Pyridine analogs as C5A antagonists

Abstract

The present invention provides novel compounds of Formula I which are antagonists of the C5a receptor. Compounds of the present invention are useful for the treatment of various C5a-mediated diseases and disorders; accordingly the present invention provides a method for the treatment of C5a-mediated diseases using the novel compounds described herein, as well as pharmaceutical compositions containing them.

1 .- 26 . (canceled) 
   
   
       27 . A compound of Formula I 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salts thereof; 
       k is 0, 1, 2 or 3; 
       R 2  and R 3  are each hydrogen; 
       R 1  is selected from the group consisting of
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) —OC 1-6 alkyl, 
 (4) —SC 1-6 alkyl, 
 (5) —C 2-6 alkenyl, 
 (6) —C 3-6 cycloalkyl, 
 (7) aryl, 
 (8) heteroaryl, 
 (9) heterocyclic, 
 (10) —C 1-6 alkylaryl, 
 (11) —C 1-6 alkylheteroaryl 
 (12) —C 1-6 alkylheterocyclic, 
 (13) —O-aryl, 
 (14) —O-heteroaryl, 
 (15) —O-heterocyclic, 
 (16) —OC 1-6 alkylaryl, 
 (17) —OC 1-6 alkylheteroaryl 
 (18) —OC 1-6 alkylheterocyclic, 
 (19) halo, 
 (20) —CN, 
 (21) —NO 2 , 
 (22) —C(O)—C 1-6 alkyl, 
 (23) —C(O)-aryl, 
 (24) —C(O)-heteroaryl, 
 (25) —C(O)-heterocyclic, 
 (26) —C(O)—C 1-6 alkyl, 
 (27) —NH—C 1-6 alkyl, 
 (28) —N(C 1-6 alkyl)(C 1-6 alkyl) 
 (29) —C(O)—NH 2 , 
 (30) —C(O)—NH—C 1-6 alkyl, 
 (31) —C(O)—N(C 1-6 alkyl)(C 1-6 alkyl), and 
 (32) S(O)n-C 1-6 alkyl, 
 
       wherein definitions (1) to (18) and (22) to (32) are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxyl, —CN, —NO 2 , NH 2 , 
       R 4  and R 5  are each independently selected from the group consisting of
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) —OC 1-6 alkyl, 
 (4) —SC 1-6 alkyl, 
 (5) —C 2-6 alkenyl, 
 (6) —C 3-6 cycloalkyl, 
 (7) aryl, 
 (8) heteroaryl, 
 (9) heterocyclic, 
 (10) —C 1-6 alkylaryl, 
 (11) —C 1-6 alkylheteroaryl 
 (12) —C 1-6 alkylheterocyclic, 
 (13) —O-aryl, 
 (14) —O-heteroaryl, 
 (15) —O-heterocyclic, 
 (16) —OC 1-6 alkylaryl, 
 (17) —OC 1-6 alkylheteroaryl, 
 (18) —OC 1-6 alkylheterocyclic, 
 (19) halo, 
 (20) —CN, 
 (21) —NO 2 , 
 (22) —C(O)—C 1-6 alkyl, 
 (23) —C(O)-aryl, 
 (24) —C(O)-heteroaryl, 
 (25) —C(O)-heterocyclic, 
 (26) —C(O)—C 1-6 alkyl, 
 (27) NH 2 , 
 (28) —NH—C 1-6 alkyl, 
 (29) —N(C 1-6 alkyl)(C 1-6 alkyl) 
 (30) —C(O)—NH 2 , 
 (31) —C(O)—NH—C 1-6 alkyl, 
 (32) —C(O)—N(C 1-6 alkyl)(C 1-6 alkyl), 
 (33) —SH, and 
 (34) S(O)n-C 1-6 alkyl, wherein n is 1 or 2; 
 
