5-phenyl-4-methyl-thiazol-2-yl-amine derivatives as inhibitors of phosphatidylinositol 3 kinase enzymes (pi3) for the treatment of inflammatory diseases

Abstract

Compounds of Formula I: in free or salt form, wherein R a , R b , R 2 , R 3 , R 4 and R 5 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         in free or salt form, wherein 
         R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by pyridyl, R 3  is R 6 , and R 4  is fluoro or C 1 -C 8 -haloalkyl, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by hydroxy or nitrile, R 3  is R 6 , and R 4  is hydrogen or C 1 -C 8 -haloalkyl, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by nitrile, R 3  is fluoro, and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C a -alkyl, R b  is C 1 -C 8 -alkyl substituted by hydroxy, R 3  is fluoro, and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by di(C 1 -C 8 -alkyl)amino, R 3  is R 6 , and R 4  is C 1 -C 8 -haloalkyl, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by —O—C 1 -C 8 -alkyl-OH, R 3  is R 6 , and R 4  is fluoro or C 1 -C 8 -haloalkyl, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is —CH(CH 3 )—CH 2 —OH, R 3  is R 6 , and R 4  is fluoro, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by pyrrolidinyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is C 1 -C 8 -haloalkyl, 
         or R a  is hydrogen or C 1 -C a -alkyl, R b  is C 1 -C 8 -alkyl substituted by oxazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is nitrile or imidazolyl, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by imidazolyl, R 3  is R 6 , and R 4  is fluoro, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by benzoimidazolyl, R 3  is R 6 , and R 4  is fluoro, 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by isoxazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by pyrrolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by pyrazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by —CO—O—CH 3 , —CO—O-butyl, —CO-di(C 1 -C 8 -alkyl)amino, —NH—CO—C 1 -C 8 -alkyl, —SO 2 —C 1 -C 8 -alkyl, —CO—NH—R c  where R c  is napthyl, or by —CO—NH—C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkyl)-amino, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is —CH(CH 3 )—CO—NH—C 1 -C 8 -alkyl or —CH(CH 3 )—CO—O—C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C a -alkyl, R b  is C 1 -C 8 -alkyl substituted by —CH(OH)—CH 2 —OH, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by C 1 -C 8 -alkoxy, or by —S—C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by a 5- or 6-membered heterocyclic ring having three or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, —C 1 -C 8 -alkyl-di(C 1 -C 8 -alkyl)amino, or by C 3 -C 8 -cycloalkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by oxazolyl substituted by C 3 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is C 1 -C 8 -alkyl substituted by imidazolyl substituted by C 1 -C 8 -alkyl optionally substituted by hydroxy or C 1 -C 8 -alkoxy, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C a -alkyl, R b  is C 1 -C 8 -alkyl substituted by —CO-Het where Het is a 5- or 6-membered heterocyclic ring having two or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 , 
         or R a  is hydrogen or C 1 -C 4 -alkyl, R b  is an aza-bicyclo[3.2.1]oct-3-yl ring optionally substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 , 
         or R a  and R b  together form an azetidine ring substituted by C 1 -C 8 -alkoxycarbonyl or nitrile, R 3  is R 6 , and R 4  is R 7 , 
         or R a  and R b  together form a pyrrolidine ring substituted by —CO—NH 2  or nitrile, R 3  is R 6 , and R 4  is R 7 , 
         or R a  and R b  together form an imidazo-pyridine ring, R 3  is R 6 , and R 4  is R 7 ; 
         R 2  is C 1 -C 4 -alkyl or halogen; 
         R 5  is hydrogen, halogen or C 1 -C 8 -alkyl; 
         R 6  is halo, —SO 2 —CH 3 , —SO 2 —CF 3 , carboxy, —CO—NH 2 , —CO-di(C 1 -C 8 -alkyl)amino, or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by halo, cyano, oxo, hydroxy, carboxy, nitro, C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxy optionally substituted by aminocarbonyl, or C 1 -C 8 -alkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylamino or di(C 1 -C 8 -allyl)amino; 
         R 7  is hydrogen, halo, —SO 2 —CH 3 , nitrile, C 1 -C 8 -haloalkyl, imidazolyl, C 1 -C 8 -alkyl, —NR 8 R 9 , or —SO 2 —NR 8 R 9 ; and 
         R 8  and R 9  are independently hydrogen, amino, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, or C 1 -C 8 -alkyl optionally substituted by hydroxy, 
         or R 8  and R 9  together form a 5- to 10-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by halo, cyano, oxo, hydroxy, carboxy, nitro, C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxy optionally substituted by aminocarbonyl, or C 1 -C 8 -alkyl optionally substituted by hydroxy, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by pyridyl, R 3  is R 6 , and R 4  is fluoro or C 1 -C 8 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by hydroxy or nitrile, R 3  is R 6 , and R 4  is hydrogen or C 1 -C 8 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by nitrile, R 3  is fluoro, and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by hydroxy, R 3  is fluoro, and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by di(C 1 -C 8 -alkyl)amino, R 3  is R 6 , and R 4  is C 1 -C 8 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by —O—C 1 -C 8 -alkyl-OH, R 3  is R 6 , and R 4  is fluoro or C 1 -C 8 -haloalkyl,   or R a  is hydrogen, R b  is —CH(CH 3 )—CH 2 —OH, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by pyrrolidinyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is C 1 -C 8 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by oxazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is nitrile or imidazolyl,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by imidazolyl, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by benzoimidazolyl, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by isoxazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by pyrrolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by pyrazolyl substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by —CO—O—CH 3 , —CO—O-butyl, —CO-di(C 1 -C 8 -alkyl)amino, —CO—NH 2 , —NH—CO—C 1 -C 8 -alkyl, —SO 2 —C 1 -C 8 -alkyl, —CO—NH—R c  where R c  is napthyl, or by —CO—NH—C 1 -C 8 -alkyl optionally substituted by di(C 1 -C 8 -alkylamino, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is —CH(CH 3 )—CO—NH—C 1 -C 8 -alkyl or —CH(CH 3 )—CO—O—C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by —CH(OH)—CH 2 —OH, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by C 1 -C 8 -alkoxy, or by —S—C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by a 5- or 6-membered heterocyclic ring having three or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, —C 1 -C 8 -alkyl-di(C 1 -C 8 -alkyl)amino, or by C 3 -C 8 -cycloalkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by oxazolyl substituted by C 3 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by imidazolyl substituted by C 1 -C 8 -alkyl optionally substituted by hydroxy or C 1 -C 8 -alkoxy, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 8 -alkyl substituted by —CO-Het where Het is a 5- or 6-membered heterocyclic ring having two or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is an aza-bicyclo[3.2.1]oct-3-yl ring optionally substituted by C 1 -C 8 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form an azetidine ring substituted by C 1 -C 8 -alkoxycarbonyl or nitrile, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form a pyrrolidine ring substituted by —CO—NH 2  or nitrile, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form an imidazo-pyridine ring, R 3  is R 6 , and R 4  is R 7 ;   R 2  is C 1 -C 4 -alkyl or halogen;   R 5  is hydrogen;   R 6  is halo or —SO 2 —CH 3 ; and   R 7  is hydrogen, halo, —SO 2 —CH 3 , nitrile, C 1 -C 8 -haloalkyl or imidazolyl.   
     
