CN115448906B - 2-anilinopyrimidine derivative and preparation method and application thereof - Google Patents

2-anilinopyrimidine derivative and preparation method and application thereof Download PDF

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CN115448906B
CN115448906B CN202211174061.0A CN202211174061A CN115448906B CN 115448906 B CN115448906 B CN 115448906B CN 202211174061 A CN202211174061 A CN 202211174061A CN 115448906 B CN115448906 B CN 115448906B
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cancer
cancer cells
cells
cell
egfr
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CN115448906A (en
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蒋宇扬
李安祺
刘子建
初碧珠
张存龙
吴伟彬
陈妍
李露露
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Shenzhen Berry Biomedical Technology Co ltd
Shenzhen Kivita Innovative Drug Institute
Shenzhen University
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Shenzhen Berry Biomedical Technology Co ltd
Shenzhen Kivita Innovative Drug Institute
Shenzhen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The invention belongs to the field of medicines, and relates to a 2-anilinopyrimidine derivative, and a preparation method and application thereof. The 2-anilinopyrimidine derivative is a compound shown in a formula I, or a pharmaceutically acceptable salt or tautomer thereof or prodrug molecule thereof. Experiments show that the compound shown in the formula I has a certain inhibitory activity on an epidermal growth factor receptor, can effectively inhibit proliferation of various tumor cells, and has potential for research and development of tumor drugs.

Description

2-anilinopyrimidine derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a 2-anilinopyrimidine derivative with EGFR and ALK inhibition activity, and a preparation method and application thereof.
Background
The tumor molecular targeting therapy is a new tumor therapeutic means which is rapidly developed in recent years, and the principle is a therapeutic method for selectively killing tumor cells based on the inhibition of key factors or proteins closely related to the growth and development of tumors by targeted chemical or biological means. Compared with the traditional anticancer micromolecule medicine, the tumor targeting medicine has the characteristics of strong pertinence, relatively less side effect, good treatment effect and the like, so that the tumor targeting medicine is widely focused, and the tumor targeting therapy is one of the development trends of tumor therapy.
Epidermal Growth Factor Receptor (EGFR) is a receptor type tyrosine protein kinase, plays an important role in vital activities such as proliferation, differentiation, apoptosis and angiogenesis, and is also found to be overactivated or continuously activated in various tumor cells such as lung cancer, breast cancer and prostate cancer. Among them, EGFR mutation is one of the most important drivers in lung cancer patients, and the mutation rate thereof reaches more than 50% especially in Asians. Gefitinib (Gefitinib), a small molecule inhibitor of EGFR marketed in 2003, is used in the treatment of advanced stages of non-small cell lung cancer (NSCLC) and is now also commonly used as a first line medication in EGFR mutated NSCLC patients.
EGFR inhibitor development has been divided into three generations according to the drugs on the market to date. The first generation of EGFR includes the aforementioned Gefitinib and Erlotinib, icontinib, etc., which are directed to NSCLC patients with EGFR in which L858R or del19 mutation is present, and have achieved remarkable clinical efficacy. However, some patients develop drug resistance after 10 to 12 months of drug administration, and the patients can be found to have mainly undergone T790M mutation by gene sequencing and the like, and more than 50% of drug-resistant patients have undergone T790M secondary mutation. In order to solve the problem of first generation inhibitor resistance, second generation EGFR inhibitors have been developed. The second generation inhibitors are irreversible inhibitors, which are inhibitors of wild-type EGFR (EGFR wt ) Also has strong inhibition effect, thus having great toxicity. Second generation EGFR inhibitors that have been marketed include Afatinib and dacominib, but at the clinically Maximum Tolerated Dose (MTD), do not solve the problem of resistance caused by the T790M mutation well. The third generation EGFR inhibitor truly solves the drug resistance problem caused by the T790M mutation, and the American FDA accelerated approval of the Ornitinib (Osimertinib) is obtained in the 11 th month of 2015, so that the drug resistance problem caused by the T790M mutation can be effectively treated in clinic for NSCLC patients with drug resistance, and great success is achieved. However, it is inevitable that some patients who benefit from the treatment for 9 to 14 months have new drug resistance, and researches show that 20 to 40% of patients have drug resistance of Osimertinib due to the occurrence of C797S point mutation. The C797S point mutation refers to the conversion of cysteine to serine at position 797 of EGFR, and position 797 is one of the important sites for covalent binding of osiert inib to EGFR, so that both cannot bind, ultimately resulting in resistance to osiert inib. Currently, no EGFR inhibitors against C797S mutation are marketed, so EGFR inhibitors with high selectivity for C797S are urgently needed to solve the problem of resistance to the third generation inhibitors.
Anaplastic Lymphoma Kinase (ALK) also belongs to receptor type tyrosine kinase, and EML4-ALK chimeric protein generated by mutation of echinoderm microtubule binding protein (EML 4) and ALK fusion gene can promote dimerization of ALK, and related signal channels are continuously activated, so that occurrence and development of cancers are promoted. In smoking patients with NSCLC, EML4-ALK gene fusion mutation occurred in 2.9%; in non-smoking patients, EML4-ALK mutation occurs in 9.4%, so ALK is also one of the main types of mutation in addition to EGFR mutation. With the development of genetic sequencing technology, the simultaneous presence of EGFR and ALK rearrangements is continually being discovered. The literature reports that 2 patients are found to have EML4-ALK fusion mutation after gene sequencing of 14 patients with the resistance to the Orientinib, which also implies that EGFR/ALK dual-target inhibitors can be used for target drug treatment of lung cancer in the future and have a certain potential for solving the problem of resistance to the EGFR.
Disclosure of Invention
The invention aims to provide a 2-anilinopyrimidine derivative inhibitor with EGFR and ALK inhibition activity and a preparation method thereof.
In order to achieve the above purpose, the present invention provides a 2-anilinopyrimidine derivative, wherein the 2-anilinopyrimidine derivative is a compound shown in formula I, or a pharmaceutically acceptable salt or tautomer thereof or a prodrug molecule thereof;
wherein:
R 1 is that
R 2 Is that
R 3 Is hydrogen, halogen (Cl or Br), trifluoromethyl, nitro, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 A cycloalkoxy group;
x, Y, Z are each independently CH or N. Preferably, X is N and Y, Z is CH.
In the present invention, the pharmaceutically acceptable salt may be an inorganic acid salt or an organic acid salt; specifically, the inorganic acid salt is selected from any one of the following inorganic acid salts: hydrochloric acid, sulfuric acid, and phosphoric acid; the organic acid salt is selected from any one of the following organic acid salts: acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
The compounds of the present invention may exist in different polymorphic forms.
According to a preferred embodiment of the present invention, the compound of formula I is selected from any one of the following:
the invention also provides a preparation method of the 2-anilinopyrimidine derivative, which comprises the following steps:
reacting a compound shown in a formula IA with a compound shown in a formula IB in a solvent under an acidic condition to obtain a compound shown in a formula I:
R 1 、R 2 、R 3 x, Y and Z are as defined in claim 1.
