Macrocyclic compounds for inhibition of tumor necrosis factor alpha

1. A compound represented by formula VII:

including pharmaceutically acceptable salts thereof, wherein:

R 50 is benzyl, phenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl -4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl, wherein the benzyl, biphenyl-4-yl or phenylethyl group in R 50 is optionally substituted on a terminal phenyl ring with a single substituent selected from the group consisting of halo, methoxy, CF 3 , hydroxy, cyano, and C 1 -C 4 alkyl; or is optionally substituted with chloro at each of the 2 and 4 positions of the terminal phenyl ring;

R 51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, or 4-(pyridin-3-yl)benzyl, wherein the biphenyl group in R 51 is optionally monosubstituted at the 4-position of the terminal phenyl ring with amino, halo or hydroxy;

R 52 is phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, heteroarylmethyl, 4-(heteroaryl)benzyl, or biphenyl-4-ylmethyl, wherein the phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl or biphenyl-4-ylmethyl group in R 52 is optionally on a terminal phenyl ring with 1 to 2 substituents independently selected from the group consisting of halo, methoxy, hydroxy, C 1 -C 4 alkyl, and C 1 -C 4 haloalkyl;

R 53 is hydrogen or methyl;

X is —OH, —N(R W )—[C(R V ) 2 ] 1-4 —COOH, —N(R W )—[C(R V ) 2 ] 1-3 —SO 3 H, —N(R W )—[C(R V ) 2 ] 0-4 —S(O) 2 CH 3 , or —N(R W )—[C(R V ) 2 ] 1-3 -1H-tetrazol-5-yl, wherein:

R W represents hydrogen, methyl or benzyl; and

each R V independently represents hydrogen, —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkyl-heterocyclyl, —(C 1 -C 6 )-alkyl-carbocyclyl, or —CO 2 -alkyl, wherein each R V is optionally substituted with a substituent selected independently from the group consisting of —NH 2 , —NH—C(O)—(C 1 -C 4 )-alkyl and —OH; or

two R V are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring,

the stereochemistry at (1) is the same as the stereochemistry at (3); and

the stereochemistry at (1) is opposite the stereochemistry at (2).

2. The compound of claim 1 , wherein:

R 50 is benzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2,4-dichlorobenzyl, 3-methoxybenzyl, 4-hydroxybenzyl, 4-cyanobenzyl, 4-methoxybenzyl, 4-t-butylbenzyl, phenylethyl, 2-fluorophenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl;

R 51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(4-aminophenyl)benzyl, 4-(4-bromophenyl)benzyl, 4-(4-fluorophenyl)benzyl, or 4-(4-hydroxyphenyl)benzyl;

R 52 is 2,4-dichlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, biphenyl-4-ylmethyl, indol-3-ylmethyl, thien-2-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(pyridin-2-yl)benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, naphthyl, naphthylmethyl, phenylethyl, thiazol -3ylmethyl, 4-(thien-2-yl)benzyl, furan-2ylmethyl, N-phenyl-1H-triazol-4ylmethyl, 4-(4-fluorophenyl)benzyl, or 4-(4-chlorophenyl)benzyl; and

X is —N(CH 3 )CH 2 SO 3 H, —N(CH 3 )CH(benzyl)COOH, —N(CH 3 )CH(CH 3 )COOH, —NHCH 2 COOH, —NHCH 2 SO 3 H, —NHCH 2 -1H-tetrazol-5-yl, —NH(CH 2 ) 2 COOH, —NH(CH 2 ) 2 SO 3 H, —NH(CH 2 ) 3 COOH, —NH(CH 2 ) 3 SO 3 H, —NH(CH 2 ) 2 -1H-tetrazol-5-yl, —NHCH(4-hydroxybenzyl)COOH, —NHCH(benzyl)COOH, —NHCH(benzyl)-1H-tetrazol-5-yl, —NHCH(CH 2 OH)COOH, —NHCH(phenylethyl)COOH, or —NHS(O) 2 CH 3 .

3. The compound of claim 1 , wherein the compound is Compound 482:

4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.