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

A compound of structural formula I:

• or a pharmaceutically acceptable salt or solvate 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 and R2 are each independently selected from the group consisting of 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;
• or R1 and R2 together with the atoms to which they are attached form a fused 7- to 11-membered non-aromatic heterocyclic ring optionally fused with a benzo ring system and optionally containing an additional heteroatom selected from oxygen, sulfur, and nitrogen;
• or R1 and R2 together with the atoms to which they are attached form a fused 4-azatricyclo[4.3.1.13,8]undecane ring;
• said fused ring systems being unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-3 alkyl, and C1-3 alkoxy;
• 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, (CH2)n-heteroaryl, and (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 each 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;
• or two R5 substituents together with the atoms to which they are attached form a 5- to 8-membered ring optionally containing 1-2 heteroatoms independently selected from oxygen, sulfur, and nitrogen;
• 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, and 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 NC0-4 alkyl;
• and
• each R7 is hydrogen or R6.