Cyclic 2-aminopyrimidine compound as well as pharmaceutical composition and application thereof

Abstract

Provided are a cyclic 2-aminopyrimidine compound having a structure represented by formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a prodrug molecule thereof, and an application thereof. The compound can be used for effectively inhibiting the activity of EGFR (epidermal growth factor receptor) protein kinase drug-resistant mutants (such as EGFRT790M and EGFR19del / T790M / C797S and the like), and can be used for overcoming the clinical drug resistance of tumor patients with non-small cell lung cancer and the like induced by the existing third-generation selective EGFRT790M small-molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686) and the like. # imgabs0 #

Description

Cyclic 2-aminopyrimidine compounds and pharmaceutical compositions and applications thereof Technical Field

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

[0002] Continuous proliferation is one of the most important characteristics of tumor cells. Furthermore, the continued development and proliferation of tumor cells can damage the structure and function of tissues and organs, ultimately leading to death from organ failure. Normally, cell proliferation is strictly regulated by cell proliferation signals, but tumor cells can evade these signals through a series of mutations. Therefore, blocking these mechanisms through drugs is an important approach to cancer treatment.

[0003] Receptor tyrosine kinases, represented by EGFR, are key proteins for receiving growth factor-mediated proliferation signals. Tumor cells can exploit EGFR mutations to lock the protein in its active conformation, allowing it to continuously activate downstream proliferation-related signaling pathways independent of exogenous ligands. Approximately 20% of patients with non-small cell lung cancer harbor EGFR mutations and exhibit EGFR mutation-dependent tumor cell proliferation. The majority of these mutations are exon 19 deletion mutations and exon 21 point mutations (L858R). Consequently, a variety of therapies targeting EGFR mutations have been introduced clinically in recent years, including monoclonal antibodies panitumumab and cetuximab, which competitively block EGFR binding to ligands such as EGF and TGF-α, and kinase inhibitors such as gefitinib and osimertinib, which mimic ATP structure and block EGFR phosphorylation. EGFR inhibition has significantly improved the survival of patients with non-small cell lung cancer. For example, gefitinib has increased survival 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, launched in 2003 and 2004, both develop drug resistance after a period of treatment, manifesting as decreased sensitivity of tumor cells to the drugs. A major cause (approximately 25%) is a second point mutation (T790M) in the kinase domain of EGFR. This mutation, while hindering drug binding by creating an amino acid that increases steric hindrance, reduces the drug's ability to bind to EGFR. It also enhances the interaction between the kinase and its substrate, ATP, thereby inactivating competitive tyrosine kinase inhibitors.

[0005] The inhibitor osimertinib, launched in 2015, effectively overcomes the resistance problem associated with the T790M point mutation by incorporating covalent interactions. It was initially approved as a second-line treatment for patients who develop resistance to gefitinib. Furthermore, further studies have shown that osimertinib, when used as a first-line treatment, can achieve superior efficacy compared to traditional EGFR therapies and is effective in patients with brain metastases. Therefore, covalently bound EGFR inhibitors, such as osimertinib, are expected to become the preferred treatment for patients with non-small cell lung cancer for the foreseeable future.

[0006] However, osimertinib can also develop resistance. Studies have shown that a third point mutation (C797S) in the kinase domain can eliminate the ability of the covalently bound inhibitor to form a covalent bond, rendering the drug inactive. This type of mutation has been found in approximately 10-20% of osimertinib-resistant patients.

[0007] Currently, there are no clinical inhibitors targeting the EGFR T790M / C797S point mutation for the treatment of osimertinib resistance. A few inhibitors have been reported, but most have significant drawbacks. For example, the allosteric inhibitor EAI045 and its derivatives are ineffective against EGFR activating mutations caused by exon 19 deletions. The ALK inhibitor brigatinib, as well as the quinazoline EGFR inhibitors reported by Park et al., lack sufficient cellular activity, requiring brigatinib to be combined with an antibody to exert its in vivo efficacy.

[0008] Summary of the Invention

[0009] In view of the above problems, the present invention provides a new class of cyclic 2-aminopyrimidine compounds or pharmaceutically acceptable salts or stereoisomers thereof, which can effectively inhibit EGFR protein kinase resistant mutants (such as EGFR L858R / T790M ,EGFR L858R / T790M / C797S ,EGFR 19del / T790M / C797S etc.) can be used to treat hyperproliferative diseases such as cancer.

[0010] The present invention includes the following technical solutions.

[0011] A cyclic 2-aminopyrimidine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof:

[0012] Wherein: A is selected from: CR5, N;

[0013] B is selected from: CR7, N;

[0014] D, E, Q, and P are independently selected from: CR8, N;

[0015] X is selected from: -O-, -O(=O)C-, -S-, -S(=O)2-, -S(=O)-, -C(=O)O-, -C(=O)NH-, -CH2-, -C=C-, -NH-, -NH(C=O)-;

[0016] R1 is selected from: hydrogen, hydroxyl, C6~C 10 Aryl, 5-10 membered heteroaryl, -C(=O)R9, -S(=O)2R9, -S(=O)R9, -P(=O)(R9)2, R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 3-8 membered heterocyclic group; each R9 is independently selected from: R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C1-C8 alkoxy, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted C3~C8 epoxyalkyl, amino, C1~C8 alkylamino, (C1~C8 alkyl)2amino; each R 10 are independently selected from: hydrogen, deuterium, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, 3-8 membered heterocyclic group, halogen, hydroxyl, cyano, amino, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 、C6~C 10 Aryl, 5-10 membered heteroaryl; each R 11 Each independently selected from: C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl;

[0017] R2, R3, R4, R5, R7, and R8 are independently selected from hydrogen, halogen, cyano, nitro, amino, 5-10 membered heteroaryl, C6-C 10 Aryl, R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C2-C8 alkenyl, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted C1-C8 alkoxy, R 10 Substituted or unsubstituted C3-C8 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R12 )2; each R 12 are independently selected from: hydrogen, C1-C8 alkyl;

[0018] Alternatively, R2, R3 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 5-8 membered heterocyclic ring, R 10 a substituted or unsubstituted 5-10 membered heteroaromatic ring;

[0019] Alternatively, R4, R7 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 5-8 membered heterocyclic ring, R 10 a substituted or unsubstituted 5-10 membered heteroaromatic ring;

[0020] R6 is selected from: -NR 13 R 14 、-CR 13 R 14 R 15 、-(CH2) n R 13 R 14 R 15 、-(CH2) n NR 13 R 14 ; Each R 13 and each R 14 are independently selected from: hydrogen, R 10 Substituted or unsubstituted C1-C8 alkyl, or R 13 、R 14 Together with the N or C to which it is connected, it forms a substituted or unsubstituted 3-12 membered heterocyclic group; R 15 Selected from: hydrogen, C1-C8 alkyl; n is selected from: 1, 2, 3;

[0021] R is selected from: hydrogen, C1-C8 alkyl, -C(=O)R 11 、-C(=O)N(R 12 )2, or, R and the carbon to which it is attached together form -C(=O);

[0022] L is selected from: R 16 Substituted or unsubstituted C1-C8 alkylene, R 16 Substituted or unsubstituted C2-C8 alkenyl;

[0023] R 16is selected from the group consisting of: hydrogen, deuterium, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C3-C8 cycloalkyl, amino, halogen, hydroxy, cyano, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, 3-8 membered heterocyclic group; or, two R groups connected to the same carbon atom 16 or two R connected to two adjacent carbon atoms 16 Connected to form a C3~C8 cycloalkyl group.

