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Anaplastic lymphoma kinase (ALK) inhibitor, and preparation method and application thereof

A technology for selecting compounds, used in antitumor drugs, pharmaceutical formulations, organic active ingredients, etc.

Active Publication Date: 2018-07-13
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, resistance to ceritinib and others is inevitable

Method used

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  • Anaplastic lymphoma kinase (ALK) inhibitor, and preparation method and application thereof
  • Anaplastic lymphoma kinase (ALK) inhibitor, and preparation method and application thereof
  • Anaplastic lymphoma kinase (ALK) inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
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specific Embodiment approach

[0070] The compounds of the present invention and their preparation methods and uses are illustrated below in conjunction with the examples.

[0071] Process 1.:

[0072]

[0073] The compounds shown in the present invention can be prepared according to the route described in Scheme 1. The product obtained from the reaction in scheme 1 can be obtained by conventional separation techniques, such traditional techniques include but not limited to filtration, distillation, crystallization, chromatographic separation and the like. Starting materials can be synthesized in-house or purchased from commercial establishments such as, but not limited to, Adrich or Sigma. These starting materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in this invention may be obtained using synthetic methods as single isomers or as mixtures of isomers.

[0074] Step A: 2,4-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrol...

Embodiment 1

[0223] Example 1: N2-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-N4-(2-(isopropylsulfonyl Acyl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0224]

[0225] Step 1: 4-Chloro-N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)-7-(4-methoxybenzyl)- 6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine

[0226]

[0227] According to general synthetic method A, 2,4-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (intermediate i , 680 mg), 1-(4-amino-3-methoxyphenyl)-N, N-dimethylpiperidin-4-amine (603 mg) and trifluoroacetic acid (0.16 ml, 250 mg) followed by Added to 40 ml of ethylene glycol monomethyl ether: trifluoroethanol (2:1, v / v) mixed solvent, heated at 120°C to reflux for 24h, the reaction solution was concentrated under reduced pressure, and the obtained residue was washed with a small amount of dichloro After methane and water were dissolved, adjusted to pH = 8 with saturated sodium bicarbonate solution, extracted...

Embodiment 2

[0233] Example 2: N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl)phenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0234]

[0235] The target compound was obtained by the same procedure as in Example 1 using different reactants. 1 H-NMR (400MHz, DMSO-d 6 ): δ=8.53-8.50 (2H, m), 7.70 (2H, dt, J 1 =6.8,J 2 =8.3Hz), 7.59-7.55(1H, m), 7.27(1H, s), 7.14(1H, d, J=7.2Hz), 6.77(1H, s), 6.60(1H, d, J=2.4Hz ), 6.43 (1H, dd, J 1 =2.4,J 2 =8.7Hz), 3.79(3H, s), 3.66(2H, d, J=11.8Hz), 3.53(2H, t, J=8.5Hz), 3.40(1H, sept, J=6.8Hz), 2.80- 2.76(2H, m), 2.64-2.59(2H, m), 2.56-2.51(2H, m), 2.39-2.28(5H, m), 2.15(3H, s), 1.84(2H, d, J=12Hz ), 1.51 (2H, dq, J 1 =3.2,J 2 = 12 Hz), 1.23 (2H br s), 1.17 (6H, d, J = 6.8 Hz). ESI MS m / z: 621.28[M+H] + .

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Abstract

The invention relates to a compound as shown in a formula (I) which is described in the specification, and a pharmaceutical composition and a preparation method thereof. The compound can be used as anALK inhibitor for treatment of diseases mediated by ALK. The invention further relates to application of the compound as shown in the formula (I) and the pharmaceutical composition thereof to preparation of drugs used for treating diseases mediated by ALK.

Description

technical field [0001] The present invention relates to novel pyrrolopyrimidine derivatives with protein kinase inhibitory activity, their preparation method, pharmaceutical composition, and the use of such compounds and their pharmaceutical compositions in treating diseases related to protein kinases. Background technique [0002] Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily, which is closely related to the occurrence and development of tumors. Originally, ALK was discovered as an activated fusion oncogene in anaplastic large cell lymphoma, and 21 fusion forms of EML4-ALK have been identified so far. In addition, ALK can also fuse with NPM, TFG, KIF5B, KLC1, PTPN3, STRN and other genes (Lancet Oncology, 2015, 16(13), e510-e521, OncoTargets and Therapy, 2014, 7, 375-385), among which Including systemic tissue dysplasia, inflammatory myofibroblastic tumor, non-small cell lung cancer, etc. (Biochem J, 2...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04A61K31/519A61P35/00
Inventor 刘国成焦楠王树龙闵汪洋刘希杰孙莹张慧
Owner SHOUYAO HLDG BEIJING CO LTD
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