CN115448906A - 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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CN115448906A
CN115448906A CN202211174061.0A CN202211174061A CN115448906A CN 115448906 A CN115448906 A CN 115448906A CN 202211174061 A CN202211174061 A CN 202211174061A CN 115448906 A CN115448906 A CN 115448906A
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CN115448906B (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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Abstract

The invention belongs to the field of medicines, and relates to a 2-anilinopyrimidine derivative as well as 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 molecules thereof. Experiments show that the compound shown in the formula I has certain inhibitory activity on epidermal growth factor receptors, can effectively inhibit the proliferation of various tumor cells, and has the potential of being developed as 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 (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) inhibitory activity, and a preparation method and application thereof.
Background
The principle of the tumor molecule targeted therapy is a treatment method for selectively killing tumor cells by inhibiting key factors or proteins closely related to the growth and development of tumors through a targeted chemical or biological means. Compared with the traditional anticancer micromolecular drugs, the tumor targeted drug has the characteristics of strong pertinence, relatively less side effect, good treatment effect and the like, so that the tumor targeted drug is widely concerned, and the targeted treatment of the tumor is one of the development trends of the tumor treatment.
Epidermal Growth Factor Receptor (EGFR), a receptor-type tyrosine protein kinase, plays an important role in life activities such as proliferation, differentiation, apoptosis, angiogenesis, etc., and is also found to be over-activated or continuously activated in various tumor cells such as lung cancer, breast cancer, and prostate cancer. Among them, mutations of EGFR are one of the most important drivers in lung cancer patients, and the mutation rate thereof reaches more than 50% in asian people. Gefitinib (Gefitinib), a small molecule inhibitor of EGFR, marketed in 2003, is used in the treatment of advanced non-small cell lung cancer (NSCLC), and is now also commonly used as a first-line drug for NSCLC patients with EGFR mutations.
EGFR inhibitors have been developed to date according to the marketed drug for three generations. The first generation of EGFR includes the aforementioned Gefitinib and Erlotinib, icintinib, etc., which is directed to NSCLC patients with EGFR having L858R or del19 mutation, and has significant clinical effect. However, some patients can generate drug resistance after 10-12 months of drug use, and can be found to mainly generate T790M mutation through gene sequencing and the like, and more than 50 percent of drug-resistant patients generate T790M secondary mutation. To address the drug resistance problem of first generation inhibitors, second generation EGFR inhibitors have been developed. The second generation of inhibitors belong to the group of irreversible inhibitors, which act on wild-type EGFR (EGFR) wt ) Also has strong inhibiting effect, thus having high toxicity. Second-generation EGFR inhibitors including Afatinib and dacatinib have been marketed, but the problem of drug resistance caused by T790M mutation cannot be solved well at the clinical Maximum Tolerated Dose (MTD). The third-generation EGFR inhibitor really solves the problem of drug resistance caused by the T790M mutation, and the American FDA accelerated approval of marketed Oxititinib (Osimetinib) is obtained 11 months in 2015, so that the third-generation EGFR inhibitor can be clinically and effectively used for treating NSCLC patients with drug resistance caused by the T790M mutation, and has great success. However, the new drug resistance phenomenon of part of beneficial patients after 9-14 months of treatment is inevitable, and researches show that 20-40% of patients have drug resistance of the Osimertinib due to the C797S point mutation. The C797S point mutation refers to the conversion of cysteine at position 797 of EGFR into serine, and position 797 is one of important sites for covalent binding of the Osimetinib and the EGFR, so that the two cannot be combined, and finally the drug resistance of the Osimetinib is caused. Currently, no EGFR inhibitor aiming at C797S mutation is on the market, so that an EGFR inhibitor with high selectivity for C797S is urgently needed to solve the problem of drug resistance of the third-generation inhibitor.
