Amino quinazoline derivatives as P2X3 inhibitors

Patent metadata

Field	Value
Publication number	US-12466820-B2
Application number	US-202017615017-A
Country	US
Kind code	B2
Filing date	May 28, 2020
Priority date	May 31, 2019
Publication date	Nov 11, 2025
Grant date	Nov 11, 2025

Abstract

The present invention relates to compounds of formula I inhibiting P2X purinoceptor 3; particularly the invention relates to compounds that are amino quinazoline 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 P2X3 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 (C 3 -C 8 )heterocycloalkyl, (R A R B )N, heteroaryl, aryl, wherein any of such alkyl, heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl-, halo, CN, (R A R B )NC(O)-, (C 1 -C 6 )haloalkyl-, R A O—, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 7 )cycloalkyl-, R C SO 2 -, (R A R B )N-;
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is selected from the group consisting of heteroaryl (C 1 -C 4 )alkyl-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, heteroaryl-(C 1 -C 6 )hydroxyalkyl, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-, aryl-(C 1 -C 4 )alkyl-, (R A R B )N(C 1 -C 6 )alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene-, R A O(C 1 -C 4 )alkylene-, wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, R A O(C 1 -C 4 )alkylene-, (C 1 -C 6 )haloalkyl, halo, oxo, R A O-, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, heteroaryl, (R A R B )N—, —NHC(O)R C , —C(O)N(R A R B ), —SO 2 N(R A R B ), —O(C 1 -C 4 )alkylene-N(R A R B ), aryl optionally substituted by halo, —OR C , aryl-(C 1 -C 4 )alkyl-, —C(O)R A ,
R A and R B are at each occurrence independently H or selected from the group consisting of (C 1 -C 4 )alkyl-, (C 3 -C 8 )cycloalkyl-, (C 1 -C 6 )haloalkyl, or
R A and R B may form together with the nitrogen atom to which they are attached 5- or 6-membered saturated heterocyclic monocyclic ring system optionally further consisting of a heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups selected from (C 1 -C 4 )alkyl and oxo;
R C is at each occurrence H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N—, aryl-(C 1 -C 4 )alkyl-;
Y is selected from the group consisting of —OR D , R C SO 2 , NHSO 2 R C , heteroaryl, (C 3 -C 8 )heterocycloalkyl, wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl, and —C(O)N(R A R B );
R D is at each occurrence selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl-(C 1 -C 6 )alkyl-, R C OC(O)(C 1 -C 4 )alkylene-, (R A R B )N(C 1 -C 6 )alkylene-, (C 3 -C 8 )heterocycloalkyl, (C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl, R C O(C 1 -C 4 )alkylene-, (R A R B )N(O)C(C 1 -C 4 )alkylene, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups selected from (C 1 -C 3 )alkyl-;
J is H or selected from the group consisting of (C 1 -C 6 )alkyl, (R A R B )N—, (C 1 -C 6 )haloalkyl, —OR C and halo.

