Substituted piperidines thiazolyl acetamides as glycosidase inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10913733-B2
Application number	US-201616061988-A
Country	US
Kind code	B2
Filing date	Dec 14, 2016
Priority date	Dec 18, 2015
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

The present invention is directed to thiazolyl piperidine compounds of the general structural formula I:

which are inhibitors of O-GlcNAcase. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which O-GlcNAcase is involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which O-GlcNAcase is involved.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is benzodioxolyl, dihydrobenzodioxinyl, oxoisoindolinyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl or indolyl, wherein the benzodioxolyl, dihydrobenzodioxinyl, oxoisoindolinyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl or indolyl is optionally substituted with one or more substituents selected from the group consisting of R 1a , R 1b and R 1c ;
R 2 is hydrogen or methyl;
R 3 is hydrogen or methyl;
R 4 is hydrogen or methyl; and
R 1a , R 1b and R 1c are independently halogen, C 1-6 alkyl, —OH, —O—C 1-6 alkyl, —O—C 3-6 alkenyl, —NO 2 , —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —C(═O)—C 1-6 alkyl, —C(═O)O—C 1-6 alkyl, —OC(═O)O—C 1-6 alkyl, —S(═O) 2 NH 2 , S(═O) 2 N(C 1-6 alkyl) 2 , or phenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, —OCH 3 , —O(CH 2 ) 2 OCH 3 , —C(═O)—C 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 and —NHC(═O)(C 1-6 alkyl), and further wherein the —O—C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, —OCH 3 , —C(═O)—C 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , and —NHC(═O)(C 1-6 alkyl).

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of R 1a , R 1b and R 1c .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is phenyl or pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of R 1a and R 1b ; and
R 1a and R 1b are independently F, C 1-3 alkyl, -OH, or -O-C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 , and further wherein the -O-C 1-3 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is phenyl or pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of R 1a , R 1b and R 1c ; and
R 1a , R 1b and R 1c are independently halogen, C 1-6 alkyl, -OH, or -O-C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 , and further wherein the -O-C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is phenyl or pyridyl, each of which is optionally substituted with one or more substituents selected from the group consisting of R 1a , R 1b and R 1c ; and
R 1a , R 1b and R 1c are independently F, C 1-3 alkyl, -OH, or -O-C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 , and further wherein the -O-C 1-3 alkyl is optionally substituted with one or more substituents selected from the group consisting of F, -OH, and -OCH 3 .

6. The compound of claim 1 , wherein the compound is of formula Ia:

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

8. A method for inhibiting O-linked N-acetylglucosaminidase activity in a human patient, comprising administering to a human patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the human patient has a disease or disorder selected from the group consisting of consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, glaucoma, schizophrenia, mild cognitive impairment, neuropathy, and cancer.

10. The method of claim 9 , wherein the human patient has been diagnosed with a need for treatment of the disease or disorder prior to administering the compound of claim 9 , or a pharmaceutically acceptable salt thereof.

11. A compound selected from the group consisting of:
N-(5-((4-(3,4-dimethoxybenzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-((6-fluoropyridin-3-yl)methylene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-((6-hydroxypyridin-3-yl)methylene)piperidin-1-yl)methyl)thiazol-2-ypacetamide;
N-[5-({4-[(4-hydroxyphenyl)methylidene]-piperidin-1-yl)methyl)-1,3-thiazol-2-yl]acetamide;
4-((142-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)methyl)phenyltert-butyl carbonate;
N-[5-({4-[(6-aminopyridin-3-yl)methylidene]piperidin-1-yl(methyl)-1,3-thiazol-2-yl]acetamide;
N-(5-((4-(3-(hydroxymethyl)-benzylidene)piperidin-1-yl)methypthiazol-2-y)pacetamide;
N-(5-((4-((1H-pyrazol-4-yl)methylene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
4-((1-((2-acetamidothiazol-5-yl)methyl)-piperidin-4-ylidene)methyl)benzamide;
2-(3-((142-acetamidothiazol-5-yl)methyl)-piperidin-4-ylidene)methyl)phenyl)-acetamide;
N-(5-((4-(4-(trifluoromethoxy)benzylidene)-piperidin-1-yl)methypthiazol-2-y)pacetamide;
N-(5-((4-(4-ethylbenzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-(4-methylb enzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-(4-ethoxybenzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-(pyrimidin-5-ylmethylene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-[5-({4-[(2,3-dimethoxyphenyl)methylidene]piperidin-1-yl}methyl)-1,3-thiazol-2-yl]acetamide;
N-(5-((4-(4-(N,N-dimethyl sulfamoyl)benzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-{[4-(1H-indo1-5-ylmethylidene)piperidin-1-yl]methyl}-1,3-thiazol-2-ypacetamide;
N-(5-{[441,3-benzodioxo1-5-ylmethylidene)piperidin-1-yl]methyl}-1,3-thiazol-2-ypacetamide;
N-(5-{[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethylidene)piperidin-1-yl]methyl}-1,3-thiazol-2-yl)acetamide;
N-(5-((4-((1-oxoisoindolin-5-yl)methylene)piperidin-1-yl)methypthiazol-2-ypacetamide;
N- [5-({4-[(4-hydroxy-3-methoxyphenyl)methylidene]piperidin-1-yl }methyl)-1,3-thiazol -2-yl]acetamide;
N45-({4-[(3-hydroxy-4-methoxyphenyl)methylidene]piperidin-1-yl}methyl)-1,3-thiazol-2-yl]acetamide;
methyl4-((1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)methyl)benzoate;
N-{5-[(4-{[4-(hydroxymethyl)phenyl]-methylidene}piperidin-1-yl)methyl]-1,3-thiazol-2-yl}acetamide;
N-(5-((4-(4-(fluoromethyl)benzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-(4-(2-fluoroethyl)-benzylidene)piperidin-1-yl)methyl)thiazol-2-yl)acetamide;
N-(5-((4-(4-(2-fluoroethyl)benzylidene)-piperidin-1-yl)methyl)thiazol-2-yl)-N-methylacetamide;
4-[(1-{[2-(acetylamino)-1,3-thiazol-5-yl]methyl}piperidin-4-ylidene)methyl]benzoic acid;
4-[(1-{[2-(acetylamino)-1,3-thiazol -5-yl]methyl}piperidin-4-ylidene)methyl]-N-methylbenzamide;
4-((1-((2-acetamidothiazol-5-yl)methyl)piperidin-4-ylidene)methyl)-N,N-dimethylbenzamide;
N-[5 -({4-[(4-fluorophenyl)methylidene]piperidin-1-yl }methyl)-1,3-thiazol-2-yl]acetamide;
N-(5-{[4-(phenyl-methylidene)pi

Assignees

• Merck Sharp & Dohme
• Alectos Therapeutics Inc

Inventors

• Mceachern Ernest J
• Selnick Harold G
• Zhou Yuanxi

Classifications

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title