[0024] In some embodiments, the cyclic 2-aminopyrimidine compound has the structure shown in the following formula (II):

[0025] In some embodiments, A is selected from the group consisting of: CH, N.

[0026] In some embodiments, B is selected from: CR7, N; R7 is selected from: hydrogen, C5-C6 cycloalkyl, C2-C6 alkenyl, C1-C5 alkyl.

[0027] In some embodiments, B is selected from CR7, N; and R7 is selected from hydrogen, cyclopentyl, methylvinyl, 2-methylpropenyl, isobutyl, 3,3-dimethylbutenyl, 3,3-dimethylbutyl.

[0028] In some embodiments, E is CH; D is CH or N; and Q is N.

[0029] In some embodiments, E is CH; D is CH or N; Q is N; and P is CH.

[0030] In some embodiments, E is CH; D is CH or N; Q is N; and P is N.

[0031] In some embodiments, R1 is selected from: R1 is selected from: hydrogen, -C(=O)R9, -S(=O)2R9, -S(=O)R9, -P(=O)(R9)2, R 10 Substituted or unsubstituted C1~C4 alkyl; each R9 is independently selected from: C1~C4 alkyl, C1~C4 alkoxy, amino, C1~C4 alkylamino, (C1~C4 alkyl)2amino, halogen-substituted C1~C4 alkyl; R1 is independently selected from: hydrogen, deuterium, C1~C4 alkyl, C1~C4 alkoxy, halogen, hydroxyl, cyano, amino.

[0032] In some embodiments, R1 is selected from: R1 is selected from: hydrogen, ethylsulfonyl, methylsulfonyl, propylsulfonyl, methyl, ethyl, propyl, acetyl, trifluoroformyl, aminoacyl, methylaminoacyl, dimethylaminoacyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, -P(=O)(OCH3)2, -P(=O)(CH3)2.

[0033] In some embodiments, R2 and R3 are independently selected from hydrogen, halogen, cyano, nitro, amino, R 10 Substituted or unsubstituted C1-C4 alkyl, R 10 Substituted or unsubstituted C2-C4 alkenyl, R 10 Substituted or unsubstituted C3-C6 cycloalkyl, R 10 Substituted or unsubstituted C1-C4 alkoxy, R 10 Substituted or unsubstituted C3-C6 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R 12 )2;

[0034] Each R in R2 and R3 10 are independently selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, cyano, and amino;

[0035] Each R in R2 and R3 11 Each independently selected from: C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl;

[0036] Each R in R2 and R3 12 are independently selected from: hydrogen, C1-C4 alkyl;

[0037] Alternatively, R2, R3 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C5-C6 cycloalkyl, R 10 Substituted or unsubstituted 5-6 membered heterocyclic ring, R 10 a substituted or unsubstituted 5- to 6-membered heteroaromatic ring.

[0038] In some embodiments, R2 is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, nitro, amino, trifluoromethyl, acetamido, acrylamido, isobutyramide, propionamido, and cyano; R3 is hydrogen;

[0039] Alternatively, R2, R3 and the carbon atom to which they are connected together form: a benzene ring, a pyrrole ring, a thiophene ring, a pyrazole ring, a pyrazole ring, a pyridine ring, or a furan ring.

[0040] In some embodiments, when R4 is selected from hydrogen or methyl; R2 is not hydrogen.

[0041] In some embodiments, R4 is selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, R 10Substituted or unsubstituted C1-C4 alkyl, R 10 Substituted or unsubstituted C2-C4 alkenyl, R 10 Substituted or unsubstituted C3-C6 cycloalkyl, R 10 Substituted or unsubstituted C1-C4 alkoxy, R 10 Substituted or unsubstituted C3-C6 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R 12 )2;

[0042] Each R in R4 10 are independently selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, cyano, and amino;

[0043] Each R in R4 11 Each independently selected from: C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl;

[0044] Each R in R4 12 Each is independently selected from: hydrogen, C1-C4 alkyl.

[0045] In some embodiments, R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, deuterated methoxy, trifluoromethoxy, cyclopropyloxy, trifluoromethyl, and cyclopropyl.

[0046] In some embodiments, R4 is selected from: hydrogen, methyl; R2 is selected from: chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, nitro, amino, trifluoromethyl, acetamide, acrylamide, isobutyramide, propionamide, cyano; R3 is hydrogen.

[0047] In some embodiments, R4 is selected from: methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, deuterated methoxy, trifluoromethoxy, cyclopropyloxy, trifluoromethyl, cyclopropyl, isopropyl, ethyl; R2 is selected from: hydrogen, chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, nitro, amino, trifluoromethyl, acetamido, acrylamido, isobutyramido, propionamido, cyano; R3 is hydrogen.

[0048] In some embodiments, R1 is selected from ethylsulfonyl, methylsulfonyl, and propylsulfonyl; one of R2 and R4 is hydrogen, and the other is not hydrogen; and R3 is hydrogen.

[0049] In some embodiments, R6 is selected from: -NR 13 R14 、-CR 13 R 14 R 15 、-(CH2) n R 13 R 14 R 15 、-(CH2) n NR 13 R 14 ; Each R 13 and each R 14 are independently selected from: hydrogen, C1-C4 alkyl, dimethylamino-substituted C1-C4 alkyl, or R 13 、R 14 Together with the N or C to which it is connected, it forms R 17 substituted or unsubstituted 3-12 membered heterocyclic group; R 15 Selected from: H, C1-C4 alkyl;

[0050] Each R 17 are independently selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkyl substituted with hydroxy, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, halogen, hydroxy, cyano, amino, R 18 substituted or unsubstituted 3-8 membered heterocyclic group, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 , or R 17 Together with the carbon atom to which it is attached, it forms C(=O); R 18 Selected from: hydrogen, C1-C8 alkyl.

[0051] In some embodiments, each R 17 are independently selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkyl substituted with hydroxy, C5-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, dimethylamino, halogen, hydroxy, cyano, amino, R 18 substituted or unsubstituted 3-8 membered heterocyclic group, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 , or R 17 Together with the carbon atom to which it is attached, it forms C(=O); R 18 Selected from: hydrogen, C1-C4 alkyl;

[0052] R 17 Each R in 11 They are independently selected from: C1-C4 alkyl, C1-C4 alkoxy.

