Cyclic 2-aminopyrimidine compounds and uses thereof

Abstract

The present invention relates to the field of chemical medicine, and relates to a cyclic 2-aminopyrimidine compound having a structure shown in formula (1) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof and uses thereof; the compound of the present invention can effectively inhibit EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR 19del / T790M / C797S ) activity and can overcome the existing third-generation selective EGFR T790M Clinical drug resistance in patients with non-small cell lung cancer and other tumors induced by small molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), and Rociletinib (CO‑1686).

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to a cyclic 2-aminopyrimidine compound and a use thereof. Background Art

[0002] Continuous proliferation is one of the most important characteristics of tumor cells. At the same time, the continuous development and proliferation of tumor cells can destroy the structure and function of tissues and organs, leading to the patient's death from organ failure. Usually, cell proliferation is strictly regulated by cell proliferation signals, but tumor cells can escape the regulation of proliferation signals through a series of mutations. Therefore, blocking the relevant mechanisms of tumor cells through drugs is an important means of tumor treatment.

[0003] Among them, receptor tyrosine kinases represented by EGFR are key proteins that receive growth factor proliferation signals. Tumor cells can fix the protein in its active conformation through EGFR mutations, allowing it to continuously activate downstream proliferation-related signaling pathways without relying on exogenous ligands. Among patients with non-small cell lung cancer, about 20% of patients have EGFR mutations and show EGFR mutation-dependent tumor cell proliferation, most of which are deletion mutations in exon 19 (19deletion mutation) and point mutations in exon 21 (L858R). Therefore, in recent years, a variety of treatments targeting EGFR mutations have been applied to clinical practice, such as monoclonal antibodies panitumumab and cetuximab that competitively block EGFR binding to ligands such as EGF and TGF-α, and kinase inhibitors gefitinib and osimertinib that simulate ATP structure and block EGFR phosphorylation. The use of EGFR inhibition therapy has greatly improved the survival of patients with non-small cell lung cancer. Taking gefitinib as an example, its use has increased the survival of patients from less than 10 months with traditional chemotherapy to nearly 30 months. The above evidence shows that EGFR is a reliable and effective drug target.

[0004] The EGFR kinase inhibitors gefitinib and erlotinib, which were launched in 2003 and 2004, will develop drug resistance after a period of use, which is reflected in the decreased sensitivity of tumor cells to the drug. One of the main reasons (about 25%) is the second point mutation (T790M) in the kinase region of EGFR. On the one hand, this mutation hinders the binding of drugs through amino acids with increased steric hindrance, reducing the drug's binding ability to EGFR, and on the other hand, it enhances the interaction between kinase and substrate ATP, thereby making competitive tyrosine kinase inhibitors inactive.

[0005] The inhibitor osimertinib, which was launched in 2015, effectively overcomes the drug resistance problem of the T790M point mutation by introducing covalent interaction forces. It was first approved as a second-line drug for patients who develop drug resistance after using gefitinib. At the same time, further studies have shown that when osimertinib is used as a first-line drug, it can achieve better results than traditional EGFR therapy and can effectively target patients with brain metastases. Therefore, covalently bound EGFR inhibitors represented by osimertinib will become the first choice for patients with non-small cell lung cancer in the foreseeable future.

[0006] However, osimertinib can also cause drug resistance. Studies have shown that the third point mutation (C797S) in the kinase region can eliminate the ability of the covalently bound inhibitor to form a covalent bond, causing the drug to lose its inhibitory activity. This type of mutation has been found in about 10-20% of patients who are resistant to osimertinib.

[0007] At present, there are no inhibitors targeting EGFR C797S point mutations for the treatment of clinical resistance to osimertinib. A few inhibitors have been reported in the literature, most of which have obvious disadvantages. For example, the allosteric inhibitor EAI045 and its derivatives cannot act on EGFR with exon 19 deletion activating mutations, while the ALK inhibitor brigatinib and the quinazoline EGFR inhibitors reported by Park et al. lack sufficient cell activity. Brigatinib needs to be used in combination with antibodies to exert its in vivo efficacy. Summary of the invention

[0008] Based on this, the present invention provides a cyclic 2-aminopyrimidine compound, which can effectively inhibit EGFR protein kinase resistant mutants (such as EGFR L858R / T790M ,EGFR L858R / T790M / C797S ,EGFR 19del / T790M / C797S ) activity.

[0009] A cyclic 2-aminopyrimidine compound having a structure shown in Formula 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof:

[0010]

[0011] Where:

[0012] X and Y are independently selected from CR5R6, O, NR 13 , S, S=O, S(O)2, C=O, NH(C=O);

[0013] R1 is selected from: hydrogen, hydroxyl, carbonyl, aryl, heteroaryl, sulfonyl, phosphorus oxygen, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted alkyl or cycloalkyl containing N, S, O heteroatoms, and the substituents are independently selected from halogen, alkyl, cycloalkyl, alkyl containing N, S, O, cycloalkyl containing N, S, O, hydroxyl, cyano, amino, ester, amide, aryl, aryl containing N, S, O, and sulfonyl;

[0014] R2, R3, R5, R6, R 13 Each of the substituents is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, trifluoromethyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C3-C6 cycloalkyloxy, wherein the substituents are independently selected from the group consisting of halogen, alkyl, cycloalkyl, alkyl containing N, S, O, C3-C6 cycloalkyl containing N, S, O, hydroxyl, cyano, amino, ester, amide, aryl, aryl containing N, S, O, and sulfonyl;

[0015] R4 is selected from: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted cycloalkyl containing N, S, O, the substituents include C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 epoxyalkyl, amino, ester, cyano, amide, thioamide; R4 also includes -(CH2) m NR8R9, -(CH2) m OCR7R8R9 or -(CH2) m CR7R8R9; wherein m is selected from: 0, 1, 2, 3 or 4;

[0016] R7 is selected from: hydrogen or C1-C3 alkyl;

[0017] R8 and R9 are independently selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, or R8, R9 and the N or C connected thereto form a substituted or unsubstituted monocyclic, condensed, spirocyclic or bridged ring containing heteroatoms;

[0018] L is selected from: substituted or unsubstituted straight-chain C2-C8 alkyl, substituted or unsubstituted straight-chain C2-C8 alkenyl, wherein one or more methylene groups in the alkyl and alkenyl groups can be independently replaced by O, S and NR 14 , wherein one or more S, N or C in the straight chain may together form a substituted or unsubstituted monocyclic, condensed, spirocyclic or bridged ring containing heteroatoms, and the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amide, aryl, heteroaryl, and sulfonyl;

[0019] R14 Selected from: hydrogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkyl containing N, S, O, cycloalkyl containing N, S, O, hydroxyl, cyano, amino, ester, amide, aryl, aryl containing N, S, O, sulfonyl.

[0020] In some embodiments, the cyclic 2-aminopyrimidine compound is:

[0021]

[0022] wherein n is selected from 3 to 10;

[0023] X and Y are independently selected from CR5R6, O, NR 13 , S, S=O, S(O)2, C=O, NH(C=O).

[0024] In some embodiments, the cyclic 2-aminopyrimidine compound is:

[0025]

[0026] Wherein, n1 and n2 are selected from 1 to 6;

[0027] X and Y are independently selected from CR5R6, O, NR 13 , S, S=O, S(O)2, C=O, NH(C=O).

[0028] In some embodiments, the cyclic 2-aminopyrimidine compound is:

[0029]

[0030] Wherein, n1 and n2 are selected from 1 to 6; Ring A is selected from aryl, C3 to C6 cycloalkyl, C3 to C6 epoxyalkyl, and aryl containing N, S, and O;

[0031] X and Y are independently selected from CR5R6, O, NR 13 , S, S=O, S(O)2, C=O, NH(C=O).

[0032] In some embodiments, R1 is S(O)2R 12 , R 12 Selected from: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 epoxyalkyl.