More specifically, the catalyst can be prepared according to the following reaction scheme:
wherein R is 1 、R 2 、R 3 X, Y and Z are as described above.
The reaction route mainly comprises the following reaction steps:
and a step a), carrying out substitution reaction on the compound shown in the formula Ia and a fluorine-containing aromatic ring under alkaline conditions to obtain the compound shown in the formula Ib. Preferably, the reaction takes N, N-dimethylformamide as a solvent, cesium carbonate as a basic reagent, the reaction temperature is 90 ℃, and the reaction time is 24 hours.
And b), carrying out reduction reaction on the compound shown in the formula Ib and hydrogen under the action of a catalyst to obtain the compound shown in the formula Ic. Preferably, the reaction is carried out in absolute ethanol; the catalyst is 10% palladium carbon; the reaction temperature is room temperature; the reaction time was 6 hours.
And c), carrying out nucleophilic substitution reaction on the compound shown in the formula Ic and the terminal hydroxyl of the corresponding ethanol derivative containing the aliphatic heterocycle under alkaline conditions to obtain the compound shown in the formula Id. Preferably, the base required for the reaction is sodium hydride; the reaction is carried out in absolute ethanol; the reaction temperature is 0 ℃; the reaction time is 8-12 hours.
Step d) Compounds of formula Ie and corresponding compounds containing R under basic conditions 2 And carrying out nucleophilic substitution reaction on the terminal primary amine of the group to obtain the compound shown in the formula If. Preferably, the base required for the reaction may be selected from one or more of triethylamine, diisopropylethylamine, ammonia water, sodium methoxide, ethanolamine, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium iodide, etc.; the reaction temperature is 80 ℃; the reaction time is 0.5-3 hours.
And e), carrying out substitution reaction on the compound shown in the formula If and terminal primary amine of the compound shown in the formula Id under an acidic condition to obtain the compound shown in the formula I. Preferably, the acid required for the reaction is p-toluenesulfonic acid monohydrate; the reaction is carried out in 2-pentanol; the reaction temperature is 90 ℃; the reaction time was 5 hours.
Without describing the starting material syntheses and intermediates, the compounds are commercially available or prepared using standard methods or using commercially available compounds using the extension methods of the examples herein.
It is a further object of the present invention to provide the use of the compounds of formula I and pharmaceutically acceptable salts thereof. Specifically, the 2-anilinopyrimidine derivative disclosed by the invention can be applied to the preparation of the following products:
1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) Eukaryotic tumor cell proliferation inhibitors;
4) An inhibitor of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
The epidermal growth factorSub-receptors (EGFR) include, but are not limited to EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR (epidermal growth factor receptor) del19/T790M/C797S At least one of them.
The Anaplastic Lymphoma Kinase (ALK) includes, but is not limited to ALK wt 、ALK L1196M And at least one of EML 4-ALK.
The eukaryote is preferably a mammal; the tumor cell is preferably a cancer cell; more preferably, the cancer cell is a leukemia cancer cell, a lymphoma cell, a lung cancer cell, a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, a human brain glioma cell, a melanoma cancer cell, a glioblastoma cell, a nasopharyngeal cancer cell, a liver cancer cell, a brain cancer cell, a pancreatic cancer cell, a uterine cancer cell, a testicular cancer cell, a skin cancer cell, a gastric cancer cell, a colon cancer cell, a bladder cancer cell, or a rectal cancer cell.
The leukemia cancer cells are specifically human Chronic Myelogenous Leukemia (CML) cell line K562; the lymphoma cell is specifically human histiocyte lymphoma cell U937; the lung cancer cell is specifically human lung cancer cell strain HCC827; the breast cancer cells are specifically human breast cancer cells MCF-7, T47D and MDA-MB-231; the ovarian cancer cells are specifically A2780; the cervical cancer cells are specifically human cervical cancer cell line Hela; the human brain glioma cells are specifically U251; the melanin cancer cells are specifically A375; the glioblastoma cells are specifically human glioblastoma cell A172 and human brain astrocyte tumor cell U-118MG; the nasopharyngeal carcinoma cell is specifically a nasopharyngeal carcinoma cell line CNE-2; the liver cancer cell is a specific human liver cancer cell HepG2.
The tumor is cancer, and the cancer is specifically leukemia, lymphoma, lung cancer, melanin cancer, glioblastoma, cervical cancer, nasopharyngeal carcinoma, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.
The invention also provides a product, the active ingredient of which is the 2-anilinopyrimidine derivative; the product is at least one of the following:
1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) Eukaryotic tumor cell proliferation inhibitors;
4) An inhibitor of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
The limitation of each product is the same as the previous one, and the description thereof is omitted here.
The compound shown in the structural formula I or pharmaceutically acceptable salt thereof can also be used for preparing medicines for preventing and/or treating tumors. The medicine for preventing and/or treating tumor prepared by using the compound shown in the structural formula I or the pharmaceutically acceptable salt thereof as an active ingredient also belongs to the protection scope of the invention.
An Epidermal Growth Factor (EGFR) inhibitor, an Anaplastic Lymphoma Kinase (ALK) inhibitor, a eukaryotic tumor cell proliferation inhibitor and a medicament for preventing and/or treating tumors, which are prepared from a compound shown in a formula I or pharmaceutically acceptable salts thereof, can be introduced into a body such as muscle, intradermal, subcutaneous, intravenous and mucosal tissues by injection, nasal drops, eye drops, permeation, absorption and physical or chemical mediation; or mixed or wrapped with other substances and introduced into the body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. which are conventional in the pharmaceutical field.
The tumor preventing and/or treating medicine prepared with the compound shown in the structural formula I or the pharmaceutically acceptable salt thereof can be prepared into various forms such as injection, tablet, powder, granule, capsule, oral liquid, ointment, cream and the like. The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
The test proves that the compound provided by the invention can inhibit the growth of various tumor cells and inhibit EGFR family protease, and can particularly effectively inhibit the activity of EGFR protein kinase resistant mutants, such as EGFR del19/T790M/C797S And EGFR (epidermal growth factor receptor) L858R/T790M/C797S Can overcome clinical resistance of NSCLC patients induced by the existing third-generation EGFR inhibitor drugs such as Osimertinib and the like. At the same time for ALK wt Has better inhibition effect. The compound provided by the invention has the advantages of easily available raw materials, simple preparation method and good anticancer effect proved by experiments, and has good application prospect in the field of anti-tumor drug design and research and development.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention are described below, it should be understood that the present invention may be embodied in various forms and should not be limited to the embodiments set forth herein.
The experimental methods described in the following examples, unless otherwise specified, are all conventional methods of organic synthesis; the reagents and biological materials, unless otherwise specified, are commercially available.
