Phthalazine derivatives as P2X3 inhibitors

Patent metadata

Field	Value
Publication number	US-12534455-B2
Application number	US-202118038802-A
Country	US
Kind code	B2
Filing date	Nov 26, 2021
Priority date	Nov 27, 2020
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

The present invention relates to compounds of formula (I) inhibiting P2X purinoceptor 3; particularly the invention relates to compounds that are phthalazine derivatives, methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful in the treatment of many disorders associated with P2X 3 receptors mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

First claim

The invention claimed is:

1 . A compound of formula (I)

wherein
Z is selected from the group consisting of (5-6 membered)-heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more selected from the group consisting of (C1-C3) alkyl- and halo;
R 1 is H or (C1-C4) alkyl;
R 2 is selected from the group consisting of heteroaryl and (C 3 -C 8 ) cycloalkyl-, wherein any of such heteroaryl may be optionally substituted by one or more selected from the group consisting of (C1-C3) alkyl, (C1-C6) haloalkyl and halo;
R 3 is H or (C1-C4) alkyl;
Y is selected from the group consisting of H, (C1-C4) alkyl-, (C3-C8) cycloalkyl-, (C3-C8) heterocycloalkyl, and (C3-C8) heterocycloalkyl-(C1-C4) alkyl-,
or stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

2 . The compound of formula (I), or stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, according to claim 1 , wherein the compound selected from the group consisting of:
N-((6-Methylpyridazin-3-yl) methyl)-7-(5-methylpyrimidin-2-yl)-4-(tetrahydro-2H-pyran-4-yl) phthalazin-1-amine, N-(Cyclopropylmethyl)-7-(4-fluorophenyl) phthalazin-1-amine, 7-(4-Fluorophenyl)-N-((6-methylpyridazin-3-yl) methyl) phthalazin-1-amine, (R)-4-Cyclopropyl-7-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) phthalazin-1-amine, (R)-4-Cyclopropyl-7-(4-fluorophenyl)-N-(1-(6-methylpyridazin-3-yl) ethyl) phthalazin-1-amine, (R)-7-(4-Fluorophenyl)-4-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) phthalazin-1-amine, (R)-7-(4-Fluorophenyl)-N-(1-(6-methylpyridazin-3-yl) ethyl)-4-(tetrahydro-2H-pyran-4-yl) phthalazin-1-amine, 7-(5-Fluoropyridin-2-yl)-N-((6-methylpyridazin-3-yl) methyl)-4-(tetrahydro-2H-pyran-4-yl) phthalazin-1-amine, 7-(5-Fluoropyridin-2-yl)-N-((6-methylpyridazin-3-yl) methyl)-4-((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1-amine, 7-(5-Fluoropyridin-2-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl)-4-(tetrahydro-2H-pyran-4-yl) phthalazin-1-amine, N-[(6-Methylpyridazin-3-yl) methyl]-7-(5-methylthiazol-2-yl) phthalazin-1-amine, 7-(5-Methylthiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl) methyl)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) methyl) phthalazin-1-amine, N-((6-Methylpyridazin-3-yl) methyl)-7-(5-methylthiazol-2-yl)-4-((tetrahydro-2H-pyran-4-yl) methyl) phthalazin-1-amine, 7-(1-Methylpyrazol-3-yl)-N-[1-(6-methylpyridazin-3-yl) ethyl]-4-tetrahydropyran-4-yl-phthalazin-1-amine, and 4-Cyclopropyl-7-(1-methyl-1H-pyrazol-3-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl) phthalazin-1-amine.

3 . The compound of formula (I), or stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, according to claim 1 , wherein Y and R 1 are H, represented by the formula (Ia)

wherein
Z is selected from the group consisting of (5-6 membered)-heteroaryl and aryl, wherein any of such heteroaryl and aryl may be optionally substituted by one or more selected from the group consisting of (C 1 -C 3 ) alkyl- and halo;
R 2 is selected from the group consisting of heteroaryl and (C 3 -C 8 ) cycloalkyl-, wherein any of such heteroaryl may be optionally substituted by one or more (C 1 -C 3 ) alkyl-;
R 3 is H or (C 1 -C 4 ) alkyl.

4 . A pharmaceutical composition comprising the compound or stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, of claim 1 , either alone or in combination with another one or more active ingredient, in admixture with one or more pharmaceutically acceptable carrier or excipient.

5 . The pharmaceutical composition according to claim 4 , formulated for oral administration.

6 . A method of treating a disease involving one or more P2X 3 receptors, comprising administering to a subject in need thereof the pharmaceutical composition of claim 4 , wherein the disease is a respiratory disease selected from the group consisting of cough, sub-acute cough, chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and bronchospasm.

7 . The method of claim 6 , wherein the disease is chronic cough.

8 . The method according to claim 6 , wherein the pharmaceutical composition is orally administered.

9 . The method according to claim 7 , wherein the pharmaceutical composition is orally administered.

Assignees

• Chiesi Farm Spa

Inventors

• Fiorelli Claudio
• Bruno Paolo
• Biagetti Matteo
• Baker-Glenn Charles
• Van De Poöel Hervè

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D403/12

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

• C07D237/34

  with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title