Amino-oxazine and amino-dihydrothiazine compounds as beta-secretase modulators and methods of use

摘要

The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I wherein A1, A2, A3, A4, A5, A6, L, R2, R7, X, Y and Z of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.;

主权项

1. A compound of Formula I:or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
A1 is CR6; A2 is CR5; A3 is CR4; A4 is N; A5 is CR1; A6 is CR8; L is —C(═O)NH—, —C(═O)N(CH3)—, —NH—, —N(CH3)— or —O—; each of R1, R4, R5 and R8, independently, is H, F, Cl, Br, CF3, OCF3, C1-6-alkyl, CN, OH, —OC1-6-alkyl, —NHC1-6-alkyl or —C(O)C1-6-alkyl, wherein the C1-6-alkyl and C1-6-alkyl portion of —OC1-6-alkyl, —NHC1-6-alkyl and —C(O)C1-6-alkyl are optionally substituted with 1-3 substituents of F, oxo or OH; each of R2 and R7, independently, is F, Cl, Br, I, haloalkyl, haloalkoxyl, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, —Si(CH3)3 or a ring selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, tetrazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein the C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl and ring are optionally substituted, independently, with 1-3 substituents of R9; R6 is H, halo, haloalkyl, haloalkoxyl, C1-6-alkyl, CN, OH, OC1-6-alkyl, NHC1-6-alkyl or C(O)C1-6-alkyl; each R9, independently, is halo, haloalkyl, haloalkoxyl, CN, OH, NO2, NH2, acetyl, —C(O)NHCH3, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, piperazinyl, oxetanyl or dioxolyl, wherein each of the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino, C1-3thioalkoxyl or oxetanyl; X is —O— or —S—; Y is —CH2; and Z is CH2.