Substituted benzene compounds

Abstract

The present invention relates to azole compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

1 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Z is NR 7 R 8 , OR 7 , S(O) a R 7 , or CR 7 R 8 R 14 , in which a is 0, 1, or 2; 
 each of R 5 , R 9 , and R 10 , independently, is H or C 1 -C 6  alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; 
 R 6  is H, halo, cyano, azido, OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR b C(O)R a , —S(O) b R a , —S(O) b NR a R b , or R S2 , in which R S2  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 5- or 6-membered heteroaryl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R a  and R b , independently is H or R S3 , and R S3  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; or R a  and R b , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom; and each of R S2 , R S3 , and the 4 to 12-membered heterocycloalkyl ring formed by R a  and R b , is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 2  is H, halo, cyano, —OR c , —NR c R d , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —NR d C(O)R c , —NR d C(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R d , or R S4 , in which each of R c  and R d , independently is H or R S5 , each of R S4  and R S5 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R c  and R d , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S4 , R S5 , and the 4 to 12-membered heterocycloalkyl ring formed by R c  and R d , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 3  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR e , COOR e , —S(O) 2 R e , —NR e R f , and —C(O)NR e R f , each of R e  and R f  independently being H or C 1 -C 6  alkyl optionally substituted with OH, O—C 1 -C 6  alkyl, or NH—C 1 -C 6  alkyl, or -Q 3 -T 3  is oxo; or -Q 2 -T 2  is oxo; or any two neighboring -Q 2 -T 2 , when R 6  is C 6 -C 10  aryl or 5- or 6-membered heteroaryl, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; 
 R 7  is -Q 4 -T 4 , in which Q 4  is a bond, C 1 -C 4  alkyl linker, or C 2 -C 4  alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 4  is H, halo, cyano, NR g R h , —OR g , —C(O)R g , —C(O)OR g , —C(O)NR g R h , —C(O)NR g OR h , —NR g C(O)R h , —S(O) 2 R g , or R S6 , in which each of R g  and R h , independently is H or R S7 , each of R S6  and R S7 , independently is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 14-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R S6  and R S7  is optionally substituted with one or more -Q 5 -T 5 , wherein Q 5  is a bond, C(O), C(O)NR k , NR k C(O), NR k , S(O) 2 , NR k S(O) 2 , or C 1 -C 3  alkyl linker, R k  being H or C 1 -C 6  alkyl, and T 5  is H, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q  in which q is 0, 1, or 2 and R q  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5  is H, halo, hydroxyl, or cyano; or -Q 5 -T 5  is oxo; 
 each of R 8 , and R 12 , independently, is H, halo, hydroxyl, COOH, cyano, R S8 , OR S8 , or COOR S8 , in which R S8  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C 1 -C 6  alkylamino, or di-C 1 -C 6  alkylamino, and R S8  is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, and di-C 1 -C 6  alkylamino; or R 7  and R 8 , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R 7  and R 8 , together with the C atom to which they are attached, form C 3 -C 8  cycloalkyl or a 4 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 12-membered heterocycloalkyl rings or C 3 -C 8  cycloalkyl formed by R 7  and R 8  is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6  is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3  alkyl linker, R m  being H or C 1 -C 6  alkyl, and T 6  is H, halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p  in which p is 0, 1, or 2 and R p  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6  is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6  alkyl, hydroxyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6  is H, halo, hydroxyl, or cyano; or -Q 6 -T 6  is oxo; 
 R 14  is absent, H, or C 1 -C 6  alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; 
 X is a monocyclic or bicyclic 5 to 10-membered saturated, unsaturated, or aromatic ring containing 2-4 heteroatom ring members and optionally substituted with one or more -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; and 
 n is 0, 1, 2, 3, 4, or 5. 
 
     
     
         2 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of D 1 , D 2 , and D 3 , independently, is CR 901  or N, provided that at least one of D 1 , D 2 , and D 3  is N; 
 D 4  is O, S, or NR 902 ; and 
 each R 901  and R 902 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         3 . The compound of  claim 2 , wherein (i) D 1  is N; each of D 2  and D 3 , independently, is CR 901 ; and D 4  is NR 902 ; or (ii) each of D 1  and D 2 , independently, is CR 901 ; D 3  is N; and D 4  is NR 902 ; or (iii) each of D 1  and D 2  is N; D 3  is CR 901 ; and D 4  is NR 902 ; or (iv) each of D 1  and D 3  is, independently, CR 901 ; D 2  is N, and D 4  is NR 902 ; or (v) D 1  is N; each of D 2  and D 3 , independently, is CR 901 ; and D 4  is O or S. 
     
