CN106565612B - Diphenylethyllene pyrimidines, composition and application thereof - Google Patents

Diphenylethyllene pyrimidines, composition and application thereof Download PDF

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CN106565612B
CN106565612B CN201610938467.XA CN201610938467A CN106565612B CN 106565612 B CN106565612 B CN 106565612B CN 201610938467 A CN201610938467 A CN 201610938467A CN 106565612 B CN106565612 B CN 106565612B
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phenyl
amine
ethenyl
pyrimidinyl
compound
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CN106565612A (en
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马晓东
宋安然
王璐红
刘贺
张宝璟
王长远
孟强
舒晓宏
甄宇红
刘克辛
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Dalian Medical University
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Dalian Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to diphenylethyllene pyrimidines, composition and application thereof, diphenylethyllene pyrimidines are specially general formula (I) compound represented, and each substituent group of general formula (I) is defined in the description.The invention further relates to the general formula (I) compound represented or its pharmaceutically acceptable salts, or containing its pharmaceutical composition by inhibiting EGFR skin factor receptor protein tyrosine kinases, and then tumor disease is treated, especially it is used to treat the purposes of non-small cell lung cancer, Small Cell Lung Cancer, squamous cell carcinoma or cancer of pancreas.

Description

Distyryl pyrimidine compound, composition and application thereof
Technical Field
The invention relates to a distyryl pyrimidine compound, a composition and application thereof, belonging to the technical field of medicines.
Background
Protein Tyrosine Kinases (PTKs) regulate a series of physiological and biochemical processes such as growth, differentiation and apoptosis of cells by controlling signal transduction pathways of the cells. Receptor-type tyrosine kinases are a class of relatively large kinases that span the cell membrane, having a ligand-binding extracellular domain, a transmembrane domain, and an intracellular domain that functions as a kinase-phosphorylating specific tyrosine residues and thereby affecting cell proliferation. Abnormal expression of the kinase has been found in common human cancers (e.g., lung, breast, stomach, ovarian, lymphoma). Protein tyrosine kinase has become one of the important targets for research and development of antitumor drugs.
Epidermal growth factor receptor tyrosine kinase (EGFR) is one of the earliest discovered protein tyrosine kinases, the intracellular domain of EGFR has an ATP binding site, and an EGFR inhibitor can competitively bind with the ATP binding site, so that the phosphorylation process of EGFR is inhibited, the conduction of downstream signals is blocked, and the growth, differentiation and metastasis of tumor cells are inhibited (Yun, et al. cancer Cell 2007,11, 217-227). The biochemical process of EGFR as an anti-tumor target has been elucidated, the crystal structure and active site thereof have been clarified, and the drugs gefitinib (gefitinib), erlotinib (erlotinib), afatinib (afatinib) and the like targeting this have been applied clinically, and with the intensive study of the structure and activity relationship of EGFR, many EGFR inhibitors having more excellent effects (EP 0566226, WO9961428, WO0051587, WO0375947, WO0132651, WO9633980, WO9630347, US7709479, US6716847, US6593333, US6251912, CN201080060451.4, CN201110191525.4 and the like) have been discovered. However, these drugs inevitably have a problem of poor resistance to drugs. The research shows that: the mutation of The amino acid from The790 to Met790 (T790M) is The major cause of resistance in this class of drugs. There are clinical case data showing that approximately 60% of patients have acquired resistance due to mutation at the T790M site. Therefore, the development of novel EGFR inhibitors with stronger drug resistance, less toxicity and stronger activity has very important practical value.
Osimetinib (AZD9291) is an orally irreversible, T790M mutation selective EGFR inhibitor, EGFR inhibitor deleted for Exon 19 in LoVo cellsL858R/T790MAnd EGFRWTIC of5011.44 and 493.8nM, respectively, were approved by the US FDA for marketing (WO 2013014448) at 2015 12 for treatment of EGFRT790MDrug-resistant lung cancer. Rociletinib (CO-1686, AVL-301) is another irreversible, mutation-selective EGFRT790MInhibitors acting on EGFR in cell-free assaysT790MAnd EGFRWTK ofi21.5nM and 303.3nM, respectively, are currently in phase III studies (WO 2012061299). Others such as HM61713, EGF816, PF-0674777Avitinib, ASP8273 is also a new class of egfr t inhibitors entering clinical research (Ma et al, j.med.chem.,2016, DOI: 10.1021/acs.jmedchem.5b00840.) referred to patents such as: US20120157426, US8563568B2, CN102740847, CN102083800, CN 102146076.
