Chromene and 1,1a, 2,7b - tetrahidrociclopropa c chromene piridopirazinadionas as modulators of g-secretase

摘要

The related drug components and their use in the treatment of neurodegenerative diseases are also described. Claim 1: a compound (1) having a formula structure,Or a pharmaceutically acceptable salt, wherein: a selects (2) a (5) from the formula compound group;X is heteroaryl (5 to 14 members) containing 1-3 heteroatoms; R¹ is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy,C₃₋₈ cycloalkyl and C₂₋₆ alkenyl;where the C₁₋₆ alkyl,C₁₋₆ alkoxy,C₃₋₈ cycloalkyl and C₂₋₆ alkenyl are optionally substituted with one to three substituents each independently selected from the group consisting of fluorine, hydroxy and C₁₋₆ alkoxy;7491 and 7495;In each case, the group consisting of hydrogen, fluorine, cyanogen, hydroxy and hydrocarbyl c833136 is selected independently;C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ hydroxyalkyl,C₁₋₆ haloalkyl,C₂₋₆ alkenyl,1. C 83228331 asphae. Cycloquilo c8322338s and phenyl; alquenilo c83228331;1. C 83228331 asphaC₃₋₈ cycloalkyl and phenyl are optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy, C₁₋₃ alkyl,C₁₋₃ hydroxyalkyl and fluorine; or R²ᵃ and R²ᵇ together with the carbon atoms to which they bind form a C₃₋₈ cycloalkyl or a (4 to 10 membered) heterocycloalkyl,wherein the C₃₋₈ cycloalkyl and the (4 to 10 membered) heterocycloalkyl are optionally substituted with one to three R⁸;R8308;]C₁₋₆ alkoxy and C₁₋₆alkoxy C₁₋₆,where the C₁₋₆ alkyl,alcoxi C o alcoxi C alquilo Cthey are optionally substituted with one to three substituents independently selected from the group consisting of cyano, hydroxy and fluorine; or R⁴ᵃ and R⁴ᵇ together with the carbon atom to which they form form a C₃₋₈ cycloalkyl,wherein the C₃₋₈ cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluorine, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ hydroxyalkyl,a. Halide c83218c831832626;R8309;; 74919 and r8309;; 74955;at each occurrence, they are independently selected from the group consisting of hydrogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy,and C₁₋₆alkyl C₁₋₆alkoxy,where the C₁₋₆ alkyl,C₁₋₆ alkoxy,or C₁₋₆alkyl C₁₋₆alkoxy,they are optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy and fluorine; or R⁵ᵃ and R⁵ᵇ together with the carbon atoms to which they are attached form a C₃₋₈ cycloalkyl wherein the C₃₋₈ cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluorine, hydroxy , C₁₋₆ alkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ hydroxyalkyl,a. Halide c83218c831832626;R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, cyano, halogen, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CAnd halide c83218c831832626,Y-Or8313;The condition is that r8310 and r8311 cannot be two kinds of hydrogen Xi; r831222;at each occurrence, it is independently selected from the group consisting of cyano, halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy,alcoxi C alquilo Ce. Hydroxialquilo c83216c8318326 and halogeoquilo c833213126;R⁹ is selected from the group consisting of hydrogen and C₁₋₆ alkyl;wherein the C₁₋₆ alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy and fluorine; z is an integer selected from 1 or 2; and is an integer selected from 1, 2, 3 or 4; the wavy line is a bond that connects to any carbon atom in ring B or ring C that is chemically permissible; m is an integer selected from 1, 2, 3 or 4; n is an integer selected from 0 or 1; W is carbon or oxygen; Ring B is optionally substituted with up to five R¹⁰,wherein each R¹⁰ is independently selected from the group consisting of halogen, cyano. hydroxy, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,C₁₋₆ haloalkoxy,1. C8332121 aspha-SF₅ and C₃₋₆ cycloalkyl,wherein the C₃₋₆ cycloalkyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,and C₁₋₆ haloalkoxy;or two R¹⁰ substituents taken together with the carbon atoms to which they are attached form a C₃₋₆ terminal cycloalkyl which is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl and C₁₋₆ haloalkoxy;Ring C is optionally substituted with up to four R¹¹ such that the substitution occurs in any carbon atom that is chemically permissible, and wherein each R¹¹ is independently selected from the group consisting of halogen, cyano, hydroxy, C₁₋ alkyl ₆,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,C₁₋₆ haloalkoxy,1. C8332121 aspha-SF832525,C₃₋₆ cycloalkyl,And straight propylene (4-6 members)wherein the C₃₋₆ cycloalkyl and the heterocycloalkyl portions (4 to 6 members) are optionally substituted with up to three halogens, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy,C₁₋₆alkoxyC alcoalkyl or hydroxyalkylC₁₋₆;or two R¹¹ taken together with the carbon atoms to which they bind form a C₃₋₆ cycloalkyl or a heterocycloalkyl (from 4 to 6 members) in which the C₃₋₆ cycloalkyl and portions of heterocycloalkyl (from 4 to 6 members) each is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,and C₁₋₆ haloalkoxy;Ring D is optional up to 4.1km,R2 is independent of the group composed of halogen, cyanogen, hydroxyl and c832131 asphaC₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,C₁₋₆ haloalkoxy. Cilt alkylthio,-SF₅. C₃₋₆ cycloalkyl and heterocycloalkyl (4 to 6 members),wherein the C₃₋₆ cycloalkyl and the heterocycloalkyl (4 to 6 members) are optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl,C₁₋₆ alkoxy,alcoxi C alquilo CC₁₋₆ haloalkyl,and C₁₋₆ haloalkoxy;This is a double or simple link.