US 12,637,451 B2Granted

Amino quinazoline derivatives as P2X3 inhibitors

AssigneeChiesi Farmaceutici S.p.A.

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

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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).

Claims11

Dependent claims

A compound of formula (I)

wherein
Z is selected from the group consisting of (C3-C8)heterocycloalkyl, (RARB)N—, heteroaryl, aryl,
wherein any of such alkyl, heteroaryl, heterocycloalkyl and aryl may be optionally substituted by one or more groups selected from (C1-C3)alkyl-, halo, CN, (RARB)NC(O)—, (C1-C6)haloalkyl-, RAO—, (RARB)N(C1-C6)alkylene-, (C3-C7)cycloalkyl-, RCSO2—, (RARB)N—;
R1 is H or (C1-C4)alkyl;
R2 is selected from the group consisting of heteroaryl(C1-C4)alkyl-, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl-(C1-C6)hydroxyalkyl-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, aryl-(C1-C4)alkyl-, (RARB)N(C1-C6)alkylene-, (RARB)N(O)C(C1-C4)alkylene- and RAO(C1-C4)alkylene- wherein any of such alkyl, alkylene, aryl, heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C1-C3)alkyl, RAO(C1-C4)alkylene-, (C1-C6)haloalkyl, halo, oxo, RAO—, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, heteroaryl, (RARB)N—, —NHC(O)RC, —C(O)N(RARB), —SO2N(RARB), —O(C1-C4)alkylene-N(RARB), aryl optionally substituted by halo, —ORC, aryl-(C1-C4)alkyl-, —C(O)RA;
RA and RB are at each occurrence independently H or selected from the group consisting of (C1-C4)alkyl-, (C3-C8)cycloalkyl-, (C1-C6) haloalkyl, or RA and RB may form together with the nitrogen atom to which they are attached a 5- or 6-membered saturated heterocyclic monocyclic ring system optionally containing a further heteroatom which is nitrogen or oxygen, which may be optionally substituted by one or more groups selected from (C1-C4)alkyl and oxo;
RC is at each occurrence H or selected from the group consisting of (C1-C6)alkyl, (RARB)N—, aryl-(C1-C4)alkyl-;
Y is selected from the group consisting of —ORD, RCSO2, —NHSO2RC, heteroaryl, (C3-C8)heterocycloalkyl,
wherein any of such heteroaryl and heterocycloalkyl may be optionally substituted by one or more groups selected from (C1-C3)alkyl, —C(O)N(RARB);
RD is selected from the group consisting of H, (C1-C6)alkyl, (C3-C8)heterocycloalkyl-(C1-C6)alkyl-, RCOC(O)(C1-C4)alkylene-, (RARB)N(C1-C6)alkylene-, (C3-C8)heterocycloalkyl, (C3-C8)cycloalkyl-(C1-C6)alkyl-, RCO(C1-C4)alkylene-, (RARB)N(O)C(C1-C4)alkylene-, wherein any of such heterocycloalkyl may be optionally substituted by one or more groups selected from (C1-C3)alkyl-;
J is H or selected from the group consisting of (C1-C6)alkyl, (RARB)N—, (C1-C6)haloalkyl, —ORC and halo.

8 more elements

A compound selected from the group consisting of

6-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine,
N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylpyridin-2-yl)quinazolin-4-amine,
N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)-2-(trifluoromethyl)quinazolin-4-amine,
N-((6-methylpyridazin-3-yl)methyl)-6-(5-methylpyridin-2-yl)quinazolin-4-amine,
N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-6-(5-methylthiazol-2-yl)quinazolin-4-amine,
2-chloro-6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine,
N2-cyclopropyl-6-(4-fluorophenyl)-N4-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazoline-2,4-diamine,
6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-morpholinoquinazolin-4-amine,
2-((2-(cyclopropylamino)-6-(4-fluorophenyl)quinazolin-4-yl)amino)propanamide,
N-cyclopropyl-2-((2-(cyclopropylamino)-6-(4-fluorophenyl)quinazolin-4-yl)amino)propanamide,
6-(4-fluorophenyl)-2-methyl-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine,
N-((6-methylpyridin-3-yl)methyl)-6-(5-methylthiophen-2-yl)quinazolin-4-amine,
N-((6-methylpyridin-3-yl)methyl)-6-(p-tolyl)quinazolin-4-amine,
N-((6-methylpyridazin-3-yl)methyl)-6-(2-methylpyrimidin-5-yl)quinazolin-4-amine,
(R)-6-(4-fluorophenyl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine,
6-(4-fluorophenyl)-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)quinazolin-4-amine,
2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzonitrile,
2-(4-(((6-methylpyridin-3-yl)methyl)amino)quinazolin-6-yl)benzamide,
6-(4-fluorophenyl)-N-((6-methylpyridin-3-yl)methyl)quinazolin-4-amine formate,
6-(4-fluorophenyl)-N-((6-methylpyridazin-3-yl)methyl)quinazolin-4-amine,
N-((3,5-difluoropyridin-2-yl)methyl)-6-(4-fluorophenyl)quinazolin-4-amine hydrochloride,
6-(4-fluorophenyl)-N-methyl-N-(1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl) quinazolin-4-amine,
(R)-6-(3,3 difluoropyrrolidin-1-yl)-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine,
(R)-6-morpholino-N-(1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinazolin-4-amine,
(R)-1-methyl-4-(4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)amino) quinazolin-6-yl)piperazin-2-one,
N-((6-methylpyridazin-3-yl)methyl)-6-morpholinoquinazolin-4-amine,
Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazolin-4-amine,
Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazolin-4-amine,
Single enantiomer 1 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine,
Single enantiomer 2 of N2-cyclopropyl-6-(4-fluorophenyl)-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine,
Single enantiomer 1 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-2-morpholino-quinazolin-4-amine,
Single enantiomer 2 of 6-(4-fluorophenyl)-N-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-2-morpholino-quinazolin-4-amine,
Single enantiomer 1 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine, and
Single enantiomer 2 of 6-(4-fluorophenyl)-N2,N2-dimethyl-N4-[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]quinazoline-2,4-diamine.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/615,056Filed 28 May 2020
Priority: EP 1917760431 May 2019
Published: US 2023/0092892 A123 Mar 2023
Granted: 26 May 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 417/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/14
Drugs for disorders of the respiratory system: antitussive agents
C07D 239/94
With hetero atoms directly attached in position 4: nitrogen atoms