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

Patent metadata

Field	Value
Publication number	US-9085576-B2
Application number	US-201414199844-A
Country	US
Kind code	B2
Filing date	Mar 6, 2014
Priority date	Mar 8, 2013
Publication date	Jul 21, 2015
Grant date	Jul 21, 2015

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 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.

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;
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)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;
each of R 1 and 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;
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 , —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-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, tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein each of the cyclopropylmethoxy, 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, cyclopentyl, cyclohexyl, C 1-3 alkylamino-, C 1-3 dialkylamino, C 1-3 thioalkoxyl 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.

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

3. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each of R a and R b , independently, is H, F, CH 3 , CH 2 F, CHF 2 or CF 3 .

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

5. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each of R a and R b , independently, is H or F.

6. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 , independently, is H, F or CF 3 ; and each of R a and R b , independently, is H or F.

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

8. The compound according to claim 6 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 , CF 3 , CH 2 F or CHF 2 .

9. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is —NH—CH 2 —R 9 or —NH—C(═O)—R 9 ;
or R 7 is

wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl, CCH 3 or N.

10. The compound according to 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;
each of R a and R b , independently, is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , SCH 3 , NHCH 3 , C(O)CH 3 or CH 2 OCHF 2 ;
each of R 1 and R 2 , independently, is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , SCH 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 2 H, CH 2 F, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , SCH 3 , NHCH 3 or C(O)CH 3 .

11. The compound according to claim 6 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
each of R 1 and R 2 , independently, is H, F or CF 3 ;
each of R a and R b , independently, is H or F;
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 or

wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl, CCH 3 or N.

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

13. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 7 is

wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl, CCH 3 or N.

14. The compound according to claim 1 , 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, provided only one of A 5 and A 8 is N, and wherein each of R 4 , R 5 , R 6 and R 8 , independently, is H, F, Cl, CF 3 , CF 2 H, CH 2 F or CH 3 .

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

Assignees

• Amgen Inc

Inventors

• Minatti Ana Elena
• Low Jonathan D
• Allen Jennifer R
• Amegadzie Albert
• Brown James
• Frohn Michael J
• Guzman-Perez Angel
• Harrington Paul E
• Lopez Patricia
• Ma Vu Van
• Nishimura Nobuko
• Qian Wenyuan
• Rumfelt Shannon
• Rzasa Robert M
• Sham Kelvin
• Smith Adrian L
• White Ryan
• Xue Qiufen

Classifications

• A61P43/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D265/12

  condensed with carbocyclic rings or ring systems · CPC title