Protein kinase inhibitors and uses thereof

Abstract

Described herein are benzisoxazole compounds of formula I: or a pharmaceutically acceptable derivative or prodrug thereof, wherein A-B is N—O or O—N; Ar is an optionally substituted C 5-10 aryl group; R 1 is hydrogen or an optionally substituted group selected from C 1-10 aliphatic, C 5-10 aryl, C 6-12 aralkyl, C 3-10 heterocyclyl, or C 4-12 heterocyclylalkyl; and T, n, R 2 and R 3 are as described in the specification. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK-3 and JAK mammalian protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

1 - 10 . (canceled)  
   
   
       11 . A composition comprising a compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 A-B is N—O or O—N;  
 Ar is an optionally substituted C 5-10  aryl group;  
 T is a C 1-4  alkylidene chain wherein one or two methylene units of T are optionally and independently replaced by O, NR, S, C(O), C(O)NR, NRC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, CO 2 , OC(O), NRCO 2 , or OC(O)NR;  
 n is zero or one;  
 R 1  is hydrogen or an optionally substituted group selected from C 1-10  aliphatic. C 5-10  aryl, C 6-12  aralkyl, C 3-10  heterocyclyl, or C 4-12  heterocyclylalkyl;  
 each R 2  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6  aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic);  
 each R 3  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6  aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic); and  
 each R is independently selected from hydrogen, a C 1-8  aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur,  
 and a pharmaceutically acceptable carrier, adjuvant or vehicle, additionally comprising an additional therapeutic agent selected from an a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.  
 
   
   
       12 . (canceled)  
   
   
       13 . A method of treating or lessening the severity of a GSK-3- or JAK-mediated disease or condition in a patient, comprising the step of administering to said patient: 
 a compound of formula I:                          or a pharmaceutically acceptable salt thereof, wherein:    A-B is N-0 or O—N;    Ar is an optionally substituted C 5-10  aryl group;    T is a C 1-4  alkylidene chain wherein one or two methylene units of T are optionally and independently replaced by O, NR, S, C(O), C(O)NR, NRC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, CO 2 , OC(O), NRCO 2 , or OC(O)NR;    n is zero or one;    R 1  is hydrogen or an optionally substituted group selected from C 1-10  aliphatic, C 5-10  aryl, C 6-12  aralkyl, C  3-10  heterocyclyl, or C 4-12  heterocyclylalkyl;    each R 2  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic);    each R 3  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic), and    each R is independently selected from hydrogen, a C 1-8  aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur.    
   
   
       14 . The method according to  claim 13 , wherein said GSK-3-mediated disease is selected from diabetes, Alzheimer's disease, Huntington's disease, Parkinson's, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, ischemia/reperfusion and baldness.  
   
   
       15 . The method according to  claim 13 , wherein said JAK-mediated disease is selected from an immune response, an autoimmune disease, a neurodegenerative disease, or a solid or hematologic malignancy.  
   
   
       16 . (canceled)  
   
   
       17 . The method according to  claim 13 , comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferatic agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder, wherein: 
 said additional therapeutic agent is appropriate for the disease being treated; and    said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.    
   
   
       18 . A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 A-B is N—O or O—N;  
 Ar is an optionally substituted C 5-10  aryl group;  
 T is a C 1-4  alkylidene chain wherein one or two methylene units of T are optionally and independently replaced by O, NR, S, C(O), C(O)NR, NRC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, CO 2 , OC(O), NRCO 2 , or OC(O)NR;  
 n is zero or one;  
 R 1  is hydrogen or an optionally substituted group selected from C 1-10  aliphatic, C 5-10  aryl, C 6-12  aralkyl, C 3-10  heterocyclyl, or C 4-12  heterocyclylalkyl;  
 each R 2  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic);  
 each R 3  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6  aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic); and  
 each R is independently selected from hydrogen, a C 1-8  aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur.  
 
   
   
       19 . A method of inhibiting the phosphorylation of β-catenin in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 A-B is N—O or O—N;  
 Ar is an optionally substituted C 5-10  aryl group:  
 T is a C 1-4  alkylidene chain wherein one or two methylene units of T are optionally and independently replaced by O, NR, S, C(O), C(O)NR, NRC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, CO 2 , OC(O), NRCO 2 , or OC(O)NR;  
 n is zero or one:  
 R 1  is hydrogen or an optionally substituted group selected from C 1-10  aliphatic, C 5-10  aryl, C 6-12  aralkyl, C 3-10 heterocyclyl, or C 4-12  heterocyclylalkyl;  
 each R 2  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic);  
 each R 3  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6  aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic); and  
 each R is independently selected from hydrogen, a C 1-8  aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur.  
 
   
   
       20 . A composition for coating an implantable device comprising a compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 A-B is N—O or O—N;  
 Ar is an optionally substituted C 5-10  aryl group;  
 T is a C 1-4  alkylidene chain wherein one or two methylene units of T are optionally and independently replaced by O, NR, S, C(O), C(O)NR, NRC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, CO 2 , OC(O), NRCO 2 , or OC(O)NR;  
 n is zero or one;  
 R 1  is hydrogen or an optionally substituted group selected from C 1-10  aliphatic, C 5-10  aryl, C 6-12  aralkyl, C 3-10  heterocyclyl, or C 4-12  heterocyclylalkyl;  
 each R 2  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic);  
 each R 3  is independently selected from R, halo, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6  aliphatic); and  
 each R is independently selected from hydrogen, a C 1-8  aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form a 4-8 membered heterocyclic ring having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, and a carrier suitable for coating said implantable device.  
 
   
   
       21 . An implantable device coated with a composition according to  claim 20.