Diaza heterocyclic amide compounds and their uses

A method of treating a condition or disorder responsive to the inhibition of 11β-HSD1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula (I):

• a pharmaceutically acceptable salt, or stereoisomer thereof, or a mixture thereof, wherein:
• X is —C(R1)(R2)(R3)
• R1, R2 and R3 are independently selected from (C1-C3)alkyl, hydroxy, and (C1-C3)haloalkyl;
• R4 is selected from hydroxyl, (C1-C8)alkyl, (C1-C8)alkoxy, and (C3-C8)heterocycloalkyl;
• R5 is selected from hydrogen, (C1-C8)alkyl, and halogen, wherein when X is halogen, then R5 is not hydrogen;
• R6 is selected from hydrogen, (C1-C8)alkyl, aryl, heteroaryl, and (C1-C8)haloalkyl;
• R7 is selected from hydrogen and (C1-C8)alkyl;
• R8, R9 and R10 are independently selected from hydrogen, halogen, and (C1-C8)alkyl;
• optionally, R9 is combined with R6 or R7 to form a bridged bicyclic ring;
• Q is selected from the group consisting of a bond, (C3-C8)cycloalkyl Sn—(C1-C8)alkyl-Sn, and (C1-C8)alkylene optionally interrupted with one or more oxygens;
• wherein n, at each occurrence, is 0 or 1;
• Y is selected from the group consisting of hydrogen, aryl, heteroaryl, (C2-C8)alkenyl, (C3-C8)heterocycloalkyl, and (C3-C8)cycloalkyl;
• wherein when Q is a bond, then Y is not hydrogen;
• R12 is selected from hydrogen, (C1-C8)alkyl optionally interrupted with one or more oxygens, —C(O)—(C1-C8)alkyl, —SO2—(C1-C8)alkyl and (C3-C8)heterocycloalkyl(C1-C4)alkyl;
• the subscript m is 1 or 2;
• wherein any cycloalkyl portion, heterocycloalkyl portion, aryl portion or heteroaryl portion is optionally substituted with from one to four members selected from oxo, aryl(C1-C4)alkyl, heteroaryl(C1-C4)alkyl, halogen, cyano, nitro, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl, aryl, heteroaryl, —C(O)R′, —C(O)OR′, —NR′C(O)OR″, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R″, —SO2R″, —SO2N(R′)2, —N(R′)2 and —NR′C(O)R′;
• wherein each occurrence of R′ is independently hydrogen or an unsubstituted member selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl and aryl(C1-C6)alkyl;
• optionally, two R′ groups, when attached to the same nitrogen atom, is combined with the nitrogen atom to which they are attached to form a heterocycle or a heteroaryl group,
• wherein each occurrence of R″ is independently an unsubstituted member selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl and aryl(C1-C6)alkyl;
• a pharmaceutically acceptable salt, and stereoisomer thereof, or a mixture thereof.
• wherein said compound is other than
• 2-[[4-[(4-methylphenyl)sulfonyl]-1-piperazinyl]carbonyl-benzoic acid,
• 1-(4-methylbenzoyl)-4[(4-methylphenyl)sulfonyl])-piperazine,
• 1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindo-2-yl)-1-oxopropyl]-4-[(4-methylphenyl)sulfonyl]-piperazine,
• N-[2-(4-fluorophenyl)ethyl]-4-[(4-methylphenyl)sulfonyl]-gamma-oxo-1-piperazinebutanamide,
• 3-chloro-N-(2-[4-[(4-methylphenyl)sulfonyl]-1-piperazineyl]-2-oxoethyl]-5-nitro benzamide,
• 1-[[4-(2-methylphenyl)-5-(4-pyridinyl)-4H-1,2,4-triazol-3-ylthio]acetyl]-4-[(4methylphenyl)sulfonyl]-piperazine,
• 1-[[[3,4-3,4-dihydro-4-oxo-3-phenyl-2-quinazolinyl ]thio]acetyl]-4[(4-methylphenyl)sulfonyl]-piperazine,
• 1-[(4-methylphenyl)sulfonyl]-4-[[5,6,7,8-tetrahydro[1]benzothieno[2,3-d]-pyrimidin-4-yl)thio]acetyl]-piperazine,
• 1-[[[3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]thio]acetyl]-4-[[4-methylphenyl)sulfonyl]-piperazine,
• 1-[(2,4-dimethylphenyl)sulfonyl]-4-(phenylacetyl)-piperazine or
• 2-(methylthio)-2-[4-[(4-methylphenyl)sulfonyl]-1-piperazinyl]-2-oxoethyl benzoic acid;
• and
• said condition or disorder is diabetes, syndrome X, obesity, hypertriglyceridemia, hyperinsulinemia, age-related cognitive disorders, dementia, depression, osteoporosis, an inflammatory disorder or an immune disorder.