Compositions 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 said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

We claim:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein: 
 X is oxygen or sulfur;  
 Y is nitrogen or CR; 
 each occurrence of R is independently hydrogen, an optionally substituted C 1-6  aliphatic group, or Ar;  
 
 Z 1  is nitrogen or CR x ; wherein 
 R x  is —R, halogen, —N(R) 2 , —NO 2 , —CN, —CO 2 R, —OR, or —SR; wherein 
 two R bound to the same nitrogen atom may be taken together with that nitrogen atom to form a five or six membered heterocyclic or heteroaryl ring having one to two additional heteratoms independently selected from oxygen, nitrogen, or sulfur;  
 
 
 Z 2  is nitrogen or CR y , provided that Z 1  and Z 2  are not simultaneously nitrogen; wherein 
 R y  is —R 1 , —CN, halogen, —NO 2 , —Ar, —T—Ar, or —T—R; or 
 R x  and R y  are taken together to form a five to seven membered optionally substituted partially unsaturated or fully unsaturated ring having zero to two heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein: 
 each substitutable ring nitrogen of the ring formed by R x  and R y  is optionally substituted;  
 
 
 
 R 1  is hydrogen or an optionally substituted C 1-6  aliphatic group; 
 each Ar is independently a three to six membered optionally substituted heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a five or six membered optionally substituted 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 optionally substituted 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—, —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 five or six membered optionally substituted monocyclic aryl ring having zero to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an eight to ten membered optionally substituted partially unsaturated or fully unsaturated bicyclic ring having zero to four heteroatoms independently selected from nitrogen, oxygen, or sulfur.  
 
     
     
         2 . The compound according to  claim 1 , wherein: 
 X is oxygen or sulfur;    Y is nitrogen or CR; 
 each occurrence of R is independently hydrogen, C 1-6  aliphatic, or Ar wherein: 
 R is optionally substituted with one to three groups independently selected from oxo, —CO 2 R′, —Ar, —OR′, —N(R′) 2 , —SR′, —NO 2 , halogen, or —CN; wherein 
 each R′ is independently hydrogen or C 1-6  aliphatic, or two R′ bound to the same nitrogen atom may be taken together with that nitrogen atom to form a five or six membered heterocyclic or heteroaryl ring optionally having one or two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;  
 
 
   Z 1  is nitrogen or CR x ; wherein 
 R x  is —R, halogen, —N(R) 2 , —NO 2 , —CN, —CO 2 R, —OR, or —SR; wherein 
 two R bound to the same nitrogen atom may be taken together with that nitrogen atom to form a five or six membered heterocyclic or heteroaryl ring having one to two additional heteratoms independently selected from oxygen, nitrogen, or sulfur;  
 
   Z 2  is nitrogen or CR y , provided that Z 1  and Z 2  are not simultaneously nitrogen; wherein 
 R y  is —R 1 , —CN, halogen, —NO 2 , —Ar, —T—Ar, or —T—R; or 
 R x  and R y  are taken together to form a five to seven membered partially unsaturated or fully unsaturated ring having zero to two heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein: 
 each substitutable ring nitrogen of the ring formed by R x  and R y  is optionally and independently substituted by —R, —C(O)R, —CO 2 R, —SO 2 R, —C(O)N(R) 2  or —SO 2 N(R) 2 , and  
 one to three substitutable ring carbons of the ring formed by R x  and R y  are optionally and independently substituted with —R, —OR, —N(R) 2 , —SR, —NO 2 , —CN or halogen;  
 
 
   R 1  is hydrogen or a C 1-6  aliphatic optionally substituted with one to three groups independently selected from oxo, —CO 2 R′, phenyl, —OR′, —N(R′) 2 , —SR′, —NO 2 , halogen, or —CN; 
 each Ar is independently a three to six membered heterocyclic ring having one to two heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a five or six 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; and  
 Ar is optionally substituted with one to three groups independently selected from —R, —OR, —SR, —CN, —NO 2 , oxo, halogen, —N(R) 2 , —C(O)R, —OC(O)R, —CO 2 R, —SO 2 R, —SO 2 N(R) 2 , —N(R)SO 2 R, —C(O)N(R), —C(O)N(R) 2 , —OC(O)N(R), —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)N(R) 2 , or —N(R)CO 2 (R);  
 
   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—, —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; and    Ring D is a five or six membered 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, wherein: 
 Ring D is optionally substituted with one to three substituents independently selected from —R, —T—R, —T—Ar, halogen, —CN, —NO 2 , or —Ar.  
   
     
     
         3 . The compound according to  claim 2 , wherein: 
 Z 1  is CR y ;    Z 2  is CR x ; and 
 R x  and R y  are taken together to form a five to seven membered partially unsaturated or fully unsaturated ring having zero to two heteroatoms independently selected from oxygen, sulfur, or nitrogen, wherein: 
 each substitutable ring nitrogen of the ring formed by R x  and R y  is optionally substituted by R, —C(O)R, —CO 2 R, —SO 2 R, —C(O)N(R) 2  or —SO 2 N(R) 2 , and  
 one to three substitutable ring carbons of the ring formed by R x  and R y  are optionally and independently substituted with —R, —OR, —N(R) 2 , —SR, —NO 2 , —CN or halogen.  
 
   
     
     
         4 . The compound according to  claim 3 , wherein: 
 R x  and R y  are taken together to form an optionally substituted benzo, pyrido, cyclopento, cyclohexo, thieno, piperidino, or imidazo ring; and    Q is —N(R′)—, —S—, or a valence bond.    
     