[0053] In some embodiments, R6 is selected from:

[0054] In some embodiments, R is selected from hydrogen, methoxycarbonyl, isopropyloxycarbonyl, carbamoyl, methyl, ethoxycarbonyl, or R together with the carbon atom to which it is attached forms C(=O).

[0055] In some embodiments, L is selected from: R 16 Substituted or unsubstituted C2-C6 alkylene, R 16 Substituted or unsubstituted C2-C6 alkenyl;

[0056] R 16 is selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, amino, halogen, hydroxy, cyano, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino; or, two R groups connected to the same carbon atom 16 Connected to form a cyclopropyl group.

[0057] In some embodiments, L is selected from: -(CH2)2-, -(CH2)3-, -(CH2)4-,

[0058] The present invention also provides the use of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule, including the following technical solutions.

[0059] Use of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule in the preparation of EGFR inhibitors.

[0060] The use of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule in the preparation of mutant EGFR inhibitors, wherein the mutant EGFR is EGFR T790M , EGFR T790M / C797S , EGFR 19del / T790M / C797S , EGFR L858R / T790M , EGFR L858R / C797S , EGFR L858R / T790M / C797S .

[0061] Use of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule in the preparation of drugs for preventing and / or treating tumors.

[0062] In some embodiments, the tumor is a malignant tumor with EGFR gene mutation.

[0063] In some embodiments, the tumor is EGFR 19del / T790M / C797S Mutation, EGFR T790M Mutation, EGFR T790M / C797S Mutation, EGFR L858R / T790M Mutation, EGFR L858R / C797S Mutation and / or EGFR L858R / T790M / C797S of malignant tumors.

[0064] 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 tumor, colon cancer, rectal cancer or glioma.

[0065] The present invention also provides a pharmaceutical composition for preventing and / or treating tumors, which includes the following technical solutions.

[0066] A pharmaceutical composition for preventing and / or treating tumors is prepared from active ingredients and pharmaceutically acceptable excipients. The active ingredients include the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule.

[0067] The present invention also provides a method for preventing and / or treating tumors, comprising: administering to a patient a safe and effective amount of the cyclic 2-aminopyrimidine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof; and / or,

[0068] Administer a safe and effective amount of the pharmaceutical composition of the present invention.

[0069] 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 tumor, colon cancer, rectal cancer or glioma.

[0070] The present invention also provides a method for selectively inhibiting mutant EGFR kinase activity, comprising: administering to a patient a safe and effective amount of the cyclic 2-aminopyrimidine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof; and / or,

[0071] Administer a safe and effective amount of the pharmaceutical composition of the present invention.

[0072] In some embodiments, the mutant EGFR is EGFR T790M , EGFR T790M / C797S , EGFR 19del / T790M / C797S , EGFRL858R / T790M , EGFR L858R / C797S , EGFR L858R / T790M / C797S .

[0073] Compared with the prior art, the present invention has the following beneficial effects:

[0074] (1) The cyclic 2-aminopyrimidine compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule can inhibit the EGFR family protease, thereby inhibiting the growth of various tumor cells. Compared with wild-type cancer cells, the compound of the present invention has a higher selectivity for mutant cancer cells. The compound of the present invention is particularly effective in inhibiting EGFR protein kinase resistant mutants (such as EGFR T790M , EGFR T790M / C797S , EGFR 19del and EGFR L858R / T790M / C797S , EGFR 19del / T790M / C797S etc.) activity, and can selectively act on EGFR L858R / T790M , EGFR 19del and 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).

[0075] (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. They can be used to treat hyperproliferative diseases such as tumors in humans and other mammals. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] FIG1 shows the inhibition of EGFR phosphorylation levels by compounds in cells with different EGFR mutations. DETAILED DESCRIPTION

[0077] In the compounds described herein, when any variable (e.g., R9, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at every other occurrence. Similarly, combinations of substituents and variables are permitted so long as such combinations result in a stable compound. A line drawn from a substituent into the ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, this means that such bonds are attached only to any suitable carbon atom of an adjacent ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns in the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available raw materials using techniques in the art and the methods set forth below. If a substituent is itself substituted with more than one group, it will be understood that these groups may be on the same carbon atom or on different carbon atoms so long as the structure is stable.

[0078] The phrase "R f "substituted," "Rsubstituted" is considered equivalent to the phrase "substituted with at least one substituent," and preferred embodiments in this case will have 1-4 substituents which may be the same or different from each other.

[0079] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, the definition of "C1-C8" in "C1-C8 alkyl" includes groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms in a straight or branched arrangement. For example, "C1-C4 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and isobutyl.

[0080] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0081] The term "alkoxy" refers to a group having an -O-alkyl structure, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, etc.

[0082] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (including monocyclic, spirocyclic, fused, bridged, etc.), wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon.

[0083] The term "heteroaryl" refers to an aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N or S. Heteroaryl groups within the scope of the present invention include, but are not limited to, quinazoline, quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, and the like.

[0084] The term "halogen" or "halo" refers to chlorine, fluorine, bromine and iodine.

[0085] The present invention includes free forms of compounds of formula (I), as well as pharmaceutically acceptable salts and stereoisomers thereof. Stereoisomers according to the present invention are, depending on their structure, enantiomers, diastereomers, syn- / anti-isomers, cis- / trans-isomers, epimers and (E)- / (Z)-isomers. Compounds of formula (I) can be used in the context of the present invention in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in the latter case racemates being preferred.

[0086] The term "free form" refers to an amine compound in a non-salt form. Pharmaceutically acceptable salts encompassed include not only exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of the free forms of all compounds of formula (I). The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, 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 differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention, such acid and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0087] 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 an excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

[0088] Therefore, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reacting an alkaline compound of this invention with an inorganic or organic acid. 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, and the like, 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, and the like.

[0089] If the compound of the present invention is acidic, 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, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. 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, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0090] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977: 66: 1-19, describe in more detail the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts.

[0091] Since deprotonated acidic moieties such as carboxyl groups in the compounds may be anionic under physiological conditions, and this charge may then be balanced by internal cationic protonated or alkylated basic moieties such as tetravalent nitrogen atoms, it should be noted that the compounds of the present invention are potential inner salts or zwitterions.

[0092] In one embodiment, the present invention provides a method for treating hyperproliferative diseases or symptoms such as tumors in humans or other mammals using a compound having a structure represented by formula (I) and a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the compounds designed by the present invention and pharmaceutically acceptable salts thereof can be used to treat or control 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, etc.

[0094] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount and pharmaceutically acceptable excipients.

[0095] The "active ingredient" of the present invention includes the compound of formula I of the present invention.

[0096] The "active ingredient" and pharmaceutical composition of the present invention can be used as a mutant EGFR inhibitor. In another preferred embodiment, they are used to prepare a drug for preventing and / or treating tumors.

[0097] "Safe and effective amount" means the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0098] "Pharmaceutically acceptable excipients" refer to: one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be sufficiently pure and have sufficiently low toxicity.

