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  together form an optionally substituted aryl of formula: 
 
       
       
         
           
           
               
               
           
         
         
           Y 1  is NR 2 , where R 2  and R 1  together with the nitrogen atoms to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ring; 
           Y 2  is —O— or —C(R 6 ) 2 —; 
           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; 
           provided that at least one of the following occurs: 
           (1) at least one of R 3  and R 4  are halo or 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 a optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; 
           (2) 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; 
           (3) Y is NR 2 ; 
           (4) Y 2  is —C(R 6 ) 2 —; and one R 6  is hydrogen, halo, or optionally substituted C 1 -C 6 alkyl, and the other R 6  is halo or 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; 
           (5) Y 2  is —O—; and A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring; provided that the compound is not 2-(4-bromobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide or 2-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)thiazole-4-carboxamide; 
           (6) the carbonyl moiety and L are substituted other than 1,3- on ring A; 
           or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof. 
         
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein the moiety: 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         wherein
 X 6 , X 7 , X 8  and X 9  are each N 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. 
 
       
     
     
         4 - 20 . (canceled) 
     
     
         21 . The compound of  claim 3 , wherein each R 10  is independently cyano, halo or optionally substituted alkyl. 
     
     
         22 . The compound of  claim 3 , wherein X 6 , X 7 , X 8  and X 9  are each CH. 
     
     
         23 . The compound of  claim 1 , wherein Y 2  is O. 
     
     
         24 . The compound of  claim 1 , wherein R 3  is hydrogen or fluoro. 
     
     
         25 . 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. 
     
     
         26 . 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. 
     
     
         27 . The compound of  claim 1 , wherein L is absent, —S(O) 2 — or —C(R 8 ) 2 —. 
     
     
         28 . 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. 
     
     
         29 . The compound of  claim 1 , wherein R 9  is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl. 
     
     
         29 . The compound of  claim 1 , wherein the compound is of Formula IVa, IVb, IVc, IVd, IVe, IVf or IVg: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; 
         wherein 
         q is 0, 1 or 2; 
         R 4  is H, halo, or optionally substituted C 1 -C 6  alkyl; 
         A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl 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, or optionally substituted C 1 -C 6  alkyl, or two R 8  together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; 
         R 9  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; and 
         each R 10  is independently cyano, halo, optionally substituted C 1 -C 6  alkyl, or —S(O) 2 —C 1 -C 6  alkyl. 
       
     
     
         30 . A compound or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof that is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         31 . A pharmaceutical composition comprising a compound from  claim 1  and an excipient. 
     
     
         32 . A pharmaceutical composition comprising a compound from  claim 30  and an excipient. 
     
     
         33 . 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, Behget'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.