Therapeutic heterocyclic compounds
Compounds having the following Formula I and/or Formula II and methods of their use and preparation are disclosed:
1. A compound of Formula I:
wherein
X 1 at each location in Formula I is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location in Formula I is independently N, CH, or CR 1 ;
X 5 is CH, CX R , or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , or —CF 3 , wherein n is 0-5 and where if n is >1, R 1 can be independently the same or different from each other;
R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
2. A compound of Formula I a :
wherein
X 1 at each location of Formula Ia is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location of Formula Ia is independently N, CH, or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , or —CF 3 , wherein R 1 can be independently the same or different from each other;
R 2 is absent when X 2 is N; or R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
3. A compound of Formula I b :
wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
4. A compound of Formula I c :
wherein
R 1 is halogen;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
5. A compound of Formula I e :
wherein
R 1 is halogen;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
6. A compound of Formula I f :
wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,
or a pharmaceutically acceptable salt thereof.
7. A compound of Formula I h :
wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a 5-10 membered mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is C 1-3 alkyl or C 1-3 haloalkyl,
or a pharmaceutically acceptable salt thereof.
8. A compound of Formula I i :
wherein
X 1 at each location in Formula Ii is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location in Formula Ii is independently N, CH, or CR 1 ;
X 5 is N, CH, or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , C 1-3 haloalkyl, or C 1-6 alkyl, wherein n is 0-5 and R 1 can be independently the same or different from each other;
R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, C 1-6 alkyl, and —C(O)N(R 5 )(R 6 );
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle;
R 5 is hydrogen or C 1-6 alkyl; and
R 6 is hydrogen or C 1-6 alkyl,
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro, chloro, or bromo.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or C 1-3 alkyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is a 5-10 membered mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one or two substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl.
13. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, —CF 3 , —CHF 2 , —OCF 3 , or C 4-6 heterocycle.
15. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
17. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
18. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
22. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.