Inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme

A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof

• wherein
• one of A1, A2, A3 and A4 is selected from the group consisting of alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl1, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl, heterocyclealkyl, heterocycleoxyalkyl, —S(C)2—N(R5R6), —NR7—[C(R8R9)]n—C(O)—R10, —O—[C(R11R12)]p—C(O)—R13, —OR14a, —N(R15R16), —CO2R17, —C(O)—N(R18R19), —C(R20R21)—OR22, —C(R23R24)—N(R25R26), and heterocycle, with the exception that 5 membered heterocycles may not contain two oxygen atoms, and the remaining members of the group consisting of A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl, heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl, aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, —S(O)2—N(R5R6), —NR7—[C(R8R9)]n—C(O)—R10, —O—[C(R11R12)]p—C(O)—R13, —OR]14b, —N(R15R16), —CO2R17, —C(O)—N(R18R19), —C(R20R21)—OR22, and —C(R23R24)—N(R25R26);
• n is 0 or 1;
• p is 0 or 1;
• D is selected from the group consisting of a bond, —C(R27R28)—X— and —C(R27R28)—C(R29R30)—X—;
• E is selected from the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and the heterocycle are appended to the parent molecular moiety through an available carbon atom, or R4 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• X is selected from the group consisting of a bond, —N(R31)—, —O—, —S—, —S(O)— and —S(O)2—;
• R1 is selected from the group consisting of hydrogen and alkyl;
• R2 is selected from the group consisting of hydrogen, alkyl and cycloalkyl;
• R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• R5 and R6 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R5 and R6 together with the atom to which they are attached form a heterocycle;
• R7 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
• R8 and R9 are each independently selected from the group consisting of hydrogen and alkyl, or R8 and R9 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• R10 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and —N(R32R33);
• R11 and R12 are each independently selected from the group consisting of hydrogen and alkyl or R11 and R12 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• R13 is selected from the group consisting of hydroxy and —N(R34R35);
• R14ais selected from the group consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
• R14bis selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
• R15 and R16 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R15 and R16 together with the atom to which they are attached form a heterocycle;
• R17 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
• R18 and R19 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, alylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R18 and R19 together with the atom to which they are attached form a heterocycle;
• R20, R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
• R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
• R25 and R26 are each independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or R25 and R26 together with the nitrogen to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
• R27 and R28 are each independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heteroaryl and heterocycle or R27 and R28 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R27 and R29 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R28 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• R29 and R30are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and —N(R36R37), or R29 and R30 together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and R4 together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle, or R29 and E together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
• R31 is selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R31 and E together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle, or R31 and R4 together with the atoms to which they are attached form a heterocycle;
• R32 and R33 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R32 and R33 together with the atom to which they are attached form a heterocycle;
• R34 and R35 are each independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or R34 and R35 together with the atom to which they are attached form a heterocycle;
• and
• R36 and R37 are each independently selected from the group consisting of hydrogen, alkyl and aryl.