Inhibitors of the myst family of lysine acetyl transferases
Provided herein are compounds of Formula (I). Methods for the preparation of the compounds of Formula (I) and intermediates useful in the preparation of the compounds of Formula (I) are described herein. The compounds of Formula (I) may be useful as inhibitors of the MYST family of lysine acetyltransferases (KATs) for the treatment of and/or prophylaxis of hyperproliferative diseases, disorders or conditions such as cancer. In particular, the compounds of Formula (I) are useful for the inhibition of KAT6A and KAT6B which are enzymes frequently mutated, overexpressed, amplified and/or translocated in cancer altering their normal expression, activity and function. The use of the compounds of Formula (I) in the manufacture of pharmaceutical compositions or for treating cancers is further described, including for treating cancer in combination with other anti-cancer agents.
1. A compound of Formula (I):
R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkyl-C 1 -C 6 alkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; or 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ;
each R 1a is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -cycloalkyloxy;
each R 1b is independently selected from hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyalkyloxy, —O-alkylene-NR 1b1 R 1b4 , —O-alkylene-C(O)OR 1b1 , —O-alkylene-O-alkylene-NR 1b1 R 1b4 ,
cyano, —(CH 2 ) 0-2 C(O)—OR 1b1 , —(CH 2 ) 0-2 C(O)NR 1b1 R 1b2 , —(CH 2 ) 0-2 NR 1b1 C(O)R 1b3 , —(CH 2 ) 0-2 OH, and C 3 -C 8 -cycloalkyloxy;
R 1b1 is hydrogen or C 1 -C 6 alkyl; R 1b2 is hydrogen or C 1 -C 6 alkyl; R 1b3 is hydrogen or C 1 -C 6 alkyl; and R 1b4 is hydrogen,
R 2 is:
each R 2b is independently hydrogen, halo, —(CH 2 ) 0-2 OH, C 1 -C 3 alkyl, cyclopropyl, cyano, —CHF 2 , —CF 3 , C 1 -C 4 alkoxy, —OCHF 2 , —OCF 3 , or C 3 -C 8 cycloalkyloxy;
each R 2e is independently hydrogen, —OH, halo, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, halo-C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyloxy;
wherein,
one X 1 is CR 3 and the other X 1 are independently selected from N and CR 2b ;
R 2d is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 8 -cycloalkyloxy;
R 3 is —(CH 2 ) 0-2 Y or —(CH 2 ) 0-2 -L-Y;
L is -L 1 -L 2 -L 3 -, where L 1 , L 2 and L 3 are each independently a bond, —CRR—, 0, S(O) 0-2 , C(O) or NR, where each R is independently H or alkyl;
Y is a 5-membered monocyclic heteroaryl substituted with R Y and optionally substituted with R 2e ; Y is a 6-membered monocyclic aryl or heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is an 8-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is a 9-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1, 2, or 3 R 2e ; Y is a 10-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1, 2, or 3 R 2e ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is a 4-9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is
Y is —(CH 2 ) 0-3 NR 3b R Y ; or Y is —(CH 2 ) 0-3 NR 3b C(O)R Y ;
R Y is —(CH 2 ) 0-3 NR 3b C(O)R 3a , —(CH 2 ) 0-2 NR 3b S(O) 2 R 3a , —C(O)R 3a , —S(O) 2 R 3a , —C(O)NR 3b R 3a C 3 -C 8 heterocycloalkyl substituted with —C(O)R 3a ; —(CH 2 ) 0-3 NR 3b (C 1 -C 6 alkylene)NR 3b1 C(O)R 3a , —(CH 2 ) 0-3 NR 3b (C 1 -C 6 alkylene)NR 3b1 S(O) 2 R 3a , —(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 alkylene)NR 3b1 C(O)R 3a , or —(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 alkylene)NR 3b1 S(O) 2 R 3a ,
R 3a , R 3b and R 3b1 are selected from (i), (ii) or (iii):
(i) one of R 3a , R 3b and R 3b1 is selected from group a): C 1 -C 6 alkyl substituted with 1 or 2 halo which are independently selected; C 1 -C 6 alkyl substituted with cyano; C 1 -C 6 alkyl substituted with fluoroalkoxy; C 1 -C 6 alkyl substituted with aryloxy or heteroaryloxy, each of which is optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkenyl substituted with cyano; C 2 -C 6 alkenyl substituted with halo; —CH═CH—CH 2 —NR 3c R 3d ; —CH═CH—CH 2 —O—C 1 -C 6 alkyl; C 3 -C 8 cycloalkenyl; —C(O)—C 3 -C 8 cycloalkyl; C 2 -C 6 alkynyl; —CH═CH—CH 2 —NR 3c R 3d ; CH═CH—CH 2 —OH; —CH═CH—CH 2 —O—C 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetraflurophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl; and the others of R 3a , R 3b and R 3b1 are selected from group b): hydrogen, and C 1 -C 6 alkyl; or
