Triazolopyrimidine compounds and uses thereof
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating a PRC2-mediated disease or disorder: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and n are as defined herein.
1. A compound of Formula (IA):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently H or halogen;
R 3 is independently selected from: halogen, phenyl, and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A ;
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 6 alkyl substituted with 0-1 R 3B ), C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, R 3C , —OR 3C , —C(═O)R 3D , NR 3E R 3F ,—C(═O)NR 3E R 3F , —NHC(═O)R 3D , —S(═O) 2 R 3D , —S(═O) 2 NR 3E R 3F ,—NHS(═O) 2 (C 1 -C 4 alkyl), and —CR 3C R 3E R 3G ;
R 3B is independently selected from: OH, NR e R f , C 1 -C 4 alkoxy, —C(═O)NR e R f , —S(═O) 2 (C 1 -C 4 alkyl), —NHC(═O)(C 1 -C 4 alkyl), and a 5- to 6-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycloalkyl is substituted with 0-2 R c ;
each R 3 C is independently selected from: C 3 -C 6 cycloalkyl, phenyl, and a 4- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein each moiety is substituted with 0-2 R c ;
each R 3 D is independently selected from: C 1 -C 4 alkyl and R 3C ;
R 3E and R 3G are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each R 3F is independently selected from: H and C 1 -C 4 alkyl substituted with 0-1 R d ;
R 4 is independently selected from: H, halogen and C 1 -C 4 alkyl;
R 5 is independently selected from OH and C 1 -C 4 alkyl;
each R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and benzyl;
R b is independently selected from: halogen, OH and C 1 -C 4 alkoxy;
each R c is independently selected from: ═O, halogen, OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;
R d is independently selected from: OH and NR e R f ;
R e and R f are, at each occurrence, independently selected from: H and C 1 -C 4 alkyl;
each p is independently selected from 0, 1 and 2; and
m and n are, at each occurrence, independently selected from 0 and 1.
2. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, R 3C , —C(═O)R 3D , NR 3E R 3F , —C(═O)NR 3E R 3F , —S(═O) 2 R 3D , —S(═O) 2 NHR 3F , —NHS(═O) 2 (C 1 -C 4 alkyl), —O—C 3 -C 6 cycloalkyl, and
R a is independently selected from: H, →O, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), and C 3 -C 6 cycloalkyl;
R 4 is H;
m is independently selected from 0 and 1; and
n is 0.
3. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 1 is independently H or F;
R 2 is H; and
R 3 is independently selected from: phenyl, and a 6-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N and NR a ; wherein said phenyl and heteroaryl are substituted with 0-3 R 3A .
4. A compound or a pharmaceutically acceptable salt thereof, according to claim 3 , wherein:
R 3 is independently selected from: phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl; wherein each moiety is substituted with 0-3 R 3A .
5. A compound or a pharmaceutically acceptable salt thereof, according to claim 4 , wherein:
R 3 is independently selected from:
6. A compound or a pharmaceutically acceptable salt thereof, according to claim 4 , wherein:
R 3 is independently selected from:
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —C(═O)N(C 1 -C 4 alkyl)(CH 2 ) 2 N(C 1 -C 4 alkyl) 2 , —CH 2 NHC(═O)(C 1 -C 4 alkyl), —S(═O) 2 R 3D , —S(═O) 2 NH(C 1 -C 4 alkyl substituted with 0-1 OH), —NHS(═O) 2 (C 1 -C 4 alkyl), NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl,
R 3B is independently selected from: OH, NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),
R 3D is independently selected from: C 1 -C 4 alkyl and 1H-piperidin-4-yl; and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).
7. A compound or a pharmaceutically acceptable salt thereof, according to claim 6 , wherein:
R 3 is independently selected from:
each R 3A is independently selected from: halogen, CN, —(O) m —(C 1 -C 4 alkyl substituted with 0-1 R 3B ), C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , —C(═O)N(C 1 -C 4 alkyl)(CH 2 ) 2 N(C 1 -C 4 alkyl) 2 , —CH 2 NHC(═O)(C 1 -C 4 alkyl), —S(═O) 2 (C 1 -C 4 alkyl), NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl,
R 3B is independently selected from: OH, N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)N(C 1 -C 4 alkyl) 2 , —S(═O) 2 (C 1 -C 4 alkyl),
and
each R a is independently selected from: H, C 1 -C 4 alkyl, —C(═O)H, —C(═O)(C 1 -C 4 alkyl), and —CO 2 (C 1 -C 4 alkyl).
8. A compound or a pharmaceutically acceptable salt thereof, according to claim 7 , wherein:
each R 3A is independently selected from: F, Cl, CH 3 , —CH 2 OH, CH 2 F, CHF 2 , CF 3 , CN, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCHF 2 , —C(═O)N(CH 3 ) 2 , —CH 2 NHC(═O)CH 3 , —S(═O) 2 CH 3 , NH 2 , cyclopropyl,
9. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said compound is of Formula (IA-1):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is F; and
R 3A is independently selected from: F, CH 3 , —CH 2 OH, CH 2 F, CHF 2 , CF 3 , and —OCH 3 .
10. A compound according to claim 1 , wherein:
R 1 is independently H or F;
R 2 is H;
R 3 is independently a 5-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heteroaryl is substituted with 0-3 R 3A ; and
R a is independently selected from: H, C 1 -C 4 alkyl substituted with 0-1 R b , —C(═O)H, —C(═O)(C 1 -C 4 alkyl), —CO 2 (C 1 -C 4 alkyl), C 3 -C 6 cycloalkyl, and benzyl.
11. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein:
R 3 is independently selected from:
12. A compound or a pharmaceutically acceptable salt thereof, according to claim 11 , wherein:
R 1 is F.
13. A compound or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein said compound is selected from
14. A compound according to claim 1 , wherein said compound is selected from:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 1 .
16. The compound:
17. The compound:
18. A compound according to claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
19. A compound according to claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
20. A compound according to claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
21. A compound according to claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 17 .
23. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 18 .
24. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 19 .
25. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 20 .
26. A pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a compound or a pharmaceutically acceptable salt thereof, according to claim 21 .