2-Amino-6-(difluoromethyl)-5,5-difluoro-6-phenyl-3,4,5,6-tetrahydropyridines as BACE1 Inhibitors

Patent metadata

Field	Value
Publication number	US-2016130267-A1
Application number	US-201514933301-A
Country	US
Kind code	A1
Filing date	Nov 5, 2015
Priority date	Nov 10, 2014
Publication date	May 12, 2016
Grant date	—

Abstract

The present invention is directed to novel inhibitors of the BACE1 enzyme. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders for which the reduction of Aβ deposits is beneficial such as Alzheimer's disease.

First claim

1 . A compound of formula I

wherein Ar is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, and where the Ar is optionally substituted with one or more substituent selected from halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl or C 1 -C 6 alkoxy; and
R 1 is hydrogen, halogen, C 1 -C 3 fluoroalkyl or C 1 -C 3 alkyl;
or a pharmaceutically acceptable salt thereof.

2 . A compound according to claim 1 , wherein the compound is of formula Ia

or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 1 , wherein R 1 is F or H.

4 . The compound according to claim 1 , wherein Ar is optionally substituted with one or more F, Cl, Br, CN, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl or C 1 -C 3 alkoxy.

5 . The compound according to claim 1 , wherein Ar is optionally substituted pyridyl.

6 . The compound according to claim 1 , wherein Ar is optionally substituted pyrimidyl.

7 . The compound according to claim 1 , wherein Ar is optionally substituted pyrazinyl.

8 . The compound according to claim 1 , wherein Ar is optionally substituted oxazolyl.

9 . The compound according to claim 1 , wherein Ar is optionally substituted thiazolyl.

10 . The compound according to claim 1 , wherein the compound is selected from the group consisting of:
(1) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-chloropicolinamide; (2) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-fluoropicolinamide; (3) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide; (4) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-2-methyloxazole-4-carboxamide; (5) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypicolinamide; (6) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide; (7) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyanopicolinamide; (8) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-4-methylthiazole-2-carboxamide; (9) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxypyrimidine-2-carboxamide; (10) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-methoxy-3-methylpyrazine-2-carboxamide; (11) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide; (12) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenye-5-bromopicolinamide; (13) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetr ahydropyridin-2-yl)-4-fluorophenye-5-(methoxy-d3)picolinamide; and (14) (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-(methoxy-d3)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.

11 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

12 . A method of treating a disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof, wherein the disease is selected from the group consisting of familial Alzheimer's disease, sporadic Alzheimer's disease, preclinical Alzheimer's disease, prodromal Alzheimer's disease, mild cognitive impairment, Down's syndrome and cerebral amyloid angiopathy.

13 . The method of claim 12 wherein the disease is familial Alzheimer's disease.

14 . The method of claim 12 wherein the disease is sporadic Alzheimer's disease.

15 . The method of claim 12 wherein the disease is preclinical Alzheimer's disease.

16 . The method of claim 12 wherein the disease is prodromal Alzheimer's disease.

17 . The method of claim 12 wherein the disease is mild cognitive impairment.

18 . The method of claim 12 wherein the disease is Down's syndrome.

19 . The method of claim 12 wherein the disease is cerebral amyloid angiopathy.

Assignees

• Lundbeck & Co As H

Inventors

• Juhl Karsten
• Tagmose Lena
• Marigo Mauro

Classifications

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/444 Primary

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · 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

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title