Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

PIM kinase inhibitors

An alkyl, selected technology, applied in the field of medicinal chemistry, can solve the problems of low cytostatic activity, low bioavailability, high toxicity, etc., and achieve the effects of high bioavailability, strong drug efficacy, and low toxicity and side effects

Active Publication Date: 2022-04-29
HANGZHOU BANGSHUN PHARM CO LTD
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Japan's Sumitomo Pharmaceutical has developed a PIM inhibitor TP-3654 (WO2013013188), but its cytostatic activity is low, toxicity is high, and bioavailability is low

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • PIM kinase inhibitors
  • PIM kinase inhibitors
  • PIM kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: 6-(((1-methylpiperidin-4-yl)methyl)amino)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b] Pyridazine-2-carboxylic acid (Compound 6)

[0217]

[0218] (1) Ethyl 3-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate

[0219] Dissolve ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (1.0 g, 3.92 mmol) in dichloromethane (15 mL), add NBS (1.1 g, 5.88 mmol), and the The reaction system was stirred overnight at room temperature. Water was added to the reaction liquid, and the liquid was extracted and separated with dichloromethane. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by a reverse-phase column to obtain 3-bromo-6-chloroimidazo[1,2-b]pyridazine- 2-Carboxylic acid ethyl ester (310 mg, yield: 24%), yellow solid. MS(ESI):m / z 305.8[M+H] + .

[0220] (2) Ethyl 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine-2-carbox...

Embodiment 2

[0224] Example 2: N-((1-methylpiperidin-4-yl)methyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridin-6-amine (Compound 7)

[0225]

[0226] (1) 6-Chloro-3-(pyridin-3-yl)imidazo[1,2-a]pyridine

[0227] Referring to the method of step (2) of Example 1, using 3-bromo-6-chloroimidazo[1,2-a]pyridine (200mg, 0.86mmol), pyridin-3-ylboronic acid (105mg, 0.86mmol) as raw materials , the product 6-chloro-3-(pyridin-3-yl)imidazo[1,2-a]pyridine (67 mg, yield: 34%) was obtained as a yellow oily liquid. MS(ESI):m / z 230[M+H] + .

[0228] (2) N-((1-methylpiperidin-4-yl)methyl)-3-(pyridin-3-yl)imidazo[1,2-a]pyridin-6-amine

[0229] Referring to the method in step (3) of Example 1, using 6-chloro-3-(pyridin-3-yl)imidazo[1,2-a]pyridine (67mg, 0.29mmol), (1-methylpiperidine- Starting from 4-yl)methylamine (37.6 mg, 0.29 mmol), N-((1-methylpiperidin-4-yl)methyl)-3-(pyridin-3-yl)imidazol[1,2 -a] Pyridin-6-amine (10.9 mg, yield: 11%), white solid. MS(ESI):m / z 323.2[M+H] + . 1 H NMR (400MHz, DMSO-d ...

Embodiment 3

[0230] Example 3: 1-methyl-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl) Piperidine-4-carboxylic acid (Compound 8)

[0231]

[0232] (1) 6-Chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine

[0233] Referring to the method of step (2) of Example 1, using 3-bromo-6-chloroimidazo[1,2-b]pyridazine (800mg, 3.44mmol), (3-(trifluoromethoxy)phenyl) Boronic acid (708.4mg, 3.44mmol) was used as raw material to obtain the product 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (560.2mg, yield: 52%), yellow solid. MS(ESI):m / z314.0[M+H] + .

[0234] (2) 1-(tert-butoxycarbonyl)-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino )methyl)piperidine-4-carboxylic acid

[0235] Referring to the method of step (3) of Example 1, using 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (510mg, 1.63mmol), 4 -(Aminomethyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (466mg, 1.63mmol) a...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a compound with a structure as shown in a general formula (I), a deuterated substance, a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound and the deuterated substance, the stereoisomer or the pharmaceutically acceptable salt. The compound provided by the invention has a good PIM kinase inhibition effect, is a novel, high-activity and low-toxicity ideal PIM inhibitor, can be used for treating and / or preventing diseases such as hematoma such as acute myelogenous leukemia, myelofibrosis and chronic lymphocytic leukemia, solid tumors such as gastric cancer and prostate cancer, and has a wide application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a PIM kinase inhibitor, its pharmaceutical composition, a preparation method and its use in the preparation, prevention and / or treatment of medicines for indications related to PIM signaling pathways. Background technique [0002] The proviral integration site of murine leukemia virus (PIM) kinase is a serine / threonine protein kinase composed of three isoforms, PIM1, PIM2, and PIM3. PIM1 and PIM2 are highly expressed in hematological and solid tumors, and PIM3 is highly expressed in hepatocellular, pancreatic, and colon cancers. [0003] PIM kinase is a downstream molecule of the JAK / STAT pathway, and the JAK pathway plays an important role in autoimmune diseases. Literature studies have shown that PIM-1 inhibitors are effective in mouse inflammatory bowel disease models. Prompt the application of PIM kinase inhibitors in autoimmune diseases. [0004] In addition, PIM kinase ca...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D487/04C07D519/00C07D471/04A61K31/5025A61K31/4545A61K31/55A61P35/00A61P29/00A61P35/02A61P1/00A61P19/08A61P37/06
CPCC07D487/04C07D519/00C07D471/04A61P35/00A61P29/00A61P35/02A61P1/00A61P19/08A61P37/06Y02P20/55
Inventor 杨欣崔荣殷建明郑鹛陈南雨吕裕斌
Owner HANGZHOU BANGSHUN PHARM CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com