Compositions useful as inhibitors of protein kinases

Abstract

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

1 - 34 . (canceled) 
     
     
         35 . A method of inhibiting Aurora-2, GSK-3, or Src kinase activity in:
 (a) a patient; or   (b) a biological sample;
 which method comprises administering to said patient, or contacting said sample with: 
 a) a compound of formula Ia: 
   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 2  is —R, oxo, halogen, —CN, —NO 2 , —CO 2 R, -T-Ar, or -T-R; 
         R 2′  is R, or
 R 2  and R 2′  are taken together to form a optionally substituted 5-7 membered, partially unsaturated or fully unsaturated ring having zero to two ring heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:
 each substitutable ring nitrogen of the ring formed by R 2  and R 2′  is optionally substituted; 
 
 
         each occurrence of R is independently hydrogen, an optionally substituted C 1-6  aliphatic group, or Ar; 
         Z 1  is CR x ; 
         Z 2  is CR y ; 
         R x  and R y  are taken together to form an optionally substituted 6 membered partially unsaturated or fully unsaturated carbocyclic ring; 
         R 1  is hydrogen or an optionally substituted C 1-6  aliphatic group; 
         each Ar is independently an optionally substituted 3-6 membered heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 5 or 6 membered aryl ring having zero to three heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:
 Ar is optionally fused to a five or six membered partially unsaturated, or fully unsaturated ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
 
         T is a C 1-4  alkylidene chain wherein one methylene unit of T is optionally replaced by —O—, —S—, —C(O)—, —CO 2 —, —NR—, —NRC(O)—, —NRC(O)NR—, —C(O)C(O)—, —OC(O)NR—, —NRCO 2 —, —SO 2 NR—, —NRSO 2 —, or —NRSO 2 NR—; 
         Q is —N(R′)—, —S—, —O—, —C(R′) 2 —, or a valence bond, wherein
 each R′ is independently hydrogen or C 1-6  aliphatic; and 
 
         Ring D is a 5 or 6 membered optionally substituted monocyclic aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an eight to ten membered partially unsaturated or fully unsaturated bicyclic ring having zero to four heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
 b) a composition of comprising a compound according to formula Ia, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
 
       
     
     
         36 . The method of  claim 35 , wherein the method comprises inhibiting Aurora-2, GSK-3, or Src activity. 
     
     
         37 . A method of treating or lessening the severity of a disease or condition selected from cancer, a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient:
 a) a compound of formula Ia; or   b) a composition of comprising a compound according to formula Ia, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.   
     
     
         38 . The method according to  claim 37 , comprising the additional step of administering to said patient an additional therapeutic agent 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 destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, 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.   
     
     
         39 . The method according to  claim 37 , wherein said disease is cancer, allergy, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig's disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, rheumatoid arthritis, baldness, or leukemia. 
     
     
         40 . The method according to  claim 39 , wherein said disease is selected from cancer, diabetes, Alzheimer's disease, osteoporosis, transplant rejection, stroke, rheumatoid arthritis or schizophrenia. 
     
     
         41 . The method according to  claim 40 , wherein said cancer is selected from colon, stomach, breast, hepatic, pancreatic, or ovarian cancer or certain B-cell leukemias and lymphomas. 
     
     
         42 . A method for treating or lessening the severity of a stroke, wherein said method comprises administering to a patient in need thereof an effective amount of a composition of comprising a compound according to formula Ia, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.