Example 1
5-chloro-N 2 - ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl-N 4 -phenylpyrimidine-2, 4-diamine
Example 1A
2-fluoro-4- (3-methoxy-4-nitrophenoxy) pyridine
2, 4-difluoropyridine (0.500 g,4.34 mmol) was treated with 25mLN, N-dimethylformamide was dissolved, cesium carbonate (2.83 g,8.68 mmol) and 3-methoxy-4-nitrophenol (0.73 g,4.34 mmol) were added, and the temperature was raised to 90℃for 24 hours. After the reaction was completed, extraction was performed with ethyl acetate and water, the organic layer was extracted with water layer several times until colorless, and the organic layer was collected and purified by silica gel column chromatography to obtain 0.841g of pale yellow solid, yield 73.7%. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J＝5.8Hz,1H),8.00(d,J＝8.9Hz,1H),6.84(s,2H),6.74(dd,J＝8.9,2.3Hz,1H),6.52(s,1H),3.96(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.73,166.61,166.33,163.97,158.54,155.30,149.28,149.10,128.19,111.38,111.26,111.22,105.63,98.60,98.19,56.87.。
example 1B
4- ((2-fluoropyridin-4-yl) oxy) -2-methoxyaniline
10mL of absolute ethanol was used to dissolve example 1A (0.841 g,3.18 mmol), 10% palladium on carbon reagent (0.170 g, 20% of the starting material) containing 55% water was added, the air was replaced with hydrogen, and the reaction was repeated a plurality of times to ensure complete hydrogen replacement and the reaction was carried out at room temperature for 6 hours. After the completion of the reaction, excess palladium on carbon was removed by filtration through celite, the filtrate was collected, and the solvent was removed by rotary evaporation under reduced pressure to give 0.547g of a pale yellow thick liquid product in 70.7% yield. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,DMSO-d6)δ8.07(d,J＝5.8Hz,1H),6.82(dd,J＝5.8,1.0Hz,1H),6.72–6.65(m,2H),6.56–6.50(m,2H),4.80(s,2H),3.74(s,3H). 13 C NMR(101MHz,DMSO)δ170.03,169.91,166.17,163.87,149.16,148.98,147.48,143.54,136.32,113.96,113.09,110.65,110.62,104.76,96.59,96.17,56.03.
example 1C
2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) aniline
1-hydroxyethyl-4-methylpiperazine (0.389 g,2.69 mmol) was dissolved in 8mL of N, N-dimethylformamide, stirred in an ethanol solution at 0℃for 10 minutes, 60% sodium hydride (0.112 g,2.81 mmol) was added, and after stirring for 20 minutes, the temperature was slowly raised, and after 1 hour, example 1B (0.547 g,2.25 mmol) was dissolved in 4mL of N, N-dimethylformamide and added to the reaction mixture, and the temperature was raised to room temperature overnight. After completion of the reaction, the mixture was extracted with ethyl acetate and water, the aqueous layer was extracted with ethyl acetate several times, and the organic layer was collected and purified by silica gel column chromatography to give 0.572g of a pale yellow oily product in 71.1% yield. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝5.9Hz,1H),6.65(s,1H),6.49(d,J＝9.2Hz,3H),6.10(d,J＝2.0Hz,1H),4.35(t,J＝5.7Hz,2H),3.77(s,3H),2.73(d,J＝5.8Hz,2H),2.51(d,J＝33.7Hz,8H),2.26(s,3H).
example 1D
2, 5-dichloro-N-phenylpyrimidin-4-amine
2,4, 5-trichloropyrimidine (0.500 g,2.73 mmol) was dissolved in 5mL of dimethyl sulfoxide, a small amount of tetrabutylammonium iodide was added, aniline (0.281g, 3.00 mmol) and triethylamine (0.302 g,3.00 mmol) were added after the solution became yellow, and the temperature was raised to 80℃for overnight reaction. After the completion of the reaction, the aqueous layer was extracted with ethyl acetate and water repeatedly, and the organic layer was collected, and the product was separated by a silica gel column to obtain 0.455g of a yellow solid product in 85.1% yield. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.58(dd,J＝8.6,1.1Hz,2H),7.46–7.31(m,2H),7.19(d,J＝7.4Hz,1H). 13 C NMR(101MHz,DMSO)δ157.64,157.38,155.84,137.88,129.00,125.46,123.93,114.05.
5-chloro-N 2 - ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl-N 4 -phenylpyrimidine-2, 4-diamine
Example 1C (0.171 g,0.477 mmol), example 1D (0.137 g, 0.578mmol) and other reagents included tris (dibenzylideneacetone) dipalladium (0.022 g,2.39x10-3 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (0.030 g, 47.7x10) -3 mmol) and potassium tert-butoxide (0.077 g,0.687 mmol) were placed in a sealed tube, protected by argon, and after addition of 5mL of 1, 4-dioxane, the solution was degassed by argon. The reaction was carried out at 120℃for 24 hours, after the completion of the reaction, extraction was carried out with ethyl acetate and water, the organic layer was collected and the product was separated by a silica gel column method, and 0.151g of a pale yellow solid product was collected in a yield of 56.3%. The nuclear magnetic characterization data are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.6Hz,1H),8.09(s,1H),7.99(d,J＝5.9Hz,1H),7.59(d,J＝7.6Hz,2H),7.49(s,1H),7.38(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H),7.09(s,1H),6.63–6.57(m,2H),6.55(d,J＝2.2Hz,1H),6.19(d,J＝2.1Hz,1H),4.41(t,J＝5.8Hz,2H),3.85(s,3H),2.77(t,J＝5.8Hz,2H),2.53(d,J＝40.1Hz,8H),2.28(s,3H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.51,165.54,157.65,155.86,154.32,149.03,148.27,147.86,137.72,128.91,126.61,124.61,122.26,119.72,112.62,107.09,103.77,97.19,63.62,57.10,55.90,54.96,53.38,45.99 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 562.2333, found 562.2289.
Example 2
(2- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide
Example 2 was essentially identical to the synthesis of example 1, with the conversion of aniline in example 1D to 2- (dimethylphosphino) aniline, and the remaining synthesis steps and conditions were essentially identical to example 1. The nuclear magnetic characterization and high resolution mass spectrum data are as follows: 1 H NMR(400MHz,Chloroform-d)δ10.78(s,1H),8.50(ddd,J＝8.6,4.4,1.1Hz,1H),8.31–8.25(m,1H),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.43(s,2H),7.28–7.19(m,1H),7.05(tdd,J＝7.5,2.4,1.1Hz,1H),6.57(d,J＝2.3Hz,2H),6.47(d,J＝2.2Hz,1H),6.13(d,J＝2.1Hz,1H),4.34(s,2H),3.79(s,3H),2.69(s,2H),2.57–2.45(m,4H),2.44–2.33(m,4H),2.21(d,J＝2.5Hz,3H),1.78(s,3H),1.75(s,3H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.95,167.44,165.50,165.45,157.34,155.92,154.87,149.18,148.37,147.84,147.68,145.67,143.57,119.87,114.80,113.12,112.48,107.05,104.37,103.83,97.18,63.58,57.04,55.89,54.90,53.31,45.92,18.87,18.16 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 638.2411, found 638.2369.
