Imidazopyrimidines as EED inhibitors and the use thereof
The present disclosure provides compounds represented by Formula I: wherein R 1 , R 2 , R 3 , and R 4 are as defined in the specification, and the salts and solvates thereof. Compounds of Formula I are EED inhibitors. EED inhibitors are useful for the treatment of cancer and other diseases.
1. A compound of Formula II:
wherein:
R 1 is aralkyl;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
X is selected from the group consisting of —C(R 5a )(R 5b )—, —C(═O)—, and —S(═O) 2 —;
R 5a and R 5b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
Y is selected from the group consisting of —C(R 6a )(R 6b )—, —S—, —O—, and —N(R 7 )—; or
X and Y taken together form a 5-membered heteroarylenyl;
Z is —C(R 6c )(R 6d ) m —;
R 6a and R 6b are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
each R 6c and R 6d is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl;
m is 0, 1, or 2;
R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 4 -C 8 heterocyclo, hydroxyalkyl, (alkoxy)alkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;
R 8a , R 8b , and R 8c are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, carboxamido, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, (heterocyclo)C 1 -C 4 alkyl, and alkylsulfonyl;
is a fused phenyl, fused 5-membered heteroaryl, or fused 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of Formula III:
wherein L is selected from the group consisting of —C(R 8b )═ and —N═, or a pharmaceutically acceptable salt or solvate-thereof.
3. The compound of claim 1 of Formula IV:
wherein L is selected from the group consisting of —C(R 8b )═ and —N═, or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein Z is —CH 2 —, or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein:
X is selected from the group consisting of —C(R 5a )(R 5b )—, —C(═O)—, and —S(═O) 2 —; and
Y is selected from the group consisting of —C(R 6a )(R 6b )—, —S—, —O—, and —N(R 7 )—, or a pharmaceutically acceptable salt or solvate-thereof.
6. The compound claim 1 , wherein X is —C(═O)—, or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein Y is —N(R 7 )—, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein X and Y taken together form a 5-membered heteroarylenyl, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein:
R 1 is R 1 -1:
R 12a , R 12b , and R 12c are each independently selected from the group consisting of hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
W is selected from the group consisting of —CH 2 — and —C(═O)—; and
t is 1 or 2,
or a pharmaceutically acceptable salt or solvate-thereof.
10. The compound of claim 9 , wherein:
R 12a is fluoro; and
R 12b and R 12c are independently selected from the group consisting of hydrogen and fluoro,
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt or solvate-thereof.
12. The compound of claim 1 selected from group consisting of:
4-ethyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;
12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-(2,2,2-trifluoroethyl)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;
4-cyclopropyl-12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one;
12-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-4-isopropyl-7-(trifluoromethyl)-4,5-dihydro-3H-2,4,8,11,12a-pentaazabenzo[4,5]cycloocta[1,2,3-cd]inden-3-one; and
11-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-4H-3-thia-2,5,10,11a-tetraazadibenzo[cd,f]azulene 3,3-dioxide,
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method of treating cancer wherein the cancer is a lymphoma, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.