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 promotes dimerization of ALK, so that related signal pathways are continuously activated, and occurrence and development of cancer are promoted. In 2.9% of smoking patients with NSCLC, the EML4-ALK gene fusion mutation occurs; in patients without smoking, 9.4% of the patients developed the EML4-ALK mutation, and therefore ALK is also one of the major types of mutations other than EGFR mutation. With the development of gene sequencing technology, the simultaneous occurrence of EGFR and ALK rearrangements is continuously discovered. The literature reports that 2 patients have EML4-ALK fusion mutation after gene sequencing of 14 patients with drug resistance to oxitinib, and the suggestion that the EGFR/ALK double-target inhibitor can be used for target drug treatment of lung cancer in the future and has certain potential for solving the drug resistance problem of EGFR.
Disclosure of Invention
The invention aims to provide a 2-anilinopyrimidine derivative inhibitor with EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) inhibitory activity and a preparation method thereof.
In order to achieve the above objects, the present invention provides a 2-anilinopyrimidine derivative, wherein the 2-anilinopyrimidine derivative is a compound represented by formula I, or a pharmaceutically acceptable salt or tautomer thereof, or a prodrug molecule thereof;
Figure BDA0003864594330000031
wherein:
R 1 is composed of
Figure BDA0003864594330000032
R 2 Is composed of
Figure BDA0003864594330000033
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 and Z are each independently CH or N. Preferably, X is N, Y and Z are 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 salts formed by any one of the following inorganic acids: hydrochloric acid, sulfuric acid, and phosphoric acid; the organic acid salt is selected from salts formed by any one of the following organic acids: acetic acid, trifluoroacetic acid, malonic acid, citric acid, and p-toluenesulfonic acid.
The compounds of the invention may exist in different polymorphic forms.
According to a preferred embodiment of the invention, the compound of formula I is selected from any one of the following:
Figure BDA0003864594330000034
Figure BDA0003864594330000041
Figure BDA0003864594330000051
the invention also provides a preparation method of the 2-anilinopyrimidine derivative, which comprises the following steps:
reacting a compound shown as a formula IA with a compound shown as a formula IB in a solvent under an acidic condition to obtain a compound shown as a formula I:
Figure BDA0003864594330000052
R 1 、R 2 、R 3 x, Y and Z are as defined in claim 1.
More specifically, the compound can be prepared according to the following reaction route:
Figure BDA0003864594330000053
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:
step a) a compound shown in formula Ia and a fluorine-containing aromatic ring are subjected to substitution reaction under alkaline conditions to obtain a compound shown in formula Ib. Preferably, the reaction takes N, N-dimethylformamide as a solvent and cesium carbonate as an alkali 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 anhydrous ethanol; the catalyst is 10% palladium carbon; the reaction temperature is room temperature; the reaction time was 6 hours.
Step c) nucleophilic substitution reaction of the compound of formula Ic with the terminal hydroxyl group of the corresponding ethanol derivative containing aliphatic heterocycle under alkaline condition to obtain the compound of formula Id. Preferably, the base required for the reaction is sodium hydride; the reaction is carried out in absolute ethyl alcohol; the reaction temperature is 0 ℃; the reaction time is 8-12 hours.
Step d) reacting a compound of formula Ie with a corresponding compound comprising 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 one or more selected from triethylamine, diisopropylethylamine, aqueous ammonia, 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 synthesis and intermediates, the compounds are commercially available or can be prepared using standard methods or using commercially available compounds using the extended methods of the examples herein.
It is a further object of the present invention to provide the use of compounds of formula I and pharmaceutically acceptable salts thereof. Specifically, the 2-anilinopyrimidine derivative can be applied to preparation of the following products:
1) Epidermal Growth Factor Receptor (EGFR) inhibitors;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) An inhibitor of proliferation of eukaryotic tumor cells;
4) Eukaryotic tumor cell metastasis inhibitors;
5) An angiogenesis inhibitor;
6) A medicine for preventing and/or treating tumor.
The Epidermal Growth Factor Receptor (EGFR) includes but is not limited to EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR del19/T790M/C797S At least one of them.
The Anaplastic Lymphoma Kinase (ALK) includes but is not limited to ALK wt 、ALK L1196M And 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 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 stomach cancer cell, a colon cancer cell, a bladder cancer cell, or a rectal cancer cell.