       wherein definitions (1) to (18) and (22) to (32) and (34) are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxyl, —CN, —NO 2 , NH 2 ; 
       R 6  is hydrogen or C 1-3 alkyl, optionally substituted with 1, 2 or 3 substituents selected from 
       R 6  is hydrogen or C 1-3 alkyl, optionally substituted with 1, 2 or 3 substituents selected from
 (1) -halo, 
 (2) —NR 7 R 8 , 
 (3) aryl, 
 (4) —OC 1-3 alkyl, 
 (5) —SC 1-3 alkyl, and 
 (6) —S(O) 2 C 1-3 alkyl, 
 (7) hydroxyl; 
 
       each R 7  and each R 8  are each independently hydrogen or C 1-3 alkyl, optionally substituted with 1, 2 or 3 substituents selected from
 (1) -halo, 
 (2) C 1-3 alkyl, 
 (3) —OC 1-6 alkyl, 
 (4) —SC 1-6 alkyl, 
 (5) —S(O) 2 C 1-6 alkyl, 
 
       Ar is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substitutents selected from
 (1) -halo, 
 (2) C 1-6 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (3) —NR 7 R 8 , 
 (4) aryl, 
 (5) —OC 1-6 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (6) —SC 1-6 alkyl, 
 (7) —S(O) 2 C 1-6 alkyl; 
 
       Ar 1  is aryl or heteroaryl or C 3-6 cycloalkyl, optionally substituted with 1, 2 or 3 substitutents selected from
 (1) -halo, 
 (2) C 1-6 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (3) —NR 7 R 8 , 
 (4) aryl, 
 (5) —OC 1-6 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (6) —SC 1-6 alkyl, and 
 (7) —S(O) 2 C 1-6 alkyl. 
 
     
   
   
       28 . A compound of  claim 27  wherein:
 R 1  is selected from the group consisting of
 (1) —C 1-6 alkyl, 
 (2) —OC 1-6 alkyl, 
 (3) —SC 1-6 alkyl, 
 (4) —C 2-6 alkenyl, and 
 (5) —C 3-6 cycloalkyl; 
   wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxyl, —CN, —NO 2 , and NH 2 .   
   
   
       29 . A compound according to  claim 27  wherein:
 R 4  and R 5  are each hydrogen.   
   
   
       30 . A compound according to  claim 27  wherein:
 k is 1.   
   
   
       31 . A compound according to  claim 27  wherein Ar and Ar 1  are each independently an optionally substituted phenyl or pyridyl. 
   
   
       32 . A compound according to  claim 27  wherein:
 R 1  is selected from the group consisting of
 (1) —C 1-3 alkyl, 
 (2) —OC 1-3 alkyl, 
 (3) —SC 1-3 alkyl, 
 (4) —C 2-4 alkenyl, and 
 (5) —C 3-6 cycloalkyl; 
   wherein definitions (1) to (5) are optionally substituted with 1, 2 or 3 substituents selected from the group consisting of halo, hydroxyl, —CN, —NO 2 , and NH 2 .   
   
   
       33 . A compound according to  claim 27  wherein:
 Ar and Ar 1  are each optionally substituted with 1, 2 or 3 substituents selected from
 (1) -halo, 
 (2) C 1-4 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (3) —NR 7 R 8 , 
 (4) phenyl, 
 (5) —OC 1-4 alkyl, optionally substituted with 1, 2, 3 or 4 halo groups, 
 (6) —SC 1-4 alkyl; and 
 R 7  and R 8  are each independently hydrogen or methyl. 
   
   
   
       34 . A pharmaceutical composition comprising a compound according to  claim 27  or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
   
   
       35 . A Method of treatment or prevention of a C5a mediated disease or disorder comprising administering to a subject in need of such treatment or prevention, a therapeutically effective amount of a compound according to claim  1  or a pharmaceutically acceptable salt. 
   
   
       36 . A Method of antagonizing C5a in a subject, comprising administering to a subject in need of such antagonism, a therapeutically effective amount of a compound according to  claim 27  or a pharmaceutically acceptable salt. 
   
   
       37 . A method according to  claim 27 , wherein the disease or disorder is rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, ischemic heart diseases, reperfusion injury, sepsis, psoriasis, atherosclerosis, inflammatory bowel diseases, adult respiratory distress syndrome, asthma, COPD and Alzheimer's disease.