[0033] In some embodiments, R2 is selected from hydrogen, halogen, aryl halide, cyano, trifluoromethyl;

[0034] In some embodiments, R3 is selected from hydrogen, trifluoromethyl, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted alkyl containing N, S, O, substituted or unsubstituted C3-C6 cycloalkyl containing N, S, O;

[0035] In some embodiments, the R4 is selected from:

[0036] or

[0037] In some embodiments, the cyclic 2-aminopyrimidine compound is selected from one of the following:

[0038]

[0039]

[0040] The present invention also provides the use of cyclic 2-aminopyrimidine compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof or prodrug molecules thereof.

[0041] Use of the above-mentioned cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of mutant EGFR inhibitors.

[0042] Use of the above-mentioned cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of drugs for preventing and treating tumors.

[0043] In some embodiments, the tumor is a malignant tumor with EGFR gene mutation.

[0044] In some embodiments, the tumor is EGFR L858R / T790M / C797S EGFR 19del / T790M / C797S Mutation of malignant tumors.

[0045] In some embodiments, the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer or glioma.

[0046] The invention also provides a pharmaceutical composition for preventing and treating tumors.

[0047] The specific technical solutions are as follows:

[0048] A pharmaceutical composition comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises the above-mentioned cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] (1) The cyclic 2-aminopyrimidine compounds of the present invention or their pharmaceutically acceptable salts or stereoisomers or prodrug molecules can inhibit EGFR family proteases, thereby inhibiting the growth of various tumor cells. Compared with wild-type cancer cells, the compounds of the present invention have higher selectivity for mutant cancer cells. The compounds of the present invention are particularly effective in inhibiting EGFR protein kinase resistant mutants (such as EGFR T790M and EGFR T790M / C797S ) activity, which can selectively act on EGFR L858R / T790M EGFR 19del EGFR L858R / T790M / C797S Lung cancer cells can overcome the existing third-generation selective EGFR T790M Clinical drug resistance in patients with non-small cell lung cancer and other tumors induced by small molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), and Rociletinib (CO-1686).

[0051] (2) The compounds of the present invention can be used to prepare anti-tumor drugs and can overcome the drug resistance induced by existing drugs such as gefitinib, erlotinib, and especially osimertinib (AZD9291). They are a novel class of protein kinase inhibitors that can overcome the drug resistance of existing EGFR tyrosine kinase inhibitors and have selectivity and good pharmacokinetic properties, and can be used to treat hyperproliferative diseases such as tumors in humans and other mammals. DETAILED DESCRIPTION

[0052] The present invention is further described in detail below with reference to specific embodiments.

[0053] In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any component, its definition at each occurrence is independent of the definition at every other occurrence. Likewise, combinations of substituents and variables are permitted as long as such combinations render the compound stable. Lines drawn from substituents into the ring system indicate that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are attached only to any appropriate carbon atom of the adjacent ring. It is to be understood that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials by techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is to be understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stable.

[0054] The term "alkyl" as used herein refers to a saturated chain alkyl group, and "chain alkyl" refers to a straight chain or branched chain alkyl group, such as a C1-C4 alkyl group refers to a saturated straight chain or branched chain alkyl group having 1 to 4 carbon atoms, wherein examples of straight chain alkyl groups include but are not limited to ethyl, n-propyl, etc., and examples of branched chain alkyl groups include but are not limited to isopropyl, tert-butyl, etc.;

[0055] The term "cycloalkyl" refers to an alkyl group having a cyclic structure, such as a C3-C4 cycloalkyl group refers to an alkyl group having a cyclic structure with 3 to 4 carbon atoms. Examples include but are not limited to cyclopropyl, cyclobutyl, methyl-substituted cyclopropyl, and the like.

[0056] The term "alkoxy" refers to a straight or branched alkyl group containing an oxygen atom at the terminal end, and examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

[0057] As used herein, "halo" or "halo" refers to chlorine, fluorine, bromine and iodine.

[0058] The present invention provides a compound of formula 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof,

[0059]

[0060] Wherein, R1, R2, R3, R4, X, Y and L are as defined above.

[0061] The present invention includes free forms of compounds of formula 1, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to amine compounds in non-salt form. Pharmaceutically acceptable salts included include not only exemplary salts of specific compounds described herein, but also typical pharmaceutically acceptable salts of free forms of all compounds of formula 1. The free forms of specific salts of the compounds can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with an appropriate dilute aqueous solution of a base, such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, a dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form is somewhat different from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purpose of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0062] Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting a free base with a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reacting with an appropriate inorganic or organic base.

[0063] Therefore, the pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting alkaline compounds of this invention with inorganic or organic acids. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0064] If the compound of the present invention is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guazine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0065] Berg et al., Pharmaceutical Salts J. Pharm. Sci. 1977:66:1-19, describes in more detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

[0066] Since under physiological conditions deprotonated acidic moieties such as carboxyl groups in the compounds may be anionic, and this charge may then be balanced by internal cationic protonated or alkylated basic moieties such as quaternary nitrogen atoms, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0067] In addition to standard methods known in the literature or exemplified in the experimental procedures, the compounds of the present invention may be prepared by the reactions shown in the schemes listed in the following specific examples. Therefore, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims, and for clarity, a single substituent is shown attached to a compound where multiple substituents are allowed under the definition of Formula 1 above.

[0068] The compound having the structure of Formula 1 provided by the present invention and its pharmaceutically acceptable salt can be used to treat transitional proliferative diseases or symptoms such as tumors in humans or other mammals. In particular, it can be used to treat or control transitional proliferative diseases such as non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal carcinoma, head and neck tumors, colon cancer, rectal cancer, glioma, etc.

[0069] Drug metabolites and prodrugs: Metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present invention and their pharmaceutically acceptable salts in vivo, are also included in the claims of this application.

[0070] Pharmaceutical composition: The present invention also provides a pharmaceutical composition, which comprises an active ingredient within a safe and effective amount range and a pharmaceutically acceptable carrier. The "active ingredient" described in the present invention refers to the compound of formula 1 described in the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.

[0071] The "active ingredient" and pharmaceutical composition of the present invention can be used as an EGFR protease inhibitor. In another preferred embodiment, it is used to prepare a drug for preventing and / or treating tumors.

[0072] The present invention is beneficial in that:

[0073] (1) Provide a novel cyclic 2-aminopyrimidine compound.

[0074] (2) This type of compound can effectively inhibit the effects of EGFR protein kinase-resistant mutants and can be used to prepare anti-tumor drugs.

[0075] (3) This class of compounds can overcome the drug resistance induced by existing drugs such as gefitinib, erlotinib, and especially osimertinib (AZD9291), are selective for wild-type EGFR, and have good pharmacokinetic properties.

[0076] Example 1

[0077] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC57866)

[0078]

[0079] The synthetic route is as follows:

[0080]

[0081] Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (3)

[0082]

[0083] 6-Methoxy-1H-indole (1g, 6.79mmol) was dissolved in 25mL dry dichloromethane, and the system was replaced with argon, and then placed in an ice bath and cooled to 0°C. A 3mol / L methylmagnesium bromide ether solution (3.4mL, 10.18mmol) was added dropwise to the solution. After the addition was complete, 2,4,5-trichloropyrimidine (1.25g, 6.79mmol) was dissolved in another 25mL dry dichloromethane, and the solution was added dropwise to the reaction system. After the addition was completed, the reaction was moved to room temperature and continued to react for 3 hours. During the process, the reaction progress was monitored by TLC (developing solvent was petroleum ether: ethyl acetate = 5:1, v / v). After the reaction was completed, the ice bath was restored, and water (50mL) was added dropwise to quench, and a yellow solid was precipitated during the process. The above mixture was filtered, and the filter cake was washed twice with ethyl acetate until the filter cake was light yellow. The filter cake was collected and dried to obtain 1.1 g of the title compound as a light yellow solid, with a yield of 55%.

[0084] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.69(s,1H),8.62(s,1H),8.39(d,1H),7.03(s,1H),6.91(d,J=8.7Hz,1H),3.81(s,3H).

