Compounds for treatment of complement mediated disorders

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

Q 1 is C(R 1 R 1′ );

Q 2 is C(R 2 R 2′ );

Q 3 is C(R 3 R 3′ );

X 1 is N and X 2 is CH;

R 1 , R 1′ , R 2 , R 2′ , R 3 , and R 3′ are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 thioalkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)OR 9 , —OC(O)R 9 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —O(heteroaryl), —NR 9 C(O)OR 10 , C 1 -C 2 haloalkyl, C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl) and C 1 -C 2 haloalkoxy, where R 9 and R 10 are independently chosen at each occurrence from hydrogen, C 1 -C 6 alkyl, and (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl;

or R 1 and R 1′ or R 3 and R 3′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently chosen from N, O, or S;

or R 2 and R 2′ may be taken together to form a 3- to 6-membered carbocyclic spiro ring,

or R 2 and R 2′ may be taken together to form a 3- to 6-membered heterocyclic spiro ring,

each of which spiro ring is unsubstituted or substituted with one or more halogen or methyl substituents;

or R 1 and R 2 may be taken together to form a 3-membered carbocyclic ring;

or R 1 and R 2 may be taken together to form a 4- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S;

or R 2 and R 3 , if bound to adjacent carbon atoms, may be taken together to form a 3- to 6-membered carbocyclic ring or a 3- to 6-membered heterocyclic ring;

each of which non-spiro ring may be unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

A is

R 6 is independently chosen from

—CHO, —C(O)NH 2 , —C(O)NH(CH 3 ), C 2 -C 6 alkanoyl

hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO 2 NH 2 , —C(NH 2 )C 1 -C 3 alkyl, —C(NH 2 )C 1 -C 3 haloalkyl, —CF(C═CH 2 ), —C(═NCN)C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —P(O)(OR 9 ) 2 , —OC(O)R 9 , —C(O)OR 9 , —C(O)N(CH 2 CH 2 R 9 )(R 10 ), —NR 9 C(O)R 10 , phenyl, or 5- to 6-membered heteroaryl

each R 6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C 1 -C 2 alkyl, C 1 -C 4 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C(O)alkyl, C(O)cycloalkyl, C(O)aryl, C(O)heterocycle, and C(O)heteroaryl;

R 8 and R 8′ are independently chosen from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and (C 1 -C 4 alkylamino)C 0 -C 2 alkyl, or R 8 and R 8′ are taken together to form an oxo group;

X 12 is N or CR 12 ;

X 13 is N or CR 13 ;

R 12 and R 13 are independently chosen from (q) and (r),

(q) hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy,

(r) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , C 1 -C 6 thioalkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —OC(O)R 9 , and —C(NR 9 )NR 9 R 10 , each of which (r) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH 2 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and each of which (r) is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

where R 17 is hydrogen or C 1 -C 6 alkyl and R 18 and R 18′ are independently chosen from hydrogen, halogen, and methyl; and m is 0, 1, 2, or 3;

B is a monocyclic or bicyclic carbocyclic or carbo cyclic-oxy group or a monocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and from 4 to 7 ring atoms per ring, or

B is a C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group; or

B is —(C 0 -C 4 alkyl)(aryl), —(C 0 -C 4 alkyl)(heteroaryl), or —(C 0 -C 4 alkyl)(biphenyl)

each of which B is unsubstituted or substituted with one or more substituents independently chosen from (w) and (x) and 0 or 1 substituents chosen from (y) and (z)

(w) halogen, hydroxyl, —COOH, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, —C 0 -C 4 alkylNR 9 R 10 , —SO 2 R 9 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

(x) nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, -JC 3 -C 7 cycloalkyl, —B(OH) 2 , -JC(O)NR 9 R 23 , -JOSO 2 OR 21 , SR 9 , —C(O)(CH 2 ) 1-4 S(O)R 21 , —O(CH 2 ) 1-4 S(O)NR 21 R 22 , -JOP(O)(OR 21 )(OR 22 ), -JP(O)(OR 21 )(OR 22 ), -JOP(O)(OR 21 )R 22 , -JP(O)(OR 21 )R 22 , -JOP(O)R 21 R 22 , -JP(O)R 21 R 22 , -JSP(O)(OR 21 )(OR 22 ), -JSP(O)(OR 21 )(R 22 ), -JSP(O)(R 21 )(R 22 ), -JNR 9 P(O)(NHR 21 )(NHR 22 ), -JNR 9 P(O)(OR 21 )(NHR 22 ), -JNR 9 P(O)(OR 21 )(OR 22 ), -JC(S)R 21 , -JNR 21 SO 2 R 22 , -JSO 2 NR 9 COR 22 , -JSO 2 NR 9 CONR 21 R 22 , -JNR 21 SO 2 R 22 , -JC(O)NR 21 SO 2 R 22 , -JC(NH 2 )NR 22 , -JC(NH 2 )NS(O) 2 R 22 , -JOC(O)NR 21 R 22 , -JNR 21 C(O)OR 22 , -JNR 21 OC(O)R 22 , —(CH 2 ) 1-4 C(O)NR 21 R 22 , -JNR 9 C(O)R 21 , -JC(O)R 21 , -JNR 9 C(O)NR 10 R 22 , —CCR 21 , —(CH 2 ) 1-4 OC(O)R 21 , and -JC(O)OR 23 ;