     
         3 . The compound according to  claim 1 , wherein
 R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by pyridyl, R 3  is R 6 , and R 4  is fluoro or C 1 -C 4 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by hydroxy or nitrile, R 3  is R 6 , and R 4  is hydrogen or C 1 -C 4 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by nitrile, R 3  is fluoro, and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by hydroxy, R 3  is fluoro, and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by di(C 1 -C a -alkyl)amino, R 3  is R 6 , and R 4  is C 1 -C 4 -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by —O—C 1 -C 4 -alkyl-OH, R 3  is R 6 , and R 4  is fluoro or C 1 -C a -haloalkyl,   or R a  is hydrogen, R b  is —CH(CH 3 )—CH 2 —OH, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C a -alkyl substituted by pyrrolidinyl substituted by C 1 -C a -alkyl, R 3  is R 6 , and R 4  is C 1 -C a -haloalkyl,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by oxazolyl substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is nitrile or imidazolyl,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by imidazolyl, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by benzoimidazolyl, R 3  is R 6 , and R 4  is fluoro,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by isoxazolyl substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by pyrrolyl substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by pyrazolyl substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by —CO—O—CH 3 , —CO—O-butyl, —CO-di(C 1 -C 4 -alkyl)amino, —CO—NH 2 , —NH—CO—C 1 -C 4 -alkyl, —SO 2 —C 1 -C 4 -alkyl, —CO—NH—R c  where R c  is napthyl, or by —CO—NH—C 1 -C 4 -alkyl optionally substituted by di(C 1 -C 4 -alkyl)amino, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is —CH(CH 3 )—CO—NH—C 1 -C 4 -alkyl or —CH(CH 3 )—CO—O—C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by —CH(OH)—CH 2 —OH, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by C 1 -C 8 -alkoxy, or by —S—C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by a 5- or 6-membered heterocyclic ring having three or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 8 -alkyl, —C 1 -C 8 -alkyl-di(C 1 -C 4 -alkyl)-amino, or by C 3 -C 5 -cycloalkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C a -alkyl substituted by oxazolyl substituted by C 3 -C 5 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by imidazolyl substituted by C 1 -C 4 -alkyl optionally substituted by hydroxy or C 1 -C 4 -alkoxy, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is C 1 -C 4 -alkyl substituted by —CO-Het where Het is a 5- or 6-membered heterocyclic ring having two or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being optionally substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, that ring being substituted by oxo, R 3  is R 6 , and R 4  is R 7 ,   or R a  is hydrogen, R b  is an aza-bicyclo[3.2.1]oct-3-yl ring optionally substituted by C 1 -C 4 -alkyl, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form an azetidine ring substituted by C 1 -C 4 -alkoxycarbonyl or nitrile, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form a pyrrolidine ring substituted by —CO—NH 2  or nitrile, R 3  is R 6 , and R 4  is R 7 ,   or R a  and R b  together form an imidazo-pyridine ring, R 3  is R 6 , and R 4  is R 7 ;   R 2  is C 1 -C 4 -alkyl or halogen;   R 5  is hydrogen;   R 6  is halo or —SO 2 —CH 3 ; and   R 7  is hydrogen, halo, —SO 2 —CH 3 , nitrile, C 1 -C 4 -haloalkyl or imidazolyl.   
     
     
         4 - 7 . (canceled) 
     
     
         8 . The compound according to  claim 1  in combination with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance. 
     
     
         9 . (canceled) 
     
     
         10 . A pharmaceutical composition, comprising:
 the compound according to  claim 1 , and a pharmaceutically acceptable excipient.   
     
     
         11 . (canceled) 
     
     
         12 . A method to treat respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, Crohn's disease, septic shock, proliferative disorders such as cancer, atherosclerosis, allograft rejection following transplantation, diabetes, stroke, obesity or restenosis in a subject in need thereof, comprising:
 administering to said subject an effective amount of a compound according to  claim 1 , in free form or salt form.   
     
     
         13 . (canceled)