Carbocycle-substituted purine and 7-deazapurine compounds
View Patent ↗The present invention relates to carbocycle-substituted purine and 7-deazapurine compounds of Formula (I). The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders, by administering these compounds and pharmaceutical compositions to subjects in need thereof.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
each of G and J, independently, is H, halo, C(O)OH, C(O)O-C 1 -C 6 alkyl or OR a , R a being H, C 1 -C 6 alkyl or C(O)-C 1 -C 6 alkyl, wherein C(O)O-C 1 -C 6 alkyl, C 1 -C 6 alkyl or C(O)-C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
Q is H, NH 2 , NHR b , NR b R c , R b , or OR b , in which each of R b and R c 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 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M 1 -T 1 in which M 1 is a bond or C 1 -C 6 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxyl and T 1 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R b and R c , together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O-C 1 -C 6 alkyl, OC(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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R b , R c , and T 1 is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
X is CR x , in which R x is H, halo, hydroxyl, carboxyl, cyano, or R S1 , R S1 being amino, C 1 -C 6 alkoxyl, 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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R S1 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
L 1 is N(Y), S, SO, or SO 2 ;
L 2 is CO or absent when L 1 is N(Y) or L 2 is absent when L 1 is S, SO, or SO 2 , in which Y is H, R d , SO 2 R d , or COR d when L 2 is absent, or Y is H or R d when L 2 is CO, R d being 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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R d being optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 alkylsulfonyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O-C 1 -C 6 alkyl, OC(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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;
each of R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 , independently, is H, halo, hydroxyl, carboxyl, cyano, R S2 , R S2 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and each R S2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 8 is H, halo or R S3 , R S3 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R S3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C 1 -C 6 alkoxyl, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
R 9 is
in which each of R e , R f , R g , and R h , independently is -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O-C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being 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 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O-C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R i is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR j , or CR j R k , each of R j and R k independently being H or C 1 -C 6 alkyl, or R j and R k taken together, with the carbon atom to which they are attached, form a C 3 -C 10 cycloalkyl ring, and E is -M 3 -T 3 , M 3 being a bond or C 1 -C 6 alkyl linker optionally substituted with halo or cyano, T 3 being C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, halo, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C 1 -C 6 alkoxyl;
m is 1 or 2; and
n is 1 or 2.
2. The compound of claim 1 , wherein at least one of m and n is 2.
3. The compound of claim 1 , wherein the compound is of Formula (II)
4. The compound of claim 1 , wherein each of G and J is independently OR a , in which R a is H.
5. The compound of claim 1 , wherein L 1 is N(Y), SO or SO 2 .
6. The compound of claim 1 , wherein Y is R d , in which R d is C 1 -C 6 alkyl.
7. The compound of claim 1 , wherein L 2 is absent.
8. The compound of claim 1 , wherein at least one of R e , R f , R g , and R h is halo, C 1 -C 6 alkoxyl optionally substituted with one or more halo, C 1 -C 6 alkylsulfonyl optionally substituted with one or more halo, or C 1 -C 6 alkyl optionally substituted with one or more halo.
9. The compound of claim 1 , wherein at least one of R e , R f , R g , and R h is selected from the group consisting of F, Cl, CF 3 , OCF 3 , SO 2 CF 3 , C 1 -C 4 alkyl, and C 1 -C 4 alkoxyl.
10. The compound of claim 1 , wherein R i is H or C 1 -C 6 alkyl.
11. The compound of claim 1 , wherein E is -M 3 -T 3 , M 3 being a bond or C 1 -C 3 alkyl linker, T 3 being phenyl, naphthyl, thienyl, cyclopropyl, or cyclohexyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with C 1 -C 4 alkyl, 5 to 6-membered heteroaryl optionally substituted with C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl.
12. The compound of claim 11 , wherein T 3 is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylsulfonyl, C 6 -C 10 aryl, and C 6 -C 10 aryloxyl, and C 7 -C 14 alkylaryl.
13. The compound of claim 1 , wherein X is CH.
14. The compound of claim 1 , wherein Q is NH 2 or NHR b , in which R b is -M 1 -T 1 , M 1 being a bond or C 1 -C 6 alkyl linker and T 1 being C 3 -C 8 cycloalkyl.