In view of the urgent need for cancer treatment, there is a need in the art to develop new drugs with better efficacy.
Disclosure of Invention
One of the purposes of the invention is to provide a distyryl pyrimidine compound or pharmaceutically acceptable salt thereof, wherein the distyryl pyrimidine compound has good antitumor activity.
The invention also aims to provide a pharmaceutical composition containing the distyryl pyrimidine compound or the pharmaceutically acceptable salt thereof.
The invention further aims to provide the distyryl pyrimidine compound or the pharmaceutically acceptable salt thereof, or the application of the composition.
To this end, in one aspect, the present invention provides a compound of formula (i) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (i) has the following structure:
R1selected from chlorine, fluorine, trifluoromethyl or nitro;
R2selected from hydrogen, methyl, methoxy or cyano; preferably, R2Selected from hydrogen;
(R3)nin each R3Independently selected from hydrogen, methyl, methoxy, hydroxy, fluoro, chloro or bromo;
n = an integer between 1 and 4; preferably, n =1 or 2;
x is selected from NH or O.
As a specific embodiment of the present invention, the compound represented by the general formula (I) of the present invention has the structure represented by I-1 to I-44:
the structural compound shown above is a distyryl pyrimidine compound. The screening of the anti-tumor activity shows that the compounds have stronger capacity of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells. As a molecule with novel structure, the compound has the potential of being developed into a novel high-efficiency EGFR inhibitor, and has great application value in treating related tumor diseases, particularly non-small cell lung cancer, squamous cell carcinoma or pancreatic cancer.
The structures represented by the foregoing I-1 to I-44 have the following names, respectively:
(i-1) N- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-2) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-3) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-4) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-5) N- [3- [ [ 5-chloro-2- [ [4- [2-3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-6) N- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-7) N- [3- [ [ 5-chloro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-8) N- [3- [ [ 5-chloro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-9) N- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-10) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-11) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-12) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-13) N- [3- [ [ 5-nitro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-14) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-15) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-16) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-17) O- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-18) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-19) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-20) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-21) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-22) O- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-23) O- [3- [ [ 5-chloro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-24) O- [3- [ [ 5-chloro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-25) O- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-26) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-27) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-28) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-29) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-30) O- [3- [ [ 5-fluoro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-31) O- [3- [ [ 5-fluoro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-32) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-33) O- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-34) O- [3- [ [ 5-nitro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-35) O- [3- [ [ 5-nitro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-36) O- [3- [ [ 5-nitro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-37) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-38) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-39) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-40) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-41) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl-3-methyl-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-42) O- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl-3-methoxy-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-43) N- [3- [ [ 5-fluoro-2- [ [4- [2- (4-fluoro-1-phenyl-3-cyano-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-44) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3-fluoro-1-phenyl-2-methyl-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide.
In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound represented by the general formula (i) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
the compounds of the invention are bases, wherein the desired salt form may be prepared by suitable methods known in the art, including treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or treatment of the free base with organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (pyrasidyl 1 acid), e.g. glucuronic acid or galacturonic acid, α -hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like.
The pharmaceutical compositions of the invention will generally contain one compound of the invention. However, in some embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the present invention may optionally further comprise one or more other pharmaceutically active compounds.
The invention also provides the distyryl pyrimidine compounds or pharmaceutically acceptable carriers thereof, and the pharmaceutical composition can inhibit the tumor proliferation by inhibiting EGFR (epidermal growth factor receptor) tyrosine kinase. In particular to the application of the compound in preparing a medicament for treating non-small cell lung cancer, squamous cell carcinoma or pancreatic cancer.
