Tricyclic urea compounds as JAK2 V617F inhibitors

Patent metadata

Field	Value
Publication number	US-11780840-B2
Application number	US-202117365789-A
Country	US
Kind code	B2
Filing date	Jul 1, 2021
Priority date	Jul 2, 2020
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

Abstract

The present application provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.

First claim

What is claimed is:

1. A compound, which is selected from:
3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-phenyl-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(benzofuran-5-yl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
3-(2-hydroxyethyl)-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-1H-pyrazol-4-yl)-3-methyl-1-phenyl-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
3-methyl-7-(4-((methyl(3-(methylsulfonyl)propyl)amino)methyl)phenyl)-1-phenyl-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(3-fluoro-4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3-methyl-1-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(4-(4-ethylpiperazin-1-yl)phenyl)-3-methyl-1-(pyridin-2-yl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclohexyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(tert-butyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclohexyl-3-methyl-7-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclopentyl-3-ethyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-(tetrahydro-2H-pyran-3-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(4-(4-ethylpiperazin-1-yl)phenyl)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(4-(4-ethylpiperazin-1-yl)phenyl)-3-methyl-1-(2-oxo-2-(piperidin-1-yl)ethyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-isopropyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclohexyl-8-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-isobutyl-8-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclobutyl-8-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
8-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-1-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
8-(4-methoxyphenyl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(tert-butyl)-8-(4-methoxycyclohex-1-en-1-yl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
4-(1-isopropyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzonitrile;
1-(4-(1-isopropyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile;
4-((4-(1-isopropyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)-1H-pyrazol-1-yl)methyl)benzoic acid;
1-cyclopentyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclopentyl-3-methyl-7-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(4-(1-cyclopentyl-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile;
1-(4-(1-cyclopentyl-3-methyl-7-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile;
1-cyclopentyl-8-(4-methoxycyclohex-1-en-1-yl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclopentyl-8-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
8-cyclopropyl-1,3-dimethyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
8-(6-methoxypyridin-3-yl)-1,3-dimethyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
4-(1-isopropyl-3-methyl-2-oxo-7-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzonitrile;
4-(7-(4-(4-acetylpiperazin-1-yl)phenyl)-1-isopropyl-3-methyl-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzonitrile;
4-(7-(3,6-dihydro-2H-pyran-4-yl)-1-isopropyl-3-methyl-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzonitrile;
4-(7-(3,6-dihydro-2H-pyran-4-yl)-1-isopropyl-3-methyl-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzonitrile;
1,3-dimethyl-8-phenyl-7-(pyridin-3-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1,3-dimethyl-8-phenyl-7-(piperidin-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-(2-hydroxyethyl)-1,3-dimethyl-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
7-isobutyryl-1,3-dimethyl-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-isopropyl-3-methyl-7-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(bicyclo[2.2.1]heptan-2-yl)-3-methyl-7-(1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)-8-phenyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one; and
3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-8-phenyl-1-(tetrahydro-2H-pyran-4-yl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
or a pharmaceutically acceptable salt thereof.

2. A compound, which is selected from:
1-cyclopentyl-7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-indazol-5-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
3-methyl-8-(1-methyl-1H-indazol-5-yl)-7-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-(4-(3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile;
1-(4-(7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1-isopropyl-3-methyl-2-oxo-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile;
7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-3-methyl-8-(4-(1-morpholinocyclopropyl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclopentyl-3-methyl-8-(1-methyl-1H-indazol-5-yl)-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-3, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one;
1-cyclopentyl-3-methyl-8-(1-methyl-1H-indazol-5-yl)-7-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridi

Assignees

• Incyte Corp

Inventors

• Ai Yanran
• Atasoylu Onur
• Bai Yu
• Barbosa Joseph
• Burns David M
• Levy Daniel
• Douty Brent
• Feng Hao
• Konkol Leah C
• Lai Cheng-Tsung
• Liu Xun
• Mei Song
• Pan Jun
• Wang Haisheng
• Wu Liangxing
• Yao Wenqing
• Yue Eddy W

Classifications

• C07D471/14 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

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61P37/00 Primary

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title