Amino heteroaryl 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 ring A, B1, B2, B3, L, R1, R4, ring Z, m and p 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 (AD), 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 or pharmaceutically acceptable salt thereof, wherein
A is a 5- or 6-membered aryl or heteraryl ring; each of B1, B2 and B3, independently, is N, —CF, —CCH3 or CH; L is —CR2R2—(CR3R3)—, —CR2R2—O—, —CR2═CR3—, —C═C—, C3-8cycloalkyl, tetrahydrofuranyl or tetrahydropyranyl, wherein the C3-8cycloalkyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with 1-4 substituents of R4, and wherein
each R2, independently, is H, C1-3alkyl or F; andeach R3, independently, is H, C1-6alkyl, C3-6cycloalkyl, —OH, —OC1-4alkyl, halo, haloalkyl, CN, —NH2 or —NHC1-6alkyl; each R1 independently, is F, Cl, Br, CF3, OCF3, C1-6-alkyl, CN, OH, —OC1-6-alkyl, —S(O)nC1-6-alkyl, —NH2, CN, —NHC1-6-alkyl, —C(O)C1-6-alkyl, —C(O)-cycloalkyl or —C(O)NRaRb wherein Ra is H or C1-6alkyl and Rb is R4; alternatively, Ra and Rb taken together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic heterocycle, wherein the cycloalkyl of the —C(O)-cycloalkyl and monocyclic heterocycle are optionally substituted with 1-3 substituents of R4; each R4, independently, is halo, haloalkyl, CN, OH, NO2, NH2, acetyl, oxo, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl or a fully saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, haloalkoxyl, 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, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl; Z is a 6-membered monocyclic or 10-membered bicyclic aryl ring or 5- or 6-membered monocyclic or 9-10-membered bicyclic heteraryl ring; m is 0, 1, 2, 3, 4 or 5; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5.