The invention provides an application of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in preparation of an EGFR (epidermal growth factor receptor) protein tyrosine kinase inhibitor.
The invention provides a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof, or application of a pharmaceutical composition in preparing a medicament for treating tumors. Preferably, the tumor is selected from one or more of non-small cell lung cancer, squamous cell carcinoma and pancreatic cancer, further preferably non-small cell lung cancer or pancreatic cancer. More preferably, the use is primarily by inhibiting EGFR epidermal factor receptor protein tyrosine kinase.
Detailed Description
The present invention is further described and explained below in conjunction with specific examples, which are not intended to limit the scope of the present invention.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
EXAMPLE 1 preparation of target molecules
The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the silica-amine plate used in Thin Layer Chromatography (TLC) is 0.15-0.2 mm, and the thin layer chromatography separation and purification product is 0.4-0.5 mm.
The raw materials used in the present invention are mainly purchased from chemical reagents of national medicine group, Beijing coupled technology, Inc., Aladdin chemical reagents, Inc., Darriy Chemicals, etc.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The route adopted by the invention synthesizes the compound of the invention:
the synthetic route, reagent and condition of compound (I) are (a) acryloyl chloride and NaHCO3Acetonitrile, rt, 0.5h, 98%; (b) Fe-NH4Cl，EtOH-H2O (v: v =1:1), 50 ℃ to rt, 3h, 90%; (c)2, 4-dichloropyrimidine, diisopropylethylamine, 1, 4-dioxane, 60 ℃, 24h and 85 percent; (d) m-nitrophenol, K2CO3，DMF，rt，2h，97%；(e)Fe-NH4Cl，EtOH-H2O (v: v =1:1), 70 ℃, 2h, 90%; (a) acryloyl chloride, NaHCO3Acetonitrile, rt, 0.5h, 95%; (g) trifluoroacetic acid, 2-BuOH, 100 ℃, overnight, 61%. R1、R2And (R)3）nAs defined above.
Synthesis of Compound 2
Taking m-nitroaniline (5.525 g,40 mmol) and NaHCO3(5.04 g,60 mmol) in 20mL acetonitrile, slowly adding 1 (4.345 g,48 mmol), reacting at room temperature for 0.5h, cooling after the reaction is finished, adding 100mL water, precipitating off-white solid, filtering, drying to obtain white solid, and directly reacting in the next step without purification.
Synthesis of Compound 3
Take 2 (40 mmol) and NH4Cl (5.4 g,100 mmol) in 40mL EtOH-H2Adding Fe powder (4.48 g,80 mmol) into O (v: v =1:1), heating to 50 ℃, reacting for 3 hours, filtering while the reaction is still hot, washing filter residue with a small amount of DMF, collecting filtrate, and extracting 3-membered wine with DCMAnd 5 times, combining organic phases, washing with supersaturated salt water, taking the organic phase, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain brown semisolid.
Synthesis of intermediate M4
Taking 2, 4-dichloro-5-R1Adding pyrimidine (32 mmol) into dioxane (10 mL), adding DIPEA (6.45 g,48 mmol) under stirring, dissolving c (5.185 g,32 mmol) in dioxane (10 mL), slowly adding into a reaction bottle, heating to 60 ℃ for reacting overnight, adding water after reaction, stirring, standing, precipitating, and filtering to obtain light yellow brown solid M4.
Synthesis of Compound 6
5 (40 mmol) was placed in a reaction flask, DMF (10 mL) was added and K was added with stirring2CO3(8.34 g,60 mmol), dissolving m-nitrophenol (40 mmol) in DMF (10 mL), slowly adding into a reaction bottle, reacting at normal temperature for 2h, adding 100mL of water after reaction, separating out off-white solid, filtering, drying to obtain white solid, and directly reacting in the next step without purification.
Synthesis of Compound 7
Take 6 (40 mmol) and NH4Cl (5.4 g,100 mmol) in 40mL EtOH-H2Adding Fe powder (4.48 g,80 mmol) into O (v: v =1:1), heating to 70 deg.C, reacting for 2 hr, filtering while hot, washing the residue with small amount of DMF, collecting filtrate, extracting with ethyl acetate for 3-5 times, mixingWashing the organic phase with supersaturated salt water, taking the organic phase, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain the final product, wherein the final product is directly reacted in the next step without purification.