[0099] "Compatibility" herein means that the components in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0100] Examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0101] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0102] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0103] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:

[0104] (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;

[0105] (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

[0106] (c) humectants, for example, glycerin;

[0107] (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0108] (e) a buffering solvent, for example, paraffin;

[0109] (f) absorption accelerators, for example, quaternary ammonium compounds;

[0110] (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate;

[0111] (h) adsorbents, for example, kaolin; and

[0112] (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0113] The solid dosage forms can also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.

[0114] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0115] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0116] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0117] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypoglycemic drugs).

[0118] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage at the time of administration is a pharmaceutically effective dosage. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0119] Combination therapy: Compounds of Formula (I) may be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's route of administration and dosage remain unchanged, while the compound of Formula (I) is administered simultaneously or subsequently. When a compound of Formula (I) is administered simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of Formula (I) is preferably used. Combination therapy also includes administering a compound of Formula (I) and one or more other known drugs during overlapping time periods. When a compound of Formula (I) is administered in combination with one or more other drugs, the dosage of the compound of Formula (I) or the known drug may be lower than when administered alone.

[0120] Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to:

[0121] Estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins / cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, drugs that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-α, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, etc.

[0122] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0123] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0124] The following are specific examples.

[0125] Example 1

[0126] 2 5 -Chloro-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC871)

[0127] Step 1. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-6-methoxy-1H-indole (3)

[0128] 6-Methoxy-1H-indole (1 g, 6.79 mmol) was dissolved in 25 mL of dry dichloromethane. After the system was replaced with argon, it was cooled to 0°C in an ice bath. A 3 mol / L methylmagnesium bromide solution in ether (3.4 mL, 10.18 mmol) was added dropwise to the solution. After the addition was complete, 2,4,5-trichloropyrimidine (1.25 g, 6.79 mmol) was dissolved in another 25 mL of dry dichloromethane and added dropwise to the reaction system. After the addition was complete, the reaction was brought to room temperature and continued for 3 hours. The reaction progress was monitored by TLC (developing solvent: petroleum ether:ethyl acetate = 5:1, v / v). After the reaction was completed, the ice bath was restored and water (50 mL) was added dropwise to quench the reaction. A yellow solid precipitated during the reaction. The resulting mixture was filtered, and the filter cake was washed twice with ethyl acetate until it turned 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%.

[0129] 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).

[0130] Step 2. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-6-methoxy-1H-indole (4)

[0131] 3-(2,5-Dichloropyrimidin-4-yl)-6-methoxy-1H-indole (1.1 g, 3.74 mmol) was dissolved in 10 mL of DMF and the reaction mixture was cooled to 0°C in an ice bath. A 60% mass fraction of sodium hydride (0.22 g, 5.61 mmol) dispersed in mineral oil was added portionwise. The reaction was continued in an ice bath for 10 minutes. Ethylsulfonyl chloride (0.42 mL, 4.49 mmol) was then slowly added. After addition, the reaction mixture was brought to room temperature and continued for 1 hour. The reaction progress was monitored by TLC (developing solvent: petroleum ether:ethyl acetate = 5:1, v / v). After completion of the reaction, water (50 mL) was added to quench the reaction, resulting in the precipitation of a white solid. The resulting mixture was filtered, and the filter cake was washed with methanol. The filter cake was collected and dried to yield 1.2 g of the title compound as a white solid in an 83% yield.

[0132] 1 H NMR (400MHz, DMSO-d6) 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).

[0133] Step 3. Preparation of 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (5)

[0134] 3-(2,5-Dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-6-methoxy-1H-indole (0.2 g, 0.5 mmol) was dissolved in 3 mL of dry dichloromethane. The reaction solution was cooled to -40°C. A 1 mol / L solution of boron tribromide in dichloromethane (3 mL, 3.11 mmol) was added dropwise. After completion of the addition, the reaction was brought to room temperature and allowed to continue for 5 hours. During the reaction, samples were taken and diluted with ethyl acetate and saturated sodium bicarbonate solution. The upper layer of the mixture was monitored by TLC (developing solvent: petroleum ether:ethyl acetate = 5:1, v / v). After completion of the reaction, water (30 mL) was added to quench the reaction; a yellow solid precipitated during the reaction. The resulting mixture was filtered, and the filter cake was washed with methanol. The filter cake was collected and dried to yield 0.17 g of the title compound as a yellow solid in an 88% yield.

[0135] 1H 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).

[0136] Step 4. Preparation of 4-(2-bromo-4-nitrophenyl)morpholine (8)

[0137] 2-Bromo-1-fluoro-4-nitrobenzene (5.0 g, 22.73 mmol) was dissolved in 50 mL of DMF. Potassium carbonate (2.97 g, 45.46 mmol) and morpholine (2.97 g, 34.09 mmol) were then added. The reaction was heated in a preheated 80°C oil bath for 4 hours. Reaction progress was monitored by TLC (developing solvent: petroleum ether:ethyl acetate = 5:1, v / v). After completion of the reaction, 80 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, and concentrated. The residue was purified by flash silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 5:1, v / v). The effluent was collected and the fractions containing the target compound were concentrated to obtain 4.7 g of a yellow solid after drying, yielding 72%.

[0138] 1 H NMR (500MHz, CDCl3) δ9.10(d,J=2.8Hz,1H),8.46(dd,J=8.8,2.8Hz,1H),7.61(d,J=8.8Hz,1H),4.01-3.96(m,4H),3.17-3.11(m,4H).

[0139] Step 5. Preparation of 4-(4-nitro-2-(1H-pyrazol-4-yl)phenyl)morpholine (10)

[0140] Intermediate 8 (3.0 g, 10.45 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.78 g, 13.58 mmol), sodium carbonate (3.32 g, 31.35 mmol), and tetrakistriphenylphosphine palladium (1.21 g, 1.04 mmol) were added to a mixture of 30 mL of water and 30 mL of dioxane. The atmosphere was repeatedly purged with nitrogen three times. The resulting mixture was reacted at 95°C under a nitrogen atmosphere for 5 hours. During the reaction, thin-layer chromatography (TLC) was performed with ultraviolet monitoring at 254 nm using a mobile phase consisting of petroleum ether:ethyl acetate (5:1 v / v). After completion of the reaction, the reaction solution was diluted with 80 mL of ethyl acetate and extracted with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using a mobile phase of petroleum ether:ethyl acetate = 2:1, v / v. Fractions containing the target compound were collected and concentrated under reduced pressure to yield a yellow solid. This solid was dissolved in 15 mL of ethanol and 3 mL of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 3 hours and quenched with 50 mL of saturated aqueous sodium bicarbonate. The mixture was extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried, and concentrated to yield the target compound as a pale yellow solid (2.1 g, 73%).

[0141] 1 H NMR (500MHz, CDCl3) δ8.18(t,J=2.3Hz,1H),8.15-8.09(m,3H),7.10(dd,J=8.9,1.9Hz,1H),3.81-3.76(m,4H),3.03-2.96(m,4H).