(ii) one of R 3a , R 3b and R 3b1 is selected from group a): hydrogen; C 1 -C 6 alkyl; C 1 -C 6 alkyl substituted with aryloxy or heteroaryloxy, each of which is optionally substituted with 1-3 substituents each independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; C 2 -C 6 alkenyl; C 3 -C 8 cycloalkenyl; —C(O)—C 3 -C 8 cycloalkyl; C 2 -C 6 alkynyl; spirocycloalkyl; pyridyl; pyrimidinyl; and phenyl; and the others of R 3a , R 3b and R 3b1 are selected from group b): hydrogen, and C 1 -C 6 alkyl; or
(iii) R 3a , R 3b and R 3b1 are each independently hydrogen or C 1 -C 6 alkyl;
R 3c is hydrogen, or C 1 -C 6 alkyl, and R 3d is hydrogen, or C 1 -C 6 alkyl; or R 3c and R 3d together with the nitrogen to which they are attached form a 3-8 membered, saturated ring where the other 2-7 ring members are carbon; and
HET1 is C 3 -C 8 heterocycloalkyl;
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
2. The compound of claim 1 , wherein:
R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkyl-C 1 -C 6 alkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; or 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; 8- to 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ;
each R 1a is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -cycloalkyloxy;
each R 1b is independently selected from hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyalkyloxy, —O-alkylene-NR 1b1 R 1b4 , —O-alkylene-C(O)OR 1b1 , —O-alkylene-O-alkylene-NR 1b1 R 1b4 ,
cyano, —(CH 2 ) 0-2 C(O)OR 1b1 , —(CH 2 ) 0-2 C(O)NR 1b2 R 1b3 , —(CH 2 ) 0-2 NRC(O)R, —(CH 2 ) 0-2 OH, and C 3 -C 8 -cycloalkyloxy;
R 1b1 is hydrogen or C 1 -C 6 alkyl; R 1b2 is hydrogen or C 1 -C 6 alkyl; and R 1b3 is hydrogen or C 1 -C 6 alkyl; and R 1b4 is hydrogen,
R 2 is selected from the group consisting of
each R 2b is independently hydrogen, halo, —(CH 2 ) 0-2 OH, C 1 -C 3 alkyl, cyclopropyl, cyano, —CHF 2 , —CF 3 , C 1 -C 4 alkoxy, —OCHF 2 , —OCF 3 , or C 3 -C 8 cycloalkyloxy;
each R 2e is independently hydrogen, halo, —OH, C 1 -C 6 alkyl, halo-C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, halo-C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyloxy;
wherein,
one X 1 is CR 3 and the other X 1 are independently selected from N and CR 2b ;
R 2d is hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, or C 3 -C 8 -cycloalkyloxy;
R 3 is —(CH 2 ) 0-2 Y;
Y is a 5-membered monocyclic heteroaryl substituted with R Y and optionally substituted with R 2e ; Y is a 6-membered monocyclic heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is an 8-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is a 9-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1, 2, or 3 R 2e ; Y is a 10-membered bicyclic heteroaryl substituted with R Y and optionally substituted with 1, 2, or 3 R 2e ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is a 4-9-membered monocyclic or bicyclic heterocycloalkyl substituted with R Y and optionally substituted with 1 or 2 R 2e ; Y is
Y is —(CH 2 ) 0-3 NR 3b R Y ; or Y is —(CH 2 ) 0-3 NR 3b C(O)R Y ;
R Y is —(CH 2 ) 0-3 NR 3b C(O)R 3a , —(CH 2 ) 0-2 NR 3b S(O) 2 R 3a , —C(O)R 3a , —S(O) 2 R 3a , —C(O)NR 3b R 3a , —(CH 2 ) 0-3 NR 3b (C 1 -C 6 alkylene)NR 3b1 C(O)R 3a , —(CH 2 ) 0-3 NR 3b (C 1 -C 6 alkylene)NR 3b 1S(O) 2 R 3a , —(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 alkylene)NR 3b1 C(O)R 3a , or —(CH 2 ) 0-3 NR 3b C(O)(C 1 -C 6 alkylene)NR 3b1 S(O) 2 R 3a , or C 3 -C 8 heterocycloalkyl substituted with —C(O)R 3a ;