Synthesis of intermediate M8
7 (36 mmol) was placed in a reaction flask, acetonitrile (20 mL) was added, NaHCO was added with stirring3(4.54 g,54 mmol), slowly dripping acryloyl chloride (45 mmol) into a reaction bottle, reacting at normal temperature for 0.5h, adding water, stirring after the reaction is finished, standing, precipitating, and filtering to obtain a solid M8.
Synthesis of object (I)
Dissolving M4 or M8 (2 mmol) and substituted stilbene arylamine (2 mmol) in 10mL 2-butanol respectively, slowly dropwise adding 5 drops of trifluoroacetic acid, heating to 100 ℃, refluxing and reacting overnight, cooling after the reaction is finished, pouring into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, washing with water, drying, and performing silica gel column chromatography separation to obtain the solid (I).
The target molecule was synthesized according to the above method, and the physicochemical data of the synthesized target molecule were as follows:
(I-1) N- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ2.26(s,3H),2.36(s,3H),6.25-6.30(m,1H),5.70-5.73(m,1H),6.22-6.27(m,1H),6.42-6.49(m,1H),6.89-6.93(d,J=16,1H),7.00(s,2H),7.13-7.17(d,J=16,1H),7.33-7.35(m,4H),7.48-7.50(d,J=8,1H),7.55-7.56(d,J=4,1H),7.62-7.64（d,J=8,2H),7.89(s,1H),8.17(s,1H),9.01(s,1H),9.49(s,1H),10.21(s,1H).MS(ESI),m/z:496[M+H]+.
(I-2) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ2.28(s,6H),5.73-5.76(m,1H),6.25-6.30(m,1H),6.50-6.57(m,1H),6.89(s,1H),6.96-7.11(m,2H),7.17(s,1H),7.35-7.41(m,3H),7.53-7.41(m,4H),7.98(s,1H),8.30(s,1H),9.73(s,1H),10.18(s,1H),10.46(s,1H).MS(ESI),m/z:496[M+H]+.
(I-3) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ3.78(s,6H),5.72-5.75(m,1H),6.25-6.19(m,1H),6.39(s,1H),6.47-6.53(m,1H),6.72-6.73(d,1H,J=4),6.94-7.15(m,2H),7.28-7.38(m,4H),7.59-7.64(m,3H),7.93(s,1H),8.20(s,1H),9.19(s,1H),9.68(s,1H),10.33(s,1H).MS(ESI),m/z:528[M+H]+.
(I-5) N- [3- [ [ 5-chloro-2- [ [4- [2-3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ5.72-5.75(m,1H),6.23-6.28(m,1H),6.43-6.50(m,1H),6.99-7.30(d,1H,J=16),7.30(s,1H),7.34-7.40(m,4H),7.44(s,1H),7.57-7.62(m,5H),7.88(s,1H),8.23(s,1H),9.39(s,1H),9.79(s,1H),10.27(s,1H).MS(ESI),m/z:536[M+H]+.
(I-9) N- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ2.26(s,3H),2.36(s,3H),5.70-5.77(m,1H),6.23-6.29(m,1H),6.97-6.99(d,J=8,2H),7.15-7.19(d,J=16,1H),7.29-7.34(m,2H),7.40-7.42(m,4H),7.50-7.60(m,2H),7.76-7.78(d,J=8,2H),8.13-8.14(d,J=4,1H),9.46(s,1H),9.54(s,1H),10.52(s,1H),10.52(s,1H).MS(ESI),m/z:480[M+H]+.
(I-10) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ2.28(s,6H),5.73-5.76(m,1H),6.25-6.30(m,1H),6.45-6.52(m,1H),6.87(s,1H),6.93-7.10(m,2H),7.15(s,1H),7.31-7.39(m,3H),7.49-7.51(d,2H,J=8),7.69-7.71(d,2H,J=8),7.96(s,1H),8.13-8.14(d,1H,J=4),9.35(s,1H),9.49(s,1H),10.20(s,1H).MS(ESI),m/z:480[M+H]+.
(I-11) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ3.78(s,6H),5.72-5.75(m,1H),6.25-6.19(m,1H),6.39(s,1H),6.47-6.53(m,1H),6.72-6.73(d,1H,J=4),6.94-7.15(m,2H),7.28-7.38(m,4H),7.59-7.64(m,3H),7.93(s,1H),8.20(s,1H),9.19(s,1H),9.68(s,1H),10.33(s,1H).MS(ESI),m/z:512[M+H]+.
(I-12) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ5.73-5.76(d,1H,J=12),6.24-6.29(d,1H,J=20),6.46-6.53(m,1H),7.03-7.07(d,1H,J=16),7.33-7.37(m,2H),7.44-7.46(d,4H,J=8),7.50-7.52(d,1H,J=8),7.60-7.63(d,4H,J=12),7.99(s,1H),8.23-8.24(d,1H,J=4),9.90(s,1H),10.19(s,1H),10.29(s,1H).MS(ESI),m/z:520[M+H]+.
I-13N- [3- [ [ 5-nitro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ2.26(s,3H),2.37(s,3H),5.69-5.72(d,1H,J=12),6.21-6.25(d,1H,J=16),7.00-7.02(d,1H,J=8),7.17-7.25(m,2H),7.28-7.37(m,4H),7.39-7.42(m,1H),7.50-7.58(m,3H),7.70-7.72(d,1H,J=8),7.87(s,1H),9.10(s,1H),10.39(s,1H),10.44(s,1H),10.56(s,1H).MS(ESI),m/z:507[M+H]+.
(I-18) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl
1H NMR(DMSO-d6):δ2.28(s,6H),5.76-5.79(d,1H,J=12),6.26-6.30(d,1H,J=16),6.43-6.50(m,1H),6.87-7.08(m,4H),7.16(s,2H),7.25-7.27(d,2H,J=8),7.40-7.51(m,3H),7.65-7.69(m,2H),8.05(s,1H),9.90(s,1H),10.46(s,1H).MS(ESI),m/z:497[M+H]+.
(I-21) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):δ5.77-5.80(m,1H),6.25-6.30(m,1H),6.43-6.50(m,2H),6.98-7.06(m,2H),7.29-7.33(m,2H),7.42-7.53(m,4H),7.62-7.63(d,1H,J=4),7.66-7.70(m,1H),7.76(s,1H),8.51(s,1H),8.83(s,1H),9.96(s,1H),10.48(s,1H).MS(ESI),m/z:537[M+H]+.
Method for salifying target molecule
The preparation method of the organic acid salt comprises the following steps: dissolving a target molecule (1 mmol) in 10mL of anhydrous methanol, slowly dropwise adding a 5mL of anhydrous methanol solution of organic acid (1 mmol) in ice bath, stirring for 30 minutes at the temperature after dropwise adding, and then evaporating methanol at normal temperature to obtain the organic acid salt of the target molecule. By the method, hydrochloride (I-1-1), hydrobromide (I-1-2), sulfate (I-1-3) and hydrobromide (I-1-4) of the compound I-1 are prepared;
the preparation method of the inorganic acid salt comprises the following steps: dissolving a target molecule (1 mmol) in 10mL of anhydrous methanol, slowly dropwise adding 5mL of dry ether of inorganic acid (1 mmol) in ice bath, stirring for 30 minutes at the temperature after dropwise adding, and then evaporating the solvent at normal temperature to obtain the inorganic acid salt of the target molecule. By this method, maleate salt (I-1-5), succinate salt (I-1-6) and fumarate salt (I-1-7) of compound I-1 were prepared.
Preparation of a mixture of target molecules
And (3) putting the two target molecules with equal molar weight (1 mmol) into anhydrous methanol (5 mL), stirring for 10 minutes at room temperature, and evaporating the solvent at room temperature to obtain a mixture of the target molecules. Three mixtures of (I-1) - (I-3), (I-2) - (I-9), (I-9) - (I-10) were prepared by this method.