[0085] Step 2. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-6-methoxy-1H-indole (4)

[0086]

[0087] Dissolve 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (1.1 g, 3.74 mmol) in 10 mL DMF, and place the reaction in an ice bath to cool to 0°C. Add 60% mass fraction sodium hydride (0.22 g, 5.61 mmol) dispersed in mineral oil portion by portion, continue to react in an ice bath for 10 minutes, then slowly add ethylsulfonyl chloride (0.42 mL, 4.49 mmol). After the addition, move the reaction to room temperature and continue to react for 1 hour. During the process, monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 5:1, v / v). After the reaction is completed, add water (50 mL) to quench, and a white solid precipitates during the process. Filter the above mixture, and wash the filter cake with methanol. Collect the filter cake and dry it to obtain 1.2 g of the title compound as a white solid with a yield of 83%.

[0088] 1H NMR (400MHz, DMSO) δ8.95(s,1H),8.50(s,1H),8.32(d,J=8.9Hz,1H),7.41(d,J=2.2Hz, 1H),7.13(dd,J=8.9,2.3Hz,1H),3.87(s,3H),3.87–3.82(m,2H),1.14(t,J=7.3Hz,3H).

[0089] Step 3. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (5)

[0090]

[0091] Dissolve 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-6-methoxy-1H-indole (0.2 g, 0.5 mmol) in 3 mL of dry dichloromethane, and place the reaction in a cooling bath to -40 °C. Add 1 mol / L boron tribromide dichloromethane solution (3 mL, 3.11 mmol) dropwise. After addition, move the reaction to room temperature and continue the reaction for 5 hours. During the reaction, take a sample, dilute with ethyl acetate and saturated sodium bicarbonate solution, and take the upper layer of the mixture to monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 5:1, v / v). After the reaction is completed, add water (30 mL) to quench, and a yellow solid precipitates during the process. Filter the above mixture and wash the filter cake with methanol. Collect the filter cake and dry it to obtain 0.17 g of the title compound as a yellow solid with a yield of 88%.

[0092] 1 H NMR (400MHz, DMSO) δ9.64(s,1H),8.52(s,1H),7.78(d,J=2.4Hz,1H),7.74(d,J=9.0Hz,1H ), 6.98 (dd, J = 9.0, 2.4Hz, 1H), 3.77 (q, J = 7.3Hz, 2H), 3.33 (s, 1H), 1.12 (t, J = 7.3Hz, 3H).

[0093] Step 4. Preparation of 6-(5-amino-2-morpholinophenoxy)hexanol (8)

[0094]

[0095] 2-Fluoro-5-nitrophenol (2g, 12.73mmol) was dissolved in 15mL DMF, and then potassium carbonate (5.28g, 38.19mmol) and 6-bromohexane-1-ol (1.84mL, 14mmol) were added to the system, and the reaction was placed in a preheated 80℃ oil bath and heated for 4 hours. During the reaction, the reaction progress was monitored by TLC (developing solvent was petroleum ether: ethyl acetate = 5:1, v / v). After the raw material was completely converted, morpholine (1.66mL, 19.10mmol) was added, and the reaction was continued at 80℃ for 3 hours. After the reaction was completed, 80mL of water was added, and the organic phase was extracted with ethyl acetate. After washing the organic phase twice with saturated brine, it was dried and concentrated. The residue was added to a 100mL round-bottom flask containing reduced iron powder (2.84g, 50.92mmol) and ammonium chloride (5.45g, 101.85mmol), and dissolved with 20mL of water and 20mL of ethanol. The reaction was placed in a preheated 100°C oil bath and heated for 30 minutes. The reaction was terminated when the yellow color of the reaction solution faded. The reaction was quenched with 30 mL of saturated sodium bicarbonate solution. The mixture was filtered through a diatomaceous earth filter cake and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, and concentrated. The residue was purified by rapid silica gel column chromatography (mobile phase: dichloromethane: methanol = 100: 1, v / v), the effluent was collected portion by portion, and the components containing the target were concentrated. After drying, 1.3 g of dark brown solid was obtained, with a total yield of 34%.

[0096] 1 H NMR (400MHz, CDCl3) δ6.75(d,J=8.1Hz,1H),6.35–6.20(m,2H),3.96(t,J=6.5Hz,2H),3.86(d,J=4.7Hz,4H),3.67(t,J=6.4Hz,2H),3 .55–3.03(m,2H),3.05–2.92(m,4H),1.86(p,J=6.6Hz,2H),1.69–1.59(m,2H),1.50(ddd,J=19.5,9.1,4.7Hz,4H),1.45–1.35(m,1H).

[0097] Step 5. Preparation of 3-(5-chloro-2-((3-((6-hydroxyhexyl)oxy)-4-morpholinophenyl)amino)pyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (9)

[0098]

[0099] 6-(5-amino-2-morpholinophenoxy)hexanol (0.2g, 0.67mmol), 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (0.25g, 0.67mmol) and p-toluenesulfonic acid (0.17g, 1.02mmol) were dissolved in 5mL 1-pentanol and the reaction was heated in a preheated 140°C oil bath for 24 hours. The reaction progress was monitored by TLC during the reaction (developing solvent was dichloromethane: methanol = 50: 1, v / v). After the reaction was completed, 15mL of saturated sodium bicarbonate solution was used to quench the mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by rapid silica gel column chromatography (mobile phase was dichloromethane: methanol = 50: 1, v / v), the effluent was collected in portions, the fraction containing the target was concentrated, and 0.17g of yellow foamy solid was obtained after drying, with a yield of 40%.

[0100] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.33(s,1H),8.19(d,J=8.7Hz,1H),7.64(s,1H),7.44(d ,J=2.1Hz,1H),7.15(s,1H),6.90(d,J=8.4Hz,1H),6.84(dd,J=8.7,2.2Hz,1H),6.82–6.76( m,1H),3.97–3.87(m,4H),3.88–3.82(m,1H),3.81–3.75(m,2H),3.74–3.69(m,2H),3.42(q ,J=7.4Hz,2H),3.15–3.02(m,4H),1.78–1.71(m,2H),1.43–1.30(m,9H),0.93–0.90(m,1H).

[0101] Step 6. 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC57866)

[0102]

[0103] 3-(5-chloro-2-((3-((6-hydroxyhexyl)oxy)-4-morpholinophenyl)amino)pyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (0.17 g, 0.27 mmol) and triphenylphosphine (0.71 g, 2.7 mmol) were dissolved in 150 mL of dry dichloromethane, and the reaction was replaced with argon gas, and then placed in an ice bath and cooled to 0°C. Diisopropyl azodicarboxylate (0.53 mL, 2.7 mmol) was added to the reaction system. After the addition, the reaction was moved to room temperature for 1.5 hours. During the reaction, the reaction progress was monitored by TLC (developing solvent was petroleum ether: ethyl acetate = 2:1, v / v). After the reaction was completed, silica gel was added for adsorption. After the solvent was removed, it was purified by rapid silica gel column chromatography (mobile phase was petroleum ether: ethyl acetate = 3:1, v / v). The effluent was collected portion by portion, and the fraction containing the target product was concentrated, washed with methanol and then filtered. The filter cake was collected and dried to obtain 0.078 g of a yellow or nearly white solid with a yield of 47%.

[0104] 1 H NMR(400MHz, CDCl3)δ8.43(s,1H),8.33(s,1H),8.21(d,J=8.6Hz,1H),7.86–7.80 (m,1H),7.65–7.55(m,1H),7.16(s,1H),6.98(d,J=7.2Hz,1H),6.88(d,J=8.4Hz, 1H),6.56(d,J=6.6Hz,1H),4.46–4.37(m,2H),3.91(s,4H),3.40(dt,J=11.9,6.5 Hz,4H),3.11(s,4H),1.69–1.62(m,4H),1.46–1.35(m,4H),1.33(d,J=7.4Hz,3H).

[0105] Example 2

[0106] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-1 1 Preparation of H-5,11-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocycloundecane (HC5475)

[0107]

[0108] The synthesis method is similar to that of Example 1, except that the intermediate (7) is replaced by 5-bromopentane-1-ol.

