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

Indazole compound for inhibiting kinase activity as well as composition and application thereof

A compound, indazole technology, applied in the field of substituted indazole compounds, can solve problems such as poor absorption, distribution, metabolism and/or excretion, cost of side effects treatment, unmet clinical needs, etc.

Active Publication Date: 2018-10-09
SHENZHEN TARGETRX INC
View PDF3 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites
[0008] Therefore, this area has broad therapeutic potential for most tumor types, and there is currently a lack of treatment options in this area, and there is a clear unmet clinical need

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
  • Indazole compound for inhibiting kinase activity as well as composition and application thereof
  • Indazole compound for inhibiting kinase activity as well as composition and application thereof
  • Indazole compound for inhibiting kinase activity as well as composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0101] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found in, eg, Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0102] The reaction can be monitored according to any suitable method known in the art. For example, spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectroscopy (MS)) or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) Product formation was monitored.

[0103] Pharmaceutical compositions, prep...

Embodiment 1

[0135] Example 1 Preparation of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-(methyl-d 3 ) piperazin-1-yl)-2-((tetrahydro-2H-pyran-4-yl) amino) benzamide, namely compound T-1, molecular formula is as follows:

[0136]

[0137] Synthesize using the following route:

[0138]

[0139]

[0140] Synthesis of Step 1 Compound 3

[0141] Add toluene (100mL), compound 1 (5g, 30.30mmol), compound 2 (6.9g, 33.33mmol) and K 3 PO 4 (12.8g, 60.60mmol), vacuumize and replace with nitrogen, add Pd(PPh 3 ) 4 (770mg, 0.67mmol), vacuumize again and replace with nitrogen three times, heat up to 110°C, keep stirring for 5h. Cool to room temperature, add ethyl acetate (200 mL) to form a solid and filter, the filtrate is concentrated, and the residue is passed through a silica gel column to obtain 5.4 g of a white solid, yield 72.2%. 1 H NMR (400MHz, CDCl 3 )δ7.43-7.39(m,2H),7.18(t,J=8.8Hz,1H),6.73-6.66(m,3H),3.96(s,2H).

[0142] Synthesis of Step 2 Compound 4

[0143]Add n-buta...

Embodiment 2

[0162] Example 2 Preparation of N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazin-1-yl-2,2,3, 3,5,5,6,6-d 8 )-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, i.e. compound T-2, molecular formula is as follows:

[0163]

[0164] Adopt the following synthetic route:

[0165]

[0166]

[0167] Step 1 Synthesis of Compound 18.

[0168] Compound 17 (928 mg, 10.8 mmol) was added to a solution of compound 6 (2 g, 8.3 mmol) in DMF (10 mL) under magnetic stirring, and the mixture was stirred at room temperature overnight. Add 50 mL of water, stir for 20 minutes, a large amount of solid precipitates, filter, wash with water (20 mL), and dry to obtain 1.9 g of yellow solid, yield 74.5%. LC-MS(APCI):m / z=213.1(M+1-100) + ,313.1(M+1) + .

[0169] Synthesis of step 2 compound 19

[0170]To a solution of compound 18 (1.9 g, 6.19 mmol) in acetonitrile (10 mL) under magnetic stirring, TsOMe (1.75 g, 9.28 mmol) and K 2 CO 3 (2.56g, 18.6mmol), the mixture was stirred...

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

PropertyMeasurementUnit
massaaaaaaaaaa
Login to View More

Abstract

The invention relates to an indazole compound for inhibiting kinase activity and relates to preparation and application of the indazole compound. Specifically, the invention discloses the indazole compound shown as a formula (I), or crystal forms, prodrugs, pharmaceutically acceptable salts, stereoisomers, tautomers, solvates or pharmaceutical compositions of hydrates of the indazole compound. Thecompound and the composition containing the compound, provided by the invention, have excellent inhibition performance on kinase protein, and also have better pharmacokinetics parameter characteristics at the same time; the medicine concentration of the compound in animals can be improved and the curative effect and safety of the medicine are improved. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular, the invention relates to a substituted indazole compound, which has the activity of inhibiting protein kinase. More specifically, the present invention relates to certain deuterium-substituted N-(5-(3,5-difluorobenzyl)-1H-indazol-3-yl)-4-(4-methylpiperazine-1 -yl)-2-((tetrahydro-2H-pyran-4-yl)amino)benzamide, these deuterium-substituted compounds and compositions thereof can be used for the treatment of ALK, ROS1, TRK1, TRK2 or TRK3 etc. mediated related cancers, and these deuterium-substituted compounds have better pharmacokinetic properties. Background technique [0002] Dysfunction of protein kinases (PKs) is a hallmark of many diseases. Most of the oncogenes and proto-oncogenes associated with human cancer encode PK. Enhanced PK activity is also associated with many nonmalignant diseases such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatos...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/496A61P35/00C07B59/00
CPCA61P35/00C07B59/002C07D405/12C07B2200/05
Inventor 王义汉李焕银
Owner SHENZHEN TARGETRX INC
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