     
         5 . The compound according to  claim 4 , wherein Ring D is an optionally substituted five or six membered monocyclic aryl ring having zero to two nitrogens, or an optionally substituted nine or ten membered partially unsaturated or fully unsaturated bicyclic ring having zero to three heteroatoms independently selected from nitrogen, oxygen, or sulfur.  
     
     
         6 . The compound according to  claim 5 , wherein Ring D is optionally substituted phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl.  
     
     
         7 . The compound according to  claim 1 , wherein: 
 Z 1  is CR x ;    Z 2  is CR y ;    R x  is —R, halogen, —N(R) 2 , —NO 2 , —CN, —CO 2 R, —OR, or —SR;    R y  is —R 1 , —Ar, —T—R, or —T—Ar; and    T is —O—, —NR—, or —S—.    
     
     
         8 . The compound according to  claim 7 , wherein: 
 R x  is hydrogen, —N(R) 2 , —OR, or a C 1-4  aliphatic group;    R y  is C 1-4  aliphatic, —Ar, —T—C 1-4  aliphatic, or —T—Ar;    R is hydrogen or C 1-4  aliphatic;    Ar is optionally substituted phenyl, or a five or six membered heteroaryl or heterocyclic ring; and    Q is —N(R′)—, —S—, or a valence bond.    
     
     
         9 . The compound according to  claim 8 , wherein: 
 R x  is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl; and    R y  is 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolidinyl, imidazolyl, furanyl, thiazolyl, thienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, methoxyethylamino, methoxymethyl, methoxyethyl, ethylamino, dimethylamino, methylamino, dimethylaminopropyloxy, or acetamido.    
     
     
         10 . The compound according to  claim 9 , wherein Ring D is an optionally substituted five or six membered monocyclic aryl ring having zero to two nitrogens; or an optionally substituted nine or ten membered partially unsaturated or fully unsaturated bicyclic ring having zero to three heteroatoms independently selected from nitrogen, oxygen, or sulfur.  
     
     
         11 . The compound according to  claim 10 , wherein Ring D is optionally substituted phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl.  
     
     
         12 . The compound according to  claim 1 , wherein: 
 Z 1  is nitrogen;    Z 2 is CR y ;    R y  is —R 1 , —Ar, —T—R, or —T—Ar; and    T is —O—, —N—, or —S—.    
     
     
         13 . The compound according to  claim 12 , wherein: 
 R y  is C 1-4  aliphatic, —Ar, —T—Ar, or —T—C 1-4  aliphatic;    R is hydrogen or C 1-4  aliphatic;    Ar is optionally substituted phenyl, or a five or six membered heteroaryl or heterocyclic ring; and    Q is —N(R′)—, —S—, or a valence bond.    
     
     
         14 . The compound according to  claim 13 , wherein R y  is 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolidinyl, imidazolyl, furanyl, thiazolyl, thienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, methoxyethylamino, methoxymethyl, methoxyethyl, ethylamino, dimethylamino, methylamino, dimethylaminopropyloxy, or acetamido.  
     
     
         15 . The compound according to  claim 14 , wherein Ring D is an optionally substituted five or six membered monocyclic aryl ring having zero to two nitrogens, or an optionally substituted nine or ten membered partially unsaturated or fully unsaturated bicyclic ring having zero to three heteroatoms independently selected from nitrogen, oxygen, or sulfur.  
     
     
         16 . The compound according to  claim 15 , wherein Ring D is optionally substituted phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl.  
     
     
         17 . The compound according to  claim 1 , wherein: 
 Z 1  is CR x ;    Z 2  is nitrogen; and    R x  is —R, halogen, —N(R) 2 , —NO 2 , —CN, —CO 2 R, —OR, or —SR.    
     
     
         18 . The compound according to  claim 17 , wherein: 
 R x  is hydrogen, —N(R) 2 , —OR, or a C 1-4  aliphatic group; and    Q is —N(R′)—, —S—, or a valence bond.    
     
     
         19 . The compound according to  claim 18 , wherein: 
 R x  is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl.    
     
     
         20 . The compound according to  claim 19 , wherein Ring D is an optionally substituted five or six membered monocyclic aryl ring having zero to two nitrogens, or an optionally substituted nine or ten membered partially unsaturated or fully unsaturated bicyclic ring having zero to three heteroatoms independently selected from nitrogen, oxygen, or sulfur.  
     
     
         21 . The compound according to  claim 20 , wherein Ring D is optionally substituted phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl.  
     
     
         22 . The compound of  claim 1 , selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle.  
     
     
         24 . A composition comprising an effective amount of a compound of  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.  
     
     
         25 . The composition of  claim 23 , in an amount to detectably inhibit GSK-3, Aurora-2 or Src protein kinase activity.  
     
     
         26 . The composition of  claim 23 , additionally comprising a 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.  
     
     
         27 . 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 biological sample with:    a) a composition of  claim 23;  or    b) a compound of  claim 1 .    
     
     
         28 . The method of  claim 27 , wherein the method comprises inhibiting Aurora-2, GSK-3, or Src activity.  
     
     
         29 . 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 composition of  claim 23;  or    b) a compound of  claim 1 .    
     
     
         30 . The method according to  claim 29 , 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.    
     
     
         31 . The method according to  claim 29 , 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.  
     
     
         32 . The method according to  claim 31 , wherein said disease is cancer, diabetes, Alzheimer's disease, osteoporosis, transplant rejection, stroke, rheumatoid arthritis or schizophrenia.  
     
     
         33 . The method according to  claim 32 , wherein said cancer is selected from colon, stomach, breast, hepatic, pancreatic, or ovarian cancer or certain B-cell leukemias and lymphomas.  
     
     
         34 . 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 the composition according to  claim 23.