Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use

摘要

Disclosed are compounds represented by Formula (I):;or pharmaceutically acceptable salts, enantiomers or diastereomers thereof. Also disclosed are pharmaceutical compositions comprising the compounds of Formula (I) or pharmaceutically acceptable salts, enantiomers or diastereomers thereof for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. Values for the variables of Formula (I) are defined herein.

主权项

1. A compound represented by the following structural formula:or a pharmaceutically acceptable salt thereof, wherein:
Cy1 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from halogen, cyano, nitro, amino, hydroxy, carboxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C3-6-cycloalkyl, C3-6-cycloalkoxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-cycloalkyl, hydroxy-C2-6-alkenyl, hydroxy-C1-6-alkoxy, —R9, C4-7-cycloalkyl-C1-6-alkoxy, halo-C1-6-alkoxy, halo-C3-6-cycloalkoxy, halo-C4-7-cycloalkyl-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, halo-C1-6-alkoxy-C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkylthio, —SR9, —S(═O)R6, —S(═O)R7, —S(═O)R9, —S(═O)2R6, —S(═O)2R7, —S(═O)2R9, —NHR6, —N(R6), —C(═O)R6, —C(═O)O—C1-6-alkyl, —C(═O)NH2, —S(═O)2NH2, —C(═O)NHR6, —C(═O)NR6R6, —C(═O)R8, —S(═O)2NHR6, —S(═O)2N(R6)2, —S(═O)2R8, —NHC(═O)R6, —NHC(═O)O—C1-6-alkyl, —V1—NHC(═O)R6, —V1—NHC(═O)O—C1-6-alkyl, —NHS(═O)2R6, —V1—NHS(═O)2R6, —V1—C(═O)R6, —V1—C(═O)O—C1-6-alkyl, heteroaryl, aryl, heterocyclyl, oxo, —V1—NH2, —V1—NHR6, —V1—N(R6)2, —C(═O)R7, —C(═O)O—C3-6-cycloalkyl, —C(═O)NHR7, —C(═O)NR6R7, —C(═O)N(R7)2, —S(═O)2NHR7, —S(═O)2NR6R7, —S(═O)2N(R7)2, cyano-C1-6-alkyl, —V1—C(═O)NH2, —V1—C(═O)NHR6, —V1—C(═O)N(R6)2, —V1—C(═O)NHR7, —V1—C(═O)NR6R7 and —V1—C(═O)N(R7)2; Cy2 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from halogen, cyano, nitro, amino, hydroxy, carboxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C3-6-cycloalkyl, C3-6-cycloalkoxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-cycloalkyl, hydroxy-C2-6-alkenyl, hydroxy-C1-6-alkoxy, —R9, C4-7-cycloalkyl-C1-6-alkoxy, halo-C1-6-alkoxy, halo-C3-6-cycloalkoxy, halo-C4-7-cycloalkyl-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, halo-C1-6-alkoxy-C1-6-alkoxy, C1-6-alkylthio, —C3-6-cycloalkylthio, —SR9, —S(═O)R6, —S(═O)R7, —S(═O)R9, —S(═O)2R6, —S(═O)2R7, —S(═O)2R9, —NHR6, —N(R6), —C(═O)R6, —C(═O)O—C1-6-alkyl, —C(═O)NH2, —S(═O)2NH2, —C(═O)NHR6, —C(═O)NR6R6, —C(═O)R8, —S(═O)2NHR6, —S(═O)2N(R6)2, —S(═O)2R8, —NHC(═O)R6, —NHC(═O)O—C1-6-alkyl, —V1—NHC(═O)R6, —V1—NHC(═O)O—C1-6-alkyl, —NHS(═O)2R6, —V1—NHS(═O)2R6, —V1—C(═O)R6, —V1—C(═O)O—C1-6-alkyl, heteroaryl, aryl, heterocyclyl, oxo, —V1—NH2, —V1—NHR6, —V1—N(R6)2, —C(═O)R7, —C(═O)O—C3-6-cycloalkyl, —C(═O)NHR7, —C(═O)NR6R7, —C(═O)N(R7)2, —S(═O)2NHR7, —S(═O)2NR6R7, —S(═O)2N(R7)2, cyano-C1-6-alkyl, —V1—C(═O)NH2, —V1—C(═O)NHR6, —V1—C(═O)N(R6)2, —V1—C(═O)NHR7, —V1—C(═O)NR6R7, and —V1—C(═O)N(R7)2; Cy3 is cycloalkyl, which is substituted with 1 to 4 groups independently selected from