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Benzethers and anilines of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof

Pending Publication Date: 2022-08-18
LYNK PHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a new compound that can be used to treat diseases or disorders in mammals, including humans. The compound can be administered alone or in combination with other substances. It can also be delivered in a sustained-release form. The compound can be transformed in vivo to an active form, which improves its absorption and delivery to the body. Overall, the pated compound has improved physical and delivery properties compared to its parent compound.

Problems solved by technology

Development of JAK inhibitors for the treatment of cancer with low susceptibility to drug resistance remains challenging but necessary for improving the long-term effectiveness of this class of drugs.

Method used

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  • Benzethers and anilines of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
  • Benzethers and anilines of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
  • Benzethers and anilines of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0263]

Step 1. 4-(2-Chloro-5-methylpyrimidin-4-yl)phenol (1b)

[0264]A mixture of compound 1a (3.0 g, 18.40 mmol), (4-hydroxyphenyl)boronic acid (4.46 g, 20.24 mmol), Na2CO3 (3.90 g, 36.8 mmol) and Pd(dppf)Cl2 (942 mg, 1.288 mmol) in 1,4-dioxane / H2O (24 mL / 6 mL) was stirred at 60° C. under N2 overnight. The mixture was cooled down to RT and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE:EtOAc=2:1) to give the product (2.22 g, 55% yield) as a white solid. LC-MS (Method 2): tR=1.34 min, m / z (M+H)+=221.1.

Step 2. 4-(2-((1-Cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)phenol (1c)

[0265]A mixture of compound 1b (500 mg, 2.27 mmol), 1-cyclopropyl-1H-pyrazol-4-amine (418 mg, 3.40 mmol), Pd2(dba)3 (145 mg, 0.1589 mmol), X-Phos (151 mg, 0.32 mmol) and Cs2CO3 (1.11 g, 3.40 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. under N2 for 3 hrs. The mixture was cooled down to RT and concentrated. The residue was purified by column chromatography...

example 2

[0269]

3-(4-(2-((1-Cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)phenoxy)cyclobutanecarbonitrile (2)

[0270]Compound 2 (12.1 mg) was synthesized in 15% yield by utilizing a similar preparative procedure to the final step of Example 1 with compound 1c (65 mg, 0.211 mmol) and 3-cyanocyclobutyl methanesulfonate (129 mg, 0.741 mmol) as starting materials. LC-MS (Method 1): tR=3.75 min, m / z (M+H)+=387.2. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.48 (s, 1H), 6.99 (d, J=8.8 Hz, 2H), 5.09-5.03 (m, 0.8H), 4.80-4.77 (m, 0.2H), 3.67-3.62 (m, 1H), 3.49-3.43 (m, 2H), 3.15-3.10 (m, 0.2H), 2.99-2.92 (m, 0.4H), 2.88-2.82 (m, 1.4H), 2.43-2.35 (m, 1H), 2.20 (s, 3H), 0.99-0.89 (m, 4H).

example 3

[0271]

1-((4-(2-((1-Cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)phenoxy)methyl)cyclobutanecarbonitrile (3)

[0272]Compound 3 (27.8 mg) was synthesized in 39% yield by utilizing a similar preparative procedure to the final step of Example 1 with compound 1c (55 mg, 0.179 mmol) and (1-cyanocyclobutyl)methyl methanesulfonate (140 mg, 0.719 mmol) as starting materials. LC-MS (Method 1): tR=3.47 min, m / z (M+H)+=401.2. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.30 (s, 1H), 7.90 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.13 (d, J=8.8 Hz, 2H), 4.34 (s, 2H), 3.67-3.62 (m, 1H), 2.54-2.53 (m, 2H), 2.32-2.25 (m, 2H), 2.21 (s, 3H), 2.14-2.11 (m, 2H), 0.97-0.91 (m, 4H).

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Abstract

Provided is a novel class of orally and / or topically available, selective and potent JAK inhibitors as safe and effective therapeutics against various diseases and disorders. Also provided is pharmaceutical composition of these compounds and methods of their preparation and use thereof.

Description

PRIORITY CLAIMS AND RELATED PATENT APPLICATIONS[0001]This application claims the benefit of priority to PCT International application No. PCT / CN2019 / 081742, filed on Apr. 8, 2019, the entire content of which is incorporated herein by reference for all purposes.TECHNICAL FIELDS OF THE INVENTION[0002]The invention generally relates to novel compounds and methods for their therapeutic use. More particularly, the invention relates to a novel class of therapeutics that are safe and effective JAK inhibitors. The invention also relates to pharmaceutical compositions of these compounds and methods of preparation and use thereof against various diseases and disorders.BACKGROUND OF THE INVENTION[0003]Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the Janus kinase—Signal Transduction Activators of Transcription (JAK-STAT) pathway. There are four members in the JAK family of enzymes in humans, i.e., JAK1, JAK2, JAK3 and...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D403/12C07D401/14C07D405/14
CPCC07D403/12C07D405/14C07D401/14A61P35/00A61P37/00A61K31/506A61P29/00
Inventor LI, XIAODONGVAZQUEZ, MICHAEL LAWRENCEWAN, ZHAOKUI
Owner LYNK PHARMACEUTICALS CO LTD