Novel pyrimidine and pyridine compounds and usage thereof

Abstract

The present invention relates to novel pyrimidine and pyridine compounds of formula (I) or a pharmaceutical acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and G are as defined in the description, to pharmaceutical compositions containing them, a process for preparing them, and their use in therapy of a disease responsive to inhibition of FGFR, for example, cancer.

What is claimed is: 
     
         1 . A compound of formula (I); 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein
 X is CH 2 , Y is selected from CH 2 , O or S(O) 2 ; or X and Y together with the bond there-between form —CH═CH— or —C≡C—; 
 G is N or CH; 
 R 1  is aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halo, —NR 6 R 7 , —OR 8 , —S(O) n R 9 , —(CH 2 ) r —C(O)R 10 , —CN, —C(O)NR 6 R 7 , —NR 6 C(O)R 10 , —NR 6 S(O) n R 9 , —NR 6 S(O) n NR 11 R 12 , —NR 6 C(O)OR 8 , —NR 6 C(O)NR 11 R 12 , —NO 2 , —S(O) n NR 6 R 7 , oxo, optionally substituted alkyl, —(CH 2 ) p -optionally substituted cycloalkyl, —(CH 2 ) m -optionally substituted heterocyclyl, —(CH 2 ) q -optionally substituted heteroaryl, optionally substituted alkenyl, and optionally substituted alkynyl; 
 R 2  is independently chosen from optionally substituted C 1 -C 6  alkyl, optionally substituted C 1 -C 6  alkoxy, or optionally substituted C 3 -C 8  cycloalkyl; 
 R 3 , R 4  are independently chosen from hydrogen, halogen, —CN, or optionally substituted C 1 -C 6  alkyl, 
 R 5  is C 1 -C 6  alkyl, 
 or R 3  and R 5  together with the O atom to which R 5  is attached and the bond there-between form a 5- or 6-membered oxy-containing heterocyclic ring; 
 n is 1 or 2; 
 m, p, q and r are independently chosen from 0, 1, 2, 3, 4, 5, 6; 
 R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, each of which except for hydrogen, is optionally substituted with one or more substituents independently selected from halo, hydroxyl, mercapto, oxo, alkyl, cycloalkyl, heterocyclyl, optionally substituted amino, and optionally substituted amide, 
 wherein each optionally substituted group above for which the substituent(s) is (are) not specifically designated, can be unsubstituted or independently substituted with one or more, such as one, two or three, substituents independently chosen from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-C 1 -C 6  alkyl-, heteroaryl-C 1 -C 6  alkyl-, C 1 -C 6  haloalkyl-, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 1 -C 6  alkylphenyl, —C 1 -C 6  alkyl-OH, —C 1 -C 6  alkyl-SH, —C 1 -C 6  alkyl-O—C 1 -C 6  alkyl, —OC 1 -C 6  haloalkyl, halo, —OH, mercapto, —NH 2 , —C 1 -C 6  alkyl-NH 2 , —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)(C 1 -C 6  alkylphenyl), —NH(C 1 -C 6  alkylphenyl), cyano, nitro, oxo, —C(O)—OH, —C(O)OC 1 -C 6  alkyl, —CON(C 1 -C 6  alkyl) 2 , —CONH(C 1 -C 6  alkyl), —CONH 2 , —NHC(O)(C 1 -C 6  alkyl), —NHC(O)(phenyl), —N(C 1 -C 6  alkyl)C(O)(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl)C(O)(phenyl), —C(O)C 1 -C 6  alkyl, —C(O)C 1 -C 6  alkylphenyl, —C(O)C 1 -C 6  haloalkyl, —OC(O)C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  alkyl, —S(O)—C 1 -C 6  alkyl, —S(O) 2 -phenyl, —S(O) 2 —C 1 -C 6  haloalkyl, —S(O) 2 NH 2 , —S(O) 2 NH(C 1 -C 6  alkyl), —S(O) 2 NH(phenyl), —NHS(O) 2 (C 1 -C 6  alkyl), —NHS(O) 2 (phenyl), and —NHS(O) 2 (C 1 -C 6  haloalkyl). 
 
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein each optionally substituted group for which the substituent(s) is(are) not specifically designated can be unsubstituted or independently substituted with one or more substituents independently chosen from hydroxyl, mercapto, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —OC 1 -C 6 alkyl, —NH 2 , —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6 alkyl), cyano, nitro, oxo, —S(O) 2 —C 1 -C 6  alkyl, —S(O)—C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  haloalkyl, —C(O)—OH, —C 1 -C 6  alkyl-OH, —C 1 -C 6  alkyl-SH, heterocyclyl, or a pharmaceutical acceptable salt thereof. 
     
