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,
ring vertex a is N or C(R 2c ), ring vertex b is N or C(R 2d ), and ring vertex e is N or C(R 2e ), wherein no more than one of a, b and e is N;
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 selected from the group consisting of
a) pyrazolyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazinyl;
b) C 6-10 aryl;
c) C 3-8 cycloalkyl;
d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and
e) C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl;
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, —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, 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), and optionally two R 3 groups and the carbon atoms they are attached to form a 3-6 membered ring with 0-2 hetereoatoms as ring members selected from O, N, and S;
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 R 1 is C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
10. The compound of claim 9 , wherein R 1 is phenyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
12. The compound of claim 11 , wherein R 1 is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
14. The compound of claim 13 , wherein R 1 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of phenyl, pyrimidinyl, and pyrazinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e 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.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.
19. 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.
20. 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 .
21. 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.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is, wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents; ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and 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 .
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —X 1 —R 1 is selected from the group consisting of:
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2 and the two R 3 groups are on the same carbon atom and are combined to form oxo (═O).
30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of
31. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
32. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
33. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.
34. A compound of claim 1 , having the formula
or a pharmaceutically acceptable salt thereof.