Aminopyrimidines as SYK Inhibitors

Abstract

The present invention provides novel pyrimidine amines of formula (I) which are potent inhibitors of spleen tyrosine kinase, and are useful in the treatment and prevention of diseases mediated by said enzyme, such as asthma, COPD and rheumatoid arthritis.

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of
 (a) hydrogen, 
 (b) halogen, 
 (c) CN, 
 (d) C 1-6  alkyl optionally substituted with one or more groups independently selected from the group consisting of OR a , C 3-6 cycloalkyl, and halogen, 
 (e) C 2-6  alkenyl optionally substituted with OC 1-6 alkyl, 
 (f) C 2-6  alkynyl, 
 (g) C 3-6  cycloalkyl, 
 (h) OH, 
 (i) —O—C 1-6  alkyl optionally substituted with one or more groups independently selected from
 (i) aryl, 
 (ii) 5- or 6-membered heteroaryl optionally substituted with one or more groups independently selected from C 1-6  alkyl, 
 (iii) 4- to 8-membered heterocyclyl optionally substituted with one or more groups independently selected from oxo, halogen, C 1-6  alkyl, 
 (iv) —CO 2 R a , 
 (v) —CONR b R c , 
 (vi) —NR b R c , and 
 (vii) —OR a , 
 
 (j) -A-X, wherein A is a bond or O, X is selected from the group consisting of
 (i) 4- to 8-membered heterocyclyl optionally substituted with one or more groups independently selected from halogen, C 1-6  alkyl, —C 1-6  haloalkyl, —C 1-6  hydroxyalkyl, COR a , CO 2 R a , 
 (ii) C 3-6  cycloalkyl optionally substituted with one or more groups independently selected from C 1-6  alkyl, —OR a , —CO 2 R a , —NR b R c , 
 (iii) heteroaryl optionally substituted with a benzyl which is optionally substituted with OR a , 
 
 (k) O—CH 2 C≡C-pyrimidinyl, 
 (l) —S(O) n —C 1-6  alkyl, 
 (m) —COR a , 
 (n) —CO 2 R a , 
 (o) —CONR b R c , 
 (p) —NR b R c , 
 
 R 2  is selected from the group consisting of
 (a) H, 
 (b) halogen, 
 (c) C 1-6  alkyl, 
 (d) O—C 1-6  alkyl, 
 (e) C 1-6  haloalkyl and 
 (f) O—C 1-6  haloalkyl; or 
 
 R 1  and R 2  on adjacent carbon atoms together represent (CH 2 ) 3-4 ; 
 R 3  is H, halogen, OR a , or C 1-4 alkyl, 
 R 4  is selected from the group consisting of
 (a) H, 
 (b) halogen, 
 (c) C 1-6  alkyl optionally substituted with one or more groups independently selected from
 (i) halogen, 
 (ii) OR a , 
 (iii) OC(O)R a , 
 (iv) NR b R c , 
 (v) NHC(O)R a , and 
 (vi) NHC(O)NHR b , 
 
 (d) C 2-6  alkenyl, 
 (e) C 2-6  alkynyl, 
 (f) C 3-6  cycloalkyl 
 (g) OR a , 
 (h) NO 2 , 
 (i) NR b R c , 
 (j) NHC(O)R a , 
 (k) NHC(O)NHR b , 
 (l) NHC(O)NHC(O)NR b R c , 
 
 R 5  is selected from the group consisting of
 (a) H, 
 (b) halogen, 
 (c) C 1-8 alkyl, C 2-6 alkenyl, C 2-6  alkynyl, each of which is optionally substituted with one or more groups independently selected from R y , 
 (d) C 3-12  carbocycle, or a carbon-linked 3- to 12-membered heterocyclyl each optionally substituted with one or more groups independently selected from R z , 
 (e) heteroaryl optionally substituted with C 1-3  alkyl (optionally substituted with one or more OH or CN or heterocycle); 
 (f) —C(O)R a , 
 (g) —C(O) 2 R a , and 
 (h) —C(O)NR b R c , 
 
 R 5(i)  is selected from the group consisting of H and C 1-3 alkyl; 
 R a  is selected from the group consisting of
 (a) H, 
 (b) C 1-6  alkyl optionally substituted with one or more groups independently selected from
 (i) halogen, 
 (ii) CN, 
 (iii) OH, 
 (iv) OC 1-4 alkyl, 
 (v) heterocyclyl optionally substituted with oxo, 
 (vi) C(O)C 1-6 alkyl optionally substituted with OH, 
 (vii) CO 2 H, 
 (viii) CO 2 C 1-6 alkyl, 
 (ix) CONR b(i) R c(i) , 
 (x) SO 2 C 1-6 alkyl, 
 (xi) —NR b(i) R c(i) , 
 (xii) NR b(i) C(O)NR b(i) R c (i); 
 (xiii) phenyl, and 
 (xiv) heteroaryl optionally substituted with OH, 
 