     
         3 . The compound of formula (I) according to  claim 1  or  2 , wherein R 1  is aryl or heteroaryl, each of which is optionally substituted by one or more substituents independently selected from:
 (1) halo; 
 (2) oxo; 
 (3) optionally substituted alkyl; 
 (4) —(CH 2 ) m -optionally substituted heterocyclyl; 
 (5) —(CH 2 ) p -optionally substituted cycloalkyl; 
 (6) —(CH 2 ) q -optionally substituted heteroaryl; 
 (7) —S(O) n R 9 ; 
 (8) —(CH 2 ) r —C(O)R 10 ; 
 (9) optionally substituted alkenyl; 
 (10) optionally substituted alkynyl; 
 (11) —OR 8 ; 
 wherein n is 1 or 2; m, p, q and r are independently chosen from 0, 1, 2, 3, 4, 5, 6; R 8 , R 9  and R 10  are independently selected from hydrogen, alkyl, heterocyclyl, each of which except for hydrogen, is optionally substituted with one or more substituents independently selected from alkyl, oxo, heterocyclyl; 
 wherein “optionally substituted alkyl”, “optionally substituted heterocyclyl”, “optionally substituted cycloalkyl”, “optionally substituted heteroaryl”, “optionally substituted alkenyl” and “optionally substituted alkynyl” in R 1  above can be unsubstituted or independently substituted with one or more substituents independently chosen from hydroxyl, mercapto, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —OC 1 -C 6  alkyl, —NH 2 , —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6  alkyl), cyano, nitro, oxo, —S(O) 2 —C 1 -C 6  alkyl, —S(O)—C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  haloalkyl, —C(O)—OH, —C 1 -C 6  alkyl-OH, —C 1 -C 6  alkyl-SH, heterocyclyl, 
 or a pharmaceutical acceptable salt thereof. 
 
     
     
         4 . The compound of formula (I) according to  claim 3 , wherein R 1  is aryl or heteroaryl, each of which is optionally substituted with one or more substituents independently selected from:
 (1) halo;   (2) oxo;   (3) alkyl optionally substituted with one or more substitutents independently selected from hydroxyl, mercapto, halo, —OC 1 -C 6  alkyl, —NH 2 , —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6  alkyl), cyano, nitro, —S(O) 2 —C 1 -C 6  alkyl, —S(O)—C 1 -C 6  alkyl, —C(O)—OH;   (4) —(CH 2 ) m -heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl, —C 1 -C 6  alkyl-OH, —C 1 -C 6  alkyl-SH and oxo, wherein m is 0, 1, 2, 3, 4, 5 or 6;   (5) —(CH 2 ) p -unsubstituted cycloalkyl, wherein p is 0, 1, 2, 3, 4, 5 or 6;   (6) —(CH 2 ) q -heteroaryl optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, wherein q is 0, 1, 2, 3, 4, 5 or 6;   (7) —S(O) n R 9 , wherein R 9  is C 1 -C 6  alkyl, and n is 1 or 2;   (8) —(CH 2 ) r —C(O)R 10 , wherein R 10  is heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl and oxo, wherein r is 0, 1, 2, 3, 4, 5 or 6;   (9) unsubstituted C 2 -C 6  alkenyl;   (10) unsubstituted C 2 -C 6  alkynyl;   (11) —OR 8 , wherein R 8  is selected from hydrogen, alkyl optionally substituted with one or more substituents independently selected from heterocyclyl,   or a pharmaceutical acceptable salt thereof.   
     
     
         5 . The compound of formula (I) according to  claim 4 , wherein R 1  is a radical of the ring or ring system chosen from 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted as defined in  claim 4 , 
       or a pharmaceutical acceptable salt thereof. 
     
     
         6 . The compound of formula (I) according to  claim 4 , wherein R 1  is chosen from 
       
         
           
           
               
               
           
         
       
       each of which is optionally substituted as defined in  claim 4 , 
       or a pharmaceutical acceptable salt thereof. 
     
     
         7 . The compound of formula (I) according to  claim 1 , wherein R 8  is hydrogen, or C 1 -C 6  alkyl optionally substituted with heterocyclyl, or a pharmaceutical acceptable salt thereof. 
     
     
         8 . The compound of formula (I) according to  claim 1 , wherein R 10  is heterocyclyl optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl and oxo, or a pharmaceutical acceptable salt thereof. 
     
     
         9 . The compound of formula (I) according to  claim 1 , wherein R 1  is aryl optionally substituted by one or more substitutents independently selected from: (1) halo; (2) alkyl optionally substituted with —C(O)—OH; (3) —(CH 2 ) m -heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl, —C 1 -C 6  alkyl-OH, —C 1 -C 6  alkyl-SH and oxo, wherein m is 0, 1, 2, 3, 4, 5 or 6; (4) —(CH 2 ) q -heteroaryl optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, wherein q is 0; (5) —(CH 2 ) r —C(O)R 10 , wherein R 10  is heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl and oxo, wherein r is 0; (6) unsubstituted C 2 -C 6  alkenyl; (7) unsubstituted C 2 -C 6  alkynyl; (8) —OR 8 , wherein R 8  is selected from hydrogen, alkyl optionally substituted with one or more substituents independently selected from heterocyclyl,
 or a pharmaceutical acceptable salt thereof. 
 
