Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

A compound of Formula I

• 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 two of A4, A5, A6 and A8 is N;
• each of Ra and Rb, independently, is H, F, Cl, C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —CH2OC1-6-alkyl, —OC1-6-alkyl, —S(O)oC1-6-alkyl, —NHC1-6-alkyl or —C(O)C1-6-alkyl, wherein each of the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, and C1-6-alkyl portion of —CH2OC1-6-alkyl, —OC1-6-alkyl, —S(O)oC1-6-alkyl, —NHC1-6-alkyl and —C(O)C1-6-alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
• each of R1 and R2, independently, is H, F, Cl, C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —CH2OC1-6-alkyl, —OC1-6-alkyl, —S(O)oC1-6-alkyl, —NHC1-6-alkyl or —C(O)C1-6-alkyl, wherein each of the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, and C1-6-alkyl portion of —CH2OC1-6-alkyl, —OC1-6-alkyl, —S(O)oC1-6-alkyl, —NHC1-6-alkyl and —C(O)C1-6-alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
• R3 is C1-4alkyl, CH2OC1-4alkyl, CH2OH, C1-4haloalkyl or cyclopropyl, wherein each of the C1-4alkyl, CH2OC1-4alkyl, C1-4haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms;
• each of R4, R5, R6 and R8, independently, is H, halo, haloalkyl, haloalkoxyl, C1-4-alkyl, CN, OH, OC1-4-alkyl, S(O)oC1-4-alkyl, NHC1-4-alkyl or C(O)C1-4-alkyl;
• R7 is —NH—R9, —NH—C(═O)—R9, —C(═O)NH—R9, —O—R9 or —S—R9;
• R9 is acetyl, C1-6-alkyl, C2-4alkenyl, C2-4alkynyl or a fully or partially unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed of carbon atoms, said ring optionally including 1-4 heteroatoms if monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms selected from O, N or S, wherein the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R10;
• and
• each R10, independently, is H, halo, haloalkyl, CN, OH, NO2, NH2, SF5, acetyl, —C(O)NHCH3, oxo, cyclopropylmethoxy, 2-butynyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein each of the cyclopropylmethoxy, 2-butynyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, 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, CF3, CHF2, CH2F, methyl, methoxy, ethyl, ethoxy, CH2CF3, CH2CHF2, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, C1-3alkylamino-, C1-3dialkylamino, C1-3thioalkoxyl tetrahydropyranyl, tetrahydropyrrolyl or oxetan-3yl,
• provided the compound is not
• N-(3-((1R,5R,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
• or
• N-(3-((1R,5R,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide.