Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors

Abstract

The present invention provides compounds of formula (I) which inhibit the activity of PI 3-kinase gamma isoform, which are useful for the treatment of diseases mediated by the activation of PI 3-kinase gamma isoform.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         E is selected from N and CR E ; 
         R 1 , R 2  and R E  are independently selected from H, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl and C 3-7  cycloalkyl; 
         R 3  is selected from 
         (i) C 1-4  alkyl which is unsubstituted or substituted with 1 or more substituents, particularly 1 to 3 substituents, independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkyl, oxo, CN, —(C 0-3  alkyl)-NR 3a R 3b , C 3-7  cycloalkyl and C 3-7  heterocyclyl, and wherein the C 3-7  cycloalkyl or C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (ii) C 1-4  alkoxy which is unsubstituted or substituted with 1 or more substituents, particularly 1 to 3 substituents, independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkyl, oxo, CN, —(C 0-3  alkyl)-NR 3a R 3b , C 3-7  cycloalkyl and C 3-7  heterocyclyl, and wherein the C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (iii) C 3-7  cycloalkyl or —O—C 3-7  cycloalkyl wherein the C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (iv) a —(C 0-3  alkyl)-C 3-7  cycloalkyl or —O—(C 0-3  alkyl)-C 3-7  cycloalkyl wherein the C 3-7  cycloalkyl is spiro fused to a second C 3-7  cycloalkyl or C 3-7  heterocyclyl by one single carbon atom, and wherein the C 3-7  cycloalkyl or C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (v) a —(C 0-3  alkyl)-C 3-7  heterocyclyl or —O—(C 0-3  alkyl)-C 3-7  heterocyclyl, and wherein said C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (vi) a —(C 0-3  alkyl)-C 3-7  heterocyclyl or —(O—C 0-3  alkyl)-C 3-7  heterocyclyl, and wherein said C 3-7  heterocyclyl is spiro fused to a second C 3-7  heterocyclyl or a C 3-7  cycloalkyl by one single carbon atom, and wherein the C 3-7  heterocyclyl or C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (vii) H; 
         R 4  is selected from H and C 1-4  alkyl; or 
         R 3  and R 4  together with the nitrogen atom to which they are attached form a C 3-7  heterocyclyl, which C 3-7  heterocyclyl is optionally spiro fused to a second C 3-7  heterocyclyl or a C 3-7  cycloalkyl by one single carbon atom, and which C 3-7  heterocyclyl and C 3-7  cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         R 3a  and R 3b  are independently selected from H, C 1-4  alkyl and C 1-4  haloalkyl; 
         Y is a 5-6-membered heteroaryl, which heteroaryl is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, halogen, C 1-4  hydroxyalkyl, —(C 0-3  alkyl)-NR′R″, —(C 0-3  alkyl)-C 3-7  cycloalkyl and —(C 0-3  alkyl)-C 3-7  heterocyclyl, —(C═O)—C 3-7  heterocyclyl, —(C═O)—NR′R″, —(C 0-3  alkyl)-phenyl and —(C 0-3  alkyl)-5-6-membered heteroaryl; 
         R′ and R″ are independently selected from H and C 1-4  alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1  of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is independently selected from H, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl and C 3-7  cycloalkyl; 
         R 2  is selected from H, halogen, CF 3  and methyl; 
         R 3  is selected from 
         (i) C 1-4  alkyl which is unsubstituted or substituted with 1 or more substituents, particularly 1 to 3 substituents, independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkyl, oxo, CN, —(C 0-3  alkyl)-NR 3a R 3b , C 3-7  cycloalkyl and C 3-7  heterocyclyl, and wherein the C 3-7  cycloalkyl or C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (ii) C 1-4  alkoxy which is unsubstituted or substituted with 1 or more substituents, particularly 1 to 3 substituents, independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  haloalkyl, C 1-4  alkoxy, C 1-4  alkyl, oxo, CN, —(C 0-3  alkyl)-NR 3a R 3b , C 3-7  cycloalkyl and C 3-7  heterocyclyl, and wherein the C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (iii) —C 3-7  cycloalkyl or —O—C 3-7  cycloalkyl wherein the C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (iv) a —(C 0-3  alkyl)-C 3-7  cycloalkyl or —O—(C 0-3  alkyl)-C 3-7  cycloalkyl wherein the C 3-7  cycloalkyl is spiro fused to a second C 3-7  cycloalkyl or C 3-7  heterocyclyl by one single carbon atom, and wherein the C 3-7  cycloalkyl or C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (v) a —(C 0-3  alkyl)-C 3-7  heterocyclyl or —O—(C 0-3  alkyl)-C 3-7  heterocyclyl, and wherein said C 3-7  heterocyclyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (vi) a —(C 0-3  alkyl)-C 3-7  heterocyclyl or —(O—C 0-3  alkyl)-C 3-7  heterocyclyl, and wherein said C 3-7  heterocyclyl is spiro fused to a second C 3-7  heterocyclyl or a C 3-7  cycloalkyl by one single carbon atom, and wherein the C 3-7  heterocyclyl or C 3-7  cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         (vii) H; 
         R 4  is selected from H and C 1-4  alkyl; or 
         R 3  and R 4  together with the nitrogen atom to which they are attached form a C 3-7  heterocyclyl, which C 3-7  heterocyclyl is optionally spiro fused to a second C 3-7  heterocyclyl or a C 3-7  cycloalkyl by one single carbon atom, and which C 3-7  heterocyclyl and C 3-7  cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from hydroxy, C 1-4  hydroxyalkyl, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, oxo and —(C 0-3  alkyl)-NR 3a R 3b ; 
         R 3a  and R 3b  are independently selected from H, C 1-4  alkyl and C 1-4  haloalkyl; 
         Y is selected from the group consisting of
 thiazolyl, 
 thiadiazolyl, 
 isothiazolyl, 
 pyrazolyl, 
 pyridyl, 
 pyrimidinyl, 
 triazolyl, 
 imidazolyl, 
 oxadiazolyl, 
 isoxazolyl, 
 oxazolyl, 
 pyrrolyl, 
 thienyl, and 
 furanyl; 
 