[0142] Step 6. Preparation of 3-(4-(2-morpholino-5-nitrophenyl)-1H-pyrazol-1-yl)propan-1-ol (12)

[0143] Intermediate 10 (0.50 g, 1.82 mmol), 3-bromopropanol (0.38 g, 2.73 mmol, 1.5 equivalents), and cesium carbonate (1.78 g, 5.47 mmol) were dissolved in 10 mL of DMF. The mixture was reacted at 50°C for 3 hours. Thin-layer chromatography (TLC) was performed with UV monitoring at 254 nm using a mobile phase of dichloromethane:methanol (15:1 v / v). After completion of the reaction, the reaction solution was diluted with 20 mL of ethyl acetate and extracted with 30 mL of water. The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in a mixture of 20 mL of ethanol and 10 mL of water, and reduced iron powder (0.41 g, 7.29 mmol) and ammonium chloride (0.39 g, 7.29 mmol) were added. The mixture was heated to 95°C and reacted for 4 hours. During the reaction, thin-layer chromatography (TLC) was performed with UV monitoring at 254 nm using a mobile phase consisting of dichloromethane:methanol in a ratio of 15:1 (v / v). After completion of the reaction, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by flash column chromatography using a mobile phase consisting of dichloromethane:methanol in a ratio of 15:1 (v / v). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the target compound as a brown solid (0.42 g, 69%).

[0144] 1 H NMR (500MHz, CDCl3) δ8.00(s,1H),7.92(s,1H),6.95(d,J=8.4Hz,1H),6.76(d,J=2.8Hz,1H),6.58(dd,J=8.4,2.8Hz,1H),4.32( t,J=6.3Hz,2H),3.78-3.72(m,4H),3.66(t,J=5.7Hz,2H),2.94(s,2H),2.84-2.79(m,4H),2.12-2.02(m,2H),1.31-1.23(m,1H).

[0145] Step 7. Preparation of 3-(5-chloro-2-((3-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (13)

[0146] Intermediate 5 (0.30 g, 0.81 mmol), Intermediate 12 (0.24 g, 0.81 mmol), and p-toluenesulfonic acid (0.04 g, 0.24 mmol) were dissolved in 10 mL of sec-butanol. The mixture was heated to 100°C and reacted for 12 hours. Thin-layer chromatography (TLC) was performed with UV monitoring at 254 nm using a mobile phase consisting of dichloromethane:methanol (15:1 v / v). After completion of the reaction, the product was quenched with 20 mL of saturated aqueous sodium bicarbonate. The mixture was extracted twice with 15 mL of ethyl acetate. The organic phases were combined, dried, and concentrated. The residue was then purified by flash column chromatography using a mobile phase consisting of dichloromethane:methanol (15:1 v / v). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the target compound as a yellow solid (0.26 g, 51%).

[0147] 1 H NMR (500MHz, CDCl3) δ8.41 (s, 1H), 8.26 (d, J = 5.6Hz, 1H), 8.20-8.14 (m, 2H), 7.96 (s, 1H), 7.74(s,1H),7.32(d,J=2.1Hz,1H),7.11(d,J=8.5Hz,1H),7.07(d,J=5.6Hz,1H),7.04(dd, J=9.3,2.7Hz,1H),5.82(d,J=8.3Hz,1H),4.34-4.26(m,2H),3.99(s,2H),3.81(t,J=4.6H z,5H),3.37(q,J=7.4Hz,2H),2.97-2.89(m,5H),1.97-1.89(m,2H),1.23(t,J=7.4Hz,3H).

[0148] Step 8.2 5 -Chloro-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC871)

[0149] Intermediate 13 (0.10 g, 0.16 mmol) and triphenylphosphine (0.41 g, 1.57 mmol) were dissolved in 70 mL of THF. The mixture was cooled to 0°C, and DIAD (0.31 g, 1.57 mmol) was slowly added at this temperature. After addition, the reaction was allowed to stand at room temperature for 5 hours. The reaction was monitored by thin-layer chromatography at 254 nm UV light with a mobile phase of dichloromethane:methanol = 15:1 (v / v). After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by flash column chromatography with a mobile phase of petroleum ether:ethyl acetate = 1:1 (v / v). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain the target compound as a yellow solid (0.04 g, 41%).

[0150] 1 H NMR (500MHz, CDCl3) δ8.61 (d, J=2.7Hz, 1H), 8.47 (s, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 8.21 (d, J= 8.9Hz,1H),7.65(d,J=2.2Hz,1H),7.09(d,J=8.5Hz,1H),6.80(dd,J=8.5,2.7Hz,1H),6.67(s,1 H),6.45(dd,J=9.0,2.2Hz,1H),4.37(t,J=5.2Hz,2H),3.94(t,J=5.8Hz,2H),3.81(t,J=4.5Hz, 4H), 3.45 (q, J = 7.3Hz, 2H), 2.89 (t, J = 4.5Hz, 4H), 2.52 (p, J = 5.4Hz, 2H), 1.36 (t, J = 7.4Hz, 3H). 13 C NMR (126MHz, CDCl3) δ158.4,158.0,157.6,156.3,144.9,139.7,136.0,135.7,129.8,129.5,128.0,123.9,123.0,120. 1,119.9,117.9,117.6,117.2,117.0,112.2,102.5,67.3(2C),65.0,52.1(2C),49.0,47.4,30.5,8.1.HRMS(m / z):[M+H] + calculated for C 30 H 31 ClN7O4S, 620.1841; found, 620.1846. HPLC purity: 97.17%.

[0151] Example 2

[0152] 2 5 -Chloro-46 -methyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)pyrazole-4(1,3)-phenylcyclononaphthalene (HC8990)

[0153] The synthesis method refers to Example 1, except that the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methyl-5-nitrobenzene, and the intermediate 4 in step 3 is replaced by intermediate 3.

[0154] 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.43(s,1H),8.35(s,1H),8.29(d,J=8.8H z,1H),8.06(s,1H),7.04(s,1H),7.00(s,1H),6.97(s,1H),6.82(s,1H),6.29 (d,J=9.0Hz,1H),4.36(t,J=5.7Hz,2H),3.93(d,J=5.8Hz,2H),3.86(s,3H), 3.82(t,J=4.5Hz,4H),2.91(t,J=4.4Hz,5H),2.51-2.43(m,2H),2.42(s,4H).

[0155] Example 3

[0156] 2 5 -Chloro-1 1 , 4 6 -Dimethyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazolol-4(1,3)-phenylcyclononaphthalene (HC8991)

[0157] The synthesis method refers to Example 1, except that the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methyl-5-nitrobenzene, and the ethylsulfonyl chloride in step 2 is replaced by iodomethane.

[0158] 1H NMR(400MHz, CDCl3)δ8.77(s,1H),8.51(s,1H),8.42(s,1H),8.38(s,1H),8.28 (d,J=8.9Hz,1H),8.18(d,J=2.8Hz,1H),7.10-7.05(m,2H),6.97(s,1H),6.81( s,1H),6.31(d,J=9.0Hz,1H),4.34(t,J=5.5Hz,2H),3.92(t,J=5.6Hz,2H),3.8 5-3.73(m,4H),2.98-2.83(m,4H),2.50-2.44(m,2H),2.42(s,3H),1.28(s,3H).