The leukemia cancer cells are human Chronic Myelogenous Leukemia (CML) cell line K562; the lymphoma cells are human histiocyte lymphoma cells U937; the lung cancer cell is specifically a 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 cell is specifically a human cervical cancer cell line Hela; the human brain glioma cell is specifically U251; the melanoma cancer cell is specifically A375; the glioblastoma cells are specifically a human glioblastoma cell A172 and a human brain astrocytoma cell U-118MG; the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell strain CNE-2; the liver cancer cell is a specific human liver cancer cell HepG2.
The tumor is cancer, specifically leukemia, lymphoma, lung cancer, melanoma, glioblastoma, cervical cancer, nasopharyngeal carcinoma, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, stomach cancer, colon cancer, bladder cancer or rectal cancer.
The invention also provides a product, wherein the active ingredient of the product is the 2-anilinopyrimidine derivative; the product is at least one of the following:
1) Epidermal Growth Factor Receptor (EGFR) inhibitors;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) An inhibitor of proliferation of eukaryotic tumor cells;
4) Inhibitors of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
The definition of each product is the same as that of the previous product, and the description is omitted.
The compound shown in the structural formula I or the pharmaceutically acceptable salt thereof can also be used for preparing medicaments for preventing and/or treating tumors. The medicine for preventing and/or treating tumor, which is prepared by taking the compound shown in the structural formula I or the pharmaceutically acceptable salt thereof as the effective component, 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 by using the compound shown in the formula I or a pharmaceutically acceptable salt thereof, can be introduced into the body such as muscle, intradermal, subcutaneous, vein and mucosal tissues by injection, spraying, nasal drip, eye drop, penetration, absorption, physical or chemical mediated methods; or mixed or coated with other materials and introduced into body.
If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The medicine prepared from the compound shown in the structural formula I or the pharmaceutically acceptable salt thereof for preventing and/or treating tumors can be prepared into various forms such as injection, tablets, powder, granules, capsules, oral liquid, ointment, cream and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
Tests prove that the compound provided by the invention can inhibit the growth of various tumor cells and inhibit the generation of EGFR family protease, and particularly can effectively inhibit the activity of EGFR protein kinase drug-resistant mutants, such as EGFR del19/T790M/C797S And EGFR L858R/T790M/C797S The clinical drug resistance of NSCLC patients induced by the existing third-generation EGFR inhibitor drugs such as the Osimertinib and the like can be overcome. For ALK at the same time wt Has good inhibition effect. The compound provided by the invention has the advantages of easily available raw materials and simple preparation method, and experiments prove that the compound has a good anticancer effect and has a good application prospect in the field of design and research of antitumor drugs.
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 following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
The experimental methods described in the following examples are all conventional methods for organic synthesis unless otherwise specified; the reagents and biological materials are commercially available, unless otherwise specified.