one of R 3a , R 3b and R 3b1 is selected from group a): C 1 -C 6 alkyl substituted with 1 or 2 halo which are independently selected; C 1 -C 6 alkyl substituted with cyano; C 1 -C 6 alkyl substituted with fluoroalkoxy; C 1 -C 6 alkyl substituted with aryloxy or heteroaryloxy, each of which is optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkenyl substituted with cyano; C 2 -C 6 alkenyl substituted with halo; —CH═CH—CH 2 —NR 3c R 3d ; —CH═CH—CH 2 —O—C 1 -C 6 alkyl; C 3 -C 8 cycloalkenyl; —C(O)—C 3 -C 8 cycloalkyl; C 2 -C 6 alkynyl; —CH≡CH—CH 2 —NR 3c R 3d ; CH≡CH—CH 2 —OH; —CH≡CH—CH 2 —O—C 1 -C 6 alkyl; spirocycloalkyl substituted with cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl; tetraflurophenyl; trifluorophenyl; difluorophenyl; and monofluorophenyl; and
the others of R 3a , R 3b and R 3b1 are selected from group b): hydrogen, and C 1 -C 6 alkyl;
R 3c is hydrogen, or C 1 -C 6 alkyl, and R 3d is hydrogen, or C 1 -C 6 alkyl; or R 3c and R 3d together with the nitrogen to which they are attached form a 3-8 membered, saturated ring where the other 2-7 ring members are carbon;
HET1 is C 3 -C 8 heterocycloalkyl;
or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
3. The compound of claim 2 , wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a , or phenyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
4. The compound of claim 2 , wherein R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
5. The compound of claim 2 , wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
6. The compound of claim 2 , wherein R 1 is phenyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
7. The compound of claim 2 , wherein R 1 is phenyl-C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
8. The compound of claim 2 , wherein R 1 is naphthyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
9. The compound of claim 2 , wherein R 1 is 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
10. The compound of claim 1 , wherein each Ria is independently hydrogen; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
11. The compound of claim 2 , wherein each R 1b is independently selected from hydrogen, halo, —C(O)OH, —C(O)(OCH 3 ), C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
12. The compound of claim 2 , wherein R 2d is C 1 -C 3 alkoxy (optionally methoxy); or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
13. The compound of claim 2 , wherein each R 2b is hydrogen; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
14. The compound of claim 2 , wherein one X 1 is CR 3 and is in the meta position with respect to R 2d , one X 1 is N, and the other X 1 is CR 2b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
15. The compound of claim 2 , wherein one X 1 is CR 3 and is in the meta position with respect to R 2d and the other X 1 are CH; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
16. The compound of claim 2 , wherein R 3 is —(CH 2 )—Y; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
17. The compound of claim 2 , wherein R 3 is —(CH 2 )-L-Y; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
18. The compound of claim 2 , wherein Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; or Y is
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
19. The compound of claim 2 , wherein Y is a 5-membered monocyclic heteroaryl substituted with R Y ; Y is a pyrazolyl substituted with R Y ; Y is a 8- or 9-membered bicyclic heterocyclic substituted with R Y ; or Y is
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
20. The compound of claim 2 , wherein each R 3b and R 3b1 is hydrogen; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
21. The compound of claim 2 , wherein R Y is —(CH 2 ) 0-3 NHC(O)R 3a , —(CH 2 ) 0-2 NHS(O) 2 R 3a , —C(O)R 3a , —S(O) 2 R 3a , —(CH 2 ) 0-3 NH(C 1 -C 6 alkylene)NHC(O)R 3a , —(CH 2 ) 0-3 NH(C 1 -C 6 alkylene)NHS(O) 2 R 3a , —(CH 2 ) 0-3 NHC(O)(C 1 -C 6 alkylene)NHC(O)R 3a , —(CH 2 ) 0-3 NHC(O)(C 1 -C 6 alkylene)NHS(O) 2 R 3a , or C 3 -C 8 heterocycloalkyl substituted with —C(O)R 3a ; wherein R 3a is selected from group a); or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
