DIARYL SUBSTITUTED 5,5-FUSED RING COMPOUNDS AS C5aR INHIBITORS

The method of claim 36, wherein R1 in Formula I is selected from the group consisting of phenyl or pyridyl, wherein the group —X1—R′ is optionally substituted with 1 to 4 Rx substituents;

• ring vertices a and b are CH;
• R2b is H;
• ring vertex e is C(R2e), and R2a and R2e are independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and halogen;
• m is 0, 1 or 2 and each R3, when present, is CH3, R4 is selected from the group consisting of
• n is 0, 1 or 2 and each R5, when present, is selected from the group consisting of F, Cl, CN, CH3 and OCH3.

A method of treating a human suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I)

• or a pharmaceutically acceptable salt thereof, wherein,
• ring vertex a is N or C(R2c), ring vertex b is N or C(R2d), and ring vertex e is N or C(R2e), wherein no more than one of a, b and e is N;
• X1 is selected from the group consisting of a bond, C1-8 alkylene, C(O), C(O)—C1-4 alkylene, and S(O)2;
• R1 is selected from the group consisting of
• a) 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S;
• b) C6-10 aryl;
• c) C3-8 cycloalkyl;
• d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S;
• and
• e) C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, —C(O)NR1aR1b, and —CO2R1a;
• wherein R1a and R1b are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, and —C1-6 alkylene-C6-10 aryl;
• wherein the group —X1—R1 is optionally substituted with 1 to 5 Rx substituents;
• R2a and R2e are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, —O—C1-6 haloalkyl, —S—C1-6 alkyl, —C1-6 alkyl-O—C1-6 alkyl, —C1-6 alkyl-S—C1-6 alkyl, CN, and halogen, and at least one of R2a and R2e is other than hydrogen;
• R2b, R2c, and R2d are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, —O—C1-6 haloalkyl, —S—C1-6 alkyl, —C1-6 alkyl-O—C1-6 alkyl, —C1-6 alkyl-S—C1-6 alkyl, cyano, and halogen;
• each R3 is independently selected from the group consisting of hydroxyl, C1-4 alkyl, C1-4 haloalkyl and C1-4 hydroxyalkyl, and optionally two R3 groups on the same carbon atom are combined to form oxo (═O), and optionally two R3 groups and the carbon atoms they are attached to form a 3-6 membered ring with 0-2 hetereoatoms as ring members selected from O, N, and S;
• R4 is independently selected from the group consisting of —X2—OR4a, —X2—NR4aR4b, —X2—CONR4aR4b, —X2—NR4a—C(O)R4a, —X2—NR4a—C(O)NR4aR4b, —X2—NR4a—C(O)OR4a, —X2—NR4a—C(O)—C1-3 alkylene-OR4a and X2—NR4a—C(O)—C1-3 alkylene-NR4aR4b, wherein each X2 is independently a bond, C(O), C1-4 alkylene, C(O)—C1-4 alkylene, and C1-4 alkylene-C(O), and each R4a and R4b is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl;
• each R5 is independently selected from the group consisting of C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C1-8 haloalkoxy, C1-8 hydroxyalkyl, halogen, OH, CN, C(O)R5a and CO2R5a;
• wherein each R5a is independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl;
• each Rx is independently selected from the group consisting of halogen, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 hydroxy, C2-4 alkenyl, C3-6 cycloalkyl, CO2—C1-4 alkyl, and CONH2;
• the subscript m is 0, 1, 2, 3 or 4;
• and
• the subscript n is 0, 1, 2 or 3.