Fused piperidinyl bicyclic and related compounds as modulators of C5a receptor

A compound having the general formula (XXI)

• and pharmaceutically acceptable salts, hydrates and rotamers thereof;
• wherein
• C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S;
• and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents;
• C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S;
• and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents;
• C3 is selected from the group consisting of C1-8 alkyl or heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocycloalkyl or heterocycloalkyl-C1-4 alkyl, wherein the heteroalkyl group has from 1-3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N and S, and each C3 is optionally substituted with from 1 to 3 R3 substituents;
• each R1 is independently selected from the group consisting of halogen, —CN, —CO2Ra, —CONRaRb, —C(O)Ra, —OC(O)NRaRb, —NRbC(O)Ra, —NRbC(O)2Rc, —NRa—C(O)NRaRb, —NRaC(O)NRaRb, —NRaRb, —ORa, and —S(O)2NRaRb;
• wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo;
• each Re is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups;
• and
• optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic or heterocyclic ring;
• each R2 is independently selected from the group consisting of halogen, —CN, —NO2, —Rf, —CO2Rd, —CONRdRe, —C(O)Rd, —OC(O)NRdRe, —NReC(O)Rd, —NReC(O)2Rf, —NRdc(O)NRdRe, —NRdRe, —ORd, and —S(O)2NRdRe;
• wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo;
• each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, and optionally when two R2 groups are on adjacent atoms, they are combined to form a five- or six-membered ring;
• each R3 is independently selected from the group consisting of halogen, —CN, —Ri, —CO2Rg, —CONRgRh, —C(O)Rg, —C(O)Rj, —OC(O)NRgRh, —NRhC(O)Rg, —NRhCO2Ri, —NRgC(O)NRgRh, —NRgRh, —ORg, —S(O)2NRgRh, —O—X4Rj, —X4—NRgRh, —X4—CONRgRh, —X4—NRhC(O)Rg, X4—CO2Rg, —O—X4—CO2Rg, —NH—X4—CO2Rg, —X4—NRhCO2R, —O—X4—NRhCO2Ri, —NHRj and —NHCH2Rj, wherein X4 is a C1-4 alkylene;
• each Rg and Rh is independently selected from hydrogen, C1-8 alkyl or heteroalkyl, C3-6 cycloalkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a four-, five- or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo;
• each Ri is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
• and
• each Rj is selected from the group consisting of C3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, and wherein the aliphatic and/or cyclic portions of Rg, Rh, Ri and are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, C1-4 alkoxy, C1-4 alkoxy-C1-4 alkyl, —C(O)O—C1-8 alkyl, amino, alkylamino and dialkylamino groups, and optionally when two R3 groups are on adjacent atoms, they are combined to form a five- or six-membered ring;
• X is hydrogen or CH3;
• and
• R8 is selected from the group consisting of chloro, C2-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• R9 is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
• or
• R8 and R9 are combined to form a fused saturated or unsaturated mono- or multi-ring carbocycle in which one or more of the ring carbon atoms may be replaced independently from each other by N, S, or O.