Example 2 evaluation of biological Activity of target molecule
1. Method for testing in vitro inhibitory activity of receptor tyrosine kinase
Preparation of kinase assay buffer
first, a Kinase Detection Buffer (Kinase Detection Buffer) was dissolved at room temperature, and the presence or absence of a precipitate was observed.
② if precipitation occurs, incubation (Kinase Detection Buffer) at 37 ℃ for 15 minutes and shaking frequently to dissolve the precipitation, or, carefully remove the supernatant and remove the precipitation.
Preparation of kinase assay reagent
first, the Kinase Detection Buffer (Kinase Detection Buffer) and (KinaseDetection Substrate) were equilibrated at room temperature before use.
secondly, pouring all the Kinase Detection Buffer solution (Kinase Detection Buffer) into a brown bottle filled with a Kinase Detection Substrate (Kinase Detection Substrate) to dissolve the freeze-dried powder Substrate, thus preparing the Kinase Detection reagent.
③ lightly shaking, whirling or reversing the mixture to be mixed evenly to become a homogeneous solution, and the substrate should be dissolved within 1 minute.
and fourthly, immediately using the kinase detection reagent after the preparation, or subpackaging the reagent at-20 ℃, wherein the activity of the circulating signal is not lost after the prepared reagent is frozen and thawed for several times.
Standard Curve for conversion of ATP to ADP was generated
① Ultra PureATP and ADP provided by ① kit are diluted by kinase reaction buffer solution (kinase reaction buffer) to prepare 900 mu L of 50 mu M ATP and 500 mu L of 50 mu M ADP.
② mixing the prepared 50 μ M ATP and 50 μ M ADP solution in the previous step in 384-well plate A1-A12 according to the table 1, simulating the concentration of ATP and ADP of each conversion percentage, and mixing well.
TABLE 1 preparation of 50. mu.M series of ATP + ADP standards
Number of holes A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12
50μM ADP(μL) 100 80 60 40 20 10 5 4 3 2 1 0
50μM ATP(μL) 0 20 40 60 80 90 95 96 97 98 99 100
③ 5. mu.L of ADP-Glo is added to each wellTMReagents to terminate the kinase reaction. Incubate at room temperature for 40 minutes.
add 10 mul Kinase Detection Reagent (Kinase Detection Reagent) to each well to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
and fifthly, incubating for 30-60 minutes at room temperature, measuring fluorescence by using a multifunctional microplate reader and recording the fluorescence value.
sixthly, drawing a standard curve for converting ATP into ADP.
Determination of IC of kinase inhibitors50Value of
firstly, preparing a kinase reaction buffer (kinase reaction buffer), 50 ng/. mu.L of kinase, 0.5. mu.g/. mu.L of substrate and 125. mu.MATP according to the instructions of a promega kit.
② add 3. mu.L of kinase reaction buffer (kinase reaction buffer), 2. mu.L of 0.5. mu.g/. mu.L substrate and 125. mu.M ATP to the enzyme-free control well 1. mu.L of kinase reaction buffer (kinase reaction buffer), 2. mu.L of 50 ng/. mu.L kinase, 2. mu.L of 0.5. mu.g/. mu.L substrate and 125. mu.M ATP to the negative control well 1. mu.L of the drug to be tested, 2. mu.L of 50 ng/. mu.L kinase, 2. mu.L of 0.5. mu.g/. mu.L substrate and 125. mu.M ATP to the test well.
③ mix the plate and incubate for 60 minutes.
fourthly, 5 mu L of ADP-Glo is added into each holeTMReagents to terminate the kinase reaction. Incubate at room temperature for 40 minutes.
adding 10 mul of Kinase Detection Reagent (Kinase Detection Reagent) into each hole to convert ADP into ATP, introducing luciferase and luciferin to detect ATP, incubating at room temperature for 30-60 min, measuring fluorescence by using a multifunctional enzyme-labeling instrument, and recording the fluorescence value.
analysis of the results is shown in Table 2.