2. The compound of formula I according to claim 1 , selected from the group consisting of:
6-(1-((6-(4-Fluorophenyl)-8-methoxyquinazolin-4-yl) amino) ethyl) pyridin-2 (1H)-one,
6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl) ethyl) quinazolin-4-amine,
6-(5-fluoropyrimidin-2-yl)-8-methoxy-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl) ethyl) quinazolin-4-amine,
((R)-6-(5-fluoropyrimidin-2-yl)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl)-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
8-Methoxy-N-[(1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl) ethyl]-6-(5-methylpyrimidin-2-yl) quinazolin-4-amine,
single enantiomer 1 of N—[1-(6-methylpyridazin-3-yl) ethyl]-6-(5-methylpyrimidin-2-yl)-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
single enantiomer 2 of N—[1-(6-methylpyridazin-3-yl) ethyl]-6-(5-methylpyrimidin-2-yl)-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
6-(5-fluoro-2-pyridyl)-N-[(6-methylpyridazin-3-yl) methyl]-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
N-[(6-methylpyridazin-3-yl) methyl]-6-(5-methylpyrimidin-2-yl)-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
(R)-6-(1-methyl-1H-pyrazol-3-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl)-8-((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-4-amine,
(R)-6-(5-methylthiazol-2-yl)-N-(1-(pyridazin-3-yl) ethyl)-8-((tetrahydro-2H-pyran-4-yl) oxy) quinazolin-4-amine,
8-(2-methoxyethoxy)-N—((6-methylpyridazin-3-yl) methyl)-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
2-((4-(((6-methylpyridazin-3-yl) methyl) amino)-6-(5-methylthiazol-2-yl) quinazolin-8-yl) oxy) ethan-1-ol,
N—((6-methylpyridazin-3-yl) methyl)-6-(5-methylthiazol-2-yl)-8-(oxetan-3-ylmethoxy) quinazolin-4-amine,
N-[(6-methylpyridazin-3-yl) methyl]-6-(5-methylthiazol-2-yl)-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
(R)-2-((6-(4-fluorophenyl)-4-((1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) amino) quinazolin-8-yl) oxy) acetic acid,
2-((4-(((6-methylpyridazin-3-yl) methyl) amino)-6-(5-methylpyrimidin-2-yl) quinazolin-8-yl) oxy) acetic acid dihydrochloride,
2-((6-(4-fluorophenyl)-4-(((1-methylpiperidin-4-yl) methyl) amino) quinazolin-8-yl) oxy) acetic acid hydrochloride,
6-(4-fluorophenyl)-N—((6-methylpyridazin-3-yl) methyl)-8-(oxetan-3-yloxy) quinazolin-4-amine,
N—[1-(5-methyl-1,3,4-thiadiazol-2-yl) ethyl]-6-(5-methylthiazol-2-yl)-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
6-(5-fluoro-2-pyridyl)-N-[(1R)-1-(5-methyl-1,2,4-oxadiazol-3-yl) ethyl]-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
Single enantiomer 1 of 6-(5-methyl-2-pyridyl)-N—[1-(5-methyl-1,3,4-thiadiazol-2-yl) ethyl]-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
Single enantiomer 2 of 6-(5-methyl-2-pyridyl)-N—[1-(5-methyl-1,3,4-thiadiazol-2-yl) ethyl]-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
Single enantiomer 1 of 6-(5-fluoro-2-pyridyl)-N—[1-(3-methyl-1,2,4-oxadiazol-5-yl) ethyl]-8-tetrahydropyran-4-yloxy-quinazolin-4-amine,
6-(3-Chloro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) quinazolin-4-amine,
6-(3-chloro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-6-(4-fluoro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) quinazolin-4-amine,
(R)-6-(4-fluoro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-8-methoxy-6-(4-methyl-1H-pyrazol-1-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-6-(4-chloro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-6-(3-fluoro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-8-methoxy-6-(5-methyl-1H-pyrazol-1-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-8-methoxy-6-(3-methyl-1H-pyrazol-1-yl)-N-(1-(6-methylpyridazin-3-yl) ethyl) quinazolin-4-amine,
(R)-6-(4-chloro-1H-pyrazol-1-yl)-8-methoxy-N-(1-(2-(trifluoromethyl) pyrimidin-5-yl) ethyl) quinazolin-4-amine,
(8-methoxy-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl) ethyl)-6-(1-methyl-1H-pyrazol-3-yl) quinazolin-4-amine,
8-methoxy-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl) ethyl)-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl) ethyl)-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
6-(5-fluoropyrimidin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl) ethyl) quinazolin-4-amine,
6-(5-fluoropyrimidin-2-yl)-8-methoxy-N-(1-(5-methyl-1,3,4-thiadiazol-2-yl) ethyl) quinazolin-4-amine,
6-(5-fluoropyrimidin-2-yl)-8-methoxy-N-(1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl) quinazolin-4-amine,
8-methoxy-N-[(3-methylisoxazol-5-yl) methyl]-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
8-methoxy-6-(5-methylthiazol-2-yl)-N—[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]quinazolin-4-amine,
8-methoxy-N-[(3-methyl-1,2,4-oxadiazol-5-yl) methyl]-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
8-methoxy-N—((5-methyl-1,3,4-thiadiazol-2-yl) methyl)-6-(5-methylthiazol-2-yl) quinazolin-4-amine,
4-(((8-methoxy-6-(5-methylthiazol-2-yl) quina

Assignees

• Chiesi Farm Spa

Inventors

• Bruno Paolo
• Biagetti Matteo
• Fiorelli Claudio
• Pizzirani Daniela
• Pala Daniele
• Ronchi Paolo
• Baker-Glenn Charles
• Van De Poël Hervè
• Hirst Kim Louise
• Guariento Sara

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D409/12

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title