[0109] 1H NMR (400MHz, CDCl3) δ8.43(s,1H),8.27(s,1H),8.19(d,J=8.7Hz,1H),7.73(d,J=2.1Hz,1H),7.65(d, J=1.7Hz,1H),7.16(s,1H),7.07(dd,J=8.7,1.8Hz,1H),6.87(d,J=8.3Hz,1H),6.56(dd,J=8.3,2.1Hz ,1H),4.40–4.31(m,2H),3.93–3.86(m,4H),3.47(t,J=6.7Hz,2H),3.44–3.36(m,2H),3.14–3.05(m,4 H),1.72–1.67(m,2H),1.57–1.52(m,2H),1.50–1.42(m,2H),1.34(t,J=7.4Hz,3H),1.31–1.26(m,2H).

[0110] Example 3

[0111] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-1 1 Preparation of H-5,13-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclotridecane (HC57867)

[0112]

[0113] The synthesis method is similar to that of Example 1, except that the intermediate (7) is replaced by 7-bromoheptane-1-ol.

[0114] 1H NMR (400MHz, CDCl3) δ8.42(s,1H),8.32(s,1H),8.19(d,J=8.8Hz,1H),7.85(d,J=2.2Hz,1H),7.51(d,J =2.1Hz,1H),7.16(s,1H),6.92(dd,J=8.8,2.1Hz,1H),6.88(d,J=8.4Hz,1H),6.56(dd,J=8.4,2.2Hz,1H ),4.40–4.30(m,2H),4.00–3.79(m,4H),3.52(t,J=6.7Hz,2H),3.42(q,J=7.3Hz,2H),3.19–3.00(m,4H) ,1.79(p,J=6.1Hz,2H),1.69–1.61(m,2H),1.57–1.49(m,2H),1.34–1.22(m,5H),1.10(p,J=7.0Hz,2H).

[0115] Example 4

[0116] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-1 1 Preparation of H-5,14-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclotetradecane (HC57868)

[0117]

[0118] The synthesis method is similar to that of Example 1, except that the intermediate (7) is replaced by 8-bromooctan-1-ol.

[0119] 1H NMR (400MHz, CDCl3) δ8.42(s,1H),8.30(s,1H),8.16(d,J=8.8Hz,1H),7.93(d,J=1.9Hz,1H),7.49(d,J=1. 7Hz,1H),7.20(d,J=17.3Hz,1H),6.89(dd,J=8.5,3.9Hz,2H),6.55(dd,J=8.4,2.1Hz,1H),4.28(t,J=5.3Hz ,2H),3.98–3.86(m,4H),3.49(t,J=6.0Hz,2H),3.42(q,J=7.3Hz,2H),3.18–3.04(m,4H),1.85–1.73(m,2H) ,1.60–1.56(m,2H),1.49(dt,J=14.1,6.2Hz,2H),1.43–1.34(m,2H),1.34–1.27(m,5H),1.23–1.12(m,2H).

[0120] Example 5

[0121] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Fluoro-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC596F)

[0122]

[0123] The synthesis method is the same as that of Example 1, except that the intermediate (6) is replaced by 2,4-difluoro-5-nitrophenol.

[0124] 1H NMR (400MHz, CDCl3) δ8.47(t,J=4.9Hz,1H),8.30(t,J=4.8Hz,1H),8.19(dd,J=8.7,4.1Hz,1H), 8.01–7.86(m,1H),7.61(s,1H),7.35–7.27(m,1H),7.05–6.93(m,1H),6.83–6.68(m,1H),4.48– 4.32(m,2H),3.92–3.82(m,4H),3.43(dq,J=11.0,6.9,4.8Hz,2H),3.36(t,J=5.1Hz,2H),3.08( s,4H),1.72–1.64(m,2H),1.60–1.50(m,2H),1.45(s,2H),1.37–1.32(m,3H),1.32–1.25(m,2H).

[0125] Example 6

[0126] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Chloro-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC596C)

[0127]

[0128] The synthesis method is the same as that of Example 1, except that the intermediate (6) is replaced by 4-chloro-2-fluoro-5-nitrophenol.

[0129] 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 8.32 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.97 (s, 1H), 7.61 ( d,J=2.0Hz,1H),7.54(s,1H),6.98(dd,J=8.8,2.2Hz,1H),6.94(s,1H),4.45–4.34(m,2H) ,3.93–3.85(m,4H),3.43(q,J=7.4Hz,2H),3.31(t,J=5.8Hz,2H),3.15–3.03(m,4H),1.69 –1.61(m,2H),1.57–1.52(m,2H),1.47–1.40(m,2H),1.38–1.35(m,2H),1.33–1.30(m,3H).

[0130] Example 7

[0131] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Methyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC596M)

[0132]

[0133] The synthesis method is the same as that of Example 1, except that the intermediate (6) is replaced by 4-methyl-2-fluoro-5-nitrophenol.

[0134] 1 H NMR (400MHz, CDCl3) δ8.42 (s, 1H), 8.40 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.69 (s, 1H) ,7.58(d,J=2.0Hz,1H),6.92(dd,J=8.8,2.0Hz,1H),6.90(s,1H),6.77(s,1H),4.43 –4.34(m,2H),3.96–3.89(m,4H),3.41(dt,J=11.5,6.5Hz,4H),3.19–3.10(m,4H), 2.34(s,3H),1.66(s,4H),1.61–1.56(m,2H),1.46–1.39(m,2H),1.35–1.31(m,3H).

[0135] Example 8

[0136] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Ethyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5967)

[0137]

[0138] The synthesis method is similar to that of Example 1, except that the intermediate (8) is replaced by 6-(5-amino-4-ethyl-2-morpholinophenoxy)hexanol (14).

[0139] 1H NMR (400MHz, CDCl3) δ8.42(d,J=1.6Hz,2H),8.13(d,J=8.8Hz,1H),7.61(s, 1H),7.57(d,J=2.0Hz,1H),6.95–6.87(m,2H),6.79(s,1H),4.41–4.34(m,2H ),3.96–3.89(m,4H),3.46–3.36(m,4H),3.19–3.12(m,4H),2.69(q,J=7.6Hz ,2H),1.58(p,J=5.7Hz,2H),1.45(p,J=7.6,7.2Hz,2H),1.37–1.17(m,10H).

[0140] Preparation of intermediate 6-(5-amino-4-ethyl-2-morpholinophenoxy)hexanol (14)

[0141] Step 1. Preparation of 6-(4-bromo-2-morpholino-5-nitrophenoxy)hexanol (11)

[0142]

[0143] 4-Bromo-2-fluoro-5-nitrophenol (2 g, 8.47 mmol) was dissolved in 10 mL of DMF, and then potassium carbonate (2.34 g, 16.95 mmol) and 6-bromohexane-1-ol (1.69 g, 9.32 mmol) were added to the system. The reaction was placed in a preheated 80°C oil bath and heated for 4 hours. The reaction progress was monitored by TLC during the reaction (the developing solvent was petroleum ether: ethyl acetate = 5:1, v / v). After the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed three times with saturated brine, dried, and concentrated to obtain 2.7 g of a yellow solid with a yield of 79%.

[0144] 1 H NMR (400MHz, CDCl3) δ7.56(s,1H),7.06(s,1H),4.06(t,J=6.5Hz,2H),3.91–3.83(m,4H),3.69( t,J=6.5Hz,2H),3.30–3.17(m,4H),1.89(p,J=6.5Hz,2H),1.70–1.58(m,4H),1.54–1.49(m,3H).

