AMINE-SUBSTITUTED HETEROCYCLIC COMPOUNDS AS EHMT2 INHIBITORS AND METHODS OF USE THEREOF
The present disclosure relates to amine-substituted heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., cancer) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
1 . A compound of Formula (I0)
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer,
wherein
X 1 is N or CR 2 ;
X 2 is N or CR 3 ;
X 3 is N or CR 4 ;
X 4 is N or CR 5 ;
B is C 6 -C 10 aryl or 5- to 10-membered heteroaryl optionally substituted with one or more R 15 ;
R 1 is H or C 1 -C 4 alkyl;
each of R 2 , R 3 , R 4 , and R 5 , independently is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkoxyl, C 6 -C 10 aryl, OH, NR a R b , C(O)NR a R b , NR a C(O)R b , C(O)OR a , OC(O)R a , OC(O)NR a R b , NR a C(O)OR b , C 3 -C 8 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, are each optionally substituted with one or more of halo, OR a , or NR a R b , in which each of R a and R b independently is H or C 1 -C 6 alkyl;
R 6 is -Q 1 -T 1 , in which Q 1 is a bond, or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, oxo, or C 1 -C 6 alkoxyl, and T 1 is H, halo, cyano, or R S1 , in which R S1 is C 3 -C 8 cycloalkyl, phenyl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl and R S1 is optionally substituted with one or more of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxyl, oxo, —C(O)R c , —C(O)OR c , —SO 2 R c , —SO 2 N(R c ) 2 , —NR c C(O)R d , —C(O)NR c R d , —NR c C(O)OR d , —OC(O)NR c R d , NR c R d , or C 1 -C 6 alkoxyl, in which each of R c and R d independently is H or C 1 -C 6 alkyl;
R 7 is -Q 2 -T 2 , in which Q 2 is a bond, C(O)NR e , or NR e C(O), R e being H or C 1 -C 6 alkyl and T 2 is selected from
and tautomers thereof each of which is optionally substituted with one or more -Q 3 -T 3 , wherein each Q 3 independently is a bond or C 1 -C 3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy, and each T 3 independently is selected from the group consisting of H, halo, cyano, 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 containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR f , C(O)R f , C(O)OR f , OC(O)R f , S(O) 2 R f , NR f R g , OC(O)NR f R g , NR f C(O)OR g , C(O)NR f R g , and NR f C(O)R g , each of R f and R g independently being H, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted with C 3 -C 8 cycloalkyl, in which the C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkoxy; or -Q 3 -T 3 is oxo;
R 8 is C 1 -C 6 alkyl;
R 9 is -Q 4 -T 4 , in which Q 4 is a bond or C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl, and T 4 is H, halo, OR h NR h R i , NR h C(O)R i , C(O)NR h R i , C(O)R h , C(O)OR h , NR h C(O)OR i , OC(O)NR h R i , S(O) 2 R h , S(O) 2 NR h R i , or R S2 , in which each of R h and R i independently is H or C 1 -C 6 alkyl, and R S2 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 12-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, and S, or a 5- to 10-membered heteroaryl, and R S2 is optionally substituted with one or more -Q 5 -T 5 , wherein each Q 5 independently is a bond or C 1 -C 3 alkylene linker each optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxy, and each T 5 independently is selected from the group consisting of H, halo, cyano, 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 containing 1-4 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl, OR j , C(O)R j , C(O)OR j , OC(O)R j , S(O) 2 R j , NR j R k , OC(O)NR j R k , NR j C(O)OR k , C(O)NR j R k , and NR j C(O)R k , each of R j and R k independently being H or C 1 -C 6 alkyl; or -Q 5 -T 5 is oxo;
R 14 is H, halo, cyano, P(O)R l R m , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or —OR 6 , wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more of halo or OR 6 , and each of R l and R m independently is C 1 -C 6 alkyl; and
R 15 is H, halo, cyano, or —OR 6 .
2 . The compound of claim 1 , being of Formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
3 . (canceled)
4 . The compound of claim 1 , wherein
5 .- 7 . (canceled)
8 . The compound of claim 1 , being of any one of Formulae (I0a)-(I0l):
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
9 .- 10 . (canceled)
11 . The compound of claim 1 , being of any one of Formulae (I0a′)-(I0i′):
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
12 .- 13 . (canceled)
14 . The compound of claim 1 , being of Formula (Ia)-(Il):
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.
15 .- 18 . (canceled)
19 . The compound of claim 1 , wherein X 1 and X 3 are N, X 2 is CR 3 and X 4 is CR 5 .
20 . (canceled)
21 . The compound of claim 1 , wherein R 1 is H.
22 . (canceled)
23 . The compound of claim 1 , wherein R 3 is H or halo.
24 . (canceled)
25 . The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl.
26 .- 33 . (canceled)
34 . The compound of claim 1 , wherein R 6 is C 1 -C 6 alkyl optionally substituted with one or more of halo, cyano, hydroxyl, or C 1 -C 6 alkoxyl.
35 .- 46 . (canceled)
47 . The compound of claim 1 , wherein each Q 3 independently is a C 1 -C 3 alkylene linker, and each T 3 independently is NR f R g , each of R f and R g independently being H, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted with C 3 -C 8 cycloalkyl, in which the C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 alkoxy.
48 . The compound of claim 1 , wherein R 9 is H.
49 .- 51 . (canceled)
52 . The compound of claim 1 , wherein Q 4 is C 1 -C 6 alkylene, and T 4 is H.
53 .- 56 . (canceled)
57 . The compound of claim 1 , wherein R 14 is halo or —OR 6 .
58 . (canceled)
59 . The compound of claim 1 , wherein R 14 is —OR 6 .
60 . The compound of claim 1 , wherein R 15 is H or halo.
61 .- 86 . (canceled)
87 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
88 .- 90 . (canceled)
91 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
92 . A method of preventing or treating a blood disorder via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, the method comprising administering to a subject in need thereof a compound of claim 1 .
93 .- 118 . (canceled)