Example 1
5-chloro-N 2 - ((2- (2- (4-methylpiperazin-1-yl) ethoxy) pyridin-4-yl) oxy) phenyl-N 4 -phenylpyrimidine-2, 4-diamine
Figure BDA0003864594330000091
Example 1A
2-fluoro-4- (3-methoxy-4-nitrophenoxy) pyridine
Figure BDA0003864594330000092
2, 4-difluoropyridine (0.500g, 4.34mmol) was dissolved in 25mL of N, N-dimethylformamide, and cesium carbonate (2.831g, 8.68mmol) and 3-methoxy-4-nitrophenol (0.73g, 4.34mmol) were added, and the temperature was raised to 90 ℃ for 24 hours. After the reaction, ethyl acetate and water were used for extraction, the organic layer was extracted with a 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 with a yield of 73.7%. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000093
Example 1A (0.841g, 3.18mmol) was dissolved in 10mL of anhydrous ethanol, and 10% palladium on carbon reagent (0.170 g, 20% of the starting material) containing 55% water was added, and the reaction was repeated several times by replacing the air with hydrogen to ensure complete replacement of the hydrogen, and at room temperature for 6 hours. After the reaction is finished, the excessive palladium-carbon is removed by filtering with diatomite,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. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000101
1-hydroxyethyl-4-methylpiperazine (0.389g, 2.69mmol) was dissolved in 8mL of N, N-dimethylformamide, and after stirring for 10 minutes in an ethanol solution at 0 ℃, 60% sodium hydride (0.112g, 2.81mmol) was added, and after stirring for 20 minutes, the temperature was slowly raised, and after 1 hour, example 1B (0.547g, 2.25mmol) was dissolved in 4mL of N, N-dimethylformamide and added to the reaction mixture, and when the temperature was raised to room temperature, the mixture was allowed to stand overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate several times, and the organic layer was collected and purified by silica gel column chromatography to obtain 0.572g of a pale yellow oily product with a yield of 71.1%. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000102
2,4, 5-trichloropyrimidine (0.500g, 2.73mmol) was dissolved in 5mL of dimethyl sulfoxide, a small amount of tetrabutylammonium iodide was added and the solution was allowed to changeAfter the yellow color, aniline (0.281g, 3.00mmol) and triethylamine (0.302g, 3.00mmol) were added, and the temperature was raised to 80 ℃ for overnight reaction. After the reaction, the aqueous layer was extracted with ethyl acetate and water, and the aqueous layer was repeatedly extracted with ethyl acetate several times, the organic layer was collected, and the product was separated by a silica gel column to obtain 0.455g of a yellow solid product with a yield of 85.1%. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000111
Example 1C (0.171g, 0.477 mmol), example 1D (0.137g, 0.572mmol) and other reagents including tris (dibenzylideneacetone) dipalladium (0.022g, 2.39x10-3 mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (0.030g, 47.7 x10 mmol) -3 mmol) and potassium tert-butoxide (0.077g, 0.687mmol) were placed in a sealed tube under argon and 5mL of 1, 4-dioxane were added and degassed by bubbling argon through the solution. The reaction is carried out for 24 hours at the temperature of 120 ℃, after the reaction is finished, ethyl acetate and water are used for extraction, the organic layer is collected, the product is separated by a silica gel column method, 0.151g of light yellow solid product is collected, and the yield is 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, calculated high resolution mass spectrometry HRMS (ESI) M/z [ 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) dimethyloxyphosphorus
Figure BDA0003864594330000121
Example 2 the synthesis method is basically the same as that of example 1, the phenylamino in example 1D is changed into 2- (dimethylphosphite) aniline, and the rest of the synthesis steps and conditions are basically the same as those of example 1. Nuclear magnetic characterization and high resolution mass spectrometry data were 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) calculated M/z [ M + H ] calculation] + 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) dimethyloxyphosphorus
Figure BDA0003864594330000122
Part of the synthetic route is as follows:
Figure BDA0003864594330000123
example 3A
5-iodo-6-aminoquinoxaline
Figure BDA0003864594330000131
Dissolving 6-aminoquinoxaline (0.100g, 0.689mmol) by using 5mL of 1, 4-dioxane water solution (4), firstly adding sodium bicarbonate (0.144g, 1.722mmol) and iodine (0.437g, 1.722mmol) at the temperature of 0 ℃, stirring for half an hour, and then transferring to the 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. Nuclear magnetic characterization data of compounds: 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-Dimethylphosphoryloxyquinoxaline-6-yl
Figure BDA0003864594330000132
