Substituted benzene compounds

Abstract

The present invention relates to substituted benzene 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
 X 1  is N or CR 11 ; 
 X 2  is N or CR 13 ; 
 X 3  is N or C, and when X 3  is N, R 6  is absent; 
 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 1 , 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; 
 each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1  is a bond or C 1 -C 3  alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 1  is H, halo, hydroxyl, COOH, cyano, azido, or R S1 , in which R S1  is C 1 -C 3  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxyl, C(O)O—C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S1  is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, 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, 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, or -Q 3 -T 3  is oxo; or -Q 2 -T 2  is oxo; 
 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), 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, 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 , R 11 , R 12 , and R 13 , 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; and 
 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; 
 provided that the compound is not 
 N-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)furan-2-carboxamide, 
 N,N′-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1,3-phenylene)diacetamide, 
 N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-pivalamidobenzamide, 
 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamido)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide, 
 N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamide, 
 N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenzamide, 
 3-allyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4,5-dimethoxybenzamide, 
 4-(2-amino-2-oxoethoxy)-3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxybenzamide, 
 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-hydroxy-5-methoxybenzamide, or 
 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-4-propoxybenzamide. 
 
     
     
         2 . The compound of  claim 1 , 
       wherein
 X 1  is N or CR 11 ; 
 X 2  is N or CR 13 ; 
 X 3  is N or C, and when X 3  is N, R 6  is absent; 
 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 1 , 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; 
 each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1  is a bond or C 1 -C 3  alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6  alkoxy, and T 1  is H, halo, hydroxyl, COOH, cyano, azido, or R S1 , in which R S1  is C 1 -C 3  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  alkoxyl, C(O)O—C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, amino, mono-C 1 -C 6  alkylamino, di-C 1 -C 6  alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S1  is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, 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, —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, 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, or -Q 3 -T 3  is oxo; or -Q 2 -T 2  is oxo; 
 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), 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, 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; provided that (i) R 7  is not C(O)R g  or —S(O) 2 R g  when Z is NR 7 R 8 ; (ii) R 7  is not C 1 -C 6  alkyl when Z is OR 7 , and (iii) R 7  is not H; 
 each of R 8 , R 11 , R 12 , and R 13 , 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; and 
 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. 
 
     
     
         3 . The compound of  claim 1 , wherein the compound is of Formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         4 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein Z is NR 7 R 8 . 
     
     
         9 - 11 . (canceled) 
     
     
         12 . The compound  claim 1 , wherein 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, and each of the C 1 -C 3  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and C 3 -C 6  cycloalkyl is optionally substituted with one or more -Q 2 -T 2 . 
     
     
         13 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein R 7  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or 4 to 14-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 . 
     
     
         18 . The compound of  claim 1 , wherein R 7  is piperidinyl, tetrahydropyran, tetrahydrothiopyran, oxetanyl, azetidinyl, pyrrolidinyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 3′H-spiro[cyclohexane-1,1′-isobenzofuran]-3′-one-4-yl, 7′H-spiro[cyclohexane-1,5′-furo[3,4-b]pyridin]-7′-one-4-yl, 3′H-spiro[cyclohexane-1,1′-furo[3,4-c]pyridin]-3′-one-4-yl, 1-azaspiro[4.5]decan-2-one-8-yl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q 5 -T 5 . 
     
     
         19 - 28 . (canceled) 
     
     
         29 . The compound of  claim 1 , wherein each of R 2  and R 4 , independently is C 1 -C 3  alkyl optionally substituted with C 1 -C 6  alkoxyl. 
     
     
         30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein R 1  is H and R 3  is H. 
     
     
         32 . The compound of  claim 1 , wherein R 12  is H, methyl, ethyl, ethenyl, or halo. 
     
     
         33 - 35 . (canceled) 
     
     
         36 . The compound of  claim 1 , wherein R 8  is H, methyl, or ethyl. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The compound of  claim 1 , wherein R 13  is H or methyl and R 11  is H. 
     
     
         41 - 52 . (canceled) 
     
     
         53 . The compound of  claim 1 , wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound of  claim 1 , wherein the compound is of Formula (IIA): 
       
         
           
           
               
               
           
         
       
       wherein n is 0, 1, or 2; U is O, S, N-Q 5 -T 5 , or CH-Q 5 -T 5 ; and R 12  is Cl, Br, or methyl. 
     
     
         55 - 65 . (canceled) 
     
     
         66 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         67 . A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , N-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)furan-2-carboxamide, N,N′-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1,3-phenylene)diacetamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-pivalamidobenzamide, 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamido)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenzamide, 3-allyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4,5-dimethoxybenzamide, 4-(2-amino-2-oxoethoxy)-3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxybenzamide, 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-hydroxy-5-methoxybenzamide, or 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-4-propoxybenzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         68 . (canceled) 
     
     
         69 . The compound of  claim 1 , wherein Q 2  is a bond or an unsubstituted C 1 -C 3  alkyl linker. 
     
     
         70 . The compound of  claim 1 , wherein T 2  is 4 to 7-membered heterocycloalkyl optionally substituted with one or more -Q 3 -T 3 . 
     
     
         71 . The compound of  claim 1 , wherein 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. 
     
     
         72 . The compound of  claim 1 , wherein Q 5  is a bond and T 5  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, amino, mono-C 1 -C 6  alkylamino, or di-C 1 -C 6  alkylamino, T 5  being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C 1 -C 6  alkoxyl, or C 3 -C 8  cycloalkyl.