halogen, cyano, nitro, amino, hydroxy, carboxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C3-6-cycloalkyl, C3-6-cycloalkoxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-cycloalkyl, hydroxy-C2-6-alkenyl, hydroxy-C1-6-alkoxy, —R9, C4-7-cycloalkyl-C1-6-alkoxy, halo-C1-6-alkoxy, halo-C3-6-cycloalkoxy, halo-C4-7-cycloalkyl-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, halo-C1-6-alkoxy-C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkylthio, —SR9, —S(═O)R6, —S(═O)R7, —S(═O)R9, —S(═O)2R6, —S(═O)2R7, —S(═O)2R9, —NHR6, —N(R6), —C(═O)R6, —C(═O)O—C1-6-alkyl, —C(═O)NH2, —S(═O)2NH2, —C(═O)NHR6, —C(═O)NR6R6, —C(═O)R8, —S(═O)2NHR6, —S(═O)2N(R6)2, —S(═O)2R8, —NHC(═O)R6, —NHC(═O)O—C1-6-alkyl, —V1—NHC(═O)R6, —V1—NHC(═O)O—C1-6-alkyl, —NHS(═O)2R6, —V1—NHS(═O)2R6, —V1—C(═O)R6, —V1—C(═O)O—C1-6-alkyl, heteroaryl, aryl, heterocyclyl, oxo, —V1—NH2, —V1—NHR6, —V1—N(R6)2, —C(═O)R7, —C(═O)O—C3-6-cycloalkyl, —V1—S(═O)2R6, —C(═O)NHR7, —C(═O)NR6R7, —C(═O)N(R7)2, —S(═O)2NHR7, —S(═O)2NR6R7, —S(═O)2N(R7)2, cyano-C1-6-alkyl, carboxy-C1-6-alkyl, —V1—C(═O)NH2, —V1—C(═O)NHR6, —V1—C(═O)N(R6)2, —V1—C(═O)NHR7, —V1—C(═O)NR6R7, and —V1—C(═O)N(R7)2; or heterocyclyl, which is optionally substituted with 1 to 4 groups independently selected from halogen, cyano, nitro, amino, hydroxy, carboxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C3-6-cycloalkyl, C3-6-cycloalkoxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-cycloalkyl, hydroxy-C2-6-alkenyl, hydroxy-C1-6-alkoxy, —R9, C4-7-cycloalkyl-C1-6-alkoxy, halo-C1-6-alkoxy, halo-C-6-cycloalkoxy, halo-C4-7-cycloalkyl-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, halo-C1-6-alkoxy-C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkylthio, —SR9, —S(═O)R6, —S(═O)R7, —S(═O)R9, —S(═O)2R6, —S(═O)2R7, —S(═O)2R9, —NHR6, —N(R6), —C(═O)R6, —C(═O)O—C1-6-alkyl, —V1—S(═O)2R6, —C(═O)NH2, —S(═O)2NH2, —C(═O)NHR6, —C(═O)NR6R6, —C(═O)R8, —S(═O)2NHR6, —S(═O)2N(R6)2, —S(═O)2R8, —NHC(═O)R6, —NHC(═O)O—C1-6-alkyl, —V1—NHC(═O)R6, —V1—NHC(═O)O—C1-6-alkyl, —NHS(═O)2R6, —V1—NHS(═O)2R6, —V1—C(═O)R6, —V1—C(═O)O—C1-6-alkyl, heteroaryl, aryl, heterocyclyl, oxo, —V1—NH2, —V1—NHR6, —V1—N(R6)2, —C(═O)R7, —C(═O)O—C3-6-cycloalkyl, —C(═O)NHR7, —C(═O)NR6R7, —C(═O)N(R7)2, —S(═O)2NHR7, —S(═O)2NR6R7, —S(═O)2N(R7)2, cyano-C1-6-alkyl, carboxy-C1-6-alkyl, —V1—C(═O)NH2, —V1—C(═O)NHR6, —V1—C(═O)N(R6)2, —V1—C(═O)NHR7, —V1—C(═O)NR6R7, and —V1—C(═O)N(R7)2; or aryl or heteroaryl; R1a, R1b independently of each other are hydrogen, C1-6-alkyl, C3-6-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl or C1-3-alkyloxy-C1-3-alkyl, or R1a and R1b are joined and, together with the carbon atom they are attached, form a C3-6-cycloalkyl group, wherein the above-mentioned C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-3-alkoxy-C1-3-alkyl, and C3-6-cycloalkyl groups are optionally substituted with one to three groups independently selected from fluorine, cyano, C1-6-alkyl, oxo and hydroxy; R2 is C1-6-alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionally substituted with 1 to 4 groups