6-5 fused rings as C5a inhibitors

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein,

ring vertex A 0 is NH or C(O);

each of ring vertices A 1 and A 3 are independently selected from the group consisting of N, NH, CH, C(O) and C(R 4 );

each of ring vertices A 2 , A 5 and A 6 is independently selected from the group consisting of N, CH, and C(R 4 );

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

and no more than two of A 3 , A 4 , A 5 and A 6 are N;

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

R 1 is selected from the group consisting of heteroaryl, C 6-10 aryl, C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 3-8 cycloalkyl, four to eight membered heterocycloalkyl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; 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; 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, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl;

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 1-4 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 the ring portion having A 0 , 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, 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

wherein m is 0, 1, 2, or 3.

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, 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.

5. 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:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of heteroaryl, C6-10 aryl, —C 1-6 alkylene-heteroaryl, —C 1-6 alkylene-C 6-10 aryl, four to eight membered heterocycloalkyl, C 3-8 cycloalkyl, C 1-8 alkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a , wherein the heteroaryl group is a 5 or 6 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S, and R 1 is optionally substituted with 1 to 3 R 5 substituents.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl, phenyl, benzyl, cyclopentyl, tetrahydropyranyl, —C(O)NR 1a R 1b , —CO 2 R 1a , and C 1-8 alkyl, wherein R 1 is optionally substituted with 1 to 3 R 5 substituents.

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

each of which is optionally substituted with 1 or 2 R 5 substituents.

9. The compound of claim 8 , 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.

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

11. The compound of claim 10 , 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 ,

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

each of which is optionally substituted with 1 to 2 R 5 substituents.

13. The compound of claim 12 , wherein each R 5 is independently selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, and C 2-8 alkenyl.

14. The compound of claim 13 , wherein each R 5 is independently selected from the group consisting of Cl, F, Me, isopropyl, —CF 3 , cyclopropyl, and isopropenyl.

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

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

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

18. 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.

19. 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

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

is selected from the group consisting of

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

22. 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).

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

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

25. The compound of claim 2 , 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.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (If), (Ig), (Ih), and (Ii):

wherein p is 0, 1 or 2.

27. The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2e are both ethyl.

28. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, having a structure represented by Formula (Ik), (Il), or (Im):

wherein p is 0, 1 or 2, 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.

29. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein

p is 1 or 2;

m is 1 or 2;

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 , and —C 1-8 alkylene-NR 5a R 5b , wherein 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, wherein 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; and

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 .

30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group in Table 3 having ++ or +++ activity.

31. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

32. 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 .

33. 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.

34. The method of claim 32 , further comprising administering to the human a therapeutically effective amount of one or more additional therapeutic agents.

35. The compound of claim 1 , having the structure

36. The compound of claim 1 , having the structure

37. The compound of claim 1 , having the structure

38. The compound of claim 1 , having the structure