     
         4 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of E 1 , E 2 , and E 4 , independently, is CR 903  or N, provided that at least one of E 1 , E 2 , and E 4  is N; 
 E 3  is O, S, or NR 904 ; and 
 each of R 903  and R 904 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         9 . The compound of  claim 8 , wherein (i) E 1  is N; each of E 2  and E 4 , independently, is CR 903 ; and E 3  is NR 904 ; or (ii) each of E 1  and E 4 , independently, is CR 903 ; E 2  is N; and E 3  is NR 904 ; or (iii) each of E 1  and E 2 , independently, is CR 903 ; E 3  is NR 904 ; and E 4  is N; or (iv) each of E 1  and E 2 , independently, is CR 903 ; E 3  is O; and E 4  is N. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 G 1  is O, S, or NR 907 ; 
 each of G 2 , G 3 , and G 4 , independently, is N or CR 908 , provided that at least one of G 2 , G 3 , and G 4  is N; and 
 each of R 905 , R 906 , R 907 , and R 908 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         14 . The compound of  claim 13 , wherein (i) G 1  is NR 907 ; G 2  is CR 908 ; and each of G 3  and G 4  is N; or (ii) G 1  is NR 907 ; each of G 2  and G 4 , independently, is CR 908 ; and G 3  is N; or (iii) G 1  is NR 907 ; each of G 2  and G 4  is N, and G 3  is CR 908 ; or (iv) G 1  is NR 907 ; G 2  is N, and each of G 3  and G 4 , independently, is CR 908 . 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of J 1 , J 2 , J 3 , and J 4 , independently, is N or CR 911 , provided that at least one of J 1 , J 2 , J 3 , and J 4  is N; and 
 each of R 909 , R 910 , and R 911 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of K 1 , K 2 , K 3 , and K 4 , independently, is N or CR 914 , provided that at least one of K 1 , K 2 , K 3 , and K 4  is N; and 
 each of R 912 , R 913 , and R 914 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of U 1 , U 3 , and U 4 , independently, is N or CR 917 , provided that at least one of U 1 , U 3 , and U 4  is N; 
 U 2  is O, S, or NR 918 ; and 
 each of R 915 , R 916 , R 917  and R 918 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         24 . (canceled) 
     
     
         25 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of V 1  and V 2 , independently, is N or CR 919 , provided that at least one of V 1  and V 2  is N; V 3  is O, S, or NR 920 ; 
 each of V 4 , V 5 , and V 6  is O, S, or NR 921 , or CR 922 R 923 ; and 
 each of R 919 , R 920 , R 921 , R 922 , and R 923 , independently, is -Q 7 -T 7 , wherein Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         26 . The compound of  claim 1 , wherein X is imidazol-2-yl, imidazol-4-yl, triazol-3-yl, 3H-imidazo[4,5-c]pyridin-7-yl, 1H-benzo[d]imidazol-4-yl, 1H-indazol-7-yl, isoxazol-3-yl, thiazol-2-yl, 1H-pyrazolo[4,3-c]pyridin-7-yl, imidazo[1,2-a]pyridin-8-yl, imidazo[1,2-c]pyrimidin-8-yl, 1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-7-yl, 1,4,6,7-tetrahydropyrano[3,4-]imidazol-7-yl, or 4,5,6,7-tetrahydro-1H-benzo[d]imidazol-4-yl. 
     