independently selected from halogen, cyano, nitro, amino, hydroxy, carboxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkoxy, C3-6-cycloalkyl, C3-6-cycloalkoxy, hydroxy-C1-6-alkyl, hydroxy-C3-6-cycloalkyl, hydroxy-C2-6-alkenyl, hydroxy-C1-6-alkoxy, —R9, C4-7-cycloalkyl-C1-6-alkoxy, halo-C1-6-alkoxy, halo-C3-6-cycloalkoxy, halo-C4-7-cycloalkyl-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkoxy, halo-C1-6-alkoxy-C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkylthio, —SR9, —S(═O)R6, —S(═O)R7, —S(═O)R9, —S(═O)2R6, —S(═O)2R7, —S(═O)2R9, —NHR6, —N(R6), —C(═O)R6, —C(═O)O—C1-6-alkyl, —C(═O)NH2, —S(═O)2NH2, —C(═O)NHR6, —C(═O)NR6R6, —C(═O)R8, —S(═O)2NHR6, —S(═O)2N(R6)2, —S(═O)2R8, —NHC(═O)R6, —NHC(═O)O—C1-6-alkyl, —V1—NHC(═O)R6, —V1—NHC(═O)O—C1-6-alkyl, —NHS(═O)2R6, —V1—NHS(═O)2R6, —V1—C(═O)R6, —V1—C(═O)O—C1-6-alkyl, heteroaryl, aryl, heterocyclyl, oxo, —V1—NH2, —V1—NHR6, —V1—N(R6)2, —C(═O)R7, —C(═O)O—C3-6-cycloalkyl, —C(═O)NHR7, —C(═O)NR6R7, —C(═O)N(R7)2, —S(═O)2NHR7, —S(═O)2NR6R7, —S(═O)2N(R7)2, cyano-C1-6-alkyl, —V1—C(═O)NH2, —V1—C(═O)NHR6, —V1—C(═O)N(R6)2, —V1—C(═O)NHR7, —V1—C(═O)NR6R7 and —V1—C(═O)N(R7)2; R3 is C1-6alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-5-cycloalkyl-C1-4-alkyl, C1-3-alkoxy-C1-3-alkoxy, or C1-3-alkoxy-C1-3-alkyl, each of which is optionally substituted with one to four groups independently selected from fluorine, cyano, oxo, —R4, R4O—, (R4)2N—, R4O2C—, R4C(═O)O—, R4S, R4S(═O)—, R4S(═O)2—, R4C(═O)NR4—, (R4)2NC(═O)—, (R4)2NC(═O)O—, (R4)2NC(═O)NR4—, R4OC(═O)NR4—, (R4)2NC(═NCN)NR4—, spirocycloalkyl, heterocyclyl (which in turn is optionally substituted with C1-4-alkyl, halo-C1-4-alkyl, halogen, or oxo), heteroaryl (which in turn is optionally substituted with C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulfonyl, halogen, trifluoromethyl, di(C1-3-alkyl)amino, nitro, cyano, carboxy, aminocarbonyl, C1-4-alkylaminocarbonyl, di(C1-3-alkyl)aminocarbonyl, or oxo), aryl-amino (which in turn is optionally substituted with C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulfonyl, halogen, trifluoromethyl, di(C1-4-alkyl)amino, nitro, cyano, carboxy, aminocarbonyl, C1-4-alkylaminocarbonyl, and di(C1-3-alkyl)aminocarbonyl) and heteroarylamino (which in turn is optionally substituted with C1-4-alkyl, halo-C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C1-4-alkylsulfonyl, halogen, trifluoromethyl, di(C1-3-alkyl)amino, nitro, cyano, carboxy, aminocarbonyl, C1-4-alkylaminocarbonyl, di(C1-3-alkyl)aminocarbonyl, or oxo); R4 is independently selected from hydrogen, C1-6-alkyl and halo-C1-6-alkyl R6 is independently selected from C1-6-alkyl, C2-6-alkenyl, and C2-6-alkynyl; R7 is C3-6-cycloalkyl; R8 is heterocyclyl; R9 is C4-7-cycloalkyl-C1-6-alkyl, C3-6-cycloalkyl-C2-4-alkynyl, halo-C1-6-alkyl, halo-C2-6-alkenyl, halo-C3-6-cycloalkyl, halo-C4-7-cycloalkyl-C1-6-alkyl, C1-6-alkoxy-C1-6-alkyl, or halo-C1-6-alkoxy-C1-6-alkyl; Q is NH; and V1 is independently selected from C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, and C1-6-alkyleneoxy.