Tetrahydropyrido-pyridine and tetrahydropyrido-pyrimidine compounds and use thereof as C5A receptor modulators

1. A compound of formula (I) or a salt thereof:

wherein

X is N or CH;

Z 1 is N or CR 1c ;

Z 2 is N or CR 1d , wherein at least one of Z 1 and Z 2 is not N;

R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, cyano or halogen;

R 1b is selected from the group consisting of hydrogen, amino, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and mono- and di-C 1 -C 4 alkylamino;

R 1c is hydrogen, halogen or C 1 -C 6 alkyl;

R 1d is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

R 1e is selected from hydrogen, halogen, cyano, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxy and haloC 1 -C 6 alkoxy, sulfone, C 3 -C 7 cycloalkyl; or

R 1a and R 1b taken in combination form a 5 member saturated or unsaturated heterocyclic ring having one or two ring heteroatoms selected from N, O or S, which heterocyclic ring is substituted with 0, 1, or 2 independently selected C 1 -C 6 alkyl or halogen substituents;

wherein at least one of R 1a and R 1e is not hydrogen;

R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 4 alkyl and (CH 2 ) p NR 2a R 2b , wherein each alkyl and alkoxy group is substituted with 0 or 2 substituents selected from the group consisting of hydroxy, halogen, and C 1 -C 4 alkoxy, amino, mono- and di-C 1 -C 4 alkylamino;

p is 0 or 1;

R 2a is hydrogen, C 1 -C 6 alkyl or hydroxyC 1 -C 6 alkyl;

R 2b is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkylC 1 -C 4 alkyl, wherein each alkyl is unsubstituted or substituted with hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, or heterocycle wherein the heterocycle is a saturated, unsaturated or aromatic five or six member ring having 1 or 2 ring heteroatoms selected from N, O or S and is unsubstituted or substituted with 1 or 2 independently selected C 1 -C 4 alkyl substituents; or

NR 2a R 2b taken in combination form a 4 to 8 member saturated heterocyclic ring system having 1 or 2 rings and 0 or 1 additional ring heteroatoms selected from N, O or S, the saturated heterocyclic ring system is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, halogen, amino, mono- and di-C 1 -C 4 alkylamino, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoyl, S(O) 2 C 1 -C 4 alkyl, CH 2 C(O)(C 1 -C 4 alkoxy) and CH 2 C(O)NH 2 ;

R 3 is selected from the group consisting of substituted phenyl, substituted heteroaryl, and phenylC 1 -C 3 alkyl, wherein the heteroaryl is selected from pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, and isoxazolyl, and wherein each phenyl or heteroaryl group is substituted with 1, 2 or 3 substituents which are independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, cyano, haloC 1 -C 4 alkyl, haloC 1 -C 4 alkoxy, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and saturated oxacycle having 4, 5, or 6 ring atoms and one ring oxygen, which oxacycle is unsubstituted or substituted with 1 or 2 independently selected C 1 -C 4 alkyl substituents, and wherein each phenyl or heteroaryl comprises at least one non-hydrogen substituent ortho to the point of attachment to the remainder of the compound of formula (I);

R 4 is hydrogen or C 1 -C 4 alkyl;

R 5 is hydrogen; or

R 4 and R 5 taken in combination are oxo; and

R 6 is hydrogen at each occurrence or CR 6 2 , taken in combination, form a divalent carbonyl.

2. A compound of claim 1 , which is a compound of formula (II) or formula (III), or a salt thereof:

wherein

Z 1 is N or CH;

Z 3 is N(H), N(C 1 -C 4 alkyl), or C(R 1f );

Z 4 is N or CH;

Z 5 is N(H), N(C 1 -C 4 alkyl) or C(R 1g ), wherein one or two of Z 3 , Z 4 and Z 5 is nitrogen;

R 1f is hydrogen, C 1 -C 4 alkyl or halogen; and

R 1g is hydrogen or C 1 -C 4 alkyl.

3. A compound of claim 1 , in which R 3 is phenyl or 1H-pyrazolyl, each of which is substituted with 1 or 2 independently selected C 1 -C 4 alkyl groups and 0, 1 or 2 additional substituents selected from the group consisting of halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclopropyl, oxetanyl or 1-methyl-oxetanyl.

4. The compound of claim 2 , in which R 1a is hydrogen or methyl;

R 1e is hydrogen, halogen, cyano, methyl or trifluoromethyl, wherein at least one of R 1a and R 1e is not hydrogen;

Z 3 is C(R 1f );

Z 4 is N or CH;

Z 5 is N(H); and

R 1f is hydrogen or methyl.

5. The compound of claim 1 , wherein the

fragment of Formula (I) is selected from the group consisting of 2,6-dimethylphenyl, 2,6-diethylphenyl, 3,5-dimethyl-1H-indazol-4-yl, 3,5-dimethyl-1H-indol-4-yl, 3,5-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl and 5-trifluoromethyl-3H-pyrrolo[2,3-b]pyridin-4-yl.

6. The compound of claim 1 , in which R 4 is hydrogen.

7. The compound of claim 1 , in which X is N.

8. The compound of claim 1 , in which X is CH.

9. The compound of claim 1 , in which R 2 is hydrogen or methyl.

10. A compound of claim 1 , or a salt thereof, in which R 6 is deuterium.

11. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of claim 1 .