Amide compounds for treatment of complement mediated disorders

1. A compound of Formula I

or its pharmaceutically acceptable salt 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 chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 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 , —NR 9 C(O)OR 10 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 9 and R 10 are independently chosen from hydrogen, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), and —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);

or R 1 and R 2 are linked to form a 3- to 6-membered carbocyclic or aryl ring;

or R 2 and R 3 are linked to form a 3- to 6-membered carbocyclic ring;

or R 1 and R 1′ , or R 2 and R 2′ , or R 3 and R 3′ are linked to form a 3- to 6-membered carbocyclic spiro ring;

or R 1 and R 2 and R 2′ or R 3 and R 3′ are linked to form a 3- to 6-membered heterocyclic spiro ring;

each of which ring is 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 2 -C 4 alkynyl, 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;

or R 1 and R 1′ or R 2 and R 2′ are linked to form a carbonyl group;

or R 1 and R 2 or R 2 and R 3 can be taken together to form a carbon-carbon double bond;

A is a group selected from:

R 5 and R 6 are independently selected 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 , vinyl, C 1 -C 6 alkyl (including methyl), 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, and 5- to 6-membered heteroaryl;

R 8 and R 8′ are independently chosen from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), 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; or R 8 and R 8′ can be taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring;

X 11 is N or CR 11 ;

X 12 is CR 12 ;

X 13 is CR 13 ;

X 14 is N or CR 14 ;

one of R 12 and R 13 is chosen from R 31 and the other of R 12 and R 13 is chosen from R 32 :

R 31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), 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 31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy 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 31 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;

R 32 is selected from —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , and —NR 9 C(O)NR 24 R 25 , each of which is optionally substituted, wherein the optional substituent is selected from F, Cl, Br, cyano, hydroxyl, alkanoyl, carboxamide, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkyl sulfonyl, aminoalkyl, arylalkyl or arylalkoxy;

R 11 and R 14 are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR 9 ) 2 , —(PO)(OR 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —C 0 -C 4 alkyl(mono- and di-C 1 -C 6 alkylamino), —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 21 and R 22 are independently chosen 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;

R 23 is independently chosen from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (aryl)C 0 -C 4 alkyl, (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;

R 24 and R 25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings;

L is

R 17 is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);

R 18 and R 18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl;

m is 0, 1, 2, or 3;

B is a monocyclic or bicyclic carbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; 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; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —(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 R 33 and R 34 , and 0 or 1 substituents chosen from R 35 and R 36 ;

R 33 is independently chosen from 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;

R 34 is independently chosen from 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 , —C(O)(CH 2 ) 1-4 S(O)R 21 , —O(CH 2 ) 1 -4 S)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 , -JNR 9 S(O)NR 10 R 22 , -JNR 9 SO 2 NR 10 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 )NR 9 S(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 , -JC(O)R 24 R 25 , -JNR 9 (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 R 34 may be unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH) 2 , —S(CH 3 ) 3 , —COOH, —CONH 2 , —P(O)(OH) 2 , C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), 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;

R 35 is independently chosen from 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 R 35 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;

R 36 is independently chosen from 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 R 36 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 , —Si(CH 3 ) 2 C(CH 3 ) 3 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and

J is independently selected from a covalent bond, C 1 -C 4 alkylene, -0C 1 -C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene.

2. The compound of claim 1 , wherein the

ring is selected from:

3. The compound of claim 1 , wherein the

ring is selected from:

4. The compound of claim 1 , wherein the

ring is selected from:

5. The compound of claim 1 , wherein:

a) R 1 and R 1′ , or R 2 and R 2′ , or R 3 and R 3′ are linked to form a 3- to 6-membered carbocyclic spiro ring; or

b) R 1 and R 1′ , R 2 and R 2′ or R 3 and R 3′ are linked to form a 3- to 6-membered heterocyclic spiro ring; or

c) R 1 and R 2 are linked to form a 3- to 6-membered carbocyclic or aryl ring; or

R 2 and R 3 are linked to form a 3- to 6-membered carbocyclic ring.

