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 . Use of a compound of formula (I) 
     
       
         
         
             
             
         
       
     
     or a salt, suitably a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is C 1 -C 3 -alkyl, optionally substituted by one to seven fluoro groups; 
 R 2  is a 5-6 membered hetaroaryl group, or R 2  is phenyl having the substitution pattern, 
 
     
       
         
         
             
             
         
       
     
     where the 5-6 membered heteroaryl group is optionally fused by phenyl, a further 5-6 membered heteroaryl group, a C 4 -C 6  carbocyclic group or a 5-6 membered heterocyclyl group and where the R 2  phenyl is optionally 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, a C 4 -C 6  carbocyclic group or a 5-6 membered heterocyclyl group, where the 5-6 membered heteroaryl or fused 5-6 membered heteroaryl, phenyl or the fused phenyl 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)-(C 1 -C 4 -alkylene)-R 9 , (C 0 -C 4 -alkylene)-(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 heterocycly 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, amino or C 1 -C 3 -alkylamino; 
 Y represents hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy 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 8 -alkylamino, di-C 1 -C 8 -alkylamino or C 1 -C 8 -alkoxy groups, or Y represents the group —(C 0 -C 4 -alkylene)-N(R 1s )R 16 ; and 
 R 15  and R 16  independently represent hydrogen or C 1 -C 4 -alkyl, or R 15  is hydrogen and R 16  is C 1 -C 4 -alkyl substituted by phenyl, a 5-6 membered heteroaryl group, a C 4 -C 6  carbocyclic group or a 5-6 membered heterocyclyl group, where said rings are 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, 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, or R 15  and R 16  together with the N to which they are attached form a 5-6-membered heterocyclic ring; 
 in the treatment of a respiratory disorder. 
 
   
   
       2 . Use according to  claim 1  where the disorder is asthma or COPD. 
   
   
       3 . A compound of formula (I) as described in  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, with the proviso that the compounds N-[4-[6-(ethylamino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl urea and [4-(6-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-1,1-dimethyl carbamic acid ester are excluded. 
   
   
       4 . A compound or use of a compound according to any preceding claim, or a pharmaceutically acceptable salt or solvate thereof, where R 1  is methyl. 
   
   
       5 . A compound or use of a compound according to any preceding claim where R 2  is phenyl substituted by one, two, three or four substituents selected from
 (i) hydroxyl,   (ii) cyano,   (iii) nitro,   (iv) C 1 -C 8 -alkyl,   (v) C 1 -C 8 -haloalkyl,   (vi) C 1 -C 8 -alkoxy,   (vii) a 5-6 membered heterocyclyl group,   (viii) —O—(C 1 -C 4 -alkylene)-R 9 ,   (ix) —O—(C 2 -C 4 -alkylene)-R 10 ,   (x) —(C 0 -C 4 -alkylene)-N(R 13 )—(C 2 -C 4 -alkylene)-R 14 ,   (xi) halogen,   (xii) formyl,   (xiii) C 1 -C 8 -alkylcarbonyl,   (xiv) C 1 -C 8 -alkylaminocarbonyl,   (xv) di-C 1 -C 8 -alkylaminocarbonyl,   (xvi) C 1 -C 8 -alkylcarbonylamino,   (xvii) C 1 -C 8 -alkylsulfonylamino,   (xviii) hydroxysulfonyl,   (xix) C 1 -C 8 -alkylsulfonyl,   (xx) C 1 -C 8 -alkylaminosulfonyl,   (xxi) di-C 1 -C 8 -alkylaminosulfonyl,   (xxii) C 1 -C 8 -alkyl substituted by hydroxy,   (xxiii) C 1 -C 8 -alkoxy substituted by one or more halogens, and   (xxiv) amino,   R 9  represents carboxy, cyano or phenyl, optionally substituted by halogen, and   R 10  represents hydroxyl, C 1 -C 4 -alkoxy, an N-linked 5-6 membered heteroaryl group, or an N-linked 5-6 membered heterocyclyl, or a pharmaceutically acceptable salt or solvate thereof.   
   
   
       6 . A compound or use of a compound according to any preceding claim where R 2  is phenyl substituted by R 4 —R 8 ,
 R 4  is selected from hydrogen, C 1 -C 8 -alkoxy, and halogen,   R 5  is selected from hydrogen, hydroxyl, cyano, formyl, C 1 -C 8 -haloalkyl, carboxy, C 1 -C 8 -alkoxy, halogen, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylaminocarbonyl, methylaminocarbonyl, di-C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -thioalkyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, —(C 0 -C 4 -alkylene)-N(R 13 )—(C 2-4 -alkylene)-R 14 , and C 1 -C 8 -alkyl substituted by hydroxy,   R 6  is selected from hydrogen, hydroxyl, cyano, nitro, formyl, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, —O—(C 1 -C 4 -alkylene)-R 9 , —O—(C 2-4 -alkylene)-R 10 , halogen, C 1 -C 8 -alkylcarbonyl, amino, C 1 -C 8 -alkylaminocarbonyl, C 1 -C 8 -alkylsulfonylamino, C 1 -C 8 -alkylsulfonyl, and C 1 -C 8 -alkoxy substituted by one or more halogens,   R 7  is selected from hydrogen, hydroxyl, formyl, C 1 -C 8 -alkoxy, halogen, —O—(C 1 -C 4 -alkylene)-R 9 , C 1 -C 8 -alkylcarbonylamino, and di-C 1 -C 8 -alkylaminosulfonyl,   R 8  is selected from hydrogen, hydroxyl, C 1 -C 8 -alkoxy, —O—(C 2 -C 4 -alkylene)-R 10 , and —O—(C 1 -C 4 -alkylene)-R 9 , suitably —O-methylene-R 9 .   R 9  represents carboxy, cyano or phenyl, optionally substituted by halogen, and   R 10  represents hydroxyl, C 1 -C 4 -alkoxy, an N-linked 5-6 membered heteroaryl group, or an N-linked 5-6 membered heterocycly,   R 13  is hydrogen, and   R 14  is di-C 1 -C 8 -alkylamino, or a pharmaceutically acceptable salt or solvate thereof.   
   
   
       7 . A compound or use of a compound according to any preceding claim, or a pharmaceutically acceptable salt or solvate thereof, where R 3  is amino. 
   
   
       8 . A compound or use of a compound according to any preceding claim, or a pharmaceutically acceptable salt or solvate thereof, where Y is hydrogen. 
   
   
       9 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, according to any preceding claim and a suitable carrier or excipient. 
   
   
       10 . Use of a compound according to any one of  claims 3 - 7 , or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a disorder in which pi3 kinase is implicated.