Example 3A (0.100g, 0.37mmol), dimethylphosphine oxide (0.043 g, 0.55mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.021g, 0.037mmol), palladium acetate (0.008g, 0.037mmol) and potassium phosphate (0.117g, 0.550mmol) were placed in a lock tube under argon. After adding 2mL of N, N-dimethylformamide and 0.4mL of water, the mixture was again protected with argon, sealed and reacted at 120 ℃ overnight. After the reaction, the mixture was extracted with ethyl acetate and water, and the organic layer was collected and the product was separated by silica gel column chromatography to obtain 0.112g of a yellow solid product. Nuclear magnetic characterization data of compounds: 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) dimethyloxyphosphorus
Figure BDA0003864594330000141
Example 3C Synthesis procedure example 1D was followed, replacing aniline with example 3B, and the other reaction conditions were substantially the same as those for example 1D. Nuclear magnetic characterization data of compounds: 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) dimethyloxyphosphide
Figure BDA0003864594330000142
Example 1C (0.144g, 0.402mmol), example 3C (0.147g, 0.402mmol), p-toluenesulfonic acid monohydrate (0.153g, 0.804mmol) were dissolved in 6mL of 2-pentanol and reacted at 90 ℃ for 5 hours. After the reaction, the aqueous layer was extracted with ethyl acetate and water, and the organic layer was collected by collecting the aqueous layer and separating the product with a silica gel column to obtain 80mg of a yellow solid product. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000151
Part of the synthetic route is as follows:
Figure BDA0003864594330000152
example 4A
3- (2, 5-dichloropyrimidin-4-yl) -1H-indole
Figure BDA0003864594330000153
Indole (1.28g, 10.79mmol) was dissolved in 6mL of tetrahydrofuran, methyl magnesium bromide (3.37mL, 10.78mmol) was slowly added dropwise at 0 ℃ and stirred for 30 minutes; 2,4,5-trichloropyrimidine (1g, 5.4 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour, and after warming to 60 ℃, stirring 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 were added to yield a white solid, and the product was collected as 1.51g. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000161
Example 4A (0.100g, 0.379mmol) was dissolved in 1.5mL of tetrahydrofuran, sodium hydride (0.037g, 0.946mmol) was added at 0 deg.C, and ethylsulfonyl chloride (0.058g, 0.454mmol) was added after cooling was turned off for about 3 hours and overnight at room temperature. After the reaction, ethyl acetate and water were used for extraction, the organic layer was collected, and the product was separated by silica gel column chromatography to obtain 0.155g of a pale yellow solid product. Nuclear magnetic characterization data of compounds: 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
Figure BDA0003864594330000162
Synthesis of example 4 example 3 was followed, with example 3C being replaced by example 4B, and the other reaction conditions were substantially the same as those of the synthesis 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 -phenylpyrimidinesPyridine-2, 4-diamines
Figure BDA0003864594330000171
The synthesis was performed according to example 1, yield 61.2%. The nuclear magnetic characterization and high resolution mass spectrometry 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 ) Delta 167.57,165.49,157.64,155.89,154.28,149.08,148.28,147.86,137.75,128.88,126.63,124.60,122.31,119.80,112.60,107.16,105.08,103.77,97.17,66.83,63.32,57.58,55.90,53.92 calculated for high resolution mass spectrometry HRMS (ESI) M/z [ 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) dimethyloxyphosphorus (II) oxide
Figure BDA0003864594330000172
Synthetic methods reference example 2, yield 63.3%, nuclear magnetic characterization data is 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, HRMS (ESI) M/z calculated high resolution Mass Spectrometry [ M + H ] M/z] + 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) dimethyloxyphosphide
Figure BDA0003864594330000181
The synthesis was as in example 3 with a yield of 38.1% and the 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
Figure BDA0003864594330000191
Synthetic method reference example 4, yield 22.4%, nuclear magnetic characterization data is 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
Figure BDA0003864594330000192
The synthesis method referred to example 1, with a yield of 60.8%, the nuclear magnetic characterization and high resolution mass spectrometry data were 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 calculated high resolution mass spectrometry HRMS (ESI) M/z [ 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) dimethyloxyphosphorus
Figure BDA0003864594330000201
The synthesis method referred to example 2, yield 59.2%, nuclear magnetic characterization and high resolution mass spectrometry data 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) M/z calculation [ 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) dimethyloxyphosphide
Figure BDA0003864594330000202
Synthetic method reference example 3, 50.6% yield, nuclear magnetic characterization data 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
Figure BDA0003864594330000211
Synthetic method referenceExample 4, yield 51.5%, nmr 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) ethoxy) pyridin-4-yl) oxy) phenyl) -N 4 -phenylpyrimidine-2, 4-diamine
