Inhibitors of 11-beta hydroxysteroid dehydrogenase type I

A method of inhibiting the enzyme 11beta-hydroxysteroid dehydrogenase type I which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of a compound of the formula I

• or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein:
• Z is aryl or heterocyclyl group, and may be optionally substituted with R1, R2, R3, R4, and R5 at any available positions;
• R1, R2, R3, R4, and R5 are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R9, —NR9C(O)R9a, —NR9R9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R9 and R9a;
• or independently any two adjoining R1, R2, R3, R4, and/or R5 may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R,0, R10a, R10b, and R10c;
• R10, R10a, R10b, and R10c are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR9R9a, —C(O)R9, —NR9C(O)R9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R9 and R9a, provided that R10, R10a, R10b, and R10c are not 3-[C(O)NR9R9a] or 3-[C(O)R9] when Q is SO2NR11R11a and R11 and R11a are taken together to form a substituted piperidinyl ring;
• R9 and R9a are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl;
• L is a bond, O, S, SO2, NR4a, OCR4aR4b, CR4aR4bO, SCR4aR4b, CR4aR4bS, SO2CR4aR4b, CR4aR4bSO2, CR4aR4bCR4cR4d, CR4a═CR4b, or OCONR4b;
• R4aR4b, R4c, and R4d are independently hydrogen, alkyl or haloalkyl, wherein the alkyl and haloalkyl may be optionally substituted with R10, R10a, R10b, and R10c;
• G is a 5- or 6-memebered heteroaryl containing at least one nitrogen;
• R6, R7, and R8 are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;
• Q is SO2NR11R11a, or OCONR11R11a;
• R11 and R11a are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R10, R10a, R10b, and R10c provided that R11 or R11a is not a 6- to 10-membered heterocyclyl containing at least one nitrogen when Q is SO2NR11R11a and the other R11 or R11a is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl;
• or R11 and R11a may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R10, R10a, R10b, and R10c.

A compound of the formula I

• or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein:
• Z is aryl or heterocyclyl group, and may be optionally substituted with R1, R2, R3, R4, and R5 at any available positions;
• R1, R2, R3, R4, and R5 are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, —C(O)R9, —NR9C(O)R9a, —NR9R9a, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R9 and R9a;
• or independently any two adjoining R1, R2, R3, R4, and/or R5 may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R10, R10a, R10b, and R10c;
• R10, R10a, R10b, and R10c are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, —C(O)NR9R9a, —C(O)R9, —NR9C(O)R9a, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R9 and R9a, provided that R10, R10a, R10b, and R10c are not 3-[C(O)NR9R9a] or 3-[C(O)R9] when Q is SO2NR11R11a and R1, and R11a are taken together to form a substituted piperidinyl ring;
• R9 and R9a are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl;
• L is a bond, O, S, SO2, NR4a, OCR4aR4b, CR4aR4bO, SCR4aR4b, CR4aR4bS, SO2CR4aR4b, CR4aR4bSO2, CR4aR4bCR4cR4d, CR4a═CR4b, or OCONR4b;
• R4a, R4b, R4c, and R4d are independently hydrogen, alkyl or haloalkyl, wherein the alkyl and haloalkyl may be optionally substituted with R10, R10a, R10b, and R10c;
• G is a 5- or 6-memebered heteroaryl containing at least one nitrogen;
• R6, R7, and R8 are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, heterocyclyl, alkoxy, aryloxy;
• Q is SO2NR11R11a or OCONR11R11a;
• R11 is hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R10, R10a, R10b, and R10c;
• R11a is haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R10, R10a, R10b, and R10c;
• provided that R11 or R11a is not a 6- to 10-membered heterocyclyl containing at least one nitrogen when Q is SO2NR11R11a and the other R11
• or R11a is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl;
• or R11 and R11a may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R10, R10a, R10b, and R10c.

The compound of 3, wherein:

• R1, R2, R3, R4, and R5 are independently hydrogen, halo, cyano, haloalkyl, haloalkoxy, nitro, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, aryloxy, or heterocyclyl, wherein the haloalkyl, haloalkoxy, alkyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, alkylamino, aryl, arylalkyl, or heterocyclyl, may be optionally substituted with R9 and R9a;
• or independently any two adjoining R1, R2, R3, R4, and/or R5 may be taken together to form a fused aryl or heterocyclyl ring, which may be may be optionally substituted with R10, R10a, R10b, and R10c;
• L is OCR4aR4b or SO2CR4aR4b;
• R4a and R4b are independently hydrogen or alkyl;
• G is a 5- or 6-membered heteroaryl containing at least one nitrogen of the following structure:
• R6, R7, and R8 are independently hydrogen, halo, haloalkyl, haloalkoxy, alkyl, aryl, or heterocyclyl;
• Q is SO2NR11R11a or OCONR11R11a;
• R11 and R11a are independently hydrogen, haloalkyl, alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl, or heterocyclyl may be optionally substituted with R10, R10a, R10b, and R10c;
• or R11 and R11a may be taken together with the nitrogen to which they are attached to form a heterocyclyl ring, which may be optionally substituted with R10, R10a, R10b, and R10c;
• R10, R10a, R10b, and R10c are independently selected from hydrogen, halo, hydroxy, nitro, cyano, haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl, wherein the haloalkyl, alkyl, cycloalkyl, aryl, aryloxy, or heterocyclyl may be optionally substituted with R9 and R9a;
• and
• R9 and R9a are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclyl may be optionally substituted with halo, haloalkyl, alkyl, aryl, or heterocyclyl.