Pyrazolo [3,4-d] pyrimidine derivatives useful to treat respiratory disorders

Abstract

The present invention concerns a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, where R 1 -R 3 and Y are defined in the description, and its use in the treatment of disorders in which pi3 kinase is implicated.

1 . A method to treat a disorder in which pi3 kinase is implicated, which comprises administering to a subject in need of such treatment a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1 -C 3 -alkyl; 
 R 2  is phenyl having the substitution pattern, 
 
       
         
           
           
               
               
           
         
         wherein the R 2  phenyl is fused at R 4 -R 5 , R 5 -R 6 , R 6 -R 7  or R 7 -R 8  by a further phenyl, a 5-6 membered heteroaryl group selected from pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, a C 4 -C 6  carbocyclic group or a 5-6 membered heterocyclyl group, where the fused heteroaryl group is independently optionally substituted by one or more groups selected from List X; 
         List X represents hydroxyl, cyano, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkenyloxy, C 1 -C 8 -alkynyloxy, phenyl, a 5-6 membered heteroaryl group, a C 4 -C 6  carbocyclic group or a 5-6 membered heterocyclyl group, —(C 0 -C 4 -alkylene)-O—(C 1 -C 4 -alkylene)-R 9 , (C 0 -C 4 -alkylene)-O—(C 2 -C 4 -alkylene)-R 10 , (C 0 -C 4 -alkylene)-N(R 11 )—(C 1 -C 4 -alkylene)-R 12 , —(C 0 -C 4 -alkylene)-N(R 13 )—(C 2 -C 4 -alkylene)-R 14 , halogen, formyl, C 1 -C 8 -alkylcarbonyl, carboxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -alkylaminooxycarbonyl, di-C 1 -C 8 -alkylaminooxycarbonyl, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylamidino, —N(H)C(═NH)C 1 -C 8 -alkyl, —N(C 1 -C 8 -alkyl)C(═NH)C 1 -C 8 -alkyl, C 1 -C 8 -alkylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, aminocarbonylamino, aminocarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylaminocarbonylamino, di-C 1 -C 8 -alkylaminocarbonylamino, C 1 -C 8 -alkylaminocarbonyl(C 1 -C 8 -alkyl)amino, di-C 1 -C 8 -alkylaminocarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylcarbonylamino, C 1 -C 8 -alkylcarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylthiocarbonylamino, C 1 -C 8 -alkylthiocarbonyl(C 1 -C 8 -alkyl)amino, hydroxysulfonyl, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl or di-C 1 -C 8 -alkylaminosulfonyl, where each of the afore-mentioned hydrocarbon groups may be optionally substituted, where chemically feasible, by one or more halogen, hydroxyl, amino, C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino or C 1 -C 4 -alkoxy groups and where said cyclic groups may be optionally substituted by one or more hydroxyl, cyano, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkenyloxy, C 1 -C 8 -alkynyloxy, halogen, C 1 -C 8 -alkylcarbonyl, carboxy, C 1 -C 8 -alkoxycarbonyl, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylcarbonylamino, C 1 -C 8 -alkylcarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl or di-C 1 -C 8 -alkylaminosulfonyl groups; 
         R 9  and R 12  independently represent hydrogen, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl, halogen, cyano, nitro, C 1 -C 8 -alkylcarbonyl, carboxy, C 1 -C 8 -alkoxycarbonyl, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl, di-C 1 -C 8 -alkylaminosulfonyl, phenyl, a C-linked 5-6 membered heteroaryl group, a C 4 -C 6  carbocyclic group or a C-linked 5-6 membered heterocyclyl group, where said phenyl or cyclic groups may be optionally substituted by one or more hydroxyl, cyano, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkenyloxy, C 1 -C 8 -alkynyloxy, halogen, C 1 -C 8 -alkylcarbonyl, carboxy, C 1 -C 8 -alkoxycarbonyl, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylcarbonylamino, C 1 -C 8 -alkylcarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl or di-C 1 -C 8 -alkylaminosulfonyl groups; 
         R 10  and R 14  independently represent hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkenyloxy, C 1 -C 4 -alkynyloxy, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylcarbonylamino, C 1 -C 8 -alkylcarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylsulfonylamino, an N-linked 5-6 membered heteroaryl group or an N-linked 5-6 membered heterocyclyl, where said cyclic groups may be optionally substituted by one or more hydroxyl, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkenyl, C 1 -C 8 -alkynyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkenyloxy, C 1 -C 8 -alkynyloxy, halogen, C 1 -C 8 -alkylcarbonyl, carboxy, C 1 -C 8 -alkoxycarbonyl, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylcarbonylamino, C 1 -C 8 -alkylcarbonyl(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl or di-C 1 -C 8 -alkylaminosulfonyl groups; 
         R 11  and R 13  independently represent hydrogen or C 1 -C 6 -alkyl; 
         R 3  is hydrogen; 
         Y represents the group —N(R 15 )R 16 ; and 
         R 15  and R 16  independently represent hydrogen or C 1 -C 4 -alkyl. 
       
     
     
         2 . The method according to  claim 1 , wherein:
 List X represents hydroxyl, cyano, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, halogen, formyl, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, C 1 -C 8 -alkylsulfonyl, aminosulfonyl, C 1 -C 8 -alkylaminosulfonyl or di-C 1 -C 8 -alkylaminosulfonyl.   
     
     
         3 . The method according to  claim 1 , wherein:
 R 1  is C 1 -C 3 -alkyl;   R 2  is phenyl having the substitution pattern,   
       
         
           
           
               
               
           
         
         wherein the R 2  phenyl is fused at R 4 -R 5 , R 5 -R 6 , R 6 -R 7  or R 7 -R 8  by a heteroaryl group selected from pyrazolyl, imidazoyl, oxazolyl, and isoxazolyl, where the fused heteroaryl group is independently optionally substituted by one or more groups selected from List X; 
         List X represents hydroxyl, cyano, nitro, amino, C 1 -C 8 -alkylamino, di-C 1 -C 8 -alkylamino, or C 1 -C 8 -alkylamidino; 
         R 3  is hydrogen; 
         Y is —NH 2 . 
       
     
     
         4 . The method of  claim 1 , wherein the disorder in which pi3 kinase is implicated is a proliferative disease. 
     
     
         5 . The method of  claim 1 , wherein the disorder in which pi3 kinase is implicated is a respiratory disorder. 
     
     
         6 . The method of  claim 5  wherein the respiratory disorder is selected from asthma, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), emphysema, exacerbation of airways hyperreactivity consequent to other drug therapy, bronchitis and pneumoconiosis. 
     
     
         7 . The method of  claim 5  wherein the respiratory disorder is asthma. 
     
     
         8 . The method of  claim 5 , wherein the respiratory condition is COPD. 
     
     
         9 . The method of  claim 3 , wherein the disorder in which pi3 kinase is implicated is a proliferative disease. 
     
     
         10 . The method of  claim 3 , wherein the disorder in which pi3 kinase is implicated is a respiratory disorder. 
     
     
         11 . The method of  claim 10  wherein the respiratory disorder is selected from asthma, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), emphysema, exacerbation of airways hyperreactivity consequent to other drug therapy, bronchitis and pneumoconiosis. 
     
     
         12 . The method of  claim 10  wherein the respiratory disorder is asthma. 
     
     
         13 . The method of  claim 10 , wherein the respiratory condition is COPD.