Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1

A compound of structural formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein
• each p is independently 0, 1, or 2;
• each n is independently 0, 1, or 2;
• X is selected from the group consisting of a single bond, O, S(O)p, NR6,
• R1 is selected from the group consisting of
• arylcarbonyl,
• (CH2)n-aryl, and
• (CH2)n-heteroaryl;
• in which aryl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R5;
• R2 is selected from the group consisting of
• hydrogen,
• C1-8 alkyl,
• C2-6 alkenyl, and
• (CH2)n—C3-6 cycloalkyl;
• in which alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R8 and oxo;
• each R4 is independently selected from the group consisting of
• hydrogen,
• halogen,
• hydroxy,
• oxo,
• C1-3 alkyl, and
• C1-3 alkoxy;
• R3 is selected from the group consisting of
• hydrogen,
• C1-10 alkyl,
• C2-10 alkenyl,
• (CH2)n—C3-6 cycloalkyl,
• (CH2)n-aryl, and
• (CH2)n-heteroaryl;
• (CH2)n-heterocyclyl;
• in which aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from R5;
• and alkyl, alkenyl, and cycloalkyl are unsubstituted or substituted with one to five groups independently selected from R8 and oxo;
• R5 and R8 are independently selected from the group consisting of
• hydrogen,
• formyl,
• C1-6 alkyl,
• (CH2)n-aryl,
• (CH2)n-heteroaryl,
• (CH2)n-heterocyclyl,
• (CH2)nC3-7 cycloalkyl,
• halogen,
• OR7,
• (CH2)nN(R7)2,
• cyano,
• (CH2)nCO2R7,
• NO2,
• (CH2)nNR7SO2R6,
• (CH2)nSO2N(R7)2,
• (CH2)nS(O)pR6,
• (CH2)nSO2OR7,
• (CH2)nNR7C(O)N(R7)2,
• (CH2)nC(O)N(R7)2,
• (CH2)nNR6C(O)R6,
• (CH2)nNR6CO2R7,
• O(CH2)nC(O)N(R7)2,
• CF3,
• CH2CF3,
• OCF3,
• OCHCF2, and
• OCH2CF3;
• wherein aryl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, trifluoromethoxy, and C1-4 alkoxy;
• and wherein any methylene (CH2) carbon atom in R5 and R8 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
• or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
• each R6 is independently selected from the group consisting of
• C1-8 alkyl,
• (CH2)n-aryl,
• (CH2)n-heteroaryl, and
• (CH2)nC3-7 cycloalkyl;
• wherein alkyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, oxo, C1-4 alkoxy, C1-4 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, C1-4 alkyl, and C1-4 alkoxy;
• or two R6 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 NC1-4 alkyl;
• and
• each R7 is hydrogen or R6.