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
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  • 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 (WO20130

Method used

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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...

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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

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Application Information

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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
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