Figure BDA0003864594330000221
The synthesis method referred to example 1, with a yield of 46.4%, nuclear magnetic characterization and high resolution mass spectrometry data 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 (ESI) M/z calcd [ M + H H.M/Z calcd] + 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) dimethyloxyphosphorus (II) oxide)
Figure BDA0003864594330000222
The synthesis method is referred to example 2, the yield is 40.3%, and the nuclear magnetic characterization and high resolution mass spectrometry data are 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 ) Delta 167.72,164.43,157.34,155.99,154.80,149.27,148.28,147.94,147.78,143.62,132.23,129.72,126.80,123.08,122.70,121.07,119.89,112.45,107.64,106.93,103.83,97.11,61.12,56.51,55.97,53.92,23.42,22.42,18.92,18.21, high Resolution Mass Spectrometry (HRMS) M/z calculated [ M + H H.M.51, 55.97,53.92,23.42,22.42,18.92,18.21 ]] + 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) dimethyloxyphosphide
Figure BDA0003864594330000231
Synthetic method reference example 3, yield 42.5%, nuclear magnetic characterization data is 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
Figure BDA0003864594330000232
Synthetic methods reference example 4, with a yield of 38.8%, nuclear magnetic characterization data is 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) dimethyloxyphosphorus
Figure BDA0003864594330000241
Synthetic methods reference example 10, with a yield of 38.8%, nuclear magnetic characterization data is 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) dimethyloxyphosphide
Figure BDA0003864594330000251
Synthetic methods reference example 11, yield 35.6%, nuclear magnetic characterization data is 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
Figure BDA0003864594330000252
The synthesis was as in example 12 with 37.1% yield and the following nuclear magnetic characterization data: 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 MTT method cell proliferation inhibitory Activity test
The MTT method is adopted in the in vitro cell proliferation inhibition experiment, and the following 5 cell lines are adopted: baF3_ EGFR dTC (dTC for del19/T790M/C797S triple mutation), baF3_ EGFR LTC (LTC represents L8585R/T790M/C797S triple mutation), H1975 (L858R/T790M mutant of EGFR), H820 (del 19/T790M mutant of EGFR), A549 (wild type of EGFR).
Two kinds of BaF3 cells are suspension cells, and are cultured in PRIM-1640 culture medium containing 10% fetal calf serum (volume fraction) and 1% puro, and then are cultured at 37 deg.C in ethyl 5% CO 2 (volume fraction) under conventional conditions. .
Others are adherent cells, where A549 is in F12K medium with a volume fraction of 10% fetal bovine serum, and H1975 and H820 are in PRIM-1640 medium with 10% fetal bovine serum.
The specific operation is as follows:
all compounds were prepared as 10mM DMSO (dimethyl sulfoxide) solutions and then serially diluted in decreasing concentrations by gradient dilution.
Culturing cells, taking cells in log phase, counting tumor cells at 1.2 × 10 per well 4 -1.5×10 4 Single (suspension cell) or 6X 10 3 -9×10 3 Density dilution of individual (adherent cells) followed by addition of 99 μ L of cell-containing medium seeded in 96-well plates. The next step is a dosing step, for the suspended cells, the drug is added after the suspended cells are spread for 4 hours; for adherent cells, the cells are added after being adhered, generally 12-16 hours after plating.Then 1. Mu.L of compound solution was added to each well, so that the final concentration of compound was 100-fold equivalent to the original concentration, 3 replicate wells per concentration, IC 50 8-9 concentration gradients are set during testing. Simultaneously, two positive medicines are added in the experiment, namely a first-generation EGFR inhibitor Gefinitib and a Brigatinib with the inhibitory activity of the triple-mutation EGFR; and a control group and a blank group, both of which were added with 1. Mu.L of a pure DMSO solution. After 3 days of culture 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, centrifugal treatment is carried out on the suspension cells needing to be treated, and the adherent cells do not need to be centrifuged; removing the culture medium from each well by suction, and adding 100 mu L of DMSO solution; then shaking on a micro-oscillator for 5 minutes and a shaking table for 5 minutes respectively; finally, an enzyme-labeling instrument is used for testing the OD value at 490nm, so that the inhibition rate (Inh%) of the compound on the tumor cells at different concentrations is calculated, and an IC (integrated Circuit) is obtained by drawing an inhibition rate-concentration curve 50 The value is obtained. The test results are shown in table 1, and it can be seen that most of the compounds have certain tumor cell inhibitory activity, among which compounds 11, 12, 17, 18, etc. have good performance, good inhibitory activity on most of tumor cells, and IC thereof 50 The value reached micromolar.
