Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use

摘要

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A4, A5, A6, A8, R1, R2, R3, R7 and n of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formula II and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-II.;

主权项

1. A compound of Formula II-B or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein A4 is CR4 or N; A5 is CR5 or N; A6 is CR6 or N; A8 is CR8 or N, provided that no more than one of A4, A5, A6 and A8 is N; each of R1 and R2, independently, is H, F, Cl, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, CN, —CH2OC1-3-alkyl, —OC1-3-alkyl, wherein each of the C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl and C1-3-alkyl portion of —CH2OC1-3-alkyl and —OC1-3-alkyl are optionally substituted with 1-4 substituents of F; alternatively, each R1 taken together with the carbon atom to which they are attached form a C3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C1-3-alkyl, CH2OC1-2-alkyl or C1-3-haloalkyl on the nitrogen atom; alternatively, each R2 taken together with the carbon atom to which they are attached form a C3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C1-3-alkyl, CH2OC1-2-alkyl or C1-3-haloalkyl on the nitrogen atom; R3 is C1-4-alkyl, CH2OC1-4-alkyl, CH2OH, C1-4-haloalkyl or cyclopropyl, wherein each of the C1-4-alkyl, CH2OC1-4-alkyl, C1-4-haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms; alternatively, one R2 and R3 taken together with the carbon atoms to which they are attached form a C3-6 carbocyclic ring optionally including 1-2 heteroatoms selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C1-3-alkyl, CH2OC1-2-alkyl or C1-3-haloalkyl on the nitrogen atom; each of R4, R5, R6 and R8, independently, is H or F; each R10, independently, is H, halo, haloalkyl, CN, OH, NO2, NH2, SF5, acetyl, —C(O)NHCH3, oxo, cycloproylmethoxy, 2-butynyloxy, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C1-6-alkylamino-, C1-6-dialkylamino-, C1-6-alkoxyl, C1-6-thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, C1-6-alkylamino-, C1-6-dialkylamino-, C1-6-alkoxyl, C1-6-thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C1-3-alkylamino-, C1-3-dialkylamino, C1-3-thioalkoxyl or oxetan-3-yl; and each W, independently, is CH, CF, CCl or N.