5-aromatic alkynyl substituted benzamide compound and preparation method, pharmaceutical composition, and use thereof

Patent metadata

Field	Value
Publication number	US-10618900-B2
Application number	US-201615566418-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 15, 2015
Publication date	Apr 14, 2020
Grant date	Apr 14, 2020

Abstract

Compounds of formula I are provided. Also provided are methods of preparing the compounds of formula (I), and methods of using the compounds of formula (I) as a negative allosteric modulator of a metabotropic glutamate receptor (mGluR) subtype 5.

First claim

The invention claimed is:

1. A compound of formula I, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof:

X is CH;
R 1 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, and cyano;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered heteroaryl, substituted or unsubstituted 5-7 membered aryl-methylene, and 3-7 membered heterocyclyl-methylene, wherein each heterocyclyl independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; provided that R 2 and R 3 are not simultaneously hydrogen;
or R 2 and R 3 together with the attached N atom form a group selected from the group consisting of substituted or unsubstituted 5-20 membered hetero spirocyclic ring, and substituted or unsubstituted 4-20 membered fused heterocyclic ring; wherein substituted means one or more hydrogen atoms of the group are substituted by substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen-substituted C1-C6 alkoxy, C2-C-6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl; wherein the hetero spirocyclic ring, fused heterocyclic ring or heterocyclyl each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

 ring is selected from the group consisting of:

wherein R 4 , R 5 , and R 7 each represents 1-2 substituents on the heteroring, and each R 4 , R 5 , and R 7 is a substituent independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, hydroxyl; and
the halogen is F, Cl, Br or I.

2. The compound of claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered heteroaryl, substituted or unsubstituted 5-7 membered aryl-methylene, and 3-7 membered heterocyclyl-methylene, wherein each heterocyclyl independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; provided that R 2 and R 3 are not simultaneously hydrogen;
or R 2 and R 3 together with the attached N atom form a group selected from the group consisting of substituted or unsubstituted hetero spirocyclic ring, and substituted or unsubstituted fused heterocyclic ring; wherein substituted means one or more hydrogen atoms of the group are substituted by substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, sulfonyl, and trifluoromethyl.

3. The compound of claim 1 , wherein the

ring is selected from the group consisting of

wherein R 4 , R 5 , and R 7 each represents 1-2 substituents on the heteroring, and each substituent is independently selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy.

4. The compound of claim 1 , wherein R 2 is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, and substituted or unsubstituted pyrazinyl; wherein substituted means one or more hydrogen atoms of the group are substituted by substituents selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy;
R 3 is H;
or R 2 and R 3 together with the connected N atom form a substituted or unsubstituted group selected from the group consisting of:

wherein R 9 , R 10 , and R 13 each represent 1-4 substituents on any position of the ring, and R 11 and R 12 each represent substituents of the ring, and each substituent is independently selected from the group consisting of halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, cyano, nitro, amino, and hydroxy.

5. The compound of claim 1 , wherein the compound is selected from the following group:

No.
Name
Structure

ZD004
2-fluoro-N-(4-fluorophenyl)-5-((2-methyl- thiaZol-4-yl)ethynyl)benzamide

ZD005
(3-((2-methylthiazol-4-yl)ethynyl)phenyl) (3-trifluoromethyl-5,6-dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl)methanone

ZD007
(3-((2-methylthiazol-4-yl)phenyl)(7-oxa-2- aza-spiro[3.5]nonan-2-yl)methanone

ZD008
(3-((2-methylthiazol-4-yl)phenyl)(8-oxa- 2-aza-spiro[4.5]dec-2-yl)methanone

ZD009
N-(4-fluorophenyl)-3-((2-methylthiazol-4- yl)ethynyl)benzamide

ZD010
N-(4-cyanophenyl)-3-((2-methylthiazol-4- yl)ethynyl)benzamide

ZD011
(1-methyl-3,4-dihydro-isoquinolin-2(1H- yl-3-((2-methyl-thiazol-4-yl)ethynyl) phenyl)methanone

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Liu Hong
• Zhou Yu
• Zhang Dong
• Li Jian
• Jiang Hualiang
• Chen Kaixian

Classifications

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D277/30

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/06

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