[0159] Example 4

[0160] 2 5 -Chloro-4 5 -cyclopentyl-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9001)

[0161] Step 1. Preparation of 4-(2,6-dibromo-4-nitrophenyl)morpholine (15)

[0162] The synthesis method is similar to that of step 4 in Example 1, except that the intermediate 6 is replaced by 1,3-dibromo-2-fluoro-5-nitrobenzene. 1 H NMR (500MHz, CDCl3) δ8.45-8.33(m,2H),3.91-3.86(m,4H),3.37-3.29(m,4H).

[0163] Step 2. Preparation of 4-(2,6-dibromo-4-nitrophenyl)morpholine (16)

[0164] The synthesis method refers to step 5 of Example 1, and intermediate 8 is replaced by intermediate 15.

[0165] 1 H NMR (500MHz, cdcl3) δ8.41(d,J=2.8Hz,1H),8.09(d,J=2.8Hz,1H),7.73(s,2H),7.72(s,1H),3.77-3.74(m,4H),3.04-2.94(m,4H).

[0166] Step 3. Preparation of 3-(4-(3-(cyclopent-1-en-1-yl)-2-morpholinyl-5-nitrophenyl)-1H-pyrazol-1-yl)propan-1-ol (18)

[0167] Intermediate 16 (0.3 g, 0.73 mmol), Intermediate 17 (0.21 g, 1.09 mmol), sodium carbonate (0.23 g, 2.19 mmol, 3 equiv), and tetrakistriphenylphosphine palladium (0.1 g, 0.07 mmol, 0.1 equiv) were added to a mixture of 10 mL of water and 10 mL of dioxane. The atmosphere was repeatedly purged with nitrogen three times. The resulting mixture was reacted at 95°C for 5 hours under a nitrogen atmosphere. During the reaction, thin-layer chromatography (TLC) was performed using a mobile phase of dichloromethane:methanol = 30:1 (v / v) and monitored at 254 nm. After completion of the reaction, the reaction mixture was diluted with 20 mL of ethyl acetate and extracted with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography using a mobile phase of dichloromethane:methanol = 30:1 (v / v). Fractions containing the target compound were collected and concentrated under reduced pressure to yield a yellow solid (0.21 g, 72%).

[0168] 1 H NMR (500MHz, CDCl3) δ7.95(dd,J=2.9,1.4Hz,1H),7.89(dd,J=2.9,1.4Hz,1H),7.75(s,1H),7.65(s,1H),5.77-5.71(m,1H),4.38(t,J=6.4H z,2H),3.71-3.68(m,2H),3.63-3.60(m,4H),2.98-2.94(m,4H),2.72- 2.66(m,2H),2.59-2.54(m,2H),2.16-2.11(m,2H),2.09-2.05(m,2H).

[0169] Step 4. Preparation of 3-(4-(5-amino-3-cyclopentyl-2-morpholinophenyl)-1H-pyrazol-1-yl)propan-1-ol (19)

[0170] Intermediate 18 (0.21 g, 0.53 mmol) was dissolved in 10 mL of methanol, and 0.05 g of 10% palladium on carbon was added. The reaction system was then replaced with hydrogen gas, and the reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 5 hours. After completion of the reaction, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to give a dark yellow foamy solid (0.16 g, 83%).

[0171] 1H NMR(500MHz, CDCl3)δ7.60(s,1H),7.55(s,1H),6.59-6.53(m,1H),6.48-6. 44(m,1H),4.36-4.27(m,2H),3.76-3.70(m,2H),3.67-3.58(m,4H),3.44(h, J=8.9,8.4Hz,1H),3.14-3.04(m,2H),2.86-2.76(m,2H),2.12-2.07(m,2H), 2.06-2.00(m,2H),1.87-1.78(m,2H),1.73-1.65(m,2H),1.59-1.50(m,2H).

[0172] Step 5. Preparation of 3-(5-chloro-2-((3-(1-(3-hydroxypropyl)-1H-pyrazol-4-yl)-4-morpholinylphenyl)amino)pyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indol-6-ol (20)

[0173] The synthesis method refers to step 7 of Example 1, and intermediate 12 is replaced by intermediate 19.

[0174] 1 H NMR(500MHz, CDCl3)δ8.39(s,1H),8.36(s,1H),8.04(d,J=8.7Hz,1H),7.99(s,1H),7.80(s,1H),7.4 7(s,1H),7.38(d,J=2.1Hz,1H),6.92(s,1H),6.18(d,J=8.5Hz,1H),4.31(t,J=5.6Hz,2H),3.94(t,J= 5.2Hz,2H),3.80-3.70(m,4H),3.67(s,4H),3.50(t,J=8.7Hz,1H),3.38(q,J=7.4Hz,2H),3.16(s,2H) ,2.82(d,J=12.1Hz,2H),1.88-1.85(m,2H),1.74-1.71(m,2H),1.59-1.55(m,2H),1.29-1.27(m,3H).

[0175] Step 6.2 5 -Chloro-4 5 -cyclopentyl-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9001)

[0176] The synthesis method refers to step 8 of Example 1, and intermediate 13 is replaced by intermediate 20.

[0177] 1 H NMR (500MHz, CDCl3) δ8.36(s,1H),8.25(d,J=2.7Hz,1H),8.14(s,1H),8.04(d,J=8.9Hz,1H),7.80(s,1H),7.47(d,J= 2.2Hz,1H),7.29(s,1H),6.70(s,1H),6.68(d,J=2.7Hz,1H),6.21(dd,J=9.0,2.3Hz,1H),4.39(t,J=5.8Hz,2H),3.97 -3.90(m,2H),3.68-3.58(m,4H),3.48-3.39(m,1H),3.34(q,J=7.4Hz,2H),3.12-3.04(m,2H),2.81-2.73(m,2H),2.3 4(t,J=5.8Hz,2H),2.07-1.98(m,2H),1.85-1.75(m,2H),1.71-1.64(m,2H),1.53-1.45(m,2H),1.25(t,J=7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ157.4,156.6,156.2,155.4,147.1,140.9,139.1,136.0,134.9,132.2,128.8,128.4,122.6,121.8,120.4, 116.7,116.2,115.8,115.5,110.1,101.1,66.5(2C),63.6,50.4(2C),47.8,46.4,39.2,34.9,28.9,25.1,7.1.HRMS(m / z):[M+H] + calculated for C 35 H 39 ClN7O4S, 668.2467; found, 668.2471. HPLC purity: 98.42%.

[0178] Example 5

[0179] 2 5 -Chloro-1 1 -ethylsulfonyl-44 -morpholinyl-4 5 -Propylene-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9002)

[0180] The synthesis method refers to Example 4, except that the intermediate 17 in step 3 is replaced by 4,4,5,5-tetramethyl-2-propylene-2-propenyl-1,3,2-dioxaborolane.

