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

Patent metadata

Field	Value
Publication number	US-9725469-B2
Application number	US-201314435516-A
Country	US
Kind code	B2
Filing date	Nov 12, 2013
Priority date	Nov 15, 2012
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

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 A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , L, R 2 , R 7 , 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.

First claim

What is claimed is:

1. A compound of Formula I:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
A 1 is CR 6 ;
A 2 is CR 5 ;
A 3 is CR 4 or N;
A 4 is CR 3 or N;
A 5 is CR 1 ;
A 6 is CR 8 , provided that no more than one of A 3 and A 4 is N;
each of R 1 , R 4 , R 5 and R 8 , independently, is H, F, Cl, Br, CF 3 , OCF 3 , C 1-6 -alkyl, CN, OH, —OC 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein the C 1-6 -alkyl and C 1-6 -alkyl portion of —OC 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-3 substituents of F, oxo or OH;
R 2 is F, Cl, Br, I, haloalkyl, haloalkoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, CN, —OC 1-6 -alkyl, —SC 1-6 -alkyl, —NHC 1-6 -alkyl, —N(C 1-3 -alkyl) 2 , —NH-phenyl, —NH-benzyl, —Si(CH 3 ) 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 C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, —OC 1-6 -alkyl, —SC 1-6 -alkyl, —NHC 1-6 -alkyl, —N(C 1-3 -alkyl) 2 , —NH-phenyl, —NH-benzyl and ring are optionally substituted, independently, with 1-3 substituents of R 9 ;
each of R 3 and R 6 , independently, is H, halo, haloalkyl, haloalkoxy, C 1-6 -alkyl, CN, OH, OC 1-6 -alkyl, NHC 1-6 -alkyl or C(O)C 1-6 -alkyl;
R 7 is

wherein V is NR 9 , O or S; and
each W, independently, is CR 9 or N, provided no more than 4 W's, independently, are N;
each R 9 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, 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 -alkoxy, C 1-6 -thioalkoxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the 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 -alkoxy, C 1-6 -thioalkoxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxy or oxetan-3-yl;
X is —O— or —S—;
Y is —CH 2 —; and
Z is CH 2 , CHF, CF 2 , CH(CH 3 ), C(CH 3 ) 2 or CH(CF 3 ).

2. The compound of claim 1 having a Formula II:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
A 1 is CR 6 ;
A 2 is CR 5 ;
A 3 is CR 4 or N;
A 4 is CR 3 or N;
A 5 is CR 1 ;
A 6 is CR 8 , provided that no more than one of A 3 and A 4 is N;
each of R 1 , R 4 , R 5 and R 8 , independently, is H, F, Cl, Br, CF 3 , OCF 3 , C 1-6 -alkyl, CN, OH, —OC 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein the C 1-6 -alkyl and C 1-6 -alkyl portion of —OC 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-3 substituents of F, oxo or OH;
R 2 is F, Cl, Br, I, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —OC 1-6 -alkyl, —SC 1-6 -alkyl, —NHC 1-6 -alkyl, —N(C 1-3 -alkyl) 2 , —NH-phenyl, —NH-benzyl, —Si(CH 3 ) 3 , phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, 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, or cyclohexyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, —OC 1-6 -alkyl, —SC 1-6 -alkyl, —NHC 1-6 -alkyl, —N(C 1-3 -alkyl) 2 , —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, 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 or cyclohexyl are optionally substituted, independently, with 1-3 substituents of R 9 ;
each of R 3 and R 6 , independently, is H, halo, haloalkyl, haloalkoxy, C 1-6 -alkyl, CN, OH, OC 1-6 -alkyl, NHC 1-6 -alkyl or C(O)C 1-6 -alkyl;
R 7 is

wherein V is NR 9 , O or S; and
each W, independently, is CR 9 or N, provided no more than 4 W's, independently, are N;
each R 9 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, 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 -alkoxy, C 1-6 -thioalkoxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the 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 -alkoxy, C 1-6 -thioalkoxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxy or oxetan-3-yl;
X is —O— or —S—; and
Y is —CH 2 —.

3. The compound of claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
A 1 is CH or CF;
A 2 is CH or CF;
A 3 is CH, CF, COCH 3 or N;
A 4 is CH, CF or N;
A 5 is CH, CF or CBr;
A 6 is CH or CF;
X is —O— or —S—; and
Y is —CH 2 —.

4. The compound of claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein
each of R 1 , R 4 , R 5 and R 8 , independently, is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , NHCH 3 or C(O)CH 3 ;
R 2 is F, Cl, Br, I, haloalkyl, haloalkoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, CN, —OC 1-6 -alkyl, —SC 1-6 -alkyl, —NHC 1-6 -alkyl, —N(C 1-3 -alkyl) 2 , —NH-phenyl, —NH-benzyl, —Si(CH 3 ) 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]he

Assignees

• Amgen Inc
• Amgen Inc

Inventors

• White Ryan
• Epstein Oleg
• Human Jason B
• Zheng Xiao Mei
• Cheng Yuan
• Sham Kelvin
• Liu Qingyian
• Chen Ning

Classifications

• C07D498/20

  Spiro-condensed systems · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/20

  Spiro-condensed systems · CPC title

• C07D513/10

  Spiro-condensed systems · CPC title