[0145] Step 2. Preparation of 6-(2-morpholinyl-5-nitro-4-vinylphenoxy)hexanol (13)

[0146]

[0147] Dissolve 6-(4-bromo-2-morpholine-5-nitrophenoxy)hexanol (0.3 g, 0.74 mmol), vinyl pinacol borate (0.17 g, 1.12 mmol) and 1 mol / L sodium carbonate aqueous solution (1.5 mL, 1.5 mmol) in 5 mL 1,4-dioxane. Degas the system with a vacuum pump for 30 seconds, replace with argon, and repeat this operation twice. Add tetrakistriphenylphosphine palladium (0.086 g, 0.07 mmol) to the mixture under argon, replace the gas in the bottle with argon again, and place the reaction in a preheated 100°C oil bath for 7 hours. During the reaction, monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 2:1, v / v). After the reaction is completed, pour the reaction solution into water, extract with ethyl acetate, and dry and concentrate the organic phase. The residue was purified by flash silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate=3:1, v / v), the effluent was collected portion by portion, and the fractions containing the target compound were concentrated and dried to obtain 0.20 g of a dark yellow solid with a yield of 76%.

[0148] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=1.1Hz,1H),7.33(dd,J=10.9,1.4Hz,1H),6.94(s,1H),5.61(d,J=17.3Hz,1H),5.42(d,1H),4.09(t,J=6.4Hz,2H), 3.95–3.85(m,4H),3.69(td,J=6.5,1.4Hz,2H),3.33–3.22(m,4H),1.90( p,J=6.6Hz,2H),1.66–1.61(m,2H),1.57–1.47(m,4H),1.32–1.23(m,1H).

[0149] Step 3. Preparation of 6-(5-amino-4-ethyl-2-morpholinophenoxy)hexanol (14)

[0150]

[0151] Dissolve 6-(2-morpholinyl-5-nitro-4-vinylphenoxy)hexanol (0.20 g, 0.57 mmol) in 5 mL of methanol. Degas the system with a vacuum pump for 30 seconds, replace it with argon, and repeat this operation twice. Add 10% palladium carbon (0.02 g, containing 55% water) to the mixture under argon, replace the gas in the bottle with hydrogen, and stir at room temperature for 8 hours. During the reaction, monitor the progress of the reaction by TLC (developing solvent is dichloromethane: methanol = 15: 1, v / v). After the reaction is completed, the mixture is passed through a diatomaceous earth filter cake and the filtrate is concentrated. The residue is purified by rapid silica gel column chromatography (mobile phase is dichloromethane: methanol = 100: 1, v / v), collect the effluent portion by portion, concentrate the components containing the target, and dry to obtain 0.13 g of dark brown solid with a yield of 71%.

[0152] 1 H NMR (400MHz, CDCl3) δ6.67(s,1H),6.29(s,1H),3.95(t,J=6.4Hz,2H),3.91–3.84(m,4H),3.68(t,J=6.5Hz,2H),3.60–3.22(m ,2H),3.08–2.97(m,4H),2.48(q,J=7.5Hz,2H),1.96(s,1H),1.84(h,J=7.9,7.2Hz,2H),1.63–1.48(m,6H),1.26–1.19(m,3H).

[0153] Example 9

[0154] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Cyclopropyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5969)

[0155]

[0156] The synthesis method is similar to that of Example 8, except that the intermediate (12) is replaced by cyclopropylboronic acid.

[0157] 1H NMR (400MHz, CDCl3) δ8.45 (s, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.88 (s, 1H) ,7.70(s,1H),7.60(d,J=2.0Hz,1H),6.98(dd,J=8.8,2.1Hz,1H),6.78(s,1H),4.43 –4.36(m,2H),3.93–3.86(m,4H),3.48–3.32(m,4H),3.13–3.06(m,4H),1.71–1.63( m,2H),1.58–1.53(m,2H),1.44–1.30(m,7H),1.11–1.02(m,2H),0.75–0.67(m,2H).

[0158] Example 10

[0159] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Isopropyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5963)

[0160]

[0161] The synthesis method is the same as that of Example 8, except that the intermediate (12) is replaced by 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxolane.

[0162] 1 H NMR (400MHz, CDCl3) δ8.46(s,1H),8.41(s,1H),8.05(d,J=8.8Hz,1H),7.55(d,J=2.1Hz,1H),7.47(s,1H),6.95–6.90(m,1H),6.90–6.84(m, 2H),4.41–4.34(m,2H),3.97–3.90(m,4H),3.48–3.36(m,4H),3.26–3 .13(m,5H),1.67–1.60(m,4H),1.51–1.41(m,2H),1.32–1.25(m,11H).

[0163] Embodiment 11

[0164] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6-isobutyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5968)

[0165]

[0166] The synthesis method is similar to that of Example 8, except that the intermediate (12) is replaced by 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxybenzaldehyde.

[0167] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.41(s,1H),8.10(d,J=8.8Hz,1H),7.57(d,J=2.0Hz,1H),7.53 (s,1H),6.93–6.85(m,2H),6.72(s,1H),4.41–4.34(m,2H),3.96–3.89(m,4H),3.74(q,J=7.0Hz,1 H),3.46–3.36(m,4H),3.19–3.12(m,4H),2.53(d,J=7.3Hz,2H),1.90(dhept,J=13.6,7.1Hz,1H), 1.61–1.53(m,2H),1.45(q,J=12.7,9.7Hz,2H),1.29(dt,J=9.0,7.1Hz,7H),0.98(d,J=6.6Hz,6H).

[0168] Example 12

[0169] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -(3,3-dimethylbutyl)-4- 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5965)

[0170]

[0171] The synthesis method is similar to that of Example 8, except that the intermediate (12) is replaced by 2-(3,3-dimethyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane.

[0172] 1H NMR (400MHz, CDCl3) δ8.42(d,J=2.2Hz,2H),8.13(d,J=8.8Hz,1H),7.62–7.54(m,2 H),6.90(dd,J=8.8,2.2Hz,1H),6.87(s,1H),6.76(s,1H),4.41–4.32(m,2H),3.99 –3.88(m,4H),3.47–3.35(m,4H),3.23–3.11(m,4H),2.65–2.54(m,2H),1.70–1.64 (m,2H),1.57(d,J=6.1Hz,2H),1.56–1.44(m,4H),1.33–1.28(m,5H),1.03(s,9H).

[0173] Embodiment 13

[0174] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Cyclopentyl-4 4 -Morpholine-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC5960)

[0175]

[0176] The synthesis method is similar to that of Example 8, except that the intermediate (12) is replaced by 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane.

[0177] 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),8.41(s,1H),8.09(d,J=8.8Hz,1H),7.56(d,J=2.0Hz ,1H),7.51(s,1H),6.96(s,1H),6.92–6.85(m,2H),4.41–4.34(m,2H),3.96–3.89(m,4H ),3.47–3.36(m,4H),3.26–3.13(m,5H),2.15–2.03(m,2H),1.92–1.81(m,2H),1.79–1. 71(m,2H),1.70–1.64(m,4H),1.62–1.54(m,2H),1.51–1.40(m,2H),1.33–1.22(m,5H).

[0178] Embodiment 14

[0179] (E)-2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane-9-ene (HC614)

[0180]

[0181] The synthetic route is as follows:

[0182]

[0183] Step 16 Preparation of 6-(allyloxy)-3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indole (15)

[0184]

[0185] 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (1g, 2.69mmol) and potassium carbonate (2g, 5.47mmol) were dissolved in 20mL DMF, and 3-bromopropylene (0.48g, 4.03mmol) was added under stirring. The mixture was stirred at 60°C for 7 hours, and the reaction progress was monitored by TLC during the reaction (developing solvent was petroleum ether: ethyl acetate = 5:1, v / v). After the reaction was completed, 50mL of water was added to dilute the reaction solution, and then extracted with 30mL of ethyl acetate. The organic phase was washed twice with saturated brine (50mL*2), dried and concentrated. The residue was purified by rapid silica gel column chromatography (mobile phase was petroleum ether: ethyl acetate = 10:1, v / v), the effluent was collected in portions, the components containing the target were concentrated, and 0.31g of white solid was obtained after drying, with a yield of 28%.

