Diaryltriazoles as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1

1. A compound of structural formula II:

or a pharmaceutically acceptable salt thereof; wherein

each n is 0, 1, or 2;

each p is 0, 1, or 2;

R 8 is naphthyl or heteroaryl wherein heteroaryl is selected from the group consisting of

pyridyl,

thienyl,

furyl,

pyrazolyl,

thiazolyl,

oxazolyl,

imidazolyl,

indolyl,

benzothiophenyl,

benzofuryl, and

benzimidazolyl;

in which naphthyl and heteroaryl are substituted with one to three substituents independently selected from R 3 , R 4 , and R 5 ;

R 2 is methyl or cyclopropyl;

R 3 , R 4 , and R 5 are each independently selected from the group consisting of

hydrogen,

formyl,

C 1-6 alkyl,

C 2-6 alkenyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C 3-7 cycloalkyl,

halogen,

OR 7 ,

(CH 2 ) n N(R 7 ) 2 ,

cyano,

(CH 2 ) n CO 2 R 7 ,

NO 2 ,

(CH 2 ) n NR 7 SO 2 R 6 ,

(CH 2 ) n SO 2 N(R 7 ) 2 ,

(CH 2 ) n S(O) p R 6 ,

(CH 2 ) n SO 2 OR 7 ,

(CH 2 ) n NR 7 C(O)N(R 7 ) 2 ,

(CH 2 ) n C(O)N(R 7 ) 2 ,

(CH 2 ) n NR 6 C(O)R 6 ,

(CH 2 ) n NR 6 CO 2 R 7 ,

O(CH 2 ) n C(O)N(R 7 ) 2 ,

CF 3 ,

CH 2 CF 3 ,

OCF 3 ,

OCHCF 2 , and

OCH 2 CF 3 ;

wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 3 , R 4 , and R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

each R 6 is independently selected from the group consisting of

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl, and

(CH 2 ) n C 3-7 cycloalkyl;

wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C 1-4 alkoxy, C 1-4 alkylthio, hydroxy, amino; and aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from cyano, halogen, hydroxy, amino, carboxy, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy;

or two R 6 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl; and

each R 7 is hydrogen or R 6 .

2. The compound of claim 1 wherein R 2 is methyl.

3. The compound of claim 1 wherein R 8 is indolyl or pyrazolyl substituted with one to three substituents independently selected from R 3 .

4. The compound of claim 3 wherein R 2 is methyl.

5. A compound which is selected from the group consisting of:

4-methyl-3,5-bis[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-[4-(methylthio)-2-(trifluoromethyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-(4-pentylphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(1-methoxy-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole;

4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}-1-methyl-1H-indole;

3-(2-bromophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(7-chloro-1-methoxy-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)-4H-1,2,4-triazole;

4-[4-methyl-5-(1-methyl-1H-indol-4-yl)-4H-1,2,4-triazol-3-yl]phenol;

3-(2,4-dichlorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-[2,4-bis(trifluoromethyl)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-5-(2,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-(2-chloro-4-fluorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2,4-dichlorophenyl)-4-methyl-5-[2-(methylthio)phenyl]-4H-1,2,4-triazole;

3-(2,4-dichlorophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole;

3-(2-chlorophenyl)-5-[5-(2-chlorophenyl)-1-methyl-1H-pyrazol-3-yl]-4-methyl-4H-1,2,4-triazole;

4-[5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methyl-1H-indole;

4-methyl-3-(2-methyl-1-naphthyl)-5-[2-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazole;

3-(1,4-dichloro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(4-chloro-1-methoxy-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(1-fluoro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

N-methyl-2-{4-methyl-5-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}naphthalen-1-amine;

3,5-bis-(2,4-dimethylphenyl)-4-methyl-4H-1,2,4-triazole;

3-(2,4-dichlorophenyl)-5-[2-(ethylthio)phenyl]-4-methyl-4H-1,2,4-triazole;

3-(2-cyclopropylphenyl)-5-(2,4-dichlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-[(2-chloro-4-(ethylthio)phenyl)]-5-(2-fluorophenyl)-4-methyl-4H-1,2,4-triazole;

3-(2-methoxyphenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2,6-dichlorophenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-5-[(2-difluoromethoxy)phenyl]-4-methyl-4H-1,2,4-triazole;

3-(2-chloro-4-fluorophenyl)-5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-(2,4-dichlorophenyl)-5-[(2-difluoromethoxy)phenyl]-4-methyl-4H-1,2,4-triazole;

4-methyl-3-(2-phenoxyphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-[2-(trifluoromethoxy)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-[2-(prop-2-yn-1-yloxy)phenyl]-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-{2-[(4-chlorophenyl)thio]phenyl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-[2-(difluoromethoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-ethoxyphenyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-(2-propoxyphenyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3,5-bis(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole;

3,5-bis(2,3-dichlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-(3-chloro-2-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(5-chloro-6-methoxy-1-naphthyl)-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-[4-(4-chlorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-[4-chloro-5-(2-chlorophenyl)-1-methyl-1H-pyrazol-3-yl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

4-methyl-3-(2,4,6-trichloro-1-naphthyl)-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-4-methyl-5-[2-(trifluoromethoxy)phenyl]-4H-1,2,4-triazole;

3-(2-bromophenyl)-5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazole;

3-(2,3-dichlorophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole;

3-(2,3-dichlorophenyl)-5-(2-methoxyphenyl)-4-methyl-4H-1,2,4-triazole;

3-(2-bromophenyl)-4-methyl-5-(2-methylphenyl)-4H-1,2,4-triazole;

4-methyl-3-(2-methylphenyl)-5-[2-(trifluoromethoxyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-4-cyclopropyl-5-[(2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(4-chloro-3-methoxy-2-naphthyl)-4-methyl-5-[(2-(methylthio)phenyl]-4H-1,2,4-triazole;

3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[(2-(methylthio)phenyl]-4H-1,2,4-triazole;

3-[2-(4-chlorophenoxy)phenyl]-4-methyl-5-[(2-(methylsulfonyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-5-(2,3-dichlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-(2-bromophenyl)-5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazole;

3-[2-(4-fluorophenoxy)phenyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;

3-(2-chlorophenyl)-5-[2-chloro-3-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazole; and

4-[4-methyl-5-(1,2,3-trimethyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl]phenol;

or a pharmaceutically acceptable salt thereof.