[0181] 1 H NMR (500MHz, CDCl3) δ8.45(s,1H),8.39(d,J=2.8Hz,1H),8.24(s,1H),8.12(d,J=8.9Hz,1H),8.01-7.96(m,1 H),7.56(d,J=2.2Hz,1H),7.27(s,1H),6.87-6.82(m,1H),6.59(d,J=2.8Hz,1H),6.27(dd,J=9.0,2.3Hz,1H) ,5.20(t,J=1.8Hz,1H),4.93(dd,J=2.1,1.0Hz,1H),4.50(t,J=5.8Hz,2H),4.10-3.99(m,2H),3.65(t,J=4.6 Hz, 4H), 3.43 (q, J = 7.4Hz, 2H), 2.98 (s, 4H), 2.49-2.37 (m, 2H), 2.17 (d, J = 1.2Hz, 3H), 1.34 (t, J = 7.4Hz, 3H). 13 C NMR (126MHz, CDCl3) δ158.4,157.7,157.3,156.4,145.9,143.8,141.3,140.0,136.0,135.6,132.0,129.6 ,129.4,123.6,122.8,121.3,119.0,118.8,117.8,116.8,115.6,110.8,102.0,67.2(2C),64.5,51.6(2C), 48.9,47.4,29.8,29.7,25.5,8.1.HRMS(m / z):[M+H] + calculated for C 33 H 35 ClN7O4S, 660.2154; found, 660.2146. HPLC purity: 96.62%.

[0182] Example 6

[0183] 2 5 -Chloro-1 1 -ethylsulfonyl-4 4 -morpholinyl-4 5 -2-methylprop-1-en-1-yl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9003)

[0184] The synthesis method refers to Example 4, except that the intermediate 17 in step 3 is replaced by 4,4,5,5-tetramethyl-2-(2-methylpropen-1-yl)-1,3,2-dioxaborolane.

[0185] 1 H NMR (400MHz, DMSO-d6) δ9.77 (s, 1H), 8.63 (s, 1H), 8.19 (d, J = 11.4Hz, 2H), 8. 05(d,J=8.8Hz,1H),7.69(s,1H),7.36(s,2H),6.96(s,1H),6.38(s,1H),6.12 (d,J=9.0Hz,1H),4.39(s,2H),4.06(s,2H),3.74(d,J=7.5Hz,2H),3.53(s,4H ),2.76(s,4H),2.17(s,2H),1.91(s,3H),1.73(s,3H),1.14(t,J=7.4Hz,3H).

[0186] Example 7

[0187] 2 5 -Chloro-1 1 -ethylsulfonyl-4 4 -morpholinyl-4 5 -2-methylpropyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC90032)

[0188] The synthesis method refers to Example 4, except that the intermediate 17 in step 3 is replaced by 4,4,5,5-tetramethyl-2-(2-methylpropen-1-yl)-1,3,2-dioxaborolane.

[0189] 1H NMR (500MHz, CDCl3) δ8.42(s,1H),8.26(d,J=2.8Hz,1H),8.18(s,1H),8.07(d,J=8.9Hz,1H),7 .72(s,1H),7.51(d,J=2.2Hz,1H),7.22(s,1H),6.84(s,1H),6.68(d,J=2.8Hz,1H),6.24(dd,J =9.0,2.3Hz,1H),4.50(t,J=6.0Hz,2H),4.11-4.05(m,2H),3.65(s,5H),3.39(q,J=7.4Hz,2H) ,2.86(d,J=4.7Hz,4H),2.56(d,J=7.2Hz,2H),2.36(q,J=5.9Hz,3H),0.97(s,3H),0.95(s,3H).

[0190] Example 8

[0191] 2 5 -Chloro-4 5 -(E)-3,3-dimethylbut-1-en-1-yl)-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazolol-4(1,3)-phenylcyclononaphthalene (HC9004)

[0192] The synthesis method refers to Example 4, except that the intermediate 17 in step 3 is replaced by 2-(3,3-dimethylbut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0193] 1H NMR (500MHz, CDCl3) δ8.45(s,1H),8.37(d,J=2.7Hz,1H),8.23(s,1H),8.12(d,J=8.9Hz,1H),7.85(s,1H), 7.56(d,J=2.2Hz,1H),7.50-7.45(m,1H),6.92(d,J=2.7Hz,1H),6.80(s,1H),6.77(d,J=16.1Hz,1H),6.27( dd,J=9.0,2.3Hz,1H),6.09(d,J=16.1Hz,1H),4.49(t,J=5.8Hz,2H),4.12-3.99(m,2H),3.72(t,J=4.6Hz,4 H),3.43(q,J=7.4Hz,2H),2.94(s,4H),2.49-2.33(m,2H),1.72(s,1H),1.34(t,J=7.4Hz,3H),1.18(s,6H). 13 C NMR (126MHz, CDCl3) δ158.4,157.8,157.2,156.4,143.2,141.4,140.1,138.8,136.2,136.0,131.8,129.7,129.4,123.7,122.8,122.8 ,121.4,118.6,117.7,116.8,116.4,110.9,102.0,67.6(2C),64.5,51.4(2C),48.9,47.4,33.7,29.9,29.7(3C),8.1.HRMS(m / z):[M+H] + calculated for C 36 H 41 ClN7O4S,702.2624; found,702.2624.HPLC purity:98.11%.

[0194] Example 9

[0195] 2 5 -Chloro-4 5 -(E)-3,3-dimethylbutyl)-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazolol-4(1,3)-phenylcyclononaphthalene (HC90042)

[0196] The synthesis method refers to Example 4, except that the intermediate 17 in step 3 is replaced by 2-(3,3-dimethylbut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0197] 1 H NMR (500MHz, CDCl3) δ8.45(s,1H),8.29(d,J=2.7Hz,1H),8.22(s,1H),8.11(d,J=9.0Hz,1H),7.80(s,1H),7.5 5(d,J=2.2Hz,1H),6.85(s,1H),6.72(d,J=2.8Hz,1H),6.33-6.23(m,1H),4.52(t,J=6.0Hz,2H),4.07(t,J=5. 7Hz,2H),3.71(q,J=6.2,4.5Hz,4H),3.42(q,J=7.3Hz,2H),3.04-2.93(m,2H),2.92-2.81(m,2H),2.79-2.61( m,2H),2.41(p,J=5.8Hz,2H),1.63(s,2H),1.58-1.47(m,2H),1.34(t,J=7.4Hz,3H),1.18(s,1H),1.04(s,6H). 13 C NMR (126MHz, CDCl3) δ158.4,157.7,157.1,156.4,144.0,142.4,140.1,136.4,135.9,132.9,129.6,129.4,123.6,122.8,121.8,119.3,1 18.0,117.8,116.8,110.8,102.0,67.5(2C),64.5,51.7(2C),48.8,47.5,46.4,30.8,29.8,29.7,29.6(2C),27.3,8.1.HRMS(m / z):[M+H] + calculated for C 36 H 43 ClN7O4S, 704.2780; found, 704.2781. HPLC purity: 95.19%.

