Heterocyclic derivatives and their use in the treatment of neurological disorders

Patent metadata

Field	Value
Publication number	US-9550758-B2
Application number	US-201414482662-A
Country	US
Kind code	B2
Filing date	Sep 10, 2014
Priority date	Jan 13, 2011
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The invention relates to novel heterocyclic compounds of the formula

in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.

First claim

The invention claimed is:

1. A compound of formula (II), or a salt thereof,

in which
PG is a protecting group;
X 1 is CR 1 or N;
X 3 is CR 3 or N;
X 4 is CR 4 or N;
X 5 is CR 5 or N;
wherein at least one of X 1 , X 3 , X 4 and X 5 is N and not more than 2 of X 1 , X 3 , X 4 and X 5 are N;
R 1 is hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy, halogen-(C 1-8 ) alkoxy, (C 1-8 )alkylthio, halogen-(C 1-8 )alkylthio, (C 1-8 )alkoxy-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkoxy, (C 1-8 )alkoxy-(C 1-8 )alkylthio, (C 1-8 )alkylthio-(C 1-8 )alkyl, (C 1-8 )alkylthio-(C 1-8 )alkoxy, (C 1-8 )alkylthio-(C 1-8 )alkylthio, (C 2-8 )alkenyl, or (C 2-8 )alkynyl;
R 3 is hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy; halogen-(C 1-8 )alkoxy, (C 1-8 )alkylthio, halogen-(C 1-8 )alkylthio, (C 1-8 )alkoxy-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkoxy, (C 1-8 )alkoxy-(C 1-8 )alkylthio, (C 1-8 )alkylthio-(C 1-8 )alkyl, (C 1-8 )alkylthio-(C 1-8 )alkoxy, (C 1-8 )alkylthio-(C 1-8 )alkylthio, (C 2-8 )alkenyl, or (C 2-8 )alkynyl;
R 4 is hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy, halogen-(C 1-8 )alkoxy, (C 1-8 )alkylthio, halogen-(C 1-8 )alkylthio, (C 1-8 )alkoxy-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkoxy, (C 1-8 )alkoxy-(C 1-8 )alkylthio, (C 1-8 )alkylthio-(C 1-8 )alkyl, (C 1-8 )alkylthio-(C 1-8 )alkoxy, (C 1-8 )alkylthio-(C 1-8 )alkylthio, (C 2-8 )alkenyl, or (C 2-8 )alkynyl;
R 5 is hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy, halogen-(C 1-8 )alkoxy, (C 1-8 )alkylthio, halogen-(C 1-8 )alkylthio, (C 1-8 )alkoxy-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkoxy, (C 1-8 )alkoxy-(C 1-8 )alkylthio, (C 1-8 )alkylthio-(C 1-8 )alkyl, (C 1-8 )alkylthio-(C 1-8 )alkoxy, (C 1-8 )alkylthio-(C 1-8 )alkylthio, (C 2-8 )alkenyl, or (C 2-8 )alkynyl;
or
R 4 and R 5 , taken together, are —C(H)═C(H)—C(H)═C(H)— or a (C 1-8 )alkylene group, in which (C 1-8 )alkylene group 1 or 2 —CH 2 — ring members are optionally replaced with hetero ring members independently selected from the group, consisting of —N(H)—, —N[(C 1-8 )alkyl]-, —O—, —S—, —S(═O)— or —S(═O) 2 —;
R 6 is (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkyl, mercapto-(C 1-8 )alkyl, (C 1-8 )alkylthio-(C 1-8 )alkyl, amino-(C 1-8 )alkyl, N,N-di(C 1-4 )alkyl-amino-(C 1-8 )alkyl, (C 2-8 )alkenyl, or (C 2-8 )alkynyl;
or
R 5 and R 6 , taken together, are a (C 1-4 )alkylene group, in which (C 1 4 alkylene group 1 —CH 2 — ring member is optionally replaced with a hetero ring member independently selected from the group, consisting of —N(H)—, —N[(C 1-4 )alkyl]-, —O—, —S(═O)— or —S(═O) 2 —;
E 1 is —C(R 7 )(R 8 )—, or —C(R 7 )(R 8 )—C(R 9 )(R 10 )—;
E 2 is —C(R 11 )(R 12 )—, or —C(R 11 )(R 12 )—C(R 13 )(R 14 )—;
either
each of R 7 and R 8 is independently selected from the group, consisting of hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkyl and (C 1-8 )alkylthio-(C 1-8 )alkyl;
or
R 7 and R 8 , taken together, are oxo or —CH 2 —CH 2 —;
either
each of R 9 and R 10 is independently selected from the group, consisting of hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkyl and (C 1-8 )alkylthio-(C 1-8 )alkyl;
or
R 9 and R 10 , taken together, are oxo or —CH 2 —CH 2 —;
either
each of R 11 and R 12 is independently selected from the group, consisting of hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkyl and (C 1-8 )alkylthio-(C 1-8 )alkyl;
or
R 11 and R 12 , taken together, are oxo or —CR 15 R 16 —CR 17 R 18 —
wherein R 15 , R 16 , R 17 and R 18 are independently selected from hydrogen and fluoro; and
either
each of R 13 and R 14 is independently selected from the group, consisting of hydrogen, cyano, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, (C 1-8 )alkoxy-(C 1-8 )alkyl and (C 1-8 )alkylthio-(C 1-8 )alkyl;
or
R 13 and R 14 , taken together, are oxo or —CH 2 —CH 2 —.

2. The compound of claim 1 , or a salt thereof, in which
X 1 is CH or N;
X 3 is CH or N;
X 4 is CR 4 or N;
X 5 is CR 5 ;
wherein one and not more than one of X 1 , X 3 and X 4 is N;
R 4 is hydrogen;
R 5 is hydrogen or halogen
R 6 is methyl, fluoromethyl, difluoromethyl or trifluoromethyl;
E 1 is —C(R 7 )(R 8 )—;
E 2 is —C(R 11 )(R 12 )—;
each of R 7 and R 8 is hydrogen; and
each of R 11 and R 12 is independently selected from the group, consisting of hydrogen, (C 1-3 )alkyl and halogen-(C 1-3 )alkyl.

3. The compound of claim 1 , or a salt thereof, in which
X 1 is N;
X 3 is CR 3 ;
X 4 is CR 4 ;
X 5 is CR 5 ;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen or halogen;
R 6 is methyl, fluoromethyl or difluoromethyl;
E 1 is —C(R 7 )(R 8 )—;
E 2 is —C(R 11 )(R 12 )—;
each of R 7 and R 8 is hydrogen; and
each of R 11 and R 12 is independently selected from the group, consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and trifluoromethyl.

4. The compound of claim 3 , or a salt thereof, in which R 5 is fluoro.

5. The compound of claim 1 , wherein the compound is [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester, or a salt thereof.

6. The compound of claim 1 , wherein the compound is [(2R,5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester.

Assignees

• Badiger Sangamesh
• Chebrolu Murali
• Hurth Konstanze
• Jacquier Sebastien
• Lueoend Rainer Martin
• Machauer Rainer
• Rueeger Heinrich
• Tintelnot-Blomley Marina
• Veenstra Siem Jacob
• Voegtle Markus
• Novartis Ag

Inventors

• Badiger Sangamesh
• Chebrolu Murali
• Hurth Konstanze
• Jacquier Sebastien
• Lueoend Rainer Martin
• Machauer Rainer
• Rueeger Heinrich
• Tintelnot-Blomley Marina
• Veenstra Siem Jacob
• Voegtle Markus

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · 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