22. The compound of claim 2 , wherein R 3a is —CH 2 (halo); —(CH 2 ) 1-2 CN; —CH 2 OCH(CF 3 ) 2 ; —CH 2 O(trifluorophenyl); —CH 2 O(tetrafluorophenyl); —CH 2 O(isoxazolyl, optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl); —CH 2 O(pyrimidinyl, optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl); —CH 2 O(pyridyl, optionally substituted with 1-3 substituents each independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl); C 2 -C 6 alkenyl; C 2 -C 4 alkenyl substituted with cyano; C 2 -C 4 alkenyl substituted with halo; —CH═CH—CH 2 —NR 3c R 3d ; —CH═CH—CH 2 —O—C 1 -C 6 alkyl; tetrafluorophenyl; trifluorophenyl; C 2 -C 6 alkynyl; —CH≡CH—CH 2 —NR 3c R 3d ; or —CH≡CH—CH 2 —O—C 1 -C 6 alkyl; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
23. The compound of claim 2 , wherein R Y is
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
24. The compound of claim 2 , wherein each R 2e is hydrogen; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
25. The compound of claim 2 , wherein each R 2b is independently hydrogen or C 1 -C 3 alkyl; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
26. The compound of claim 2 , wherein R 3c and R 3d are each independently hydrogen or C 1 -C 3 alkyl; or where R 3c and R 3d , together with the nitrogen to which they are attached, form a pyrrolidinyl or piperidinyl; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
27. The compound of claim 1 , selected from
or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 , wherein:
R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkyl is optionally substituted with 1, 2, or 3 R 1a ; phenyl optionally substituted with 1, 2, or 3 R 1b ; naphthyl optionally substituted with 1, 2, or 3 R 1b ; 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; or 8-10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ;
each R 1a is independently selected from H, halo, C 1 -C 6 alkoxy, and C 3 -C 8 -cycloalkyloxy;
each R 1b is independently selected from H, halo, C 1 -C 6 alkoxy, cyano and C 3 -C 8 -cycloalkyloxy;
R 2 is:
wherein,
one X 1 is C(CH 2 R 2c ), and the other two X 1 are independently selected from N and CR 2e ;
R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 ; R 2c is a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c ; R 2c is a 8- or 9-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 ; R 2c is a 6-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with 1 or 2 R 2 93; R 2 is a 9-membered bicyclic heteroaryl substituted with R 2c2 and optionally substituted with 1 or 2 R 2c3 ; or R 2c is a 10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 2c1 ;
R 2c2 is C 1 -C 6 alkylcarbonyl, —CH 2 NH 2 , C 1 -C 6 alkoxy, —NC(C 3 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 NHC(O)R 2f , —(CH 2 ) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl;
R 2c3 is independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyloxy; and
each R 2c1 is independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyloxy, —CN, —CH 2 NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CH 2 NHC(O)R 2f , —(CH 2 ) 0-1 NHC(O)OR 2f , 5- or 6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic heteroaryl; wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl;
or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
29. The compound of claim 28 , wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a , or phenyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
30. The compound of claim 28 , wherein R 1 is C 3 -C 8 -cycloalkyl optionally substituted with 1, 2, or 3 R 1a ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
31. The compound of claim 28 , wherein R 1 is C 3 -C 8 -cycloalkylalkyl where the C 3 -C 8 -cycloalkylalkyl is optionally substituted with 1, 2, or 3 R 1a ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
32. The compound of claim 28 , wherein R 1 is phenyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
33. The compound of claim 28 , wherein R 1 is naphthyl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
34. The compound of claim 28 , wherein R 1 is 5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
35. The compound of claim 28 , wherein R 1 is 8-10-membered bicyclic heteroaryl optionally substituted with 1, 2, or 3 R 1b ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
