Carbamate and urea inhibitors of 11β-hydroxysteroid dehydrogenase 1

摘要

This invention relates to novel compounds of the invention pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

主权项

1. A compound of Formula I: wherein Cy is adamantyl, optionally substituted with 1-3 groups independently selected from halogen, cyano, hydroxy, hydroxy(C1-C3)alkyl, N(R4)2, CO2R4, CON(R4)2, CH2CON(R4)2SO2N(R4)2, SO2R4, NR4COR4 and OC(═O)N(R4)2; B is aryl, heterocyclyl or heteroaryl, each optionally substituted with 1-4 groups represented by R6; R3 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, cycloalkyl(C0-C3)alkyl, heterocyclyl(C0-C3)alkyl, aryl(C0-C3)alkyl, or heteroaryl(C0-C3)alkyl, each optionally substituted by 1-4 groups independently selected from halogen, nitro, cyano, (C1-C3)alkyl, halo(C1-C3)alkyl, halo(C1-C3)alkoxy, hydroxy(C1-C3)alkyl, OR4, N(R4)2, (CH2)xC(═NOH)NH2, (CH2)xNR4CON(R4)2, (CH2)xCON(R4)2, (CH2)xSO2N(R4)2, (CH2)xSO2R4, (CH2)xNR4COR4, (CH2)xNR4SO2R4, (CH2)xOC(═O)N(R4)2, (CH2)xOR4, (CH2)xO(CH2)xCO2R4, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted cycloalkyl, wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted with one to three groups represented by R7, wherein the (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, heterocyclyl, heteroaryl, cycloalkyl(C0-C3)alkyl, heterocyclyl(C0-C3)alkyl, alkyl portion of aryl(C0-C3)alkyl and heteroaryl(C0-C3)alkyl are further optionally substituted with oxo; each R4 is independently (a) hydrogen; or (b) (C1-C10)alkyl, or aryl(C0-C3)alkyl, each optionally substituted with 1-4 groups selected from halogen, (C1-C3)alkoxy, (C1-C3)alkyl, halo(C1-C3)alkyl, halo(C1-C3)alkoxy, cyano and nitro; each R6 is independently selected from halogen, nitro, cyano, (C1-C3)alkyl, cyclo(C3-C6)alkyl, halo(C1-C3)alkyl, hydroxy(C1-C3)alkyl, oxo, OR4, halo(C1-C3)alkoxy, (CH2)xN(R4)2, (CH2)xC(═NOH)NH2, (CH2)xNR4CON(R4)2, (CH2)xCON(R4)2, (CH2)xCO2R4, (CH2)xSO2N(R4)2, (CH2)xSO2R4, (CH2)xNR4COR4, (CH2)xNR4CO2R4, (CH2)xNR4SO2R4, (CH2)xOC(═O)N(R4)2, (CH2)xOR4, (CH2)xO(CH2)xCO2R4, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl are further optionally substituted with one to three groups represented by R7; R7 is halogen, nitro, cyano, (C1-C3)alkyl, halo(C1-C3)alkyl, cyclo(C3-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, N(R4)2, or CON(R4)2, provided that R7 also includes oxo when the heteroaryl, heterocyclyl and cycloalkyl are substituted with R7; x is 0, 1, 2 or 3; A′ is a bond, CH2, or -AO—, wherein O is connected to B; A is a bond or CH2; m is 0; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.