Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent metadata

Field	Value
Publication number	US-11230547-B2
Application number	US-201816764448-A
Country	US
Kind code	B2
Filing date	Dec 12, 2018
Priority date	Dec 18, 2017
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The instant invention provides compounds of formulas Ia and Ib which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflammation, asthma, COPD and cancer.

First claim

What is claimed is:

1. A compound or a pharmaceutically acceptable salt, wherein the compound is
4-[(1S,4R)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile;
2-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[6-(difluoromethyl)pyridin-3-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(1-hydroxy-1-methylethyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-pyridin-3-yl-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(2-fluoroethoxy)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-{(1S,4R)-5-[3-(1H-pyrrol-1-yl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(3-nitrophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[3-(1-methylcyclopropyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
3-{(1R,4S)-5-[5-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-N-methylbenzamide;
4-[(1S,4R)-5-(3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-{(1S,4R)-5-[3-(methylsulfonyl)phenyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}pyrimidine-5-carbonitrile;
4-[(1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(5-methylpyridin-3-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1H-indazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1R,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-isoquinolin-5-ylpyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-morpholin-4-ylpyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
(1R,4S)-5-[5-cyano-2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;
4-[(1S,4R)-5-(2,2-dimethylpropanoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluoro-2,2-dimethylpropanoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[(3-methyloxetan-3-yl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-{[1-(methoxymethyl)cyclopropyl]carbonyl}-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclobutylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(thiophen-2-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(1,3-oxazol-4-ylcarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(oxetan-3-ylacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-{(1S,4R)-5-[(1-methylethyl)sulfonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(1S,4R)-5-(propylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(cyclopentylsulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(1S,4R)-5-(3-fluoropropyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[4-(3-fluorophenyl)-3,3-dimethylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[4-(3-fluorophenyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-fluorophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[8-(3-fluorophenyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-propanoylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclobutylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-3-methyl-4-[(1-methylcyclopropyl)carbonyl]piperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-4-[(2,2-difluorocyclobutyl)carbonyl]-3-methylpiperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(cyclopentylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-(1-methyl-1H-pyrazol-4-yl)-4-[(3R)-3-methyl-4-(spiro[2.4]hept-1-ylcarbonyl)piperazin-1-yl]pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-{[(1R,2R)-2-methylcyclopropyl]carbonyl}piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-{[(1S,2R)-2-methylcyclopropyl]carbonyl}piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-fluorophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-3-methyl-4-(3-nitrophenyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3R)-4-(3-cyanophenyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-{(3R)-3-methyl-4-[3-(methylsulfonyl)phenyl]piperazin-1-yl}-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
3-{2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl}prop-2-yn-1-ol;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carbonitrile;
6-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-[5-(1-methylethyl)-1,3-oxazol-2-yl]-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
4-[(3R)-4-(cyclopropylcarbonyl)-3-(2-methylpropyl)piperazin-1-yl]-2-(1-methyl-H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
4-[(3S)-4-(cyclopropylcarbonyl)-3-(hydroxymethyl)piperazin-1-yl]-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-(3-methylbut-1-yn-1-yl)-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine;
2-[(3R)-4-(cyclopropylcarbonyl)-3-methylpiperazin-1-yl]-5-ethynyl-4-(1-methyl-1

Assignees

• Merck Sharp & Dohme

Inventors

• Mcgowan Meredeth A
• Katz Jason D
• Christopher Matthew
• Zhou Hua
• Witter David James
• Li Chaomin
• Lampe John
• Methot Joey L
• Achab Abdelghani A
• Fradera Xavier
• Xu Shimin

Classifications

• 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

• C07D487/08 Primary

  Bridged systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title