 (c) C 2-6 alkenyl, 
 (d) C 3-6  cycloalkyl optionally substituted with one or more groups independently selected from
 (i) OH, 
 (ii) CO 2 H, 
 (iii) CO 2 C 1-6 alkyl, 
 (iv) CONR b(i) R c (i) 
 
 (e) phenyl optionally substituted with one or more groups independently selected from
 (i) C 2-6 alkynyl, 
 (ii) CN, 
 (iii) halogen, 
 (iv) OH, 
 (vi) OC(O)C 1-6 alkyl, 
 (vii) CO 2 H, 
 (viii) CO 2 C 1-6 alkyl, 
 
 (f) heteroaryl optionally substituted with one or more groups independently selected from C 1-6 alkyl, C 1-6 haloalkyl, (CH 2 ) 0-2 CO 2 H, OH, halogen, phenyl optionally substituted with CO 2 H, and 
 (g) heterocyclyl optionally substituted with oxo, 
 
 R b  and R c  are independently selected from the group consisting of
 (a) H, 
 (b) C 1-6  alkyl optionally substituted with one or more groups independently selected from
 (i) OR a , 
 (ii) halogen, 
 (iii) heterocyclyl optionally substituted with oxo, OH, C 1-6  alkyl (optionally substituted with OH), 
 (iv) C 3-6  cycloalkyl optionally substituted with one or two groups selected from C 1-4 alkyl, CH 2 OH, CONR b(i) R c(i) , and CO 2 R a , 
 (v) heteroaryl optionally substituted with C 1-6 alkyl optionally substituted with OH, CO2H or heteroaryl optionally substituted with a heteroaryl, 
 (vi) SO 2 NR b(i) R c(i) , 
 (vii) SO 2 C 1-4 alkyl, 
 (viii) CONR b(i) R c(i) , 
 (ix) NR b(i) R c(i) , 
 (x) CO 2 R a , 
 (xi) aryl optionally substituted with one or more groups selected from halogen, OR a , C 1-6 alkyl (optionally substituted with halogen, heterocycle (optionally substituted with oxo), or OR a ), SO 2 NH 2 , and heteroaryl optionally substituted with CH 2 OH 
 (xii) SO 3 H, 
 (xiii) NR b (i)CONR b(i) R c(i) , 
 (xiv) CN, and 
 (xv) NHC(O)R a , 
 
 (c) C 3-6  alkenyl optionally substituted with F; 
 (d) C 3-6  cycloalkyl (optionally fused to a benzene ring) optionally substituted with one or more groups independently selected from
 (i) C 1-4 alkyl, 
 (ii) OR a , 
 (iii) CH 2 OH, 
 (iv) CO 2 R a , and 
 (v) CONR b(i) R c(i) , 
 
 (e) aryl optionally substituted with one or two groups independently selected from
 (i) C 1-6 alkyl (optionally substituted with OR a ), 
 (ii) CN, 
 (iii) OR a , 
 (iv) halogen, and 
 (v) OCOC 1-4 alkyl; 
 
 (f) heteroaryl optionally substituted with one or more groups independently selected from
 (i) OR a , 
 (ii) CO 2 R a  and 
 (iii) C 1-6  alkyl optionally substituted with OH, 
 
 (g) heterocyclyl optionally substituted with one or more groups indepdently selected from
 (i) oxo, 
 (ii) OH and 
 (iii)C 1-6  alkyl, or 
 
 
 R b , R c  and the nitrogen atom to which they are attached together form a 5-, 6- or 7-membered heterocycle having 0 or 1 additional heteroatom selected from O, P(O)(C 1-6 alkyl), S(O) n  and N—R x , and optionally substituted with one or more groups independently selected from
 (a) oxo, 
 (b) thioxo, 
 (c) C 1-6  alkyl optionally substituted with one or more groups independently selected from
 (i) OR a , 
 (ii) CO 2 R a , 
 (iii) OP(O)(C 1-6 alkyl) 2 , 
 (iv) aryl, and 
 (v) halogen, 
 
 (d) OR a , 
 (e) C(O)R a , 
 (f) C(O) 2 R a , 
 (g) CONR b(i) R c(i) , 
 (h) P(O)(OH) 2 , 
 (i) SO 2 R a , and 
 (j) CN, or 
 
 R b , R c  and the nitrogen atom to which they are attached together form 
 
       
         
           
           
               
               
           
         
          wherein W is CH or N; H 
       
       
         
           
           
               
               
           
         
         R b (i) and R c(i)  are independently selected from the group consisting of
 (a) H and 
 (b) C 1-6  alkyl optionallly substituted with OH, CO 2 H or CO 2 C 1-6 alkyl; or 
 