2. Cell growth experiments (MTT assay)
Cell inoculation: collecting cells in logarithmic growth phase, adjusting cell suspension concentration, inoculating 7000 cells per well and 100 μ L per well volume to 96-well plate, each set of which is provided with 3 multiple wells (the marginal wells are filled with sterile PBS);
cell culture: after the cells are attached to the wall, the culture solution in a 96-well plate is poured out and spin-dried, a blank group and a control group are cultured by using a blank culture medium, an administration group is cultured by using a drug solution with the blank culture medium as a solvent, the temperature is 37 ℃, and the CO content is 5 percent2Continuously culturing in an incubator (culturing for different times according to experimental requirements);
color generation: adding 10 μ L MTT solution (5mg/mL) into three groups of cells after culturing for 72h, terminating the culture after 4h, adding 100 μ L triple solution into each well, and oscillating on a shaking table at low speed for 10min to fully dissolve crystals;
color comparison: the absorbance (OD) of each well was measured on an ELISA detector, the wavelength of 570nm was selected, and the absorbance of each well was measured by zeroing a blank well of cell-free, i.e., blank, culture medium. The experiment was repeated three times.
The results are recorded: cell growth inhibition rate = (control absorbance value-experimental absorbance value)/control absorbance value x 100%, cell proliferation rate = (experimental absorbance value/control absorbance value) × 100;
drawing a cell growth curve: the cell growth curve was plotted with time as abscissa and inhibition/proliferation rate as ordinate.
Inhibitor concentrations were plotted in GraphPad prism5.0 plotting software in GraphPad software to determine log [ inhibitor [ ]]Variable slope model estimation of IC versus response50。
The test results are shown in table 2, and the obtained compounds have activity effects in inhibiting EGFR tyrosine kinase and resisting tumor cell proliferation.
TABLE 2
H1975 (mutant lung cancer cell line, EGFR)T790M/L858R) A549 (lung cancer cell line, EGFR)WTThe mutation of/K-ras), A431 (squamous cell line of epidermal carcinoma, EGFRoverexpression) AsPC-1 (pancreatic cancer cell line, K-ras mutation).
The above biological activity results show that the molecules of the invention are against EGFR and EGFRT790MThe kinase has strong inhibiting effect, most compounds reach the activity level of nanomolar level, and more than half of the compounds have effective inhibiting concentration IC50The value is less than 15nmol, which is significantly better than Gefitinib and Erlotinib. The result of anti-cell proliferation activity reveals that most compounds have very effective inhibition effect on drug-resistant cells H1975 of lung cancer, wherein the compounds I-2, I-3 and I-10 obviously show unexpected activity superior to Gefitinib, which indicates that the molecules are further developed into the application of drugs for resisting non-small cell lung cancer; meanwhile, most compounds also show a certain inhibiting effect on pancreatic cancer cells AsPC-1, and particularly, the activities of I-2, I-9 and I-13 are obviously superior to those of Gefitinib and Erlotinib, indicating that the molecules have further application in the aspect of pancreatic cancer drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (9)

1. A compound of formula (i) or a pharmaceutically acceptable salt thereof, said compound of formula (i) having the structure:
wherein,
R1selected from chlorine, fluorine, trifluoromethyl or nitro;
R2selected from hydrogen, methyl, methoxy or cyano;
(R3)nin each R3Independently selected from hydrogen, methyl, methoxy, hydroxy, fluoro, chloro or bromo;
n is an integer between 1 and 4;
x is selected from NH or O.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2Selected from hydrogen.
3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the general formula (I) has a structure represented by I-1 to I-44:
4. use of a compound represented by general formula (i) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the preparation of an EGFR epidermal factor receptor protein tyrosine kinase inhibitor.
5. A pharmaceutical composition comprising an effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, and a pharmaceutically acceptable carrier.
6. Use of the pharmaceutical composition of claim 5 for the preparation of an EGFR epidermal factor receptor protein tyrosine kinase inhibitor.
7. Use of a compound of formula (i) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a tumour.
8. Use according to claim 7, wherein the tumour is selected from one or more of squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma and adenocarcinoma.
9. Use according to claim 7 or 8, wherein said use is mainly achieved by inhibiting EGFR epidermal factor receptor protein tyrosine kinase.
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