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Substituted pyrimidines and uses thereof

A compound and application technology, applied in the preparation of such compounds and pharmaceutical compositions, substituted pyrimidine compounds and pharmaceutical compositions thereof, prevention or treatment of related diseases caused by excessive activation of BTK, prevention or treatment of tumors, and can solve the problem. Problems such as few types and single structure

Active Publication Date: 2022-01-14
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently there are few types of BTK inhibitors with good druggability and single structure

Method used

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  • Substituted pyrimidines and uses thereof
  • Substituted pyrimidines and uses thereof
  • Substituted pyrimidines and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] Example 1 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)methyl)amino)piperidin-1-yl)prop-2-ene-1 -ketone

[0174]

[0175] Step 1) Synthesis of methyl 6-amino-5-chloropyrimidine-4-carboxylate

[0176]

[0177] Methanol (200mL) was added to a 1L single-necked round bottom flask, thionyl chloride (11mL) was added dropwise, and then 6-amino-5-chloropyrimidine-4-carboxylic acid (20.0g, 115.6mmol) was added, at 70°C Reacted for 23 hours; stopped the reaction, cooled to room temperature, spin-dried under reduced pressure, separated and purified by column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain the title compound as a white solid (12.5g, 58% ).

[0178] MS(ESI,pos.ion)m / z:188.1[M+H] + .

[0179] Step 2) Synthesis of (6-amino-5-chloropyrimidin-4-yl)methanol

[0180]

[0181] Methyl 6-amino-5-chloropyrimidine-4-carboxylate (10.05g, 53.7mmol) and methanol (100mL) were added to a 250mL single-necked round bottom flask at 25°C, and sodiu...

Embodiment 2

[0206] Example 2 (S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)methyl)amino)pyrrolidin-1-yl)propan-2 Synthesis of -en-1-one

[0207]

[0208] Step 1) (S)-tert-butyl 3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)methyl)amino)pyrrolidine- Synthesis of 1-carboxylates

[0209] 6-amino-5-(4-phenoxyphenyl)pyrimidine-4-carbaldehyde (1.46g, 5.0mmol), (S)-1-Boc-3-aminopyrrolidine (1.07g, 5.75 mmol) and dichloromethane (20mL) were added to a 100mL single-necked round bottom flask, sodium triacetoxyborohydride (1.64g, 7.73mmol) was added, and the reaction was continued for 0.5 hours; the reaction was stopped, dichloromethane (20mL) was added and saturated Sodium bicarbonate solution (30mL), separation, the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain the title compound as a white solid (1.32g, 57%). MS(ESI,pos.ion)m / z:462.3[M+H]+; 1 HNMR (400MHz, CDCl 3 )δ(ppm)8...

Embodiment 3

[0214] Example 3 (R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)methyl)amino)pyrrolidin-1-yl)propan-2 Synthesis of -en-1-one

[0215]

[0216] Step 1) (R)-tert-butyl 3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)methyl)amino)pyrrolidine- Synthesis of 1-carboxylates

[0217] 6-amino-5-(4-phenoxyphenyl)pyrimidine-4-carbaldehyde (1.83g, 6.27mmol), (R)-1-Boc-3-aminopyrrolidine (1.35g, 7.25 mmol) and dichloromethane (40mL) were added to a 100mL single-necked round bottom flask, sodium triacetoxyborohydride (2.06g, 9.71mmol) was added, and the reaction was continued for 0.5 hours; the reaction was stopped, dichloromethane (30mL) was added and saturated Sodium bicarbonate solution (30mL), separation, the organic phase was collected, spin-dried under reduced pressure, separated and purified by column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain the title compound as a white solid (1.48g ,51%).

[0218] MS(ESI,pos.ion)m / z:462.3[M+H] + ;

[0219] ...

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Abstract

The invention belongs to the technical field of medicines, and relates to substituted pyrimidine compounds and their application, as well as pharmaceutical compositions containing the compounds, which can be used as Bruton's tyrosine kinase (BTK) inhibitors. The present invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the prevention or treatment of related diseases caused by excessive activation of BTK, including but not limited to tumors, thromboembolism, inflammatory disorders, autoimmune diseases and other diseases, In particular the use in tumors.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a compound and a pharmaceutical composition as a Bruton's tyrosine kinase (BTK) inhibitor, as well as a method and use thereof. Specifically, the present invention relates to substituted pyrimidine compounds and pharmaceutical compositions thereof, and also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the prevention or treatment of related diseases caused by excessive activation of BTK, including but not limited to Tumors, thromboembolism, inflammatory disorders, autoimmune diseases and other diseases. In particular, the compounds of the present invention and their pharmaceutical compositions are used for the prevention or treatment of tumors. Background technique [0002] Protein kinases (PK for short) are enzymes that catalyze the phosphorylation of proteins. The phosphorylation process of proteins is the last link in the tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D403/12A61P35/00A61P35/02A61P29/00A61P11/06A61P17/06A61P19/02A61P37/02A61P7/00A61P7/06A61P7/02A61P9/10A61K31/506
CPCC07D401/12C07D403/12A61P35/00A61P35/02A61P29/00A61P11/06A61P17/06A61P19/02A61P37/02A61P7/00A61P7/06A61P7/02A61P9/10
Inventor 金传飞钟文和陈康智许腾飞余天喜周克军
Owner SUNSHINE LAKE PHARM CO LTD
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