Example 3
(6- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
The partial synthetic route is as follows:
example 3A
5-iodo-6-aminoquinoxalines
6-aminoquinoxaline (0.100 g,0.689 mmol) was dissolved in 5mL of 1, 4-dioxane aqueous solution (4:1), sodium hydrogen carbonate (0.144 g, 1.720 mmol) and elemental iodine (0.433 g,1.722 mmol) were added at 0℃and stirred for half an hour before being transferred to room temperature for 4 hours; after completion of the reaction, the mixture was extracted with water and ethyl acetate, and the organic layer was collected, and the product was separated by a silica gel column to obtain 0.122g of a dark yellow solid. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,Chloroform-d)δ8.74(d,J＝2.0Hz,1H),8.53(d,J＝2.0Hz,1H),7.83(d,J＝9.0Hz,1H),7.31–7.22(m,1H). 13 C NMR(101MHz,CDCl 3 )δ171.21,149.46,145.51,144.22,141.27,138.61,130.30,120.70,67.08.
example 3B
5-dimethyloxyphosphoryl-6-aminoquinoxaline
Example 3A (0.100 g,0.37 mmol), dimethylphosphine (0.043 g,0.55 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.021 g,0.037 mmol), palladium acetate (0.008 g,0.037 mmol) and potassium phosphate (0.117 g,0.550 mmol) were placed in a vial under argon. After adding 2mL of N, N-dimethylformamide and 0.4mL of water, argon protection was again performed, and the reaction was performed overnight at 120 ℃. After the completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic layer was collected, and the product was separated by a silica gel column chromatography method to obtain 0.112g of a yellow solid product. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,Chloroform-d)δ8.63–8.40(m,2H),7.84(s,1H),7.03(d,J＝4.6Hz,1H),2.04–1.95(m,6H). 13 C NMR(101MHz,CDCl 3 )δ155.72,145.78,143.13,139.74,137.63,134.05,134.03,124.88,124.79,20.21,19.49.
example 3C
(6- ((2, 5-dichloro-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide
Synthetic method of example 3C referring to example 1D, the aniline was exchanged for example 3B, and the other reaction conditions were substantially identical to those of example 1D. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,Chloroform-d)δ13.22(s,1H),9.15(dd,J＝9.5,4.2Hz,1H),8.81–8.78(m,1H),8.74(d,J＝1.8Hz,1H),8.27(d,J＝0.9Hz,1H),8.25(d,J＝9.6Hz,1H),2.12(dd,J＝14.3,0.8Hz,7H). 13 C NMR(101MHz,CDCl 3 )δ157.26,156.90,156.90,156.37,155.99,155.00,147.84,143.63,143.61,139.44,139.37,133.98,133.96,125.68,125.59,116.46,20.72,19.99.
example 3
(6- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
Example 1C (0.144 g,0.402 mmol), example 3C (0.147 g,0.402 mmol), p-toluenesulfonic acid monohydrate (0.153 g,0.804 mmol) were dissolved with 6mL of 2-pentanol and reacted at 90℃for 5 hours. After the completion of the reaction, the aqueous layer was extracted with ethyl acetate and water several times, and the organic layer was collected and the product was separated by a silica gel column to obtain 80mg of a yellow solid product. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J＝9.5,4.1Hz,1H),8.75(s,1H),8.72(s,1H),8.35–8.29(m,1H),8.19(s,1H),8.13(d,J＝9.5Hz,1H),7.98(d,J＝5.9Hz,1H),7.51(s,1H),6.67–6.64(m,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.17(d,J＝2.1Hz,1H),4.40(t,J＝5.7Hz,2H),3.87(s,3H),2.80–2.55(m,11H),2.38(s,3H),2.14(s,3H),2.11(s,3H). 13 C NMR(101MHz,CDCl 3 )δ167.47,165.43,157.22,155.89,155.80,149.31,148.90,148.88,148.64,147.90,143.86,143.80,143.35,142.96,139.27,139.20,132.98,132.95,126.82,126.73,126.50,119.88,112.62,112.49,111.60,108.01,107.16,103.99,97.23,63.44,56.84,55.98,54.55,52.42,45.27,20.76,20.03.
example 4
5-chloro-4- (1- (ethylsulfonyl) -1H-indol-3-yl) -N- (2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) pyrimidin-2-amine
The partial synthetic route is as follows:
example 4A
3- (2, 5-dichloropyrimidin-4-yl) -1H-indole
Indole (1.28 g,10.79 mmol) was dissolved in 6mL of tetrahydrofuran, and methylmagnesium bromide (3.37 mL,10.78 mmol) was slowly added dropwise at 0deg.C and stirred for 30 min; 2,4, 5-trichloropyrimidine (1 g,5.4 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and after heating to 60℃the mixture was continued for 1.5 hours. After the reaction was completed, 634. Mu.L of acetic acid (11.06 mmol), 9.9mL of water and 2mL of tetrahydrofuran were added dropwise after cooling to room temperature, and the mixture was stirred at 60℃for 20 minutes. The organic layer was collected and 11mL of heptane was added to yield a white solid, and 1.51g of product was collected. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,DMSO-d6)δ8.69(d,J＝1.4Hz,2H),8.50(d,J＝6.9Hz,1H),7.55(s,1H),7.24(d,J＝0.6Hz,2H).
example 4B
3- (2, 5-dichloropyrimidin-4-yl) -1- (ethylsulfonyl) -1H-indole
Example 4A (0.100 g,0.379 mmol) was dissolved in 1.5mL of tetrahydrofuran, sodium hydride (0.037 g,0.946 mmol) was added at 0deg.C, and ethyl sulfonyl chloride (0.058 g,0.454 mmol) was added after 3 hours of cooling had passed off, overnight at room temperature. After the completion of the reaction, the mixture was extracted with ethyl acetate and water, and the organic layer was collected, and the product was separated by a silica gel column chromatography method to obtain 0.155g of a pale yellow solid product. Compound nuclear magnetic characterization data: 1 H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.57(s,1H),8.37(d,J＝7.9Hz,1H),7.92(d,J＝8.2Hz,1H),7.46(dd,J＝13.1,7.8Hz,2H),3.87–3.71(m,2H),1.11(t,J＝7.3Hz,3H).
