Derivatives of [1, 2, 4] triazolo [4, 3-a] pyridine as P38—MAP kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9573949-B2
Application number	US-201314895718-A
Country	US
Kind code	B2
Filing date	Jun 6, 2013
Priority date	Jun 6, 2013
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Mitogen activated protein kinase (MAPK) inhibitors disclosed herein are useful for the treatment of diseases of the respiratory tract, such as chronic eosinophilic pneumonia, asthma, COPD, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy, and airways disease that is associated with pulmonary hypertension.

First claim

The invention claimed is:

1. A compound selected from the group consisting of:
1-[3-tert-Butyl-1′-(2-[1,4]oxazepan-4-yl-ethyl)-1′H[1,4′]bipyrazolyl-5-yl]-3-{(4-[3-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(4-methyl-piperazin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{(4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-(3-tert-Butyl-1′-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1′H-[1,4′]bipyrazolyl-5-yl)-3-4-[3-(−2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;
1-[3-tert-Butyl-1′-(2-piperidin-1-yl-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-[1,4]oxazepan-4-yl-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-[4-(3-dimethylamino-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(3-dimethylamino-propyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[3-(4-methyl-piperazin-1-yl)-propyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,3′]bipyrazolyl-5-yl]-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,3′]bipyrazolyl-5-yl]-3-{4-[3-(2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[5-tert-Butyl-2-(2-dimethylamino-ethyl)-2H-pyrazol-3-yl]-3-{4-[3-(2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea formate salt;
1-{5-tert-Butyl-2-[5-(2-dimethylamino-ethoxy)-pyridin-3-yl]-2H-pyrazol-3-yl}-3-{4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{5-tert-Butyl-2-[5-(2-dimethylamino-ethoxy)-pyridin-3-yl]-2H-pyrazol-3-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{5-tert-Butyl-2-[6-(2-dimethylamino-ethoxy)-pyridin-2-yl]-2H-pyrazol-3-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{-4-[3-(2,6-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3[4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea formate salt;
1-[3-tert-Butyl-1′-(2-pyrrolidin-1-yl-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(4-methoxy-piperidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-(3-tert-Butyl-1′-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-1′H-[1,4′]bipyrazolyl-5-yl)-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-((S)-3-hydroxy-pyrrolidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(3-methoxy-pyrrolidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(ethyl-methyl-amino)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;
1-[3-tert-Butyl-1′-(2-hydroxy-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{4-[3-(1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt; and
1-{5-tert-Butyl-2-[6-(2-dimethylamino-ethoxy)-pyridazin-4-yl]-2H-pyrazol-3-yl}-3-{4-[3-(2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt,
or a pharmaceutically acceptable salt of said compound.

2. A compound or pharmaceutically acceptable salt according to claim 1 which is a compound selected from the group consisting of:
1-[3-tert-Butyl-1′-(2-[1,4]oxazepan-4-yl-ethyl)-1′H[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(4-methyl-piperazin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-{3-tert-Butyl-1′-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-1′H-[1,4′]bipyrazolyl-5-yl}-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-(3-tert-Butyl-1′-{2-[(2-methoxy-ethyl)-methyl-amino]-ethyl}-1′H-[1,4′]bipyrazolyl-5-yl)-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea;
1-[3-tert-Butyl-1′-(2-piperidin-1-yl-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-[1,4]oxazepan-4-yl-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt;
1-[3-tert-Butyl-1′-(2-dimethylamino-ethyl)-1′H-[1,4′]bipyrazolyl-5-yl]-3-[(1S,4R)-4-(3-dimethylamino-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2

Assignees

• Chiesi Farm Spa

Inventors

• Alcaraz Lilian
• Panchal Terry Aaron
• Jennings Andrew Stephen Robert
• Cridland Andrew Peter
• Hurley Christopher

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title