Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use

Abstract

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 A 4 , A 5 , A 6 , A 8 , and each of R a , R b , R 1 , R 2 , R 3 and R 7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and 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 Formulas II and III, and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
 A 4  is CR 4  or N; 
 A 5  is CR 5  or N; 
 A 6  is CR 6  or N; 
 A 8  is CR 8  or N, provided that no more than two of A 4 , A 5 , A 6  and A 8  is N; 
 each of R a  and R b , independently, is H, F, Cl, C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH; 
 R 1  and either R a  or R b  may optionally join to form a 5-membered saturated ring that includes one S heteroatom; 
 R 1  is H, F, Cl, C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl, —C 1-6 -alkylNH 2 , —C 1-6 -alkylNHC 1-6 -alkyl, —C 1-6 -alkylNHC(O)OC 1-6 -alkyl, —C 1-6 -alkylNHC(O)NHC 1-6 -alkyl, —C 1-6 -alkylNHC(O)C 1-6 -alkyl, —C(O)NH 2 , —CH═CHC(O)NH 2 , —CH═CHC(O)NHC 1-6 -alkyl, —CH═CHC(O)N(C 1-6 -alkyl) 2 , —CH═CHC(O)NHC 1-6 -alkyl-OC 1-6 -alkyl, —CH═CHC(O)-heterocyclyl, —CH═C(CH 3 )C(O)-heterocyclyl, —CH═CHC(O) 2 H, —CH═CHC(O)OC 1-6 -alkyl, —CH═CHCH 2 OH, C 1-6 -alkyl-C(O)NHC 1-6 -alkyl, C 1-6 -alkyl-C(O)N(C 1-6 -alkyl) 2 , —C(O)C 1-6 -alkyl, —C(O)C 1-6 -alkenyl, —C(O)OH, —C(O)OC 1 -C 6 alkyl, —C(O)NHC 1-6 -alkyl, —C(O)N(C 1-6 -alkyl) 2 , —C(O)NHC 3-6 cycloalkyl, —C(O)NHOC 1-6 -alkyl, —C(O)N(C 1-6 -alkyl)OC 1-6 -alkyl, —C(O)-heterocyclyl, —CH 2 -heteroaryl, or heteroaryl, wherein the heterocyclyl groups of the —CH═CHC(O)-heterocyclyl, —CH═C(CH 3 )C(O)-heterocyclyl, and —C(O)-heterocyclyl groups are fully or partially unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings that include 1 heteroatom selected from N, O, or S if the ring is a 3-membered ring, that include 1 or 2 heteroatoms independently selected from N, O, or S if the ring is a 4- or 5-membered ring, and include 1, 2, or 3 heteroatoms independently selected from N, O, or S if the ring is a 6- or 7-membered ring, wherein the heteroaryl groups of the —CH 2 -heteroaryl and heteroaryl groups is a 5- or 6-membered ring that includes 1, 2, 3, or 4 heteroatoms selected from N, O, or S, wherein each of the C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 3-6 cycloalkyl portion of C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl, C(O)C 1-6 -alkyl, —C(O)C 1-6 -alkenyl, —C(O)NHC 1-6 -alkyl, —C(O)N(C 1-6 -alkyl) 2 , —C(O)NHC 3-6 cycloalkyl, —CH═CHC(O)NHC 1-6 -alkyl and C 1-6 -alkyl-C(O)NHC 1-6 -alkyl groups are optionally substituted with 1-4 substituents of F, CN, methyl, oxo, or OH, and further wherein each of the heterocyclyl groups of the —CH═CHC(O)-heterocyclyl, —CH═C(CH 3 )C(O)-heterocyclyl, and —C(O)heterocyclyl groups is optionally substituted with 1-4 substituents independently selected from F, methyl, OH, or OCH 3 , and further wherein each of the heteroaryl groups of the —CH 2 -heteroaryl and heteroaryl groups is optionally substituted with 1-3 substituents independently selected from halo, methyl, or OH; 
 R 2  is H, F, Cl, C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl, —C(O)NH 2 , —CH═CHC(O)NHC 1-6 -alkyl, —CH═CHC(O) 2 H, —CH═CHCH 2 OH, C 1-6 -alkyl-C(O)NHC 1-6 -alkyl, —C(O)C 1-6 -alkyl or —C(O)C 1-6 -alkenyl, wherein each of the C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O) o C 1-6 -alkyl, —NHC 1-6 -alkyl, C(O)C 1-6 -alkyl, —C(O)C 1-6 -alkenyl, —CH═CHC(O)NHC 1-6 -alkyl and C 1-6 -alkyl-C(O)NHC 1-6 -alkyl, are optionally substituted with 1-4 substituents of F, CN, oxo or OH; 
 R 3  is C 1-4 alkyl, CH 2 OC 1-4 alkyl, CH 2 OH, C 1-4 haloalkyl or cyclopropyl, wherein each of the C 1-4 alkyl, CH 2 OC 1-4 alkyl, C 1-4 haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms; 
 each of R 4 , R 5 , R 6  and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl, C 1-4 -alkyl, CN, OH, OC 1-4 -alkyl, S(O) o C 1-4 -alkyl, NHC 1-4 -alkyl, C(O)C 1-4 -alkyl, C(O)OC 1-4 -alkyl, or CH 2 OH; 
 R 7  is —NH—R 9  or —NH—C(═O)—R 9 ; 
 R 9  is 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 ring is optionally substituted, independently, with 1-5 substituents of R 10 ; 
 each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHC 1-6 -alkyl, —OCH 2 C(O)NHC 1-6 -alkyl, —OCH 2 C(O)N(C 1-6 -alkyl) 2 , —OCH 2 CH 2 -pyrollidinonyl, oxo, cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 3-pentynyloxy, 2-pentyloxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylamino-, C 1-6 dialkylamino-, C 1-6 alkoxyl, —OC 2 -C 6 alkenyl, C 1-6 thioalkoxyl, —OCH 2 C 3-6 cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, imidazo-pyridinyl, dioxolyl, —O-heterocyclyl, or —OCH 2 -heteroaryl, wherein the heterocyclyl of the —O-heterocyclyl group is a 3-, 4-, 5-, 6- or 7-membered monocyclic saturated ring that includes 1 heteroatom selected from N, O, or S if the heterocyclyl ring is a 3-membered ring, that includes 1 or 2 heteroatoms independently selected from N, O, or S if the heterocyclyl ring is a 4- or 5-membered ring, and includes 1, 2, or 3 heteroatoms independently selected from N, O, or S if the heterocyclyl ring is a 6- or 7-membered ring wherein the heteroaryl group of the —OCH 2 -heteroaryl group is a 5- or 6-membered ring that includes 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and further wherein each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 2-pentyloxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylamino-, C 1-6 dialkylamino-, C 1-6 alkoxyl, C 1-6 thioalkoxyl, —OCH 2 C 3-6 cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl, dioxolyl, or —OCH 2 -heteroaryl is optionally substituted independently with 1-5 substituents of F, Cl, Br, CN, NO 2 , NH 2 , OH, oxo, CF 3 , CHF 2 , CH 2 F, methyl, methoxy, ethyl, ethoxy, CH 2 CF 3 , CH 2 CHF 2 , propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, C 1-3 alkylamino-, C 1-3 dialkylamino, C 1-3 thioalkoxyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetan-2-yl, or oxetan-3yl; and 
 the subscript o is selected from 0, 1, or 2. 
 
     
     
         2 .- 59 . (canceled)