Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-9296734-B2
Application number	US-201414192710-A
Country	US
Kind code	B2
Filing date	Feb 27, 2014
Priority date	Mar 1, 2013
Publication date	Mar 29, 2016
Grant date	Mar 29, 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 4 , A 5 , A 6 , A 8 , each of R 1 and R 2 , R 3 and R 7 of Formula I, independently, 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 III, and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-III.

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 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;
one R 1 is C 1-3 haloalkyl and the other 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)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)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;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and optionally substituted with a substituent of C 1-3 alkyl, CH 2 OC 1-2 alkyl or C 1-3 haloalkyl on the nitrogen atom;
each of R 2 , 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)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)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;
alternatively, each R 2 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and optionally substituted with a substituent of C 1-3 alkyl, CH 2 OC 1-2 alkyl or C 1-3 haloalkyl on the nitrogen atom;
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)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —NH—C(═S)—R 9 , —O—R 9 or —S—R 9 ;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl 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 C 1-6 -alkyl, C 2-4 alkenyl, C 2-4 alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ; and
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, 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, 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, C 1-3 alkylamino-, C 1-3 dialkylamino, C 1-3 thioalkoxyl oxazolyl, or oxetan-3yl,
provided that when A 4 is CR 4 , A 5 is CR 5 , A 6 is CR 6 and A 8 is CR 8 , and each of R 6 and R 8 , independently, is H, then R 5 is not H.

2. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein one R 1 is H and the other R 1 is CF 3 .

3. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each R 2 , independently, is H.

4. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 , CF 3 , CH 2 F or CHF 2 .

5. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —NH—C(═S) —R 9 , —O—R 9 or —S—R 9 ;
or R 7 is

wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N.

6. The compound according to claim 1 , or a stereoisomer 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 one of A 4 , A 5 , A 6 and A 8 is N;
one R 1 is CF 3 and the other R 1 is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OCH 3 , SCH 3 , NHCH 3 , C(O)CH 3 or CH 2 OCHF 2 ;
each R 2 , independently, is H, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OCH 3 , NHCH 3 , C(O)CH 3 or CH 2 OCHF 2 ;
R 3 is C 1-4 alkyl, C 1-4 haloalkyl, CH 2 OH, CH 2 OCHF 2 or cyclopropyl; and
each of R 4 , R 5 , R 6 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 .

7. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
one R 1 is H and the other R 1 is CF 3 ;
R 3 is CH 3 , CF 3 , CH 2 F or CHF 2 ; and
R 7 is —NH—R 9 , —NH—C(═O)-R 9 , —NH—C(═S)—R 9 or

wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N.

8. The compound according to claim 7 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is —NH—C(═O)—R 9 .

9. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is —NH—R 9 , —O—R 9 or —S—R 9 .

10. The compound according to claim 8 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
A 4 is CR 4 ;
A 5 is CR 5 or N;
A 6 is CR 6 ; and
A 8 is CR 8 or N; wherein each of R 4 , R 5 , R 6 and R 8 , independently, is H, F, CF 3 , CF 2 H, CH 2 F or CH 3 ;
provided that (1) no more than one of A 5 and A 8 is N; and (2) when A 4 is CR 4 , A 5 is CR 5 , A 6 is CR 6 and A 8 is CR 8 , and each of R 6 and R 8 , independently, is H, then R 5 is F, CF 3 , CF 2 H, CH 2 F or CH 3 .

11. A compound according to claim 1 , or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, having a Formula II:

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 R 2 , 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)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein eac

Assignees

• Amgen Inc

Inventors

• Minatti Ana Elena
• Low Jonathan D
• Allen Jennifer R
• Chen Jian
• Chen Ning
• Cheng Yuan
• Judd Ted
• Liu Qingyian
• Lopez Patricia
• Qian Wenyuan
• Rumfelt Shannon
• Rzasa Robert M
• Tamayo Nuria A
• Xue Qiufen
• Yang Bryant
• Zhong Wenge

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title