15. The compound of claim 1 , wherein Q is H.
16. The compound of claim 1 , wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are each H.
17. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 and a pharmaceutically acceptable carrier.
20. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
each of G and J, independently, is H, halo, C(O)OH, C(O)O-C 1 -C 6 alkyl or OR a , R a being H, C 1 -C 6 alkyl or C(O)-C 1 -C 6 alkyl, wherein C(O)O-C 1 -C 6 alkyl, C 1 -C 6 alkyl or C(O)-C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano hydroxyl, carboxyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 5 cycloalkyl;
Q is H, NH 2 , NHR b , NR b R c , R b , or OR b , in which each of R b and R c independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 5 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M 1 -T 1 in which M 1 is a bond or C 1 -C 6 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxyl and T 1 is C 3 -C 5 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R b and R c , together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O-C 1 -C 6 alkyl, OC(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 5 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R b , R c , and T 1 is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 5 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
X is N;
L 1 is N(Y), S, SO, or SO 2 ;
L 2 is CO or absent when L 1 is N(Y) or L 2 is absent when L 1 is S, SO, or SO 2 , in which Y is H, R d , SO 2 R d , or COR d when L 2 is absent, or Y is H or R d when L 2 is CO, R d being 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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R d being optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 alkylsulfonyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O-C 1 -C 6 alkyl, OC(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 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;
each of R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 , independently, is H, halo, hydroxyl, carboxyl, cyano, R S2 , R S2 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and each R S2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 8 is H, halo or R S3 , R S3 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R S3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C 1 -C 6 alkoxyl, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
R 9 is
in which each of R e , R f , R g , and R h , independently is -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O-C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or M(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being 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 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O-C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R i is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, 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 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR j , or CR j R k , each of R j and R k independently being H or C 1 -C 6 alkyl, or R j and R k taken together, with the carbon atom to which they are attached, form a C 3 -C 10 cycloalkyl ring, and E is-M 3 -T 3 , M 3 being a bond or C 1 -C 6 alkyl linker optionally substituted with halo or cyano, T 3 being C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, halo, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C 1 -C 6 alkoxyl;
m is 1 or 2; and
n is 1 or 2.
21. The compound of claim 20 , wherein at least one of m and n is 2.
22. The compound of claim 20 , wherein the compound is of Formula (II)
23. The compound of claim 20 , wherein each of G and J is independently OR a , in which R a is H.
24. The compound of claim 20 , wherein L 1 is N(Y), SO or SO 2 .
25. The compound of claim 20 , wherein Y is R d , in which R d is C 1 -C 6 alkyl.
26. The compound of claim 20 , wherein L 2 is absent.
27. The compound of claim 20 , wherein at least one of R e , R f , R g , and R h is halo, C 1 -C 6 alkoxyl optionally substituted with one or more halo, C 1 -C 6 alkylsulfonyl optionally substituted with one or more halo, or C 1 -C 6 alkyl optionally substituted with one or more halo.
28. The compound of claim 20 , wherein at least one of R e , R f , R g , and R h is selected from the group consisting of F, Cl, CF 3 , OCF 3 , SO 2 CF 3 , C 1 -C 4 alkyl, and C 1 -C 4 alkoxyl.
29. The compound of claim 20 , wherein R i is H or C 1 -C 6 alkyl.
30. The compound of claim 20 , wherein E is -M 3 -T 3 , M 3 being a bond or C 1 -C 3 alkyl linker, T 3 being phenyl, naphthyl, thienyl, cyclopropyl, or cyclohexyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with C 1 -C 4 alkyl, 5 to 6-membered heteroaryl optionally substituted with C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl.
31. The compound of claim 30 , wherein T 3 is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylsulfonyl, C 6 -C 10 aryl, and C 6 -C 10 aryloxyl, and C 7 -C 14 alkylaryl.
32. The compound of claim 20 , wherein Q is NH 2 or NHR b , in which R b is -M 1 -T 1 , M 1 being a bond or C 1 -C 6 alkyl linker and T 1 being C 3 -C 8 cycloalkyl.
33. The compound of claim 20 , wherein Q is H.
34. The compound of claim 20 , wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8 are each H.
35. The compound of claim 20 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 20 and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 35 and a pharmaceutically acceptable carrier.