36. The compound of claim 28 , wherein each R 1a is independently H; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
37. The compound of claim 28 , wherein each R 1b is independently selected from H, halo, and C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
38. The compound of claim 28 , wherein R 2d is halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or C 3 -cycloalkyloxy; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
39. The compound of claim 28 , wherein R 2d is C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
40. The compound of claim 28 , wherein R 2e is independently hydrogen, fluoro, C 1 -C 3 alkyl, cyclopropyl, —CHF 2 , —CF 3 , C 1 -C 4 alkoxy, —OCHF 2 , or —OCF 3 ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
41. The compound of claim 28 , wherein one X 1 is C(CH 2 R 2c ), and the other two X 1 are each CR 2e ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
42. The compound of claim 28 , wherein one X 1 is C(CH 2 R 2c ), the second X 1 is N, and the third X 1 is CR 2e ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
43. The compound of claim 28 , wherein one X 1 is C(CH 2 R 2c ), and the other two X 1 are each N; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
44. The compound of claim 28 , wherein C(CH 2 R 2c ) is in the meta-position with respect to R 2d ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
45. The compound of claim 28 , wherein the compound of Formula (I) is according to Formula (Ii):
or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
46. The compound of claim 28 , wherein R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 ; a 8- or 9-membered bicyclic heterocyclic optionally substituted with 1 or 2 R 2c1 ; a 8- or 9-membered bicyclic heterocyclic substituted with R 2c2 and optionally substituted with R 2c3 ; a 6-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with 1 or 2 R 2c3 ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
47. The compound of claim 46 , wherein R 2c is a 8- or 9-membered bicyclic heterocyclic group, wherein R 2c is optionally substituted with 1 or 2 R 2c1 ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
48. The compound of claim 46 , wherein R 2c is a 5-membered monocyclic heteroaryl substituted with R 2c2 and optionally substituted with R 2c3 ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
49. The compound of claim 46 , wherein R 2c is a 5-membered heteroaryl group fused to a nonaromatic cyclic group, wherein R 2c is substituted with R 2c2 and optionally substituted with R 2c3 ; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
50. The compound of claim 46 , wherein R 2c is a 6-membered monocyclic heteroaryl, substituted with R 2c2 and optionally substituted with 1 or 2 R 2c3 ; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
51. The compound of claim 48 , wherein R 2c2 is C 1 -C 6 alkylcarbonyl, —CH 2 NH 2 , or —CH 2 NHC(O)R 2f , —(CH 2 ) 0-1 NHC(O)OR 2f ; wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; or a pharmaceutically acceptable salt or salts thereof; and/or a stereoisomer or mixture of stereoisomers thereof.
52. The compound of claim 48 , wherein each R 2c3 is hydrogen; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
53. The compound of claim 28 , wherein each R 2c1 is hydrogen; or one R 2c1 is selected from C 1 -C 6 alkylcarbonyl, —CN, —CH 2 NH 2 , and —CH 2 NHC(O)R 2f , —(CH 2 ) 0-1 NHC(O)OR 2f , wherein R 2f is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkylC 1 -C 3 alkyl; and the other one or two R 2c1 are each hydrogen; or one R 2c1 is —CN and the other one or two R 2c1 are each hydrogen; or a pharmaceutically acceptable salt or salts thereof, and/or a stereoisomer or mixture of stereoisomers thereof.
54. The compound of claim 28 , selected from
or a regioisomer, stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof.
55. A pharmaceutical composition comprising a compound of claim 1 or claim 28 , or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.