Aminopyridines useful as inhibitors of protein kinases

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising those compounds and methods of using the compounds and compositions in the treatment of various disease, conditions, and disorders. The invention also provides processes for preparing compounds of the invention.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Ht is selected from ring I-a, I-b, or I-c: 
       
       
         
           
           
               
               
           
         
         wherein any substitutable carbon in ring I-c is optionally substituted with —R 10 ; 
         Ring D is phenyl, wherein the phenyl is optionally substituted with 1-5 —R 5 ; 
         Z 1  is N or CR 10 ; 
         each R X , R Y , and R Z  is independently H, halo, or C 1-6  aliphatic, wherein the aliphatic is optionally substituted with 1-5 groups selected from halo, —CN, and —OR; 
         each R 10  is independently selected from haloC 1-6 alkyl, C 1-6  alkyl, halo, OR, C(═O)R, CO 2 R, COCOR, NO 2 , CN, S(O)R, SO 2 R, SR, N(R 4 ) 2 , CON(R 4 ) 2 , SO 2 N(R 4 )2, OC(═O)R, N(R 4 )COR, N(R 4 )CO 2 R; 
         R 2  is H or C 1-6 alkyl; 
         each R 4  is independently selected from H, C 1-6 alkyl, or haloC 1-6 alkyl; 
         each R 5  is independently selected from halo, haloC 1-6 alkyl, C 3-6  cycloalkyl, or C 1-6 alkyl; and 
         each R is independently selected from H, C 1-6 alkyl, or haloC 1-6 alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein Ht is ring I-a: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein Ht is ring I-b: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Ht is ring I-c: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 4 , wherein Z 1  is N. 
     
     
         6 . The compound according to any one of  claims 2 - 5 , wherein R Y  is H or C 1-6  aliphatic, wherein the aliphatic optionally substituted with 1-5 halo. 
     
     
         7 . The compound according to  claim 6 , wherein R Y  is H or C 1-6  alkyl, wherein the alkyl is optionally substituted with 1-5 halo. 
     
     
         8 . The compound according to  claim 7 , wherein R Y  is H or C 1-4  alkyl, wherein the alkyl is optionally substituted with 1-5 halo. 
     
     
         9 . The compound according to  claim 8 , wherein the alkyl is methyl, ethyl, cyclopropyl, or isopropyl, wherein each alkyl is optionally substituted with 1-5 halo. 
     
     
         10 . The compound according to  claim 6 , wherein the halo is fluoro. 
     
     
         11 . The compound according to any one of  claims 2 - 10 , wherein R X  is C 1-4  alkyl. 
     
     
         12 . The compound according to any one of  claims 2 - 10 , wherein R X  is H. 
     
     
         13 . The compound according to any one of  claims 2 - 12 , wherein R Z  is C 1-4  alkyl. 
     
     
         14 . The compound according to any one of  claims 2 - 12 , wherein R Z  is H. 
     
     
         15 . The compound according to any one of  claims 1 - 3 , wherein R 2  is H or C 1-6  alkyl. 
     
     
         16 . The compound according to  claim 15 , wherein R 2  is methyl. 
     
     
         17 . The compound of  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A composition comprising a compound according to any one of  claims 1 - 16 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         19 . The composition according to  claim 18 , additionally comprising a therapeutic selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders. 
     
     
         20 . A method of inhibiting GSK-3 activity in an ex vivo or in vitro biological sample with a compound according to any one of  claims 1 - 17 . 
     
     
         21 . A method of treating or lessening the severity of a disease or condition selected from diabetes, osteoperosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, leukocytopenia, stroke, and rheumatoid arthritis, comprising the step of administering to a patient a compound according to any one of  claims 1 - 17 . 
     
     
         22 . The method of  claim 21 , wherein said disease is stroke. 
     
     
         23 . The method of  claim 21 , wherein said disease is diabetes. 
     
     
         24 . The method of  claim 21 , wherein said disease is schizophrenia. 
     
     
         25 . The method of  claim 21 , wherein said disease is bipolar disorder. 
     
     
         26 . The method of  claim 21 , wherein said disease is leukocytopenia. 
     
     
         27 . A method of treating or lessening the severity of a disease or condition selected from stroke, spinal cord injury, traumatic brain injury, Charcot-Marie-Tooth, and diabetic neuropathy comprising the step of administering to a patient a compound according to any one of  claims 1 - 17 . 
     
     
         28 . The method of  claim 27  wherein said disease or condition is stroke. 
     
     
         29 . The method of  claim 28 , wherein the compound is administered after ischemia has occurred. 
     
     
         30 . The method of  claim 28 , wherein the compound is used for post-stroke recovery. 
     
     
         31 . The method of  claim 21 , comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating diabetes, an agent for treating osteoperosis, an agent for treating Alzheimer's disease, an agent for treating Huntington's disease, an agent for treating Parkinson's disease, an agent for treating AIDS-associated dementia, an agent for treating bipolar disorder, an agent for treating amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), an agent for treating multiple sclerosis (MS), an agent for treating schizophrenia, an agent for treating leukocytopenia, an agent for treating stroke, and an agent for treating rheumatoid arthritis, wherein:
 a) said additional therapeutic agent is appropriate for the disease being treated; and   b) 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.   
     
     
         32 . The method of  claim 27 , comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating spinal cord injury, an agent for treating traumatic brain injury, an agent for treating Charcot-Marie-Tooth, or an agent for treating diabetic neuropathy. 
     
     
         33 . The method of any one of  claims 28 - 30 , in combination with physical therapy. 
     
     
         34 . A method of increasing axonal and dendritic branching in neuronal cells comprising the step of contact said cells with a compound according to any one of  claims 1 - 17 . 
     
     
         35 . A method of increasing neurogenesis in neuronal cells comprising the step of contacting said cells with a compound according to any one of  claims 1 - 17 . 
     
     
         36 . A method of increasing angiogenesis in neuronal cells comprising the step of contacting said cells with a compound according to any one of  claims 1 - 17 . 
     
     
         37 . A method of increasing plasticity of neuronal cells comprising the step of contacting said cells with a compound according to any one of  claims 1 - 17 .