[0186] 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),8.63(s,1H),8.17(d,J=2.3Hz,1H),7.85(d,J=9.1Hz,1H),7.17–7.09(m,1H),6.14(ddd,J=22.6,1 0.6,5.4Hz,1H),5.54(dd,J=17.3,1.4Hz,1H),5.44–5.33(m,1H),4.70(d,J=5.4Hz,2H),3.43(q,J=7.4Hz,2H),1.30(t,J=7.4Hz,3H).

[0187] Step 2 Preparation of 4-morpholine-3-(pent-4-ene-1-yloxy)aniline (16)

[0188] The synthesis method refers to Example 1, in step 4, 6-bromohexane-1-ol is replaced by 5-bromopentene.

[0189] 1 H NMR (400MHz, CDCl3δ6.84(d,J=8.6Hz,1H),6.63(dd,J=8.6,2.2Hz,1H),6.22(d,J=2.3Hz,1H),5.75(ddt,J=17.0,10.3,6.8Hz,1H),5.19–5.03(m,1H) ,4.96(ddt,J=17.0,2.1,0.9Hz,1H),4.45(s,2H),4.02(t,J=6.8Hz,2H),3 .84–3.75(m,4H),3.39–3.24(m,4H),2.22–2.08(m,2H),1.89–1.69(m,2H).

[0190] Step 3 Preparation of 4-(6-(allyloxy)-1-(ethylsulfonyl)-1H-indol-3-yl)-5-chloro-N-(4-morpholin-3-(pent-4-ene-1-yloxy)phenyl)pyrimidin-2-amine (17)

[0191]

[0192] The synthesis method refers to Example 1, step 5, intermediates 5 and 8 are replaced by intermediates 15 and 16 respectively.

[0193] 1H NMR (400MHz, CDCl3) δ8.44(s,1H),8.35(s,1H),8.27(d,J=8.9Hz,1H),7.50(d,J=2.3Hz,1H),7.33(d,J=2.3Hz,1H),7.16(s,1H ),7.07(dd,J=8.5,2.3Hz,1H),6.98(dd,J=8.9,2.3Hz,1H),6.90(d,J=8.5Hz,1H),6.12(ddt,J=17.1,10.6,5.3Hz,1H),5.82(dd t,J=16.9,10.1,6.7Hz,1H),5.49(dd,J=17.3,1.5Hz,1H),5.36(dd,J=10.5,1.3Hz,1H),5.08–4.95(m,2H),4.68–4.62(m,2H),4 .06–3.80(m,7H),3.41(q,J=7.4Hz,2H),3.18–2.97(m,4H),2.17(q,J=7.1Hz,2H),1.87(p,J=6.6Hz,2H),1.31(t,J=7.4Hz,3H).

[0194] Step 3(Z)-2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane-9-ene (HC614)

[0195]

[0196] 4-(6-(allyloxy)-1-(ethylsulfonyl)-1H-indol-3-yl)-5-chloro-N-(4-morpholin-3-(pent-4-ene-1-yloxy)phenyl)pyrimidin-2-amine (17) (0.05 g, 0.08 mmol) was dissolved in 50 mL of dry dichloromethane. After replacing the gas in the bottle with argon, 0.05 mL of trifluoroacetic acid was added dropwise under stirring, and the color of the solution changed to brown. After stirring at room temperature for 3 minutes, Grubbs 2nd generation catalyst (0.014 g, 0.0016 mmol) was added under argon atmosphere. After the addition was completed, the reaction was allowed to react at room temperature for 7 hours. During the reaction, the reaction progress was monitored by TLC (developing solvent: dichloromethane: methanol = 15:1, v / v). After the reaction was completed, the reaction solution was concentrated. The residue was purified by flash silica gel column chromatography (mobile phase: dichloromethane:methanol=100:1-50:1, v / v), the effluent was collected portion by portion, and the fractions containing the target compound were concentrated and dried to obtain 0.030 g of a white solid with a yield of 63%.

[0197] 1 H NMR (400MHz, CDCl3) δ8.40(d,J=10.8Hz,2H),8.31(d,J=8.9Hz,1H),7.84(d,J=2.3Hz,1H),7.57 (d,J=2.1Hz,1H),7.38(s,1H),6.89(d,J=8.4Hz,1H),6.79(dd,J=8.9,2.2Hz,1H),6.56(dd,J=8. 4,2.3Hz,1H),5.61–5.50(m,1H),5.50–5.39(m,1H),4.72(d,J=4.6Hz,2H),3.97–3.90(m,4H),3. 48–3.35(m,4H),3.19–3.04(m,4H),2.28(q,J=6.2Hz,2H),1.75–1.64(m,3H),1.38–1.29(m,3H).

[0198] Embodiment 15

[0199] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 Preparation of H-5,12-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC620)

[0200]

[0201] The synthesis method is as in Example 1, except that morpholine in step 4 is replaced by 1-methyl-4-(piperidin-4-yl)piperazine.

[0202] 1 H NMR (400MHz, CDCl3) δ8.41(s,1H),8.34(s,1H),8.20(d,J=8.8Hz,1H),7.74(d,J=2.0Hz,1H),7.59(d,J=1.8Hz,1H),7.21(d,J=20 .3Hz,1H),6.96(dd,J=8.8,1.8Hz,1H),6.87(d,J=8.4Hz,1H),6.54(dd,J=8.4,2.3Hz,1H),4.42–4.35(m,2H),3.58(d,J=11.5Hz, 2H),3.42(q,J=7.4Hz,2H),3.37(t,J=5.7Hz,2H),2.76(s,4H),2.61(t,J=11.1Hz,6H),2.52–2.45(m,1H),2.37(s,3H),1.98(d,J =11.2Hz,2H),1.84–1.74(m,2H),1.70–1.63(m,2H),1.62–1.56(m,2H),1.51–1.45(m,2H),1.34–1.28(m,5H),0.94–0.82(m,2H).

[0203] Example 16

[0204] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 6 -Methyl-4 4 -(4-methylpiperazin-1-yl)-1 1 H-5,12-Dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC6492)

[0205]

[0206] The synthesis method is as in Example 1, except that morpholine in step 4 is replaced by 1-methylpiperazine.

[0207] 1H NMR(400MHz, CDCl3)δ8.40(d,J=3.2Hz,2H),8.17(d,J=8.8Hz,1H),7.65(s, 1H),7.57(d,J=1.9Hz,1H),6.97–6.88(m,2H),6.78(s,1H),4.43–4.34(m,2 H),3.51–3.31(m,4H),3.16(s,4H),2.66(s,4H),2.39(s,3H),2.32(s,3H), 1.70–1.61(m,2H),1.60–1.53(m,2H),1.50–1.40(m,2H),1.33–1.28(m,5H).

[0208] Embodiment 17

[0209] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholine-4 6 -(Trifluoromethyl)-1 1 H-5,12-Dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC745)

[0210]

[0211] The synthesis method is the same as that of Example 1, except that the intermediate (6) is replaced by 4-trifluoromethyl-2-fluoro-5-nitrophenol.

[0212] 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),8.43(s,1H),8.09(d,J=8.8Hz,1H),7.78(s,1H),7.60(d, J=2.0Hz,1H),7.38(s,1H),7.14(s,1H),6.90(dd,J=8.8,2.1Hz,1H),4.48–4.31(m,2H),3.93 (s,4H),3.46–3.37(m,2H),3.36(t,J=5.5Hz,2H),3.17–3.11(m,4H),1.71–1.64(m,2H),1.56 (d,J=5.3Hz,1H),1.44(dt,J=12.8,7.2Hz,2H),1.32(t,J=7.4Hz,4H),1.28(d,J=2.7Hz,2H).

[0213] Embodiment 18

[0214] 2 5 -Chloro-46 -Methyl-4 4 -Morpholine-1 1 H-5,12-Dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC743)

[0215]

[0216] The synthesis method is the same as that of Example 1, except that step 2 is omitted and intermediate (6) is replaced by 2-fluoro-4-methyl-5-nitrophenol.