The inhibition ratio formula is as follows: inh% = (control OD) 490 Experimental group OD 490 ) /(control group OD) 490 Blank group OD 490 )×100％。
After the experiment, the in vitro cell proliferation inhibitory activity of the compound prepared by the present invention was obtained, and the results are shown in tables 1 and 2.
TABLE 1 inhibition of tumor cell proliferation in vitro by the compounds prepared in the examples
Figure BDA0003864594330000271
TABLE 2 in vitro tumor cell proliferation inhibitory Activity of the Compounds prepared in part of the examples
Figure BDA0003864594330000281
Note: IC (integrated circuit) 50 Indicates the median inhibitory concentration
Test example 2 EGFR enzyme inhibitory Activity test
EGFR was used as a subject to test the inhibitory activity of compounds against subtype and wild type L858R/T790M/C797S, which was performed in cooperation with Shanghai Ruizhi chemical research, inc. and Sandy pharmaceutical technology (Shanghai) Inc., and 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-porous plate; preparing a kinase solution by using a buffer solution, adding the kinase solution into the compound and the positive control group, and adding the buffer solution into the 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 then dripping the mixed solution into each group; reacting for 60 minutes at room temperature; preparing a reaction termination solution by using a buffer solution, and adding the reaction termination solution into each group; the data were read using a Caliper instrument and the inhibition rate was calculated.
TABLE 3 EGFR of all examples LTC Enzyme inhibiting activity
Figure BDA0003864594330000291
Table 4 EGFR of some examples wt Enzyme inhibiting activity
Figure BDA0003864594330000292
Table 5 EGFR of some examples LTC Enzyme inhibiting activity
Figure BDA0003864594330000293
Test example 3 ALK enzyme inhibitory Activity test
The ALK inhibitory activity test is cooperated with Sondiya pharmaceutical technology (Shanghai) Limited liability company, and a Mobility Shift Assay method (instrument Mobility modification method) is adopted to test the ALK target inhibitory activity. The test method is basically consistent with the EGFR enzyme inhibition activity test.
ALK enzyme inhibitory Activity of examples in Table 6
Figure BDA0003864594330000301
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not 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 described embodiments.

Claims (10)

1. A2-anilinopyrimidine derivative is a compound shown as a formula I, or a pharmaceutically acceptable salt, a tautomer or a prodrug molecule thereof;
Figure FDA0003864594320000011
wherein:
R 1 is composed of
Figure FDA0003864594320000012
R 2 Is composed of
Figure FDA0003864594320000013
R 3 Is hydrogen, halogen, 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 and Z are each independently CH or N.
2. The 2-anilinopyrimidine derivative 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 salts formed by any one of the following inorganic acids: hydrochloric acid, sulfuric acid, and phosphoric acid;
the organic acid salt is selected from salts formed by any one of the following organic acids: acetic acid, trifluoroacetic acid, malonic acid, citric acid, and p-toluenesulfonic acid.
