalkyl optionally substituted with one or more R 9 , C 3 -C 7  cycloalkyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 , 5 or 6 membered heterocyclyl optionally substituted with one or more R 9 , and 5 or 6 membered heterocyclyl(C 1 -C 6  alkyl) optionally substituted with one or more R 9 . 
     
     
         28 . The compound of  claim 27 , wherein R 6  is a pyridyl substituted with one, two, or three substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, —NH(Me), —NH(Et), —N(Me) 2 , —N(Et) 2 , 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 1 , selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         30 . A pharmaceutical composition, comprising a compound of any one of  claims 1  to  29 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         31 . A method of treating, ameliorating, or preventing a hematological malignancy or a solid tumor in a subject, comprising administering a therapeutically effective amount of a compound of any one of  claims 1  to  29 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 30 , to the subject in need thereof. 
     
     
         32 . The method of  claim 31 , wherein the hematological malignancy or the solid tumor is small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, ovarian cancer, gastric cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, multiple myeloma, or neuroblastoma. 
     
     
         33 . The method of  claim 32 , wherein the hematological malignancy is leukemia, lymphoma, or multiple myeloma. 
     
     
         34 . The method of any one of  claims 31  to  33 , wherein the hematological malignancy or the solid tumor is associated with one or more proteins selected from the group consisting of IL-1β, IL-2, IL-6, TNFα, CK1α, GSPT1, aiolos, ikaros, and helios, and combinations thereof. 
     
     
         35 . A method of treating, ameliorating, or preventing a disease, disorder, or condition in a subject, comprising administering a therapeutically effective amount of a compound of any one of  claims 1  to  29 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 30 , to the subject in need thereof; and wherein the disease, disorder, or condition is a neurodegenerative disease, fibrosis, lupus, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, uveitis, or chronic obstructive pulmonary disease, or combinations thereof. 
     
     
         36 . The method of  claim 34 , wherein the disease, disorder, or condition is multiple sclerosis, Alzheimer's disease, Parkinson's disease, fibrosis, lupus, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's disease, or ulcerative colitis, or combinations thereof. 
     
     
         37 . The method of  claim 34  or  36 , wherein the disease, disorder, or condition is associated with one or more proteins selected from the group consisting of IL-1β, IL-2, IL-6, TNFα, CK1α, GSPT1, aiolos, ikaros, and helios, and combinations thereof. 
     
     
         38 . The method of any one of  claims 31  to  37 , wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition is co-administered to the subject with a second therapeutic agent. 
     
     
         39 . A method of modulating activity of a protein in a biological sample, comprising contacting the biological sample with a compound of any one of  claims 1  to  29 , or a pharmaceutically acceptable salt thereof, wherein the protein is IL-1β, IL-2, IL-6, TNFα, CK1α, GSPT1, aiolos, ikaros, or helios. 
     
     
         40 . The method of  claim 39 , wherein the method inhibits the activity of the protein. 
     
     
         41 . The method of  claim 39 , wherein the method induces IL-2. 
     
     
         42 . The method of any one of  claims 39  to  41 , wherein the biological sample comprises one or more cells selected from the group consisting of small cell lung cancer cell, non-small cell lung cancer cell, breast cancer cell, prostate cancer cell, head and neck cancer cell, pancreatic cancer cell, colon cancer cell, rectal cancer cell, teratoma cell, ovarian cancer cell, gastric cancer cell, endometrial cancer cell, brain cancer cell, retinoblastoma cell, leukemia cell, skin cancer cell, melanoma cell, squamous cell carcinoma cell, liposarcoma cell, lymphoma cell, multiple myeloma cell, testicular cancer cell, liver cancer cell, esophageal cancer cell, kidney carcinoma cell, astrogliosis cell, multiple myeloma cell, and neuroblastoma cell.