Novel Heterocyclic Derivatives and Their Use in the Treatment of Neurological Disorders

Patent metadata

Field	Value
Publication number	US-2015203481-A1
Application number	US-201414482662-A
Country	US
Kind code	A1
Filing date	Sep 10, 2014
Priority date	Jan 13, 2011
Publication date	Jul 23, 2015
Grant date	—

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

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof,

in which
either
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;
or
X 1 is CR 1 or N;
X 3 is CR 3 , N or S;
X 4 is a bond;
X 5 is CR 5 , N or S;
wherein at least one of X 1 , X 3 and X 5 is N or S, not more than 2 of X 1 , X 3 and X 5 are N and not more than 1 of X 3 and X 5 are S;
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 2 is an aryl, heteroaryl or non-aromatic heterocyclyl group G 1 , which group G 1 is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of cyano, amino, amino-(C 1-8 )alkyl, N—(C 1-4 )alkyl-amino-(C 1-8 )alkyl, N,N-di(C 1-4 )alkyl-amino-(C 1-8 )alkyl, aminocarbonyl, thiocarbamoyl, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, hydroxy, oxo, (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 3-8 )cycloalkyl-(C 1-8 )alkoxy, (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, (C 2-8 )alkynyl, (C 2-8 )alkenoxy, (C 2-8 )alkynoxy and a (C 3-8 )cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclyl group G 2 , which group G 2 is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group, consisting of cyano, aminocarbonyl, halogen, (C 1-8 )alkyl, halogen-(C 1-8 )alkyl, hydroxy, (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 and (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—(C 1-4 )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—, —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 pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5- or 6-membered heteroaryl group in which structure 1, 2, 3, or 4 ring members are hetero ring members independently selected from the group consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, which group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the group, consisting of cyano, amino, aminocarbonyl, thiocarbamoyl, halogen, (C 1-4 )alkyl, halogen-(C 1-4 )alkyl, hydroxy, oxo, (C 1-4 )alkoxy, halogen-(C 1-4 )alkoxy, (C 1-4 )alkylthio, halogen-(C 1-4 )alkylthio, (C 1-4 )alkoxy-(C 1-4 )alkyl, (C 1-4 )alkoxy-(C 1-4 )alkoxy, (C 1-4 )alkoxy-(C 1-4 )alkylthio, (C 1-4 )alkylthio-(C 1-4 )alkyl, (C 1-4 )alkylthio-(C 1-4 )alkoxy, (C 1-4 )alkylthio-(C 1-4 )alkylthio, (C 2-4 )alkenyl, (C 2-4 )alkynyl, (C 2-4 )alkenoxy, and (C 2-4 )alkynoxy.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
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.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, or halogen; and R 5 is hydrogen, or halogen.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is (C 1-3 )alkyl, or halogen-(C 1-3 )alkyl.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E 1 is —C(R 7 )(R 8 )— and
either
each of R 7 and R 8 is hydrogen;
or
R 7 and R 8 , taken together, are oxo.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof,

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

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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