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Cyclic aminopyrimidine derivatives as well as kinase inhibition activity and application thereof

A technology of aminopyrimidine and derivatives, applied in the field of medicine, achieves the effects of good production feasibility, novel synthesis route and huge clinical application value

Active Publication Date: 2020-06-12
HANGZHOU BIO CREATIVITY PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Although there are many reports of macrocyclic compounds in pan-CDKs activity, the structure that selectively inhibits CDK4 / 6 activity has not been reported. Based on this, we designed a new type of macrocyclic structure that can selectively inhibit CDK4 / 6

Method used

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  • Cyclic aminopyrimidine derivatives as well as kinase inhibition activity and application thereof
  • Cyclic aminopyrimidine derivatives as well as kinase inhibition activity and application thereof
  • Cyclic aminopyrimidine derivatives as well as kinase inhibition activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Synthesis of compound T-1.

[0068]

[0069] Compound T-1: ( E )-4 4 -((4-Ethylpiperazin-1-yl)methyl)-1 4 ,2 5 -Difluoro-1 2 -Methyl-1 1 H -5-Oxa-3-aza-1(6,1)-benzo[ d ]imidazole-2(4,2)-pyrimidine-4(1,3)-benzocycloundec-8-ene was synthesized according to the general procedure shown below:

[0070]

[0071]

[0072] Scheme 1 T-1 synthetic route.

[0073] Step 1: 4-(1-(3-buten-1-yl)-4-fluoro-2-methyl-1 H -Benzo[ d ]imidazol-6-yl)-N-(3-(3-butene-1-oxyl)-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5-fluoro Synthesis of pyrimidin-2-amine (1).

[0074] Intermediate Z-1 (0.27 g, 0.8 mmol), W1-1 (0.29 g, 1.0 mmol), cesium carbonate (0.52 g, 1.6 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyl Xanthoxanthene (Xantphos, 0.093 g, 0.16 mmol) was dissolved in 10 mL of 1,4-dioxane, nitrogen was replaced three times, and Pd was added 2 (dba) 3 , heated to 90°C for 3 hours, poured the reaction solution into 30 mL water and extracted with ethyl acetate (20 mL x 2), com...

Embodiment 3

[0119] Synthesis of Compound T-3.

[0120]

[0121] Compound T-3: ( E )-4 5 -((4-Ethylpiperazin-1-yl)methyl)-1 4 ,2 5 -difluoro-1 2 -Methyl-1 1 H -5-oxa-3-aza-1 (6, 1)-benzo[d]imidazole-2 (4, 2)-pyrimidine-4 (2, 4)-pyridocycloundecane-8- Alkenes are shown as follows:

[0122]

[0123] .

[0124] Referring to the synthesis method of Example 1, a yellow solid T-3 was obtained, MS (m / z): 561.3 [M+H] + .

[0125] Synthetic route of side chain W3-1:

[0126]

[0127]

[0128] Step 1: Synthesis of (4,6-dichloropyridin-3-yl)(4-ethylpiperazin-1-yl)methanone (22).

[0129] 4,6-Dichloronicotinic acid (21, 3.8 g, 20 mmol) was dissolved in 100 mL toluene, added 3 mL thionyl chloride, reacted at 100°C for 5 hours, spin-dried the solvent, dissolved in DCM, -10°C Add ethylpiperazine (13, 2.3 g, 20 mmol) and triethylamine (2.0 g, 20 mmol) dropwise to the DCM reaction liquid under the conditions, react for 1 hour, spin to dry the solvent, dissolve in 50 mL EA, and was...

Embodiment 4

[0141] Synthesis of T-27.

[0142]

[0143] Compound T-27: (1 3 Z ,1 4 E ,10 E )--1 7 ,2 5 -difluoro-1 2 -Methyl-4 4 -((4-Ethylpiperazin-1-yl)-methyl-)-1 2 H -5-oxa-3-aza-1(5,3)-indazole-2(4,2)-pyrimidine-4(1,3)-benzocyclododec-10-ene is as follows The general operation shown is synthetic:

[0144]

[0145]

[0146]

[0147] Synthetic route of Scheme 8 T-27.

[0148] step 1:( E )-N-(3-((6-bromo-5-hexen-1-yl)oxy) 4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5-fluoro -4-(7-fluoro-3-iodo-2-methyl-2 H -Synthesis of indazol-5-yl)pyrimidin-2-amine (27).

[0149] Intermediate Z-2 (0.32 g, 0.8 mmol), W1-2 (0.4 g, 1.0 mmol), cesium carbonate (0.52 g, 1.6 mmol), Xantphos (0.093 g, 0.16 mmol) were dissolved in 10 mL of 1,4- In dioxane, replace nitrogen three times, add Pd 2 (dba) 3 , heated to 90°C and reacted for 3 hours, poured the reaction solution into 30 mL water and extracted with ethyl acetate (20 mLx 2), combined the organic phases, washed with saturated...

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Abstract

The invention discloses cyclic aminopyrimidine derivatives as well as kinase inhibition activity and application thereof, and particularly discloses cyclic aminopyrimidine derivatives having structures as shown in a general formula (I) and pharmaceutically acceptable salts, esters or solvent compounds thereof. The derivatives can inhibit the activity of kinase, are inhibitors for a variety of kinases, can be more widely applied to treatment of cancers, and have huge clinical application prospects. The general formula (I) is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a cyclic aminopyrimidine derivative and its inhibitory effect on kinases, and also includes a preparation method of the derivative and a pharmaceutically acceptable salt, ester or solvate, and is a variety of kinase inhibitors , has the purpose of treating cancer, and has a huge application prospect. Background technique [0002] Cancer is still the number one killer of human health. According to the statistics of the National Institutes of Health (NIH), in 2012, there were 14.1 million new cases worldwide and 8.2 million cancer-related deaths. In 2012, 57% of new cancer cases occurred in less developed regions of the world, including Central America and Africa and parts of Asia, and 65% of cancer deaths also occurred in these regions. In 2018 alone, there were more than 1.7 million new cancer cases, and by 2030, the number of new cancer cases is expected to increase to 23.6 mill...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18C07D498/22A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D498/18C07D498/22
Inventor 盛荣张冯敏罗瑾吴立军杨欢金泽武熊晓红钱扬
Owner HANGZHOU BIO CREATIVITY PHARM TECH CO LTD
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