Permeable glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9611275-B2
Application number	US-201314399146-A
Country	US
Kind code	B2
Filing date	May 3, 2013
Priority date	May 8, 2012
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

The present invention is directed to compounds and pharmaceutical formulations comprising these compounds which are useful as O-linked N-acetylglucosaminidase (O-GlcNAcase) inhibitors, and thus may be useful for the treatment of certain disorders such as Alzheimer's disease including reducing NFTs and/or hyperphosphorylated tau. The invention is also directed to use of the compounds as O-GlcNAcase imaging agents.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
each R is independently H or C(O)CH 3 ;
R 1 and R 2 are independently (a) hydrogen, (b) C1-6alkyl optionally substituted with 1 to 3 substituents selected from F, —OH, —OCH 3 and —CH 3 or (c)C1-6alkoxy optionally substituted with 1 to 3 substituents selected from F, —OH, —OCH 3 and —CH 3 ;
or R 1 and R 2 may be joined together with the nitrogen atom to which they are attached to form azetidine, pyrrolidine, piperidine or isoxazolidine;
R 3 is C1-10alkyl optionally substituted with 1 to 3 fluoro;
R 4 is hydrogen or C1-10alkyl optionally substituted with phenyl;
R 5 is
(A) C1-8alkyl optionally substituted with one substituent selected from the group consisting of:
(1) fluoro,
(2) morpholino,
(3) C3-6cycloalkyl,
(4) pyridinyl optionally substituted with C1-6alkyl,
(5) phenyl optionally substituted with 1 to 4 substituents selected from the group consisting of:
(a) fluoro, (b) hydroxy, (c) C1-6alkyl optionally substituted with 1 to 3 fluoro, (d) C1-6alkenyl, (e) C1-5alkoxy optionally substituted with fluoro, (f) phenyl, (g) phenyloxy, (h) benzyloxy and (i) C1-10alkylphenyl;

(B) phenyl optionally substituted with one substituent selected from the group consisting of:
(1) —NO 2 , (2) —NH 2 , (3) fluoro, (4) C1-6alkyl optionally substituted with fluoro, and (5) C1-6alkoxy optionally substituted with fluoro; and

(C) pyridinyl optionally substituted with a substituent selected from the group consisting of:
(1) fluoro, (2) C1-6alkyl optionally substituted with fluoro and (3) C1-6alkoxy optionally substituted with fluoro.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl or trifluoromethyl.

3. The compound of claim 1 of Formula (Ia):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 3 is methyl or trifluoromethyl;
R 4 is hydrogen; and
R 5 is C1-6alkyl optionally substituted with one substituent selected from the group consisting of:
(1) fluoro,
(2) morpholino,
(3) C3-6cycloalkyl,
(4) pyridinyl optionally substituted with C1-6alkyl,
(5) phenyl optionally substituted with 1 to 4 substituents selected from the group consisting of:
(a) fluoro, (b) hydroxy, (c) C1-6alkyl optionally substituted with fluoro, (d) C1-6alkenyl, (e) C1-5alkoxy optionally substituted with fluoro, (f) phenyl, (g) phenyloxy, (h) benzyloxy and (i) C11-6alkylphenyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 3 is methyl or trifluoromethyl;
R 4 is hydrogen; and
R 5 is phenyl optionally substituted with one substituent selected from the group consisting of: (1) —NO 2 , (2) —NH 2 , (3) fluoro, (4) C1-6alkyl optionally substituted with fluoro, and (5) C1-6alkoxy optionally substituted with fluoro.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 3 is methyl or trifluoromethyl;
R 4 is hydrogen; and
R 5 is pyridinyl optionally substituted with a substituent from the group consisting of: (1) fluoro, (2) C1-6alkyl optionally substituted with fluoro, and (3) C1-6alkoxy optionally substituted with fluoro.

8. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-2,2,2-trifluoro-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-phenoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-phenoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(ethylamino)-5-((R)-2,2,2-trifluoro-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-(4-nitrophenoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-(4-aminophenoxy)-2,2,2-trifluoroethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(4-nitrophenoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-1-methoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-(4-(allyloxy)benzyloxy)-2,2,2-trifluoroethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-(4-hydroxybenzyloxy)-2,2,2-trifluoroethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-1-ethoxy-2,2,2-trifluoroethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-1-ethoxy-2,2,2-trifluoroethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-1-ethoxy-2,2,2-trifluoroethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-propoxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-butoxy-2,2,2-trifluoroethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(pentyloxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(2-fluoroethoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(3-fluoropropoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(4-fluorobutoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(5-fluoropentyloxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-2,2,2-trifluoro-1-(5-fluoropentyloxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(2-morpholinoethoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-(2-cyclohexylethoxy)-2,2,2-trifluoroethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-5-((R)-1-(cyclohexylmethoxy)-2,2,2-trifluoroethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((R)-2,2,2-trifluoro-1-(3-(4-fluorophenyl)propoxy)ethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol;
(3aR,5S,6S,7R,7aR)-2-(dimethylamino)-5-((S)-2,2,2-trifluoro

Assignees

• Merck Sharp & Dohme
• Alectos Therapeutics Inc

Inventors

• Selnick Harold G
• Li Wenping
• Hostetler Eric
• Liu Kun
• Mceachern Ernest J
• Zhou Yuanxi
• Wei Zhongyong
• Mu Changwei
• Wang Yaode
• Chang Jiang

Classifications

• A61P35/00

  Antineoplastic 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

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title