Unlock instant, AI-driven research and patent intelligence for your innovation.

Alkynyl pyrimidine or alkynyl pyridine compound as well as composition and application thereof

A technology of compounds and solvates, applied in the fields of drug combination, digestive system, organic chemistry, etc., can solve the problems of side effects that limit the clinical application of drugs and no inhibitory activity.

Active Publication Date: 2020-08-04
BEIJING SCITECH MQ PHARMA LTD
View PDF1 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The second-generation CML drugs Dasatinib, Nilotinib, and Bosutinib have broad activity on Imatinib-resistant and intolerant patients, but they have no inhibitory activity on BCR-ABL T315I kinase mutation
Its severe side effects limit the clinical application of the drug

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
  • Alkynyl pyrimidine or alkynyl pyridine compound as well as composition and application thereof
  • Alkynyl pyrimidine or alkynyl pyridine compound as well as composition and application thereof
  • Alkynyl pyrimidine or alkynyl pyridine compound as well as composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0071] Preparation of some intermediates

[0072] A series intermediates

[0073] Synthesis of Intermediate A1.5-iodo-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0074]

[0075]Step 1: 4-nitropyrazole (1.13g, 10mmol), iodomethane (2.85g, 20mmol), potassium carbonate (4.14g, 30mmol) in acetone (10mL) was heated to 60°C for 12 hours, cooled, Filtration, concentration, and purification by column chromatography gave 1.1 g of the white solid product 1-methyl-4-nitro-1H-pyrazole with a yield of 85%.

[0076] Step 2: Add palladium (55% humidity on carbon, 10% mass content) to a solution of 1-methyl-4-nitro-1H-pyrazole (0.64g, 5mmol) in methanol (20mL), replace with hydrogen three times, The reaction was stirred at room temperature for 6 hours, filtered with celite, and the filtrate was concentrated to obtain 0.4 g of the target product 1-methyl-1H-pyrazol-4-amine, with a yield of 82%, MS: 98 [M+H]+.

[0077] Step 3: To a solution of 1-methyl-1H-pyrazol-4-amine (0.2g, 2mmol)...

Embodiment 1

[0152] Example 1. 4-methyl-3-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-N-(4-(( 4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0153] 5-iodo-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (30mg, 0.1mmol), 3-ethynyl-4-methyl-N-(4-(( 4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (42mg, 0.1mmol), Pd(PPh 3 ) 2 Cl 2 (4mg, 0.005mmol), CuI (2mg, 0.01mmol), DMF (1.5mL) solution of triethylamine (1.5mL) was replaced by argon, heated to 65 degrees Celsius for 15 hours, cooled, extracted with ethyl acetate, Wash with saturated brine, dry the organic phase, concentrate, and prepare a thin-layer plate (supported on silica gel, dichloromethane:methanol=10:1) for purification to obtain 35 mg of a white solid product with a yield of 60%. 1 HNMR (400MHz, DMSO-d 6 )δ10.52(s,1H),9.91(s,1H),8.65(s,2H),8.21(d,J=2.2Hz,1H),8.13(d,J=1.9Hz,1H),8.07( dd,J=8.5,2.1Hz,1H),7.92-7.89(m,2H),7.71(d,J=8.5Hz,1H),7.52-7.50(m,2H),3.82(s,3H),3.57 (...

Embodiment 2

[0155] Example 2. 3-((2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N- (4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

[0156] 2-(4-((5-iodopyrimidin-2-yl)amino)-1H-pyrazol-1-yl)ethyl-1-ol (33mg, 0.1mmol), 3-ethynyl-4-methyl -N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (42mg, 0.1mmol), Pd(PPh 3 ) 2 Cl 2 (4mg, 0.005mmol), CuI (2mg, 0.01mmol), DMF (1.5mL) solution of triethylamine (1.5mL) was replaced by argon, heated to 65 degrees Celsius for 15 hours, cooled, extracted with ethyl acetate, Wash with saturated brine, dry the organic phase, concentrate, prepare TLC plate (supported on silica gel, dichloromethane:methanol=10:1) and purify to obtain 31 mg of white solid product, yield 50%; 1 H NMR (400MHz, DMSO-d 6 )δ10.52(s,1H),9.92(s,1H),8.65(s,2H),8.21(d,J=2.2Hz,1H),8.13(d,J=2.0Hz,1H),8.06( d,J=8.2Hz,1H),7.98–7.87(m,2H),7.71(d,J=8.5Hz,1H),7.58–7.47(m,2H),4.87(t,J=5.3Hz,1H ), 4.11(t, J=5...

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 relates to alkynyl pyrimidine or alkynyl pyridine compounds represented by a formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof. The invention also discloses a pharmaceutical composition containing the compounds and an application of the compounds or the composition in preparation of drugs. The drugs can be used as kinase inhibitors suchas ABL, ABL-T315I, KIT, VEGFR-2 and the like for treating related diseases.

Description

technical field [0001] The invention relates to the field of chemical medicine. More specifically, it relates to a class of alkynylpyrimidine or alkynylpyridine compounds or their pharmaceutically acceptable salts, isomers, solvates, and crystal forms having kinase inhibitory activities such as ABL, ABL-T315I, KIT, and VEGFR-2 or prodrugs, as well as pharmaceutical compositions containing these compounds and applications of these compounds or compositions in pharmaceutical preparation. Background technique [0002] Tumor is the abnormal signal transduction of cells under the action of various carcinogenic factors, and a certain cell in some tissues loses its normal growth regulation, resulting in the disorder of cell apoptosis and continuous proliferation of cells, which in turn leads to the cloning of new organisms. formed by sexual growth. Tumor cells have the ability to grow autonomously after losing their normal growth regulation functions, and the tumor can continue t...

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): C07D403/12C07D405/14C07D401/14C07D403/14C07D417/12C07D413/12C07D409/12A61P35/00A61P35/02A61P35/04A61P27/02A61P17/06A61P19/02A61P9/10A61P11/00A61P1/16A61K31/506
CPCC07D403/12C07D405/14C07D401/14C07D403/14C07D417/12C07D413/12C07D409/12A61P35/00A61P35/02A61P35/04A61P27/02A61P17/06A61P19/02A61P9/10A61P11/00A61P1/16A61K31/506A61K31/497A61P29/00A61P37/00A61P17/14
Inventor 张强于善楠孙月明杨磊夫郑南桥
Owner BEIJING SCITECH MQ PHARMA LTD