example 4
5-chloro-4- (1- (ethylsulfonyl) -1H-indol-3-yl) -N- (2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) pyrimidin-2-amine
The synthesis of example 4 was carried out in accordance with example 3, with example 3C being replaced by example 4B, and the other reaction conditions being substantially identical to the synthesis conditions of example 3. The nuclear magnetic characterization data are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J＝0.8Hz,2H),8.41(d,J＝0.8Hz,2H),7.99(d,J＝6.0Hz,2H),7.76(s,1H),7.44–7.34(m,2H),6.68(d,J＝2.4Hz,2H),6.59–6.54(m,1H),6.19(d,J＝2.1Hz,1H),4.41(t,J＝5.7Hz,2H),3.91(s,3H),3.42(q,J＝7.4Hz,2H),2.79–2.54(m,10H),2.38(s,3H),1.30–1.27(m,4H). 13 C NMR(101MHz,CDCl 3 )δ167.42,165.46,158.19,149.30,148.82,147.90,134.87,130.44,128.74,126.33,125.55,124.07,123.37,119.70,112.94,112.75,107.21,103.95,97.29,63.52,56.90,56.02,54.63,52.57,49.01,45.37,8.12.
example 5
5-chloro-N 2 - (2-methoxy-4- ((2- (2-morpholinoethoxy) pyridin-4-yl) oxy) phenyl) -N 4 -phenylpyrimidine-2, 4-diamine
Synthetic method reference example 1, 61.2% yield. The nuclear magnetic characterization and high resolution mass spectrum data are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J＝8.7Hz,1H),8.07(s,1H),7.99(d,J＝5.9Hz,1H),7.57(d,J＝8.0Hz,2H),7.51(s,1H),7.37(t,J＝7.9Hz,2H),7.14(d,J＝11.5Hz,2H),6.63–6.52(m,3H),6.19(d,J＝2.1Hz,1H),4.41(s,2H),3.84(s,3H),3.73–3.68(m,4H),2.74(t,J＝5.7Hz,2H),2.53(dd,J＝5.7,3.7Hz,4H). 13 C NMR(101MHz,CDCl 3 )δ167.57,165.49,157.64,155.89,154.28,149.08,148.28,14786,137.75,128.88,126.63,124.60,122.31,119.80,112.60,107.16,105.08,103.77,97.17,66.83,63.32,57.58,55.90,53.92 high resolution mass spectrum HRMS (ESI) M/z calculated [ M+H ]] + 549.2017, found 549.1949.
Example 6
(2- ((5-chloro-2- ((2-methoxy-4- ((2- (2-morpholinoethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide
Synthetic method referring to example 2, yield 63.3%, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ10.78(s,1H),8.54–8.45(m,1H),8.28(d,J＝9.5Hz,1H),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.45(s,2H),7.22(d,J＝14.0Hz,1H),7.06(ddt,J＝8.8,6.7,1.6Hz,1H),6.58(s,2H),6.48(d,J＝2.2Hz,1H),6.14(d,J＝2.2Hz,1H),4.35(t,J＝5.7Hz,2H),3.79(s,3H),3.65–3.58(m,4H),2.68(t,J＝5.7Hz,2H),2.46(s,4H),1.79(s,3H),1.75(s,3H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.49,165.46,157.33,155.93,154.86,149.21,148.36,147.85,143.59,132.25,129.67,126.65,123.17,122.80,121.02,119.90,112.48,107.11,106.76,103.84,97.15,66.80,63.31,57.55,55.90,53.89,18.85,18.14 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 625.2095, found 625.2046.
Example 7
(6- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
Synthetic method referring to example 3, yield 38.1% and nuclear magnetic characterization data as follows: 1 H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J＝9.5,4.1Hz,1H),8.73(d,J＝11.2Hz,2H),8.36–8.28(m,1H),8.19(s,1H),7.98(dd,J＝5.9,1.4Hz,2H),7.51(s,1H),6.64(s,2H),6.55(dd,J＝5.9,2.2Hz,1H),6.18(d,J＝2.1Hz,1H),4.42(t,J＝5.7Hz,3H),3.87(s,3H),3.71(d,J＝4.6Hz,4H),2.77(d,J＝5.7Hz,2H),2.55(s,4H),2.12(d,J＝14.3Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ167.47,165.43,157.21,155.89,155.80,149.30,148.63,147.90,143.35,142.96,132.96,132.94,126.82,126.73,126.50,119.87,112.61,108.01,107.17,103.99,97.23,66.71,63.18,57.55,55.97,53.85,20.76,20.03.
example 8
5-chloro-N 4 - (1- (ethylsulfonyl) -1H-indol-3-yl) -N 2 - (2-methoxy-4- ((2- (2-morpholinoethoxy) pyridin-4-yl) oxy) phenyl) pyrimidine-2, 4-diamine
Synthetic method referring to example 4, yield 22.4% and nuclear magnetic characterization data as follows: 1 H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40(s,2H),7.97(dd,J＝12.6,7.0Hz,2H),7.76(s,1H),7.47–7.32(m,2H),6.67(dd,J＝4.7,2.3Hz,2H),6.56(dd,J＝5.9,2.2Hz,1H),6.20(d,J＝2.1Hz,1H),4.45(t,J＝5.6Hz,2H),3.89(s,3H),3.76–3.70(m,4H),3.41(q,J＝7.4Hz,2H),2.81(t,J＝5.6Hz,2H),2.60(d,J＝4.7Hz,4H),1.29(t,J＝7.4Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.46,165.36,158.18,157.90,156.95,149.31,148.80,147.91,134.87,130.45,128.73,126.34,125.54,124.05,123.38,119.73,118.15,116.52,112.94,112.72,107.28,103.94,97.28,66.55,63.04,57.50,56.01,53.79,49.01,8.12.
example 9
5-chloro-N 2 - (2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) -N 4 -phenylpyrimidine-2, 4-diamine
Synthetic method referring to example 1, 60.8% yield, nuclear magnetic characterization and high resolution mass spectrometryThe data are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.26(d,J＝8.5Hz,1H),8.03(s,1H),7.97(d,J＝5.8Hz,1H),7.59–7.46(m,3H),7.33(t,J＝7.7Hz,2H),7.14(d,J＝11.0Hz,2H),6.62–6.48(m,3H),6.19(s,1H),4.42(t,J＝5.4Hz,2H),3.80(s,3H),2.89(t,J＝5.4Hz,2H),2.64(s,4H),1.78(s,4H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.54,165.42,157.58,155.84,154.25,149.01,148.21,147.84,137.73,128.85,126.58,124.56,122.30,119.72,112.57,107.14,105.02,103.73,97.19,64.50,55.87,54.88,54.48,23.40 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 533.2068, found 533.2021
Example 10
(2- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine
Synthetic method referring to example 2, 59.2% yield, nuclear magnetic characterization and high resolution mass spectrometry data were as follows: 1 H NMR(400MHz,Chloroform-d)δ10.77(s,1H),8.45(dd,J＝8.4,4.3Hz,1H),8.23(d,J＝9.4Hz,1H),7.99(s,1H),7.87(d,J＝5.9Hz,1H),7.40(d,J＝19.0Hz,2H),7.23–7.12(m,1H),7.06–6.96(m,1H),6.56–6.49(m,2H),6.46–6.39(m,1H),6.11(d,J＝2.1Hz,1H),4.34(t,J＝5.7Hz,2H),3.73(s,3H),2.79(s,2H),2.55(s,4H),1.71(d,J＝13.2Hz,10H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.52,165.40,157.37,155.98,154.91,149.19,148.38,147.87,143.65,132.28,129.63,126.71,123.24,122.68,121.09,119.84,112.52,107.19,106.84,103.86,97.25,64.32,55.93,54.87,54.48,23.42,18.90,18.19 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 609.2146, found 609.2089.
