5-5 fused rings as C5a inhibitors

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein,

ring vertex A 1 is selected from the group consisting of N, CH, C(O) and C(R 4 );

ring vertex A 2 is selected from the group consisting of N, CH, and C(R 4 );

each of ring vertices A 3 , A 4 , A 5 and A 6 is independently selected from the group consisting of CH and C(R 4 );

each of the dashed bonds independently indicate a single or double bond;

R 1 is selected from the group consisting of —C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)—C 1-8 alkyl, —C(O)—C 6-10 aryl, —C(O)-heteroaryl, —C(O)—C 3-6 cycloalkyl, —C(O)-heterocycloalkyl, —C(O)NR 1a R 1b , —SO 2 —C 6-10 aryl, —SO 2 -heteroaryl, —C(O)—C 1-8 alkylene-O-heteroaryl, —C(O)—C 1-8 alkylene-O—C 6-10 aryl, —C(O)—C 1-8 alkylene-O-heterocycloalkyl, —C(O)—C 1-8 alkylene-O—C 3-6 cycloalkyl, —C(O)—C 1-8 alkylene-heteroaryl, —C(O)—C 1-8 alkylene-C 6-10 aryl, —C(O)—C 1-8 alkylene-heterocycloalkyl, —C(O)—C 1-8 alkylene-C 3-6 cycloalkyl and —CO 2 R 1a ; the heterocycloalkyl is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5 to 10 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S;

wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl;

wherein R 1 is optionally substituted with 1 to 5 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 1-6 alkyl, C 1-6 haloalkyl, halogen and hydroxyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O) or to form a three to five membered cycloalkyl ring;

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 alkylene-heterocycloalkyl, —C 1-8 alkylene-C 36 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 alkylene-O—C 1-6 alkyl, —C 1-6 alkylene-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 1-8 alkyl, and C 1-8 haloalkyl, or when R 5a and R 5b are attached to the same nitrogen atom they are combined with the nitrogen atom to form a 5 or 6-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 the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of

wherein m is 0, 1, 2 or 3; and wherein the R 4 substituents may be 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 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl represented by the structure

wherein m is 0, 1, 2, or 3; and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

4. 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, halogen, cyano, and —CO 2 R 4a ; and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of —C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)—C 1-8 alkyl, —C(O)—C 6-10 aryl, —C(O)-heteroaryl, —C(O)—C 3-8 cycloalkyl, —C(O)NR 1a R 1b , —SO 2 —C 6-10 aryl, —C(O)—C 1-8 alkylene-O—C 6-10 aryl, and —CO 2 R 1a ; wherein the heterocycloalkyl is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5 to 10 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-s haloalkyl; and R 1 is optionally substituted with 1 to 5 R 5 substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 3-6 cycloalkyl, halogen, OH, —NR 5a R 5b , and CO 2 R 5a , wherein each R 5a and R 5b is independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl optionally substituted by 1 to 3 R 5 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl substituted by 1 or 2 R 5 , wherein each R 5 is independently C 1-4 haloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl substituted by 1 or 2 CF 3 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2b , R 2c , and R 2d are each H.

15. 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 and C 1-6 haloalkyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are each independently C 1-6 alkyl.

17. 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 methyl and ethyl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are both methyl or are both ethyl.

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, 1 or 2.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C 1-4 alkyl.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (Ia), (Ib) or (Ic):

24. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (Id), (Ie), or (If):

wherein m is 0, 1 or 2; wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl; and wherein p is 0, 1 or 2.

25. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (Ig) or (Ih):

wherein m is 0, 1 or 2 and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the indole heteroaryl.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is

31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is