5-amino-oxazepine and 5-amino-thiazepane compounds as beta secretase antagonists and methods of use

Patent metadata

Field	Value
Publication number	US-9346827-B2
Application number	US-201213982222-A
Country	US
Kind code	B2
Filing date	Feb 6, 2012
Priority date	Feb 7, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

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 1 , A 3 , A 4 , A 5 , A 6 , A 8 , R 2 , R 7 , X and Y of Formula (I) 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 Formulas (II) and sub-formula embodiments of Formula (I) and (II), intermediates and processes and methods useful for the preparation of compounds of Formulas (I)-(II).

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 1 or N;
A 3 is CR 3 or N;
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 one of A 1 , A 3 , A 4 , A 5 , A 6 and A 8 is N;
each of R 9 , 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 Cl, Br, 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, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, 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, cyclopentyl, cyclohexyl or —Si(CH 3 ) 3 , 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, thienyl, pyrrolyl, 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, cyclopentyl and cyclohexyl are optionally substituted, independently, with 1-5 substituents of R 9 ;
each of R 3 and R 6 , independently, is H, halo, haloalkyl, haloalkoxyl, C 1-6 -alkyl, CN, OH, OC 1-6 -alkyl, NHC 1-6 -alkyl or C(O)C 1-6 -alkyl;
R 7 is 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 , —NHC(═O)R 9 , —C(═O)NHR 9 , —NHS(O) 2 R 9 , —S(O) 2 NHR 9 , —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, 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, 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, thienyl, pyrrolyl, 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, cyclopentyl and cyclohexyl are optionally substituted, independently, with 1-5 substituents of R 9 ;
each R 9 , independently, is halo, haloalkyl, CN, OH, NO 2 , NH 2 , 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 alkoxyl, C 1-6 thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetanyl 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 alkoxyl, C 1-6 thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C 1-3 alkylamino-, C 1-3 dialkylamino, C 1-3 thioalkoxyl, or oxetanyl; and
—X—Y— is —CR 10 R 10 —O—, —O—CR 10 R 10 —, —CR 10 R 10 —S— or —S—CR 10 R 10 , wherein each R 10 , independently, is H or F.

2. The compound of claim 1 , or a stereoisomer 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 ;
one of R 2 and R 7 , independently, is C 2-4 alkynyl, —OC 1-6 alkyl, —SC 1-6 alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, 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, cyclopentyl, or cyclohexyl, wherein the C 2-4 alkynyl, —OC 1-6 alkyl, —SC 1-6 alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, 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, cyclopentyl and cyclohexyl are optionally substituted, independently, with 1-3 substituents of R 9 ;
the other of R 2 and R 7 , independently, is phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl, wherein the phenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl are optionally substituted, independently, with 1-3 substituents of R 9 ; and
each of R 3 and R 6 , independently, is H, halo, haloalkyl, haloalkoxyl, C 1-6 -alkyl, CN, OH, OC 1-6 -alkyl, NHC 1-6 -alkyl or C(O)C 1-6 -alkyl.

3. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
R 2 is Cl, Br, C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, 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, cyclopentyl or cyclohexyl, wherein the C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl and ring are optionally substituted, independently, with 1-3 substituents of R 9 ;
each of R 1 , R 4 , R 5 and R 8 , independently, is H, F, methyl, CN or OH;
each of R 3 and R 6 , independently, is H, F, Cl, CF 3 , methyl, CN, OH, OCH 3 or NHCH 3 ;
R 7 is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, or thienyl, said ring optionally substituted, independently, with 1-3 substituents of R 9 ; and
—X—Y— is —CH 2 —O—, —O—CH 2 —, —CH 2 —S— or —S—CH 2 —.

4. A compound of claim 1 having a Formula II:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
A 3 is CR 3 or N;
A 4 is CR 4 or N, 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

Assignees

• Dineen Thomas
• Weiss Matthew
• Patel Vinod F
• Zheng Xiao Mei
• White Ryan
• Amgen Inc

Inventors

• Dineen Thomas
• Weiss Matthew
• Patel Vinod F
• Zheng Xiao Mei
• White Ryan

Classifications

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D498/20 Primary

  Spiro-condensed systems · CPC title

• C07D513/10

  Spiro-condensed systems · CPC title

• A61P25/16

  Anti-Parkinson drugs · 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