6. The compound of claim 1 , wherein the A group is

7. The compound of claim 1 , wherein the R 32 moiety has at least one substituent.

8. The compound of claim 1 , wherein R 32 is selected from —NR 9 C(O)OR 10 and —NR 9 C(O)OR 23 each of which can be optionally substituted.

9. The compound of claim 1 , wherein R 32 is selected from —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , and —NR 9 C(O)NR 24 R 25 each of which can be optionally substituted.

10. The compound of claim 8 , wherein the optional substituent is fluorine.

11. The compound of claim 9 , wherein the optional substituent is fluorine.

12. A compound of Formula I

or its pharmaceutically acceptable salt wherein:

is as defined in claim 1 ;

A is as defined in claim 1 ; and

-L-B— is selected from:

R 18 and R 18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl;

m is 0 or 1;

R 26 , R 27 , and R 28 are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl-, (heteroaryl)C 0 -C 4 alkyl-, and —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl); each of which R 26 , R 27 , and R 28 other than hydrogen, halogen, hydroxyl, nitro, and cyano, is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl-, and C 1 -C 2 haloalkoxy; and R 29 is hydrogen, C 1 -C 2 alkyl, C 1 C 2 haloalkyl or —Si(CH 3 ) 2 C(CH 3 ) 3 .

13. The compound of claim 1 , wherein B is selected from a monocyclic carbocyclic or bicyclic carbocyclic moiety which is unsubstituted or substituted with one or more substituents independently chosen from R 33 and R 34 , and 0 or 1 substituents chosen from R 35 and R 36 .

14. The compound of claim 13 wherein the monocyclic carbocyclic moiety is selected from cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl or cyclopropyl optionally substituted with halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy or phenyl.

15. The compound of claim 1 , wherein B is selected from 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; wherein B is unsubstituted or substituted with one or more substituents independently chosen from R 33 and R 34 , and 0 or 1 substituents chosen from R 35 and R 36 .

16. The compound of claim 15 , wherein the 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 is selected from pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl or piperazinyl optionally substituted with halogen, cyano, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy or phenyl.

17. The compound of claim 1 , wherein B is selected from —(C 0 -C 4 alkyl)(aryl); —(C 0 -C 4 alkyl)(heteroaryl); or —(C 0 -C 4 alkyl)(biphenyl) wherein B is unsubstituted or substituted with one or more substituents independently chosen from R 33 and R 34 , and 0 or 1 substituents chosen from R 35 and R 36 .

18. The compound of claim 17 , wherein the —(C 0 -C 4 alkyl)(aryl) group is phenyl or benzyl optionally substituted with 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, C 1 -C 2 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, or -JC 3 -C 7 cycloalkyl.

19. The compound of claim 17 , wherein the —(C 0 -C 4 alkyl)(heteroaryl) group is imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl or pyrrolyl optionally substituted with 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, or -JC 3 -C 7 cycloalkyl.

20. The compound of claim 17 , wherein the —(C 0 -C 4 alkyl)(biphenyl) group is biphenyl optionally substituted with 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, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, or -JC 3 -C 7 cycloalkyl.

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

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

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

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

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

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

27. The compound of claim 1 , wherein R 32 is selected from:

28. The compound of claim 1 , wherein R 32 is selected from:

29. The compound of claim 1 , wherein R 32 is selected from

30. The compound of claim 1 , wherein R 32 is selected from

31. The compound of claim 1 , wherein R 32 is selected from

32. The compound of claim 1 , wherein R 32 is selected from

33. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 2 , wherein R 32 is selected from —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , —NR 9 C(O)NR 10 R 23 , and —NR 9 C(O)NR 24 R 25 each of which can be optionally substituted.

37. The compound of claim 36 , wherein B is selected from:

38. The compound of claim 37 , wherein the A group is