Pyrrolopyrimidine derivatives used as protein kinase inhibitors and application thereof

A protein kinase inhibitor, pyrrolopyrimidine technology, applied to pyrrolopyrimidine derivatives as protein kinase inhibitors and their application fields, can solve the problems of poor drugability, poor oral bioavailability, weak cell activity and the like

Pending Publication Date: 2020-09-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, research on PAKs inhibition is still in its infancy, and only PF-3758309 developed by Pfizer has entered phase I clinical research; in 2006, Pfizer discovered the pyrazolopyrrolidine PAKs inhibitor PF-3758309; the compound is ATP Competitive inhibitor, has a strong inhibitory effect on all members of the PAKs family (PAK1 Ki=14nM, PAK2 Ki=190nM, PAK3 Ki=99nM, PAK4 Ki=19nM, PAK5 Ki=18nM, PAK6 Ki=17nM); 2009 PF-3758309 has entered phase I clinical research as a candidate drug, becoming the first PAKs inhibitor to enter clinical evaluation, and is expected to be used in the clinical treatment of advanced, metastatic solid tumors; however, due to its poor oral bioavailability (about 1%) , gastrointestinal adverse reactions and other factors, the phase I clinical study of PF-3758309 was forced to terminate; then Genentech reported in 2014 that a compound with a benzimidazole structure that selectively acts on class II PAKs can produce PAK4 Selective inhibition (PAK1IC 50 =5.4uM, PAK4 IC 50 =7.5nM); Although this

Method used

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  • Pyrrolopyrimidine derivatives used as protein kinase inhibitors and application thereof
  • Pyrrolopyrimidine derivatives used as protein kinase inhibitors and application thereof
  • Pyrrolopyrimidine derivatives used as protein kinase inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1: Preparation of 3-((2-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propane-1,2-diol (compound 1):

[0124]

[0125] 3-((2-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)propane-1,2-diol of the present invention can be synthesized according to the following reaction scheme:

[0126]

[0127] Preparation of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (II):

[0128] 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (I) (2g, 10.6mmol), p-toluenesulfonyl chloride (2.2g, 11.7mmol), TEA (2.15g, 21.3 mmol) and DMAP (129mg, 1.06mmol) were added to DCM (50mL), and reacted at 25°C for 1h; TLC detected that the raw material disappeared and the reaction was complete; the solvent was spin-dried, and 200mL of water was added, and a large amount of white solid was precipitated. After washing, a white solid (II) (3.44 g, 10.1 mmol) was obtained, yield: 95%. ESI-MS m / z:342.0[M+H] + . 1 H NMR (300MHz, DMSO-d 6 )δ8.13(d, J=4.0Hz, 1H), 8.04(d, J=8.4Hz, 2H), 7.57...

Embodiment 4

[0137] Example 4: N 2 -Phenyl-N 4 Preparation of -(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (compound 4):

[0138]

[0139] N of the present invention 2 -Phenyl-N 4 -(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine can be synthesized according to the following reaction scheme:

[0140]

[0141] Preparation of tert-butyl 4-((2-chloro-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (III-a) :

[0142] 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (II) (500mg, 1.47mmol), tert-butyl 4-aminopiperidine-1-carboxylate ( 441 mg, 2.21 mmol) and TEA (445 mg, 4.41 mmol) were added to 50 mL of i-PrOH, and reacted at 80°C for 4 h; After washing (30mL×3), the organic phase was dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid (III-a) (600mg, 1.19mmol), with a yield of 80.5%. ESI-MS m / z:506.3[M+H] + ;

[0143] 4-(((2-(phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a...

Embodiment 15

[0152] Example 15: 2-amino-1-(4-(((2-((3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine Preparation of -1-yl)ethan-1-one (compound 15):

[0153]

[0154] 2-amino-1-(4-(((2-((3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine- 1-base) ethane-1-one can be synthesized according to the following reaction scheme:

[0155]

[0156] N 2 -(3-fluorophenyl)-N 4 The preparation of -(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (VI-b) refers to the preparation of (VI-a):

[0157] tert-Butyl(2-(4-((2-(((3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl )-2-oxyethyl carbamate (VII-b) preparation:

[0158] Will N 2 -(3-fluorophenyl)-N 4 -(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (VI-b) (300mg, 0.924mmol), (tert-butoxycarbonyl)glycine (240mg , 1.38mmol), HATU (702mg, 1.848mmol) and DIEA (358mg, 2.77mmol) were added to DMF (20mL), and reacted at 25°C for 4h; after the reaction was complet...

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Abstract

The invention discloses pyrrolopyrimidine derivatives as protein kinase inhibitors and application thereof, and geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the pyrrolopyrimidine derivatives. In-vivo and in-vitro biological tests prove that, the compound can be used as a protein kinase inhibitor, especially can inhibit PAK4 kinase, and has a high-selectivity inhibition effect on the PAK4 kinase in a PAKs family. The activity of the PAK4 kinase in cells can be reduced or inhibited; meanwhile, the compound can also be used as the protein kinase inhibitor and can be used for inhibiting kinases such as GCK, GLK, HPK1 and TYK2 related to human autoimmunity; the compound is applied to drugs for treating and/or preventing diseases mediated by PAKs family kinase, especially hyper-proliferative diseases and/or virus-induced infectious diseases and/or cardiovascular diseases and diseases caused by autoimmunity.

Description

technical field [0001] The invention belongs to the field of medical technology, and relates to a class of pyrrolopyrimidine compounds and their analogs, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, their preparation methods and their use as therapeutic agents, especially As inhibitors of PAKs or GCK, GLK, HPK1 and TYK2 etc. and their therapeutic and / or prophylaxis of hyperproliferative diseases such as cancer, and / or virus-induced infectious diseases, and / or cardiovascular diseases and / or due to autoimmunity Application of medicines caused by diseases. Background technique [0002] Malignant tumors are serious diseases that threaten human health and life, and it is imminent to develop anti-tumor drugs with high efficiency and low toxicity. Targeted anti-tumor drugs have achieved great success in tumor treatment due to their characteristics of good specificity, high effectiveness, and low toxicity and side effects. . Protei...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P37/06A61P31/12A61P9/00A61P35/00A61P35/02
CPCC07D487/04A61P37/06A61P31/12A61P9/00A61P35/00A61P35/02
Inventor 陈亚东陆涛张明亮李红玫卢帅房小宝王蒙王聪
Owner CHINA PHARM UNIV
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