Diaryl substituted 6,5-fused ring compounds as C5aR inhibitors
The present disclosure provides, inter alia, Compounds of Formula (I) or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.
1. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein,
X 1 is selected from the group consisting of a bond, C 1-8 alkylene, C(O), C(O)—C 1-4 alkylene, and S(O) 2 ;
R 1 is pyridyl;
wherein the group —X 1 —R 1 is optionally substituted with 1 to 5 R x substituents;
R 2a and R 2e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen, and at least one of R 2a and R 2e is other than hydrogen;
R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, cyano, and halogen;
each R 3 is independently selected from the group consisting of hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 hydroxyalkyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O);
R 4 is independently selected from the group consisting of X 2 —OR 4a , —X 2 —NR 4a R 4b , —X 2 —CONR 4a R 4b , —X 2 —NR 4a —C(O)R 4a , —X 2 —NR 4a —C(O)NR 4a R 4b , —X 2 —NR 4a —C(O)OR 4a , —X 2 —NR 4a —C(O)—C 1-3 alkylene-OR 4a and —X 2 —NR 4a —C(O)—C 1-3 alkylene-NR 4a R 4b ; wherein each X 2 is independently a bond, C(O), C 1-4 alkylene, C(O)—C 1-4 alkylene, and C 1-4 alkylene-C(O), and each R 4a and R 4b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
each R 5 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, halogen, OH, CN, C(O)R 5a and CO 2 R 5a ; wherein each R 5a is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
each R x is independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxy, C 2-4 alkenyl, C 3-6 cycloalkyl, CO 2 —C 1-4 alkyl, and CONH 2 ;
the subscript m is 0, 1, 2, 3 or 4; and
the subscript n is 0, 1, 2 or 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O).
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C 1-8 alkylene.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O)—C 1-4 alkylene or S(O) 2 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d are each H; R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d are each H; R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 , when present, is selected from the group consisting of F, Cl, CN, C 1-4 alkyl and C 1-4 alkoxy.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 , when present, is selected from the group consisting of F, Cl, CN, CH 3 and OCH 3 .
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 and each R 3 , when present, is C 1-4 alkyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents; R 2b , R 2e , and R 2d are each H; R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen; m is 0, 1 or 2 and each R 3 , when present, is CH 3 , R 4 is selected from the group consisting of
n is 0, 1 or 2 and each R 5 , when present, is selected from the group consisting of F, Cl, CN, CH 3 and OCH 3 .
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —X 1 —R 1 is selected from the group consisting of:
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 2 and the two R 3 groups are on the same carbon atom and are combined to form oxo (═O).
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of
23. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
24. The pharmaceutical composition of claim 23 , formulated for oral, intravenous, transdermal or subcutaneous administration.
25. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
26. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
27. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.