Example 11
(6- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
Synthetic method referring to example 3, 50.6% yield, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ12.70(s,1H),9.07(dd,J＝9.5,4.1Hz,1H),8.69(d,J＝9.7Hz,2H),8.25(d,J＝9.4Hz,1H),8.11(s,1H),8.06(d,J＝9.5Hz,1H),7.90(d,J＝5.9Hz,1H),7.48(s,1H),6.62–6.57(m,2H),6.51(s,1H),6.15(d,J＝2.2Hz,1H),4.71–4.62(m,2H),3.82(s,3H),3.37–3.30(m,2H),3.20(s,4H),2.06(d,J＝14.2Hz,6H),1.99(s,4H). 13 C NMR(101MHz,CDCl 3 )δ167.62,164.28,157.11,155.79,155.67,149.31,148.71,148.42,147.92,143.77,143.72,143.49,143.05,139.11,139.05,132.90,128.76,126.67,126.59,126.46,125.79,119.82,112.43,111.51,107.89,107.68,103.89,97.16,61.74,56.00,54.27,53.91,23.23,20.71,19.98.
example 12
5-chloro-N 4 - (1- (ethylsulfonyl) -1H-indol-3-yl) -N 2 - (2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) pyrimidine-2, 4-diamine
Synthetic method referring to example 4, 51.5% yield, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ8.51–8.45(m,2H),8.39(d,J＝7.2Hz,2H),7.96(dd,J＝7.0,3.5Hz,2H),7.76(s,1H),7.45–7.32(m,2H),6.70–6.64(m,2H),6.58(dd,J＝5.9,2.2Hz,1H),6.21(d,J＝2.1Hz,1H),4.75(t,J＝5.1Hz,2H),3.91(s,3H),3.48–3.18(m,8H),2.07(s,4H),1.29(t,J＝7.4Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.69,164.30,158.18,157.90,156.99,149.34,148.67,147.98,134.87,130.44,128.71,126.46,125.56,124.05,123.33,119.67,118.20,116.51,112.95,112.65,107.83,103.90,97.27,61.59,56.07,54.24,53.93,49.02,23.29,8.11,1.00.
example 13
5-chloro-N 2 - (2-methoxy-4- ((2- (2- (piperidin-1-yl)) 2)) Ethoxy) pyridin-4-yl) oxy) phenyl) -N 4 -phenylpyrimidine-2, 4-diamine
Synthetic method referring to example 1, 46.4% yield, nuclear magnetic characterization and high resolution mass spectrometry data were as follows: 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J＝8.7Hz,1H),8.05(s,1H),7.98(d,J＝5.9Hz,1H),7.58–7.54(m,2H),7.49(s,1H),7.38–7.32(m,3H),7.18–7.10(m,4H),6.60(t,J＝2.8Hz,2H),6.52(dd,J＝5.9,2.2Hz,1H),6.19(d,J＝2.2Hz,1H),4.42(s,2H),3.82(s,3H),2.74(s,2H),2.50(s,5H),1.60(d,J＝5.6Hz,4H),1.42(d,J＝5.1Hz,2H). 13 C NMR(101MHz,CDCl 3 ) Delta 167.48,165.56,157.66,155.87,154.29,149.07,148.35,147.89,137.78,128.85,128.60,126.60,124.55,122.28,119.92,119.80,112.56,107.05,103.75,97.20,63.54,57.75,55.88,53.48,25.67,24.10 high resolution Mass Spectrometry HRMS (ESI) M/z calculated [ M+H ]] + 547.2224, found 547.2161.
Example 14
(2- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (piperidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine
Synthetic method referring to example 2, 40.3% yield, nuclear magnetic characterization and high resolution mass spectrometry data were as follows: 1 H NMR(400MHz,Chloroform-d)δ10.79(s,1H),8.49(dd,J＝8.5,4.4Hz,1H),8.27(d,J＝9.5Hz,1H),8.04(s,1H),7.92(d,J＝5.9Hz,1H),7.44(s,2H),7.22(ddd,J＝14.0,7.7,1.6Hz,1H),7.06(dd,J＝7.6,2.2Hz,1H),6.57(d,J＝6.7Hz,2H),6.47(dd,J＝5.7,2.2Hz,1H),6.13(d,J＝2.2Hz,1H),4.36(d,J＝5.9Hz,2H),3.78(s,3H),2.69(s,3H),2.45(s,4H),1.76(d,J＝13.1Hz,6H),1.53(d,J＝5.6Hz,5H),1.35(s,2H). 13 C NMR(101MHz,CDCl 3 )δ167.72,164.43,157.34,155.99,154.80,149.27,148.28,147.94,147.78,143.62,132.23,12972,126.80,123.08,122.70,121.07,119.89,112.45,107.64,106.93,103.83,97.11,61.12,56.51,55.97,53.92,23.42,22.42,18.92,18.21 high resolution mass spectrum HRMS (ESI) M/z calculated [ M+H ]] + 623.2302, found 623.2257.
Example 15
(6- ((5-chloro-2- ((2-methoxy-4- ((2- (2- (piperidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
Synthetic method referring to example 3, 42.5% yield, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ12.76(s,1H),9.14(dd,J＝9.5,4.1Hz,1H),8.79–8.69(m,2H),8.32(d,J＝8.4Hz,1H),8.20(s,1H),8.16–8.12(m,1H),7.99(d,J＝6.0Hz,1H),7.51(s,1H),6.66(d,J＝8.1Hz,2H),6.54(dd,J＝5.8,2.1Hz,1H),6.18(d,J＝2.2Hz,1H),4.42(t,J＝5.9Hz,3H),3.87(s,3H),3.64(s,3H),2.76(s,3H),2.52(s,5H),2.13(d,J＝14.3Hz,6H),1.62–1.57(m,5H),1.43(d,J＝6.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.43,165.47,157.24,155.90,155.81,149.31,148.91,148.71,147.94,143.81,143.34,142.97,139.28,132.99,126.83,126.47,119.91,112.61,108.01,107.11,103.99,97.25,63.31,57.60,55.97,54.66,25.47,23.96,20.77,20.04.