each of which (x) may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH) 2 , —Si(CH 3 ) 3 , —COOH, —CONH 2 , —P(O)(OH) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C 0 -C 2 alkyl(mono- and di-C 1 -C 4 alkylamino), C 1 -C 6 alkylester, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

(y) naphthyl, naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl containing 1 or 2 heteroatoms chosen from N, O, and S, and bicyclic heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and containing 4- to 7-ring atoms in each ring; each of which (y) is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —SO 2 R 9 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and

(z) tetrazolyl, (phenyl)C 0 -C 2 alkyl, (phenyl)C 1 -C 2 alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from N, O, B, and S, each of which (z) is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —SO 2 R 9 , —OSi(CH 3 ) 2 C(CH 3 ) 3 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

J is independently chosen at each occurrence from a covalent bond, C 1 -C 4 alkylene, —OC 1 -C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene;

R 21 and R 22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S; and

R 23 is independently chosen at each occurrence from (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S.

2. The compound of claim 1 , wherein the

ring is selected from:

3. The compound of claim 1 , wherein B is selected from:

4. The compound of claim 1 , wherein B is selected from:

5. The compound of claim 1 , wherein B is selected from:

6. The compound of claim 1 , wherein B is selected from:

7. The compound of claim 1 , wherein B is selected from:

8. The compound of claim 1 , wherein A is:

9. The compound of claim 8 , wherein X 12 is CR 12 and X 13 is CR 13 .

10. The compound of claim 9 , wherein R 12 is C 1 -C 6 alkyl.

11. The compound of claim 10 , wherein R 13 is hydrogen.

12. The compound of claim 10 , wherein C 1 -C 6 alkyl is methyl.

13. The compound of claim 12 , wherein R 13 is hydrogen.

14. The compound of claim 9 , wherein R 12 and R 13 are both hydrogen.

15. The compound of claim 9 , wherein the

ring is selected from:

16. The compound of claim 9 , wherein B is selected from:

17. The compound of claim 9 , wherein B is selected from —(C 0 -C 4 alkyl)(aryl), —(C 0 -C 4 alkyl)(heteroaryl), or —(C 0 -C 4 alkyl)(biphenyl) each of which B is unsubstituted or substituted with one or more substituents independently chosen from (w) and (x), and 0 or 1 substituents chosen from (y) and (z).

18. The compound of claim 9 , wherein B is aryl or heteroaryl each of which B is substituted with one or more substituents independently chosen from (w) and (x), and 0 substituents chosen from (y) and (z).

19. The compound of claim 18 , wherein B is aryl.

20. The compound of claim 18 , wherein B is heteroaryl.

21. The compound of claim 16 , wherein the

ring is selected from:

22. The compound of claim 1 , wherein A is:

23. The compound of claim 22 , wherein X 12 is CR 12 and X 13 is CR 13 .

24. The compound of claim 23 , wherein R 12 is C 1 -C 6 alkyl.

25. The compound of claim 24 , wherein C 1 -C 6 alkyl is methyl.

26. The compound of claim 22 , wherein R 12 and R 13 are both hydrogen.

27. The compound of claim 22 , wherein the

ring is selected from:

28. The compound of claim 22 , wherein B is selected from:

29. The compound of claim 22 , wherein B is selected from —(C 0 -C 4 alkyl)(aryl), —(C 0 -C 4 alkyl)(heteroaryl), or —(C 0 -C 4 alkyl)(biphenyl) each of which B is unsubstituted or substituted with one or more substituents independently chosen from (w) and (x), and 0 or 1 substituents chosen from (y) and (z).

30. The compound of claim 22 , wherein B is aryl or heteroaryl each of which B is substituted with one or more substituents independently chosen from (w) and (x), and 0 substituents chosen from (y) and (z).

31. The compound of claim 30 , wherein B is aryl.

32. The compound of claim 30 , wherein B is heteroaryl.

33. The compound of claim 28 , wherein the

ring is selected from:

34. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure:

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure:

36. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure:

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure:

38. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure:

39. The compound of claim 1 or a pharmaceutically acceptable salt thereof of structure: