Compounds, Compositions and Methods

Abstract

The present disclosure relates generally to compounds and compositions, and their use as kinase inhibitors.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is H or optionally substituted C 1 -C 6  alkyl; 
 X 1  and X 2  are each independently nitrogen or carbon, and together form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl of the formula: 
 
       
         
           
           
               
               
           
         
         wherein 
         X 3 , X 4  and X 5  are each S, O, N, NH, or CH; 
         q is 0, 1 or 2; 
         each R 10  is independently cyano, halo, optionally substituted C 1 -C 6  alkyl or —S(O) 2 —C 1 -C 6  alkyl; 
         each R 6  is independently H, halo, optionally substituted C 1 -C 6  alkyl, or two R 6  together with the carbon atom to which they are attached, form a C 1 -C 6  alken-1-yl, optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; 
         R 3  and R 4  are independently H, halo, optionally substituted C 1 -C 6  alkyl, R 3  and R 4  together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring, or R 3  and R 6  together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; 
         A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; 
         L is absent, —O—, —S—, —S(O)—, —S(O) 2 —, —NR 7 — or —C(R 8 ) 2 —; 
         R 7  is H or optionally substituted C 1 -C 6  alkyl; 
         each R 8  is independently H, halo, optionally substituted C 1 -C 6  alkyl, or two R 8  together with the carbon atom to which they are attached, form a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and 
         R 9  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; 
         or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein R 1  is methyl. 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein Y 2  is 
       
         
           
           
               
               
           
         
       
       where n is 1, 2, 3 or 4, 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein R 3  is hydrogen or fluoro. 
     
     
         13 . The compound of  claim 1 , wherein both R 3  and R 4  are fluoro, or either R 3  or R 4  are fluoro and the other is hydrogen, or R 3  and R 4  form a cyclopropyl or R 3  joins with R 6  to form a cyclopropyl. 
     
     
         14 . The compound of  claim 1 , wherein A is phenyl, phenylbenzo[d]thiazolyl, isoxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or azetidinyl. 
     
     
         15 . The compound of  claim 1 , wherein L is absent, —S(O) 2 — or —C(R 8 ) 2 —. 
     
     
         16 . The compound of  claim 1 , wherein two R 8  together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring. 
     
     
         17 . The compound of  claim 1 , wherein R 9  is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The compound of  claim 1 , wherein L is absent or —C(R 8 ) 2 —, and each R 8  is optionally substituted C 1 -C 6  alkyl or halo provided that the compound is not 5-(difluoro(phenyl)methyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide or not 5-(difluoro(phenyl)methyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide or two R 8  together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring. 
     
     
         22 . The compound of  claim 1 , wherein the carbonyl moiety and L are substituted other than 1,3- on ring A. 
     
     
         23 . The compound of  claim 1 , wherein the compound is of Formula IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . A compound, or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof that is: 
       
         
           
                 
                 
               
                     
                 
                   No. 
                   Structure 
                 
                     
                 
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   1B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   38A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   38B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   39 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   53 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   101A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   101B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   104A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   104B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   105A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   105B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   109A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   109B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   114A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   114B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   118A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   118B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   129A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   129B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   131A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   131B 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   185 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   200 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   210 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   211 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   212 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         25 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof of  claim 1  and an excipient. 
     
     
         26 . A method of treating a receptor-interacting protein kinase 1-mediated disease or disorder in a subject in need thereof comprising administering a therapeutically effective amount of the compound according to  claim 1  to the subject in need thereof, wherein the receptor-interacting protein kinase 1-mediated disease or disorder is an inflammatory disease or disorder, a necrotic cell disease, a neurodegenerative disease, a central nervous system disease, an ocular disease, a malignancy, an immune-mediated disease, an allergic disease, an autoimmune disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial or cardiac infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converting enzyme associated fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, periodontitis, trauma, ischemia, stroke, infection, lysosomal storage disease, Gaucher's disease, Krabbe disease, Niemann-Pick disease, amyotrophic lateral sclerosis (ALS/Lou Gehrig's Disease), HIV-associated dementia, retinal degenerative disease, glaucoma, age-related macular degeneration, psoriasis, psoriatic arthritis, brain injury, spinal cord injury, dementia, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr disease, Menke's disease, Wilson's disease, cerebral ischemia, Friedrich's ataxia, rheumatoid arthritis, Lewy body disease, or a prion disorder.