3. The 2-anilinopyrimidine derivative according to claim 1, wherein the compound represented by formula I is selected from any one of the following compounds:
Figure FDA0003864594320000021
Figure FDA0003864594320000031
Figure FDA0003864594320000041
4. a process for the preparation of a 2-anilinopyrimidine derivative according to any one of claims 1 to 3, comprising the steps of:
reacting a compound of formula IA with a compound of formula IB in a solvent under acidic conditions to obtain a compound of formula I:
Figure FDA0003864594320000042
R 1 、R 2 、R 3 x, Y and Z are as defined in claim 1.
5. Use of a 2-anilinopyrimidine derivative according to any one of claims 1 to 3 for the preparation of:
1) Epidermal Growth Factor Receptor (EGFR) inhibitors;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) An inhibitor of proliferation of eukaryotic tumor cells;
4) Inhibitors of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicine for preventing and/or treating tumor.
6. The use according to claim 5, wherein,
the Epidermal Growth Factor Receptor (EGFR) comprises EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR del19/T790M/C797S At least one of (1);
the Anaplastic Lymphoma Kinase (ALK) comprises ALK wt 、ALK L1196M And EML 4-ALK;
the eukaryote is a mammal;
the tumor cell is a cancer cell;
the cancer cell is leukemia cancer cell, lymphoma cell, lung cancer cell, breast cancer cell, ovarian cancer cell, cervical cancer cell, human glioma cell, melanoma cell, glioblastoma cell, nasopharyngeal carcinoma cell, liver cancer cell, brain cancer cell, pancreatic cancer cell, uterine cancer cell, testicular cancer cell, skin cancer cell, stomach cancer cell, colon cancer cell, bladder cancer cell or rectal cancer cell;
the tumor is a carcinoma.
7. The use according to claim 6, 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 cells are A2780;
the cervical cancer cell is a human cervical cancer cell line Hela;
the human glioma cell is U251;
the melanoma cancer cell is A375;
the glioblastoma cell is a human glioblastoma cell A172 and a human brain astrocytoma cell U-118MG;
the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell strain CNE-2;
the liver cancer cell is human liver cancer cell HepG2;
the cancer is leukemia, lymphoma, lung cancer, melanoma, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, stomach cancer, colon cancer, bladder cancer or rectal cancer.
8. A product, the active ingredient of which is the 2-anilinopyrimidine derivative according to any one of claims 1 to 3; the product is at least one of the following:
1) Epidermal Growth Factor Receptor (EGFR) inhibitors;
2) Anaplastic Lymphoma Kinase (ALK) inhibitors;
3) An inhibitor of proliferation of eukaryotic tumor cells;
4) Inhibitors of eukaryotic tumor cell metastasis;
5) An angiogenesis inhibitor;
6) A medicament for preventing and/or treating tumors.
9. The product of claim 8, wherein,
the Epidermal Growth Factor Receptor (EGFR) comprises EGFR L858R 、EGFR del19 、EGFR L858R/T790M 、EGFR del19/T790M 、EGFR L858R/T790M/C797S And EGFR del19/T790M/C797S At least one of (1);
the Anaplastic Lymphoma Kinase (ALK) comprises ALK wt 、ALK L1196M And EML 4-ALK;
the eukaryote is a mammal;
the tumor cell is a cancer cell;
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 glioma cell, a melanoma cell, a glioblastoma cell, a nasopharyngeal carcinoma cell, a liver cancer cell, a brain cancer cell, a pancreatic cancer cell, an uterine cancer cell, a testicular cancer cell, a skin cancer cell, a stomach cancer cell, a colon cancer cell, a bladder cancer cell or a rectal cancer cell;
the tumor is a carcinoma.
10. The product of claim 9, 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 cells are A2780;
the cervical cancer cell is a human cervical cancer cell line Hela;
the human glioma cell is U251;
the melanoma cancer cell is A375;
the glioblastoma cell is a human glioblastoma cell A172 and a human brain astrocytoma cell U-118MG;
the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell strain CNE-2;
the liver cancer cell is human liver cancer cell HepG2;
the cancer is leukemia, lymphoma, lung cancer, melanoma, glioblastoma, cervical cancer, nasopharyngeal carcinoma, hepatocarcinoma, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, metrocarcinoma, testis cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.
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