         R b (i), R c(i)  and the nitrogen atom to which they are attached together form a 5- or 6-membered heterocycle having 0 or 1 additional heteroatom selected from O, S and N—R x , and optionally substituted with one or more groups independently selected from oxo, 
         R u  is selected from the group consisting of
 (a) C 1-6  alkyl optionally substituted with one to three groups selected from halogen, OH, SO 2 R a , CONR b R c , NR b R c , phenyl, heterocyclyl and heteroaryl, 
 (b) C 3-8  cycloalkyl optionally substituted with OH, CO 2 R a , —CONH 2 , 
 (c) heterocycle optionally substituted with oxo, 
 (d) aryl optionally substituted with C 2-6 alkynyl, CN, halogen, OR a , 
 (e) heteroaryl optionally substituted with OH, 
 
         R x  is selected from the group consisting of
 (a) H, 
 (b) C 1-6  alkyl optionally substituted with heterocycle, 
 (c) phenyl optionally substituted with OH or OC 1-4 alkyl, 
 (d) —C(O)—C 1-6  alkyl, 
 (e) —C(O) 2 —C 1-6  alkyl, 
 (f) —C(O)NH 2 , —C(O)NH—C 1-6  alkyl, —C(O)N(C 1-6  alkyl) 2 , 
 (g) —C(O) 2 NHC(O)NH 2 , —C(O) 2 NHC(O)NH—C 1-6  alkyl, —C(O) 2 NHC(O)N(C 1-6  alkyl) 2 , 
 (h) —SO 2 —C 1-6  alkyl (optionally substituted with halogen), —SO 2 -heteroaryl (optionally substituted with alkyl), 
 (i) —S(O) 2 NH 2 , —S(O) 2 NH—C 1-6  alkyl, —S(O) 2 N(C 1-6  alkyl) 2 , 
 (j) —SO 2 NHC(O) 2 —C 1-6  alkyl, 
 
         R y  is selected from the group consisting of
 (a) aryl optionally substituted with one or more groups independently selected from
 (i) halogen, 
 (ii) C 1-6 alkyl optionally substituted with OH or CO 2 R a , 
 (iii) C 2-6 alkenyl optionally substituted with CO 2 R a , 
 (iv) phenyl optionally substituted with CO 2 R a , 
 (v) COR a , 
 (vi) CO 2 R a , 
 (vii) CONR b R c , 
 (viii) OR a , 
 (ix) S(O) n R a , 
 (x) SO 2 NR b R c , 
 (xi) SO 2 NHC(O)R a , 
 (xii) NO 2 , and 
 (xiii) NHC(O)R a , 
 
 (b) heteroaryl optionally substituted with one or more groups independently selected from
 (i) halogen, 
 (ii) C 1-6  alkyl optionally substituted with CO 2 R a , 
 (iii) C 3-6  cycloalkyl, 
 (iv) aryl optionally substituted with CO 2 R a , 
 (v) CONR b R c , 
 (vi) OR a , 
 (vii) SO 2 R a , and 
 (viii) CO 2 R a , 
 
 (c) C 3-8  cycloalkyl optionally substituted with one or more groups independently selected from
 (i) C 1-6  alkyl, 
 (ii) CO 2 R a , and 
 (iii) NR b R c , 
 
 (d) C 6-8 cycloalkenyl (optionally substituted with CO 2 R a ), 
 (e) halogen, 
 (f) CN, 
 (g) —C(O)R a , 
 (h) —C(O) 2 R a , 
 (i) C(O)CO 2 R a , 
 (j) —C(O)NR b R c , 
 (k) —C(O)NHC(O)NR b R c , 
 (l) —OR a , 
 (m) —OC(O)R a , 
 (n) —NR b R c , 
 (o) —NHC(O)R u , 
 (p) —NHC(O)NR b R c , 
 (q) —NHC(O)NHC(O)NH 2 , 
 (r) —NHSO m R a    
 (s) —NHSO 2 NR b R c , 
 (t) SO n R a , 
 (u) —SO 2 NR b R c , 
 (v) —SO 2 NHC(O)R a , 
 (w) —SO 2 NHC(O) 2 R a , 
 (x) SO 3 H, 
 (y) —P(O)(ORa) 2 , and 
 (z) CONHOH; 
 (aa) heterocyclyl optionally substituted with one or more groups independently selected from oxo, thioxo, C 1-6 alkyl, and CO 2 R a ; 
 
         R z  is selected from the group consisting of
 (a) a group selected from R y , 
 (b) C 1-6  alkyl optionally substituted with one or more groups independently selected from halogen, NR b R c , OR a , CN, phenyl (optionally substituted with C 1-6 alkanoic acid), CONR b R c , and —CO 2 R a , 
 (c) oxo, and 
 (d) ═NOR a , 
 
         m is 1 or 2, 
         n is 0, 1 or 2. 
       
     
     
         2 - 29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         31 . A method for the treatment or prevention of a SYK-mediated disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         32 - 35 . (canceled)