example 16
5-chloro-N 4 - (1- (ethylsulfonyl) -1H-indol-3-yl) -N 2 - (2-methoxy-4- ((2- (2- (piperidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) pyrimidine-2, 4-diamine
Synthetic method referring to example 4, yield 38.8% and nuclear magnetic characterization data as follows: : 1 H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40–8.36(m,2H),7.98–7.93(m,2H),7.76(s,1H),7.39(dddd,J＝28.0,8.2,7.2,1.2Hz,2H),6.67(dd,J＝4.6,2.3Hz,2H),6.57(dd,J＝5.9,2.1Hz,1H),6.19(d,J＝2.1Hz,1H),4.76(t,J＝5.0Hz,2H),3.90(s,3H),3.42(q,J＝7.3Hz,2H),3.27(t,J＝5.0Hz,2H),3.06(s,3H),1.96(s,4H),1.58(s,2H),1.28(d,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.68,164.30,158.17,157.89,156.99,149.33,148.66,148.00,134.87,130.45,128.71,126.46,125.55,124.03,123.32,119.66,118.21,116.49,112.95,112.66,107.79,103.89,97.21,60.80,56.35,56.06,53.82,49.03,23.14,22.24,8.11.
example 17
(2- ((5-bromo-2- ((2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine
Synthetic method referring to example 10, yield 38.8% and nuclear magnetic characterization data as follows: 1 H NMR(400MHz,Chloroform-d)δ10.62(s,1H),8.45(dd,J＝8.5,4.3Hz,1H),8.34(d,J＝8.6Hz,1H),8.24–8.20(m,1H),7.97(d,J＝5.9Hz,1H),7.54–7.45(m,2H),7.34–7.26(m,1H),7.16–7.06(m,1H),6.65–6.58(m,2H),6.55(dd,J＝5.9,2.2Hz,1H),6.19(s,1H),4.56(t,J＝5.4Hz,2H),3.86(s,3H),3.09(d,J＝5.9Hz,2H),2.90(s,4H),1.91(s,4H),1.83(d,J＝13.1Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ167.61,165.02,157.92,157.84,156.80,149.16,148.31,147.90,143.57,143.55,132.16,132.13,129.58,129.48,126.73,123.69,123.62,122.98,122.86,121.64,120.69,119.80,112.53,107.40,103.84,97.22,95.45,63.35,55.95,54.51,54.34,23.38,18.80,18.09,0.99.
example 18
(6- ((5-bromo-2- ((2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine
Synthetic method referring to example 11, yield 35.6%, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ12.57(s,1H),8.98(dd,J＝9.5,4.1Hz,1H),8.73(dd,J＝14.8,1.9Hz,2H),8.29(s,2H),8.12(d,J＝9.5Hz,1H),7.97(d,J＝5.9Hz,1H),7.53(s,1H),6.62(d,J＝7.6Hz,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.18(d,J＝2.2Hz,1H),4.53(t,J＝5.5Hz,2H),3.86(s,3H),3.05(t,J＝5.6Hz,2H),2.85(s,4H),2.12(d,J＝14.3Hz,6H),1.88(s,4H). 13 C NMR(101MHz,CDCl 3 )δ167.52,165.09,158.76,157.67,156.75,149.25,148.93,148.91,148.58,147.92,143.86,143.81,143.32,142.99,139.34,139.27,132.75,132.73,127.12,127.03,126.47,119.81,112.77,112.60,111.87,107.34,103.96,97.26,96.61,63.54,55.98,54.58,54.35,23.38,20.77,20.04.
example 19
5-bromo-N 4 - (1- (ethylsulfonyl) -1H-indol-3-yl) -N 2 - (2-methoxy-4- ((2- (2- (pyrrolidin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl) pyrimidine-2, 4-diamine
Synthetic method referring to example 12, 37.1% yield, nuclear magnetic characterization data were as follows: 1 H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.47(d,J＝8.5Hz,1H),8.38(s,1H),8.26(d,J＝7.9Hz,1H),8.00–7.91(m,2H),7.79(s,1H),7.38(d,J＝28.2Hz,2H),6.65(d,J＝9.7Hz,2H),6.56(dd,J＝5.8,2.0Hz,1H),6.20(d,J＝2.1Hz,1H),4.83–4.69(m,2H),3.89(s,3H),3.42(t,J＝7.1Hz,4H),3.32(s,2H),2.09(d,J＝3.4Hz,4H),1.28(t,J＝7.4Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.67,164.20,160.79,158.34,158.26,149.31,148.67,147.97,134.89,130.11,128.71,126.40,125.51,123.99,123.03,119.62,117.65,112.99,112.64,107.86,107.04,103.88,97.30,61.31,56.08,54.18,53.80,49.02,23.27,8.14.
test example 1, test of MTT method cell proliferation inhibition Activity
In vitro cell proliferation inhibition experiments used the MTT method, the following 5 cell lines were used: baF3_EGFR dTC (dTC represents del19/T790M/C797S triple mutation), baF3_EGFR LTC (LTC stands for L8585R/T790M/C797S triple mutation), H1975 (L858R/T790M mutation of EGFR), H820 (del 19/T790M mutation of EGFR), A549 (EGFR wild type).
Wherein the two types of BaF3 cells are suspension cells, and are prepared by using PRIM-1640 culture solution containing 10% fetal bovine serum (volume fraction) and 1% puro, and ethyl 5% CO at 37deg.C 2 (volume fraction) conventional culture under conditions. .
The other are adherent cells, wherein A549 uses F12K culture solution containing 10% fetal bovine serum by volume fraction, and H1975 and H820 use PRIM-1640 culture solution containing 10% fetal bovine serum.
The specific operation is as follows:
all compounds were prepared as DMSO (dimethyl sulfoxide) solutions at a concentration of 10mM, and then a series of compound solutions with gradually decreasing concentrations were obtained by a gradient dilution method.
Culturing cells, taking cells in logarithmic phase, counting tumor cells at 1.2X10 per well 4 -1.5×10 4 Individual (suspension cells) or 6X 10 3 -9×10 3 Density dilution of individual (adherent cells) followed by addition of 99. Mu.L of cell-containing medium was seeded in 96-well plates. The following is a dosing step, which is performed after plating for 4 hours for suspension cells; for adherent cells, the cells are required to be dosed after adherence, generally 12-16 hours after plating. Then 1. Mu.L of the compound solution was added to each well, so that the final concentration of the compound was 100-fold diluted with the original concentration, 3 wells were provided for each concentration, and IC 50 8-9 concentration gradients were set during the test. Simultaneously adding two positive medicine groups, namely a first-generation EGFR inhibitor Gefininib and Brigerinib with triple-mutation EGFR inhibition activity; and control and blank groups were set, both with 1 μl of pure DMSO solution. After 3 days of incubation of all treated cells, 10. Mu.L of 5mg/mL MTT in PBS was added to each well of the compound group and the control group, and the blank group was not added. The culture was then continued for 4 hours. Then the suspension cells need to be centrifuged in line, and the adherent cells do not need to be centrifuged; the medium of each well was aspirated and 100. Mu.L of DMSO solution was added; respectively oscillating on the micro-oscillator for 5 minutesThe clock and the cradle are rocked for 5 minutes; finally, an enzyme-labeled instrument is used for testing the OD value at 490nm, so that the inhibition rate (Inh%) of the compound on tumor cells at different concentrations is calculated, and then the IC is obtained by drawing an inhibition rate-concentration curve 50 Values. As shown in Table 1, it can be seen that most of the compounds have a certain tumor cell inhibitory activity, wherein the compounds 11, 12, 17, 18, etc. have good inhibitory activity on most of the tumor cells, and IC thereof 50 The values reached micromolar.
