6-5 fused rings as C5a 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,
the ring portion having A 0 , A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is selected from the group consisting of
wherein m is 0, 1, 2, or 3
R 1 is selected from the group consisting of
wherein R 1 is optionally substituted with 1 to 4 R 5 substituents;
R 2a and R 2e are each 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;
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 C 1-4 alkyl, C 1-4 haloalkyl and hydroxyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O);
each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —O—C 1-6 haloalkyl, halogen, cyano, hydroxyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, —NR 4a R 4b , —CONR 4a R 4b , —CO 2 R 4a , COR 4a , —OC(O)NR 4a R 4b , —NR 4a C(O)R 4b , —NR 4a C(O) 2 R 4b , and —NR 4a —C(O)NR 4a R 4b ;
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, —C 1-8 alkyl-heterocycloalkyl, —C 1-8 alkyl-C 3-8 cycloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, halogen, OH, C 2-8 alkenyl, C 2-8 alkynyl, CN, C(O)R 5a , —NR 5b C(O)R 5a , —CONR 5a R 5b , —NR 5a R 5b , —C 1-8 alkylene-NR 5a R 5b , —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, —OC(O)NR 5a R 5b , —NR 5a C(O) 2 R 5b , —NR 5a —C(O)NR 5b R 5b and CO 2 R 5a ; wherein the heterocycloalkyl group is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S;
wherein each R 5a and R 5b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl, or when attached to the same nitrogen atom R 5a and R 5b are combined with the nitrogen atom to form a five or six-membered ring having from 0 to 1 additional heteroatoms as ring vertices selected from N, O, or S; and
the subscript n is 0, 1, 2 or 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-6 hydroxyalkyl, C 1-4 haloalkyl, halogen, cyano, hydroxyl, —NH 2 , —CONR 4a R 4b , and —CO 2 R 4a ; and wherein the R 4 substituents, when present, are attached to any suitable carbon ring vertex of the bicyclic heteroaryl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 0 , A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is selected from the group consisting of:
4. The compound of claim 1 , wherein 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, —C 1-8 alkyl-heterocycloalkyl, C 3-6 cycloalkyl, halogen, —CONR 5a R 5b , —NR 5a R 5b , —C 1-8 alkylene-NR 5a R 5b , and —CO 2 R 5a , each R 5a and R 5b is independently selected from the group consisting of hydrogen and C 1-4 alkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring; and the heterocycloalkyl group is a 4 to 6 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
6. The compound of claim 5 , wherein each R 5 is independently selected from the group consisting of cyclopropyl, isopropyl, isopropyloxy, OMe, Me, Cl, F, —CONH 2 , —CF 3 , —O—CF 3 ,
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d are each H.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, and halogen.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are each independently selected from the group consisting of Me, Et, F, Cl, OMe, OCF 3 , and
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (Ic), (Id), or (Ie):
wherein m is 0, 1 or 2 and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are both ethyl.
16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
17. A method for treating a mammal suffering from or susceptible to a disease or disorder selected from the group consisting of sepsis, septic shock, inflammatory bowel disease, ischemia-reperfusion injury, and lupus nephritis, comprising administering to the mammal an effective amount of a compound of claim 1 .
18. A method of inhibiting C5a mediated cellular chemotaxis comprising contacting mammalian white blood cells with a C5a modulatory amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.