SUBSTITUTED BENZENE COMPOUNDS

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)