The inhibition rate formula is as follows: inh% = (control OD 490 Experimental group OD 490 ) /(control OD) 490 Blank OD 490 )×100％。
After the experiment, the in vitro cell proliferation inhibition activity of the compound prepared by the invention is obtained, and the results are shown in tables 1 and 2.
Table 1 in vitro tumor cell proliferation inhibitory Activity of the Compounds prepared in the examples
TABLE 2 in vitro tumor cell proliferation inhibiting Activity of the Compounds prepared in part of the examples
Note that: IC (integrated circuit) 50 Represents half inhibition concentration
Test example 2 EGFR enzyme inhibitory Activity assay
EGFR was used as a subject for testing the inhibitory activity of compounds against the L858R/T790M/C797S subtype and the wild type, which was in cooperation with Shanghai Ming Zhi Shi research Co., ltd and Murdaya medical technology (Shanghai) Co., ltd, using the Mobility Shift Assay method (instrument mobility modification method). The basic operation flow is as follows: firstly preparing a compound into a compound solution by using a buffer solution, and transferring the compound solution into a micro-pore plate; preparing kinase solution by using buffer solution, adding the kinase solution into compound lease and positive control lease, and adding the buffer solution into negative control group; reacting for 10 minutes at room temperature; preparing ATP and a substrate into a mixed solution by using a buffer solution, and dripping the mixed solution into each group; reacting for 60 minutes at room temperature; preparing a reaction stopping solution by using a buffer solution, and adding the reaction stopping solution into each group; data were read using a Caliper instrument and inhibition was calculated.
TABLE 3 EGFR for all examples LTC Enzyme inhibition Activity
TABLE 4 EGFR of some examples wt Enzyme inhibition Activity
TABLE 5 EGFR of some examples LTC Enzyme inhibition Activity
Test example 3 ALK enzyme inhibitory Activity assay
The ALK inhibition activity test cooperates with the Sandinia medical technology (Shanghai) Limited liability company, and adopts a Mobility Shift Assay method (instrument mobility change method) to test ALK target inhibition activity. The test method is substantially identical to the EGFR enzyme inhibitory activity test.
Table 6 ALK enzyme inhibitory activity of the examples
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described.

Claims (9)

1. 2-anilinopyrimidine derivatives or pharmaceutically acceptable salts thereof, wherein the 2-anilinopyrimidine derivatives are compounds shown in a formula I;
the compound shown in the formula I is selected from any one of the following:
。
2. the 2-anilinopyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;
the inorganic acid salt is selected from any one of the following inorganic acid salts: hydrochloric acid, sulfuric acid, and phosphoric acid;
the organic acid salt is selected from any one of the following organic acid salts: acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.
3. A process for the preparation of a 2-anilinopyrimidine derivative according to any one of claims 1 to 2, comprising the steps of:
reacting a compound shown in a formula IA with a compound shown in a formula IB in a solvent under an acidic condition to obtain a compound shown in a formula I:
R 1 、R 2 、R 3 x, Y and Z are as defined in claim 1.
4. Use of a 2-anilinopyrimidine derivative according to any one of claims 1 to 2 for the preparation of the following products:
1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) Eukaryotic tumor cell proliferation inhibitors;
4) An inhibitor of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
5. The use according to claim 4, wherein,
the Epidermal Growth Factor Receptor (EGFR) is EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR (epidermal growth factor receptor) del19/T790M/C797S At least one of (a) and (b);
the Anaplastic Lymphoma Kinase (ALK) is ALK wt 、ALK L1196M And at least one of EML 4-ALK;
the eukaryote is a mammal;
the tumor cells are cancer cells; the cancer cells are leukemia cancer cells, lymphoma cells, lung cancer cells, breast cancer cells, ovarian cancer cells, cervical cancer cells, human brain glioma cells, melanin cancer cells, glioblastoma cells, nasopharyngeal cancer cells, liver cancer cells, brain cancer cells, pancreatic cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells;
the tumor is a carcinoma.
6. The use according to claim 5, wherein,
the leukemia cancer cells are human Chronic Myelogenous Leukemia (CML) cell line K562;
the lymphoma cell is human histiocyte lymphoma cell U937;
the lung cancer cell is a human lung cancer cell strain HCC827;
the breast cancer cells are human breast cancer cells MCF-7, T47D and MDA-MB-231;
the ovarian cancer cell is A2780;
the cervical cancer cells are human cervical cancer cell line Hela;
the human brain glioma cell is U251;
the melanocyte is A375;
the glioblastoma cells are human glioblastoma cell A172 and human brain astrocyte tumor cell U-118MG;
the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell line CNE-2;
the liver cancer cell is human liver cancer cell HepG2;
the cancer is leukemia, lymphoma, lung cancer, melanin cancer, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.
7. A product comprising the 2-anilinopyrimidine derivative according to any one of claims 1 to 2 as an active ingredient; the product is at least one of the following:
1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) Eukaryotic tumor cell proliferation inhibitors;
4) An inhibitor of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
8. The product of claim 7, wherein,
the Epidermal Growth Factor Receptor (EGFR) is EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR (epidermal growth factor receptor) del19/T790M/C797S At least one of (a) and (b);
the Anaplastic Lymphoma Kinase (ALK) is ALK wt 、ALK L1196M And at least one of EML 4-ALK;
the eukaryote is a mammal;
the tumor cells are cancer cells; the cancer cells are leukemia cancer cells, lymphoma cells, lung cancer cells, breast cancer cells, ovarian cancer cells, cervical cancer cells, human brain glioma cells, melanin cancer cells, glioblastoma cells, nasopharyngeal cancer cells, liver cancer cells, brain cancer cells, pancreatic cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells;
the tumor is a carcinoma.
9. The product of claim 8, wherein,
the leukemia cancer cells are human Chronic Myelogenous Leukemia (CML) cell line K562;
the lymphoma cell is human histiocyte lymphoma cell U937;
the lung cancer cell is a human lung cancer cell strain HCC827;
the breast cancer cells are human breast cancer cells MCF-7, T47D and MDA-MB-231;
the ovarian cancer cell is A2780;
the cervical cancer cells are human cervical cancer cell line Hela;
the human brain glioma cell is U251;
the melanocyte is A375;
the glioblastoma cells are human glioblastoma cell A172 and human brain astrocyte tumor cell U-118MG;
the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell line CNE-2;
the liver cancer cell is human liver cancer cell HepG2;
the cancer is leukemia, lymphoma, lung cancer, melanin cancer, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.
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