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 method of treating a human suffering from or susceptible to a disease or disorder selected from the group consisting of microscopic polyangiitis, C3-glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, lupus glomerulonephritis, vasculitis, ANCA vasculitis, immuno vasculitis, Graft versus host disease, glomerulonephritis,
comprising administering to the mammal a therapeutically effective amount of 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, —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);
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 method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 in Formula (I) is selected from the group consisting of
3. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 in Formula (I) is a bond.
4. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 in Formula (I) is C(O).
5. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 in Formula (I) is C 1-8 alkylene.
6. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 in Formula (I) is C(O)—C 1-4 alkylene or S(O) 2 .
7. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —X 1 —R 1 in Formula (I) is optionally substituted with 1 to 4 R x substituents.
8. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d in Formula (I) are each H; and 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.
9. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d in Formula (I) are each H; and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.
10. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the group —X 1 —R 1 in Formula (I) is optionally substituted with 1 to 4 R x substituents; 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; 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 .
11. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 in Formula (I) is selected from the group consisting of:
12. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
in Formula (I) is selected from the group consisting of
13. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound of Formula (I) is selected from the group consisting of
14. A method of claim 1 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
15. A method of claim 1 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
16. A method of claim 1 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.