Chimeric compounds targeting proteins, compositions, methods, and uses thereof

Abstract

The present invention provides chimeric compounds that modulate protein function, to restore protein homeostasis, including cytokine, aiolos, and/or ikaros activity, TNF-alpha activity, CK1-alpha activity and cell-cell adhesion. The invention 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 protein-mediated diseases, disorders, and conditions, such as cytokine-mediated diseases, disorders, and conditions, including inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant rejection, and cancer, are provided.

1 - 116 . (canceled) 
     
     
         117 . A pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein: 
         R 1 , R 2 , R 3 , and R 4 , are each independently H, deuterium, hydroxyl, halogen, nitro, optionally substituted amino, optionally substituted C 1  to C 6  alkoxy, optionally substituted C 1  to C 6  alkyl, optionally substituted C 2  to C 6  alkenyl, optionally substituted C 2  to C 6  alkynyl, optionally substituted C 3  to C 8  carbocyclyl, optionally substituted C 6  to C 10  aryl, optionally substituted C 3  to C 8  heterocyclyl, or optionally substituted C 6  to C 10  heteroaryl; 
         each R 5  is independently H, deuterium, or optionally substituted C 1  to C 6  alkyl; 
         X is CH 2  or C═O; 
         Q is C═O, C═S; S═O, or SO 2 ; 
         n is 1 or 2; and 
         wherein at least one of R 1 , R 2 , R 3 , and R 4  is not H; and 
         at least one pharmaceutically acceptable carrier or excipient. 
       
     
     
         118 . The pharmaceutical composition of  claim 117 , wherein
 R 1  is hydroxyl, halo, nitro, optionally substituted amino, optionally substituted C 1  to C 6  alkoxy, optionally substituted C 1  to C 6  alkyl, or optionally substituted C 3  to C 8  carbocyclyl;   each of R 2 , R 3 , and R 4  is independently selected from the group consisting of H, hydroxyl, halo, nitro, optionally substituted amino, optionally substituted C 1  to C 6  alkoxy, and optionally substituted amino C 1  to C 6  alkyl.   
     
     
         119 . The pharmaceutical composition of  claim 118 , wherein X is C═O. 
     
     
         120 . The pharmaceutical composition of  claim 118 , wherein X is CH 2 . 
     
     
         121 . The pharmaceutical composition of  claim 120 , wherein n is 1. 
     
     
         122 . The pharmaceutical composition of  claim 121 , wherein R 5  is H. 
     
     
         123 . The pharmaceutical composition of  claim 122 , wherein each of R 2 , R 3 , and R 4  is independently H, hydroxyl, halo, nitro, unsubstituted C 1  to C 6  alkoxy, or unsubstituted C 1  to C 6  alkyl. 
     
     
         124 . The pharmaceutical composition of  claim 123 , wherein each of R 2 , R 3 , and R 4  is independently H or halo. 
     
     
         125 . The pharmaceutical composition of  claim 124 , wherein R 2  is halo, and each R 3  and R 4  is H. 
     
     
         126 . The pharmaceutical composition of  claim 124 , wherein R 3  is halo, and each R 2  and R 4  is H. 
     
     
         127 . The pharmaceutical composition of  claim 124 , wherein R 1  is hydroxyl, halo, nitro, unsubstituted C 1  to C 6  alkyl, unsubstituted C 3  to C 8  carbocyclyl, or unsubstituted C 1  to C 6  alkoxy. 
     
     
         128 . The pharmaceutical composition of  claim 127 , wherein R 1  is unsubstituted C 1  to C 6  alkyl or unsubstituted C 3  to C 8  carbocyclyl. 
     
     
         129 . A method of treating, ameliorating, or preventing a disease, disorder, or condition in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 117  to a subject in need thereof, wherein the diseases, disorder or condition is selected from the group consisting of treating inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer' s disease, organ transplant rejection, and cancer. 
     
     
         130 . The method of  claim 129 , wherein the disease, disorder or condition is associated with a protein activity, and wherein the protein is CK 1 -alpha, TNF-alpha, aiolos or ikaros. 
     
     
         131 . The method of  claim 130 , wherein the method inhibits the protein activity. 
     
     
         132 . The method of  claim 130 , wherein the protein is CK1-alpha. 
     
     
         133 . The method of  claim 129 , wherein the disease, disorder or condition is associated with one or more cytokines, where the cytokine is IL-1-alpha, IL-1-beta, IL-2, IL-4, IL-6, IL-10, or combinations thereof. 
     
     
         134 . The method of  claim 133 , wherein the cytokine is IL-2. 
     
     
         135 . The method of  claim 134 , wherein the method induces IL-2 production. 
     
     
         136 . The method of  claim 129 , wherein the disease, disorder or condition is cancer. 
     
     
         137 . The method of  claim 136 , wherein the cancer is leukemia.