[0217] 1 H NMR(400MHz, CDCl3)δ8.55(s,1H),8.37–8.28(m,2H),8.25(d,J=8.8Hz,1H),7 .74(s,1H),7.03(d,J=1.7Hz,1H),6.83–6.79(m,1H),6.78(s,2H),4.41–4.28( m,2H),4.00–3.87(m,4H),3.46(t,J=5.6Hz,2H),3.24–3.08(m,4H),2.34(s,3H ),1.65–1.61(m,2H),1.59–1.52(m,2H),1.48–1.41(m,2H),1.33–1.29(m,2H).

[0218] Embodiment 19

[0219] 2 5 -Chloro-1 1 -(ethylsulfonyl)-6-methyl-4- 4 -Morpholine-1 1 H-5,12-Dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC782)

[0220]

[0221] The synthesis method was similar to that of Example 1, except that the intermediate (8) was replaced by 6-(5-amino-2-morpholinophenoxy)heptane-1-ol (18).

[0222] 1H NMR (400MHz, CDCl3) δ8.42(s,1H),8.33(s,1H),8.26(d,J=8.9Hz,1H),7.87(d,J=2.3Hz,1H),7.5 5(d,J=2.0Hz,1H),7.20(s,1H),7.03(dd,J=8.9,2.1Hz,1H),6.88(d,J=8.4Hz,1H),6.57(dd,J=8. 4,2.4Hz,1H),4.48–4.29(m,2H),4.05–3.94(m,1H),3.88(t,J=4.3Hz,4H),3.42(q,J=7.4Hz,2H), 3.09(dtd,J=16.3,11.6,5.7Hz,4H),1.84–1.72(m,2H),1.33–1.28(m,6H),0.92(d,J=5.9Hz,3H).

[0223] Preparation of intermediate 6-(5-amino-2-morpholinophenoxy)heptane-1-ol (18)

[0224] Step 1 Preparation of 2-((7-(benzyloxy)heptane-2-yl)oxy)-1-fluoro-4-nitrobenzene (20)

[0225]

[0226] 2-Fluoro-5-nitrophenol (Intermediate 6, 0.5 g, 3.18 mmol), 7-(benzyloxy)heptane-2-ol (Intermediate 19, 1.06 g, 4.77 mmol), triphenylphosphine (1.25 g, 4.77 mmol) were dissolved in 15 mL of dry dichloromethane, the gas in the system was replaced with argon, and then cooled to 0°C. Diisopropyl azodicarboxylate (0.95 mL, 4.77 mmol) was slowly added while maintaining the temperature. After the addition was completed, the reaction was moved to room temperature and continued to react for 1 hour. During this period, the color of the reaction solution gradually changed from red to brown. The reaction progress was monitored by TLC during the reaction (developing solvent was petroleum ether: ethyl acetate = 5:1, v / v). After the reaction was completed, the reaction solution was concentrated. The residue was adsorbed onto silica gel and purified by rapid silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 20:1-10:1, v / v). The effluent was collected portion by portion, and the fractions containing the target compound were concentrated. After drying, 0.6 g of a yellow oil was obtained, with a yield of 70%.

[0227] 1H NMR(400MHz, CDCl3) δ7.70(d,J=7.7Hz,1H),7.31–7.27(m,1H),7.04(d,J=11.2Hz,1H),4.43(h,J =6.1Hz,1H),3.49(t,J=6.5Hz,2H),1.72–1.60(m,4H),1.57–1.44(m,4H),1.36(d,J=6.1Hz,3H).

[0228] Step 2 Preparation of 6-(5-amino-2-morpholinophenoxy)heptane-1-ol (18)

[0229]

[0230] The intermediate 20 (0.6 g, 1.66 mmol), potassium carbonate (0.46 g, 3.32 mmol) and morpholine (0.29 g, 3.32 mmol) were dissolved in 10 mL of DMF and reacted at 80 °C for 3 hours. The reaction progress was monitored by TLC during the reaction (the developing solvent was petroleum ether: ethyl acetate = 5: 1, v / v). After the reaction was completed, the reaction solution was dissolved in 30 mL of ethyl acetate, washed with 100 mL of water and saturated brine in sequence, the organic phase was concentrated, and the residue was dissolved in a mixed solvent of 8.5 mL of acetic acid, 1.5 mL of ethyl acetate and 0.5 mL of water. 0.06 g of palladium carbon was added, and the reaction was carried out at 50 °C under a hydrogen atmosphere for 6 hours. The reaction progress was monitored by TLC during the reaction (the developing solvent was petroleum ether: ethyl acetate = 5: 1, v / v and dichloromethane: methanol = 50: 1, v / v). After the reaction was completed, the reaction solution was filtered through diatomaceous earth and concentrated. The residue was purified by rapid silica gel column chromatography (mobile phase: dichloromethane: methanol = 50:1, v / v), the effluent was collected portion by portion, and the fraction containing the target compound was concentrated and dried to obtain 0.32 g of brown oil, with a yield of 62%.

[0231] Embodiment 20

[0232] (Z)-2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,13-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclotridecane-10-ene (HC8037)

[0233]

[0234] The synthesis method refers to Example 14, and the raw material 5-bromopentene in step 2 is replaced by 6-bromohexene.

[0235] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.23(s,1H),8.12(d,J=8.8Hz,1H),8.08(d,J=2.4Hz,1H),7.61–7.5 7(m,1H),7.17(s,1H),6.93–6.90(m,1H),6.88(d,J=8.6Hz,1H),6.55(dd,J=8.4,2.4Hz,1H),5.75–5.68 (m,1H),5.64–5.57(m,1H),4.76(d,J=5.5Hz,2H),3.91–3.88(m,4H),3.62(t,J=6.1Hz,2H),3.46–3.40 (m,2H),3.10–3.06(m,4H),2.12–2.06(m,2H),1.54–1.48(m,2H),1.46–1.39(m,2H),1.35–1.30(m,3H).

[0236] Embodiment 21

[0237] (Z)-2 5 -Chloro-11-(ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,11-dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocycloundecane-8-ene (HC8035)

[0238]

[0239] The synthesis method refers to Example 14, and the raw material 5-bromopentene in step 2 is replaced by 4-bromobutene.

[0240] 1H NMR (400MHz, CDCl3) δ8.44(s,1H),8.22(s,1H),8.10(d,J=8.7Hz,1H),7.94(d,J=2.3Hz,1H),7.64(d,J=1 .9Hz,1H),7.23(s,1H),6.89(d,J=8.5Hz,1H),6.85(dd,J=8.7,2.0Hz,1H),6.54(dd,J=8.5,2.4Hz,1H),5 .57(dt,J=13.6,6.7Hz,1H),5.43(dt,J=15.3,7.4Hz,1H),4.68(d,J=6.7Hz,2H),3.96–3.85(m,4H),3.57 (t,J=7.0Hz,2H),3.43(q,J=7.4Hz,2H),3.15–2.99(m,4H),2.43(q,J=7.0Hz,2H),1.34(t,J=7.4Hz,3H).

[0241] Embodiment 22

[0242] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,9,12-triazole-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC788)

[0243]

[0244] The synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 3-(2-(benzyloxy)ethoxy)propan-1-ol.

[0245] 1H NMR (400MHz, CDCl3) δ8.43(s,1H),8.27(s,1H),8.22(d,J=8.8Hz,1H),7.99(d,J=2.3Hz,1H),7.52(d,J =2.1Hz,1H),7.18(s,1H),7.09(dd,J=8.8,2.2Hz,1H),6.88(d,J=8.4Hz,1H),6.54(dd,J=8.4,2.3Hz,1H ),4.53–4.42(m,2H),3.94–3.87(m,3H),3.81–3.71(m,2H),3.59(d,J=6.6Hz,1H),3.46(t,J=5.1Hz,2H) ,3.44–3.36(m,2H),3.16–2.99(m,3H),1.71(q,J=6.8Hz,2H),1.46–1.36(m,2H),1.32(t,J=7.4Hz,3H).