         each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 1-4 alkoxyC 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4  alkoxy, C 1-4  haloalkoxy, halogen, C 1-4  hydroxyalkyl, —(C 0-3  alkyl)-NR′R″, —(C 0-3  alkyl)-C 3-7  cycloalkyl and —(C 0-3  alkyl)-C 3-7  heterocyclyl, —(C═O)—C 3-7  heterocyclyl, —(C═O)—NR′R″, —(C 0-3  alkyl)-phenyl and —(C 0-3  alkyl)-5-6-membered heteroaryl; 
         R′ and R″ are independently selected from H and C 1-4  alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound according to  claim 1 , wherein
 Y is selected from the group consisting of
 oxazol-2-yl, 
 oxazol-5-yl, 
 oxazol-4-yl, 
 thiazol-5-yl, 
 thiazol-4-yl, 
 1,3,4-thiadiazol-2-yl, 
 isothiazol-5-yl, 
 pyrazol-4-yl, 
 pyrazol-3-yl, 
 pyrazol-1-yl, 
 pyrid-4-yl, 
 pyrid-3-yl, 
 pyrid-2-yl, 
 1,2,4-triazol-1-yl, 
 1,2,3-triazol-4-yl, 
 imidazol-1-yl, 
 1,2,4-oxadiazol-5-yl, 
 1,3,4-oxadiazol-2-yl, 
 1,2,4-oxadiazol-3-yl, 
 isoxazol-5-yl, 
 isoxazol-3-yl, 
 isoxazol-4-yl, 
 pyrrol-3-yl, 
 thien-2-yl, 
 thien-3-yl, and 
 furan-3-yl, 
   each of which is unsubstituted or substituted with 1 to 3 substituents independently selected from C 1-4  alkyl, C 1-4  haloalkyl, C 1-4 hydroxyalkyl, —(C 0-3  alkyl)-C 3-7  cycloalkyl, —(C═O)—C 3-7  heterocyclyl, —(C 0-3  alkyl)-NR′R″, —(C═O)—N′R″, —(C 0-3  alkyl)-phenyl and —(C 0-3  alkyl)-pyridyl;   R′ and R″ are independently selected from H and C 1-4  alkyl;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein
 Y is selected from the group consisting of   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound according to  claim 1 , wherein
 R 3  is selected from   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or R 3  and R 4  together with the nitrogen atom to which they are attached form a ring selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound according to  claim 1  of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         E is selected from N and CR E ; 
         R 1 , R 2  and R E  are independently selected from H, halogen, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  haloalkyl, C 1-4  haloalkoxy, C 1-4  hydroxyalkyl and C 3-7  cycloalkyl; 
         Y is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 4  is H and R 3  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or R 3  and R 4  together with the nitrogen atom to which they are attached form a C 3-7  heterocyclyl selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 1  selected from Examples 1 to 143; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . A pharmaceutical composition, comprising:
 a therapeutically effective amount of the compound or salt according to  claim 1  and one or more pharmaceutically acceptable carriers.   
     
     
         9 . A pharmaceutical combination, comprising:
 a therapeutically effective amount of the compound or salt according to  claim 1  and a second active agent.   
     
     
         10 . A method of a disorder or disease mediated by the activation of PI 3-kinase gamma isoform, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt according to  claim 1 . 
     
     
         11 . A method of treating 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 and restenosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt according to  claim 1 .