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2-(2,4,5-substituted anilino)pyrimidine compounds and their applications

A compound, phenyl technology, applied to 2-(2,4,5-substituted anilino)pyrimidine compounds and their application fields, achieving excellent pharmacodynamic properties, good blood-brain barrier permeability, and high metabolic stability Effect

Active Publication Date: 2021-08-31
南京雷正医药科技有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But AZD 3759 only targets brain metastases with second-generation EGFR mutations

Method used

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  • 2-(2,4,5-substituted anilino)pyrimidine compounds and their applications
  • 2-(2,4,5-substituted anilino)pyrimidine compounds and their applications
  • 2-(2,4,5-substituted anilino)pyrimidine compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Example 1: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-hydroxymethyl-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide

[0105]

[0106] Step a: Preparation of 3-(2-chloro-pyrimidin-4-yl)-1H-indole (intermediate 1)

[0107] Dissolve indole (10.0g, 85mmol) in 1,2-dichloroethane (100mL), slowly add methylmagnesium bromide (3M, 28.5mL) dropwise at 0°C, after dropping, stir under ice bath After 15 minutes, 2,4-dichloropyrimidine (19.1 g, 128 mmol) was added to the above reaction solution all at once, and stirred overnight at room temperature. With stirring at room temperature, the above reaction solution was added dropwise to 1M dilute hydrochloric acid, a solid was precipitated, filtered with suction, and dried to obtain 11.0 g, with a yield of 56.3%.

[0108] Step b: Preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(indol-3-yl)pyrimidin-2-amine (intermediate 2)

[0109] Dissolve Intermediate 1 (11.0g, 48mmol), 4-fluoro-2-methoxy-5-nitroanil...

Embodiment 1A

[0123] Example 1A: N-(2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-hydroxymethyl-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide methanesulfonate

[0124]

[0125] At 70°C, to N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-hydroxymethyl-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide (500mg, 0.97mmol) in a mixed solvent of ethanol (10mL) and EtOAc (8mL) was slowly added dropwise methanesulfonic acid (93mg, 0.97mmol) solution in EtOAc (4 mL). Keep stirring for 1.5 hours. Filtrate while hot, and dry in vacuo at 80° C. to obtain 530 mg of a light yellow solid with a yield of 89.3%.

[0126] ESI-MS m / z:516.4[M+H] + .

[0127] 1 H NMR (400MHz, DMSO-d 6 )δ:9.55(s,1H),9.26(s,1H),8.70(s,1H),8.56(s,1H),8.31(s,1H),7.67(d,J=4.0Hz,1H), 7.35(d, J=4.0Hz, 1H), 7.27(t, J=8.0Hz, 1H), 7.16(t, J=8.0Hz, 1H), 7.05(s, 1H), 6.73-6.66(m, 1H ),6.35-6.30(m,1H),5.82-5.79(m,1H),5.63(s,2H),3.88(s,3H),3.39-3.11(m,4H),2.82(d,J=4.0 Hz,6H),2.65(s,3H),2.32(s,3...

Embodiment 2

[0128] Example 2: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methoxymethyl-indol-3-yl) pyrimidin-2-yl]amino}phenyl)prop-2-enamide

[0129]

[0130] N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-hydroxymethyl-indol-3-yl)pyrimidin-2-yl ]Amino}phenyl)prop-2-enamide (100mg, 0.194mmol) was dissolved in 2mL of dry DMF, NaH (9.3mg, 0.233mmol) was added under ice-cooling, after the addition was completed, it was reacted at 0°C for 0.5h, and then Iodomethane (33mg, 0.233mmol) was dissolved in DMF and added to the reaction solution, reacted at room temperature for 2h, the reaction solution was poured into water, extracted with DCM, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and column purified 25 mg of solid was obtained, yield: 24.3%.

[0131] ESI-MS m / z:530.4[M+H] + .

[0132] 1 H NMR (400MHz, CDCl 3 )δ:10.49(s,1H),9.65(s,1H),9.29(s,1H),8.40(d,J=4.0Hz,1H),7.98(d,J=8.0Hz,1H),7.79( s,1H),7.55(d...

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Abstract

The present invention relates to certain 2-(2,4,5-substituted anilino)pyrimidine compounds represented by the following formula I and applications thereof. These compounds or salts thereof show higher inhibition of EGFR in activated or drug-resistant mutant forms than in wild-type EGFR. Due to the reduced toxicity associated with wild-type EGFR inhibition, the compound or its salt is expected to have excellent pharmacodynamic properties, higher metabolic stability, better permeability of the blood-brain barrier, and is more suitable for use as a therapeutic agent, Especially suitable for the treatment of cancer. Therefore, these compounds or their salts can be used to prepare drugs for treating certain mutation forms of EGFR-mediated diseases, especially non-small cell lung cancer.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a 2-(2,4,5-substituted anilino)pyrimidine compound and a pharmaceutically acceptable salt thereof, which selectively inhibit the activity of the epidermal growth factor receptor (EGFR) in a mutant form. The pharmaceutical composition of the compound and its pharmaceutically acceptable salt, and their application in the preparation of medicines for treating certain mutation forms of EGFR-mediated diseases, especially non-small cell lung cancer. Background technique [0002] Epidermal growth factor receptor (EGFR), a transmembrane protein tyrosine kinase of the erbB receptor family, binds to growth factor ligands such as epidermal growth factor (EGF), and the receptor binds to additional Homodimerization of EGFR molecules or heterodimerization with another family member (eg, erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4)), homodimerization and / or heterodimerization of erbB receptors Dimerizatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D401/14C07F9/6558A61K31/506A61K31/675A61P35/00
CPCA61P35/00C07D401/14C07D403/04C07F9/65583
Inventor 范文华唐春雷范为正刘彦张晴
Owner 南京雷正医药科技有限公司
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