     
     
         10 . The compound of formula (I) according to  claim 9 , wherein R 1  is phenyl substituted by piperazinyl, which piperizinyl is optionally substituted by one or more C 1 -C 6  alkyl, preferably, R 1  is phenyl substituted by piperazinyl, which is optionally substituted by one or more methyl or ethyl, or a pharmaceutical acceptable salt thereof. 
     
     
         11 . The compound of formula (I) according to  claim 1 , wherein R 1  is pyrazolyl, which is optionally substituted with one or more substituents selected from:
 (1) alkyl optionally substituted with one or more substitutents independently selected from hydroxyl, mercapto, halo, —OC 1 -C 6  alkyl, —NH 2 , —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6  alkyl), —S(O) 2 —C 1 -C 6  alkyl, —S(O)—C 1 -C 6  alkyl;   (2) —(CH 2 ) m -heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl, wherein m is 0, 1, 2, 3, 4, 5 or 6;   (3) —(CH 2 ) p -unsubstituted cycloalkyl, wherein p is 0, 1, 2, 3, 4, 5 or 6;   (4) —(CH 2 ) q -heteroaryl optionally substituted with one or more substituents independently selected from C 1 -C 6  alkyl, wherein q is 0, 1, 2, 3, 4, 5 or 6;   (5) —S(O) n R 9 , wherein R 9  is C 1 -C 6  alkyl, and n is 1 or 2;   (6) —(CH 2 ) r —C(O)R 10 , wherein R 10  is heterocyclyl optionally substituted with one or more substitutents independently selected from C 1 -C 6  alkyl and oxo, wherein r is 0, 1, 2, 3, 4, 5 or 6,   or a pharmaceutical acceptable salt thereof.   
     
     
         12 . The compound of formula (I) according to any one of  claims 1 - 11 , wherein R 2  is chosen from C 1 -C 6  alkyl, C 1 -C 6  alkoxy optionally substituted with hydroxyl, or C 3 -C 8  cycloalkyl, or a pharmaceutical acceptable salt thereof. 
     
     
         13 . The compound of formula (I) according to  claim 12 , wherein R 2  is methyl, ethyl, methoxy, ethoxy substituted with hydroxyl, isopropoxy or cyclopropyl, or a pharmaceutical acceptable salt thereof. 
     
     
         14 . The compound of formula (I) according to any one of  claims 1 - 11 , wherein R 3 , R 4  are independently chosen from hydrogen, halogen, —CN, or unsubstituted C 1 -C 6  alkyl, R 5  is C 1 -C 6  alkyl, or R 3  and R 5  together with the O atom to which R 5  is attached and the bond there-between form a 5- or 6-membered oxy-containing heterocyclic ring, or a pharmaceutical acceptable salt thereof. 
     
     
         15 . The compound of formula (I) according to any one of  claims 1 - 11 , wherein R 4  is hydrogen, and R 3  and R 5  together with the O atom to which R 5  is attached and the bond there-between form furan or dihydrofuran ring, or a pharmaceutical acceptable salt thereof. 
     
     
         16 . The compound of formula (I) according to  claim 1 , wherein said compound is selected from Compounds 1-223 prepared in the Examples, or a pharmaceutical acceptable salt thereof. 
     
     
         17 . The compound of formula (I) according to any one of  claims 1 - 16  and/or a pharmaceutical acceptable salt thereof as a medicament. 
     
     
         18 . A pharmaceutical composition comprising at least one compound of formula (I) according to any one of  claims 1 - 16  and/or at least one pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable carrier. 
     
     
         19 . A method for in vivo or in vitro inhibiting the activity of FGFR comprising contacting FGFR with an effective amount of at least one compound of formula (I) according to any one of  claims 1 - 16  and/or at least one pharmaceutically acceptable salt thereof. 
     
     
         20 . A method for treating a disease responsive to inhibition of FGFR comprising administering to a subject in need thereof an effective amount to treat said disease of at least one compound of formula (I) according to any one of  claims 1 - 16  and/or at least one pharmaceutically acceptable salt thereof. 
     
     
         21 . The method according to  claim 20 , wherein the disease responsive to inhibition of FGFR is cancer, for example, lung cancer, stomach cancer, liver cancer, breast cancer, ovarian cancer, endometrial carcinoma, or bladder carcinoma. 
     
     
         22 . Use of at least one compound of formula (I) according to any one of  claims 1 - 16  and/or at least one pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease responsive to inhibition of FGFR. 
     
     
         23 . The use according to  claim 22 , wherein the disease responsive to inhibition of FGFR is cancer, for example, lung cancer, stomach cancer, liver cancer, breast cancer, ovarian cancer, endometrial carcinoma, or bladder carcinoma.