     
         27 . The compound of  claim 1 , wherein (i) R 6  is C 6 -C 10  aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q 2 -T 2 , wherein Q 2  is a bond or C 1 -C 3  alkyl linker, and T 2  is H, halo, cyano, —OR c , —NR c R d , —C(O)NR c R d , —NR d C(O)R c , —S(O) 2 R c , —S(O) 2 NR c R d , or R S4 , in which each of R c  and R d , independently is H or R S5 , each of R S4  and R S5 , independently, is C 1 -C 6  alkyl, or R c  and R d , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S4 , R S5 , and the 4 to 7-membered heterocycloalkyl ring formed by R c  and R d , is optionally, independently substituted with one or more -Q 3 -T 3 , wherein Q 3  is a bond or C 1 -C 3  alkyl linker and T 3  is selected from the group consisting of halo, C 1 -C 6  alkyl, 4 to 7-membered heterocycloalkyl, OR e , —S(O) 2 R e , and —NR e R f , each of R e  and R f  independently being H or C 1 -C 6  alkyl, or -Q 3 -T 3  is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S; or (ii) R 6  is halo, C 1 -C 3  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, C(O)H, or —C(O)R a , in which R a  is C 1 -C 6  alkyl or 4 to 12-membered heterocycloalkyl; or (iii) R 6  is F, Br, or Cl; or (iv) R 6  is Cl; or (v) R 6  is ethynyl substituted with one or more -Q 2 -T 2 , in which Q 2  is a bond or C 1 -C 3  alkyl linker and T 2  is C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optionally substituted with one or more -Q 3 -T 3 ; or (vi) R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         28 - 32 . (canceled) 
     
     
         33 . The compound of  claim 1 , wherein Z is NR 7 R 8 , and R 7  is C 3 -C 8  cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 . 
     
     
         34 . The compound of  claim 33 , wherein R 7  is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, piperazinyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q 5 -T 5  and R 8  is H or C 1 -C 6  alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, and di-C 1 -C 6  alkylamino. 
     
     
         35 - 43 . (canceled) 
     
     
         44 . The compound of  claim 1 , wherein n is 0, 1, or 2 and each of R 9  and R 10  is H. 
     
     
         45 . The compound of  claim 1 , wherein the compound is of formula (VIa) 
       
         
           
           
               
               
           
         
       
       wherein R 7  is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q 5 -T 5 ; n is 1 or 2; and X is 
       
         
           
           
               
               
           
         
       
       wherein
 each of D 1 , D 2 , and D 3 , independently, is CR 901  or N, provided that at least one of D 1 , D 2 , and D 3  is N; 
 D 4  is O, S, or NR 902 ; 
 each of E 1 , E 2 , and E 4 , independently, is CR 903  or N, provided that at least one of E 1 , E 2 , and E 4  is N; 
 E 3  is O, S, or NR 904 ; 
 G 1  is O, S, or NR 907 ; each of G 2 , G 3 , and G 4 , independently, is N or CR 908 , provided that at least one of G 2 , G 3 , and G 4  is N; 
 each of J 1 , J 2 , J 3 , and J 4 , independently, is N or CR 911 , provided that at least one of J 1 , J 2 , J 3 , and J 4  is N; 
 each of K 1 , K 2 , K 3 , and K 4 , independently, is N or CR 914 , provided that at least one of K 1 , K 2 , K 3 , and K 4  is N; 
 each of U 1 , U 3 , and U 4 , independently, is N or CR 917 , provided that at least one of U 1 , U 3 , and U 4  is N; 
 U 2  is O, S, or NR 918 ; and each of R 901 , R 902 , R 903 , R 904 , R 905 , R 906 , R 907 , R 908 , R 909 , R 910 , R 911 , R 912 , R 913 , R 914 , R 915 , R 916 , R 917  and R 918 , independently, is -Q 7 -T 7 , in which Q 7  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 7  is H, —OR n , —NR n R r , —C(O)R n , —C(O)OR n , —C(O)NR n R r , —S(O) 2 R n , —S(O) 2 NR n R r , or R S9 , in which each of R n  and R r , independently is H or R S10 , each of R S9  and R S10 , independently, is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R n  and R r , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S9 , R S10 , and the 4 to 12-membered heterocycloalkyl ring formed by R n  and R r , is optionally substituted with one or more -Q 8 -T 8 , wherein Q 8  is a bond or C 1 -C 3  alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 8  is selected from the group consisting of halo, cyano, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR s , COOR s , —S(O) 2 R s , —NR s R t , and —C(O)NR s R t , each of R s  and R t  independently being H or C 1 -C 6  alkyl, or -Q 8 -T 8  is oxo; or -Q 7 -T 7  is oxo; or any two neighboring -Q 7 -T 7  together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6  alkyl, cyano, C 1 -C 6  alkoxyl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 
 
     
     
         46 . The compound of  claim 1 , wherein the compound is selected from those in Tables 1 and 2, and their pharmaceutically acceptable salts thereof. 
     
     
         47 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         48 . A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         49 - 50 . (canceled)