Substituted purine and 7-deazapurine compounds
View Patent ↗The present invention relates to substituted purine and 7-deazapurine compounds. 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 (IV) or its N-oxide or a pharmaceutically acceptable salt thereof:
wherein
A is O or CH 2 ;
Q is H, NH 2 , NHR b , NR b R c , OH, 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 N or 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;
Y is H, R d , SO 2 R d , or COR d , 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 each of which C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl substituents on R d is 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 and R 2 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;
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, and
m is 0, 1, or 2.
2. The compound of claim 1 , wherein A is O.
3. The compound of claim 1 , wherein A is O and m is 2.
4. The compound of claim 1 , wherein X is N.
5. 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.
6. The compound of claim 1 , wherein R 1 and R 2 , are each H.
7. The compound of claim 1 , wherein Y is R d .
8. The compound of claim 7 , wherein R d is C 1 -C 6 alkyl optionally substituted with C 3 -C 8 cycloalkyl or halo.
9. The compound of claim 7 , wherein R d is C 3 -C 8 cycloalkyl optionally substituted with C 1 -C 6 alkyl or halo.
10. 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; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from CN, halo, C 3 -C 8 cycloalkyl, hydroxy, and C 1 -C 6 alkoxyl; C 3 -C 8 cycloalkyl optionally substituted with one or more C 1 -C 6 alkyl or CN; or 4 to 8-membered heterocycloalkyl optionally substituted with one or more substituents selected from CN, halo, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxyl.
11. The compound of claim 10 , wherein at least one of R e , R f , R g , and R h is selected from the group consisting of F; Cl; Br; CF 3 ; OCF 3 ; SO 2 CF 3 ; oxetanyl optionally substituted with one or more substituents selected from CN, halo, hydroxy, C 1 -C 6 alkyl and C 1 -C 6 alkoxyl; C 3 -C 8 cycloalkyl optionally substituted with one or more substituents selected from C 1 -C 4 alkyl; and C 1 -C 4 alkyl optionally substituted with one or more substituents selected from halo, C 3 -C 8 cycloalkyl, hydroxy and C 1 -C 6 alkoxyl.
12. A compound selected from
and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12 and a pharmaceutically acceptable carrier.
15. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 .
16. A method of treating hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 .
17. A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 .
18. A method of claim 17 , wherein the leukemia is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
19. A method of treating a MLL-rearranged leukemia, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 .
20. A method of treating a leukemia characterized by a partial tandem duplication of the MLL gene (MLL-PTD), comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 13 .