[0246] Embodiment 23

[0247] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,8,11-triazole-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocycloundecane (HC7921)

[0248]

[0249] The synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 2-(2-(benzyloxy)ethoxy)ethane-1-ol.

[0250] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),8.22(s,1H),8.13(d,J=8.8Hz,1H),7.96(d,J=2.3Hz,1H) ,7.59(d,J=2.0Hz,1H),7.32–7.29(m,1H),7.18(s,1H),6.88(d,J=8.0Hz,1H),6.56(dd,J=8 .4,2.4Hz,1H),4.48–4.42(m,2H),3.91–3.85(m,4H),3.81–3.77(m,2H),3.63(q,J=5.9,5.3 Hz,2H),3.60–3.56(m,2H),3.42(q,J=7.4Hz,2H),3.12–3.04(m,4H),1.33(t,J=7.4Hz,3H).

[0251] Embodiment 24

[0252] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 Preparation of H-5,10,13-triazole-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclotridecane (HC7922)

[0253]

[0254] The synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 4-(2-(benzyloxy)ethoxy)butanol.

[0255] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.27(s,1H),8.22(d,J=8.8Hz,1H),7.99(d,J=2.3Hz,1H),7.52(d,J =2.1Hz,1H),7.18(s,1H),7.09(dd,J=8.8,2.2Hz,1H),6.88(d,J=8.4Hz,1H),6.54(dd,J=8.4,2.3Hz,1H ),4.53–4.42(m,2H),3.94–3.87(m,3H),3.81–3.71(m,2H),3.59(d,J=6.6Hz,1H),3.46(t,J=5.1Hz,2H) ,3.44–3.36(m,2H),3.16–2.99(m,3H),1.71(q,J=6.8Hz,2H),1.46–1.36(m,2H),1.32(t,J=7.4Hz,3H).

[0256] Embodiment 25

[0257] 2 5 -Chloro-1 1 -(Ethylsulfonyl)-4- 4 -Morpholinyl-1 1 H-5,9-Dioxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-4(1,3)-benzene-7(1,4)-cyclohexanonecyclononane(HC809)

[0258]

[0259] The synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 1,4-cyclohexanedimethanol.

[0260] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),8.34(s,1H),8.25(d,J=8.9Hz,1H),7.47(d,J=2.1Hz,1H) ,7.39(d,J=2.1Hz,1H),7.12(s,1H),7.05–6.99(m,1H),6.95(dd,J=8.9,2.3Hz,1H),6.89(d ,J=8.5Hz,1H),4.13(q,J=6.9Hz,2H),3.94–3.85(m,4H),3.68(d,J=6.0Hz,2H),3.54–3.47( m,2H),3.16–3.03(m,4H),1.91–1.74(m,4H),1.31(t,J=7.4Hz,3H),1.01(t,J=10.1Hz,4H).

[0261] Example 26 Activity inhibition experiment of cyclic 2-aminopyrimidine compounds on wild-type EGFR and mutant EGFR kinases

[0262] EGFR(WT) is the wild-type epidermal growth factor receptor, EGFR(T790M) is an epidermal growth factor receptor with a mutation of amino acid 790 from threonine to methionine, EGFR(L858R) is an epidermal growth factor receptor with a mutation of amino acid 858 from leucine to arginine, EGFR(L861Q) is an epidermal growth factor receptor with a mutation of amino acid 861 from leucine to glutamine, EGFR(L858R / T790M) is an epidermal growth factor receptor with a double mutation of amino acid 858 from leucine to glutamine and amino acid 790 from threonine to methionine. EGFR(L858R / T790M / C797S) is an epidermal growth factor receptor with a triple mutation of amino acid 858 from leucine to glutamine, amino acid 790 from threonine to methionine, and cysteine ​​to serine. EGFR (19del / T790M / C797S) is a triple-mutated epidermal growth factor receptor with a partial deletion of exon 19, a mutation from threonine to methionine at position 790, and a mutation from cysteine ​​to serine at position 797.

[0263] The inhibitory effect of the compounds on kinase activity was detected by enzyme-linked immunosorbent assay (ELISA). WT EGFR was purchased from Eurofins. 19del / T790M / C797SKinase was purchased from BPS Bioscience. The main experimental steps are as follows: Enzyme reaction substrate Poly (Glu, Tyr) 4:1 Dilute to 20μg / mL with potassium-free PBS (10mM sodium phosphate buffer, 150mM NaCl, pH 7.2-7.4), and react at 37℃ for 12-16h to coat the ELISA plate. Add ATP (final concentration 5μM) solution diluted with reaction buffer (50mM HEPES pH7.4, 50mM MgCl2, 0.5mM MnCl2, 0.2mM Na3VO4, 1mM DTT) to each well, add the test compound or solvent control, then start the kinase reaction, and react at 37℃ for 1h. Wash the plate three times with T-PBS, add antibody PY99 and react at 37℃ for 0.5h. After washing the plate with T-PBS, add horseradish peroxidase-labeled IgG and react at 37℃ for 0.5h. After washing the plate again, add 2mg / mL OPD colorimetric solution and react at 25℃ in the dark for 1-10min. The reaction was terminated by adding 2M H2SO4 and detected by using a wavelength-adjustable microplate reader SPECTRA MAX 190 at a wavelength of 492 nm. 50 The values ​​were obtained from inhibition curve analysis.

[0264] Table 1 lists the compound numbers (corresponding to the compound numbers in the above examples) and the test results of the compound's inhibitory activity on various kinases.

[0265] Table 1: Inhibitory activity of cyclic 2-aminopyrimidine compounds on kinases

[0266]

[0267]

[0268] As can be seen from Table 1, the cyclic 2-aminopyrimidine compounds of the present invention inhibit the EGFR triple mutant protease, thereby inhibiting the growth of various tumor cells. The compounds of the present invention are particularly effective in selectively inhibiting the EGFR protein kinase resistant mutant (EGFR 19del / T790M / C797S ) activity, which can selectively act on EGFR L858R / T790M EGFR 19del / T790M / C797S Lung cancer cells can overcome the existing third-generation selective EGFR T790M Clinical drug resistance in patients with non-small cell lung cancer and other tumors induced by small molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), and Rociletinib (CO-1686).

[0269] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0270] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in formula (1): Where: X and Y are both O; R1 is selected from EtO2S-, hydrogen; R2 is halogen; R3 is selected from hydrogen, trifluoromethyl, halogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl; R4 is selected from: L is selected from: unsubstituted straight-chain C2-C8 alkyl, unsubstituted straight-chain C2-C8 alkenyl, wherein one or more methylene groups in the alkyl and alkenyl groups can be independently replaced by O.

2. A cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in formula (2): Where: X and Y are both O; R1 is selected from EtO2S-, hydrogen; R2 is halogen; R3 is selected from hydrogen, trifluoromethyl, halogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl; R4 is selected from: n is selected from 3 to 10.

3. A cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in formula (3): Where: X and Y are both O; R1 is selected from EtO2S-, hydrogen; R2 is halogen; R3 is selected from hydrogen, trifluoromethyl, halogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl; R4 is selected from: n1 and n2 are selected from 1 to 6.

4. A cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in formula (4): Where: X and Y are both O; R1 is selected from EtO2S-, hydrogen; R2 is halogen; R3 is selected from hydrogen, trifluoromethyl, halogen, unsubstituted C1-C6 alkyl, unsubstituted C3-C6 cycloalkyl; R4 is selected from: n1 and n2 are selected from 1 to 6; Ring A is selected from C3 to C6 cycloalkyl and C3 to C6 epoxyalkyl.

5. A cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized in that: The cyclic 2-aminopyrimidine compound is selected from the following compounds:

6. Use of the cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a mutant EGFR inhibitor, characterized in that: The mutant EGFR is a mutant EGFR 19del / T790M / C797S .

7. Use of the cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a drug for preventing and treating tumors; characterized in that: The tumor is EGFR 19del / T790M / C797S Mutation of malignant tumors.

8. A pharmaceutical composition, characterized in that The invention comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises the cyclic 2-aminopyrimidine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

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