[0198] Example 10

[0199] 2 5 -Chloro-1 1 -ethylsulfonyl-4 6 -methyl-4 4 -morpholinyl-1 1 H, 5 1Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC916)

[0200] The synthesis method refers to Example 1, except that the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methyl-5-nitrobenzene.

[0201] 1 H NMR(500MHz, CDCl3)δ8.56(s,1H),8.44(s,1H),8.33(s,1H),8.27(s,1H),8.17(d,J=8.9 Hz,1H),7.58(d,J=2.2Hz,1H),7.10(s,1H),6.94(s,1H),6.80(s,1H),6.32(dd,J=9.0,2. 3Hz,1H),4.36(t,J=5.5Hz,2H),3.98-3.89(m,2H),3.78(t,J=4.5Hz,4H),3.42(q,J=7.3 Hz,2H),2.87(t,J=4.6Hz,4H),2.47(q,J=5.6Hz,2H),2.40(s,3H),1.32(t,J=7.3Hz,3H). 13 C NMR (126MHz, CDCl3) δ158.4,157.8,157.7,156.3,144.6,139.5,135.9,133.7,129.5,129.5,125.6,124.3,123.9,123.0,1 21.6,120.0,118.9,117.6,116.9,112.0,102.3,67.3(2C),65.1,52.1(2C),48.9,47.6,30.5,18.0,8.1.HRMS(m / z):[M+H] + calculated for C 31 H 33 ClN7O4S, 634.1998; found, 634.1999. HPLC purity: 99.36%.

[0202] Example 11

[0203] 2 5 -Chloro-1 1 -ethylsulfonyl-7-methyl-4 4 -morpholinyl-1 1 H, 5 1Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9281)

[0204] The synthesis method refers to Example 1, except that the intermediate 11 in step 6 is replaced by 3-bromo-2-methyl-1-propanol.

[0205] 1 H NMR (500MHz, CDCl3) δ8.53(d,J=2.7Hz,1H),8.43(s,1H),8.39(s,1H),8.26(s,1H),8.20(d,J=8.9Hz,1H),7.60(d ,J=2.2Hz,1H),7.29(s,1H),7.06(d,J=8.6Hz,1H),6.79(dd,J=8.5,2.7Hz,1H),6.71(s,1H),6.40(dd,J=9.0,2.3H z,1H),4.37(dd,J=12.8,3.1Hz,1H),4.17(dd,J=12.8,2.7Hz,1H),3.92-3.85(m,1H),3.83-3.68(m,4H),3.65-3.5 7(m,1H),3.42(qd,J=7.3,2.2Hz,2H),2.99-2.90(m,2H),2.83-2.75(m,2H),2.75-2.68(m,1H),1.37-1.25(m,6H). 13 C NMR (126MHz, CDCl3) δ158.4,157.9,157.7,156.3,145.1,139.7,135.9,135.6,129.5,129.5,128.0,123.9,123.1,120.0,1 19.9,118.3,117.6,117.5,117.0,112.7,102.7,70.2,67.3(2C),53.6(2C),52.1,48.9,35.5,15.7,8.1.HRMS(m / z):[M+H] + calculated for C 31 H 33 ClN7O4S, 634.1998; found, 634.1994. HPLC purity: 99.02%.

[0206] Example 12

[0207] Preparation of (Z)-5'-chloro-1'(ethylsulfonyl)-4'-morpholinospiro[cyclopropane]-1,7'-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazolol-4(1,3)-phenylcyclononaphthalene (HC9282)

[0208] The synthesis method is similar to that of Example 1, except that the intermediate 11 in step 6 is replaced by 1-(bromomethyl)cyclopropylmethanol.

[0209] 1 H NMR (500MHz, CDCl3) δ8.57(d,J=2.7Hz,1H),8.50(s,1H),8.37(s,1H),8.20(s,1H),8.15(d,J=8. 9Hz,1H),7.63(d,J=2.2Hz,1H),7.21(s,1H),7.01(d,J=8.6Hz,1H),6.70(dd,J=8.6,2.7Hz,1H),6 .51(s,1H),6.47(dd,J=8.9,2.3Hz,1H),4.03(s,2H),3.79-3.69(m,4H),3.59(s,2H),3.37(q,J=7 .4Hz,2H),2.84-2.71(m,4H),1.27(t,J=7.4Hz,3H),0.86(d,J=4.5Hz,2H),0.81(d,J=4.5Hz,2H). 13 C NMR (126MHz, CDCl3) δ157.4,156.9,156.6,155.2,143.8,139.2,134.9,134.8,128.9,128.5,127.1,122.8,122.2,119.3,11 8.5,116.5,116.5,116.0,116.0,111.9,102.1,72.2,66.2(2C),55.1,51.2(2C),47.9,21.1,9.6,7.1(2C).HRMS(m / z):[M+H] + calculated for C 32 H 33 ClN7O4S, 646.1998; found, 646.1989. HPLC purity: 95.96%.

[0210] Example 13

[0211] 2 5 -Chloro-1 1 -ethylsulfonyl-4 6 -Methoxy-4 4-morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9284)

[0212] The synthesis method refers to Example 1, except that the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene.

[0213] 1 H NMR (500MHz, CDCl3) δ8.56(s,1H),8.38(s,1H),8.35(s,1H),8.17(s,1H),8.12(d,J=8.9H z,1H),7.89(s,1H),7.56(d,J=2.2Hz,1H),6.66(s,1H),6.45(s,1H),6.38(dd,J=9.0,2.2 Hz,1H),4.27(t,J=5.2Hz,2H),3.90(s,3H),3.83(t,J=5.8Hz,2H),3.73(dd,J=6.0,3.2Hz ,4H),3.36(q,J=7.4Hz,2H),2.86-2.74(m,4H),2.48-2.38(m,2H),1.27(t,J=7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ158.4,158.1,157.6,156.2,146.6,144.2,139.6,136.0,129.4,129.4,125.4,123.9,123.1,119.7,1 19.7,117.6,117.4,117.1,112.2,102.5,102.2,67.3(2C),65.0,56.0,52.2(2C),48.9,47.2,30.5,8.1.HRMS(m / z):[M+H] + calculated for C 31 H 33 ClN7O5S,650.1947; found,650.1939.HPLC purity:99.32%.

[0214] Example 14

[0215] 2 5 -Chloro-1 1 -ethylsulfonyl-4 6 -methyl-4 4 -(4-methylpiperazin-1-yl)-11 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9452)

[0216] The synthesis method is as in Example 1. In step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methyl-5-nitrobenzene, and intermediate 7 is replaced by N - Methylpiperazine instead.

[0217] 1 H NMR(500MHz, CDCl3)δ8.53(s,1H),8.37(s,1H),8.18(s,1H),8.07(d,J=8.8Hz,1H), 7.54(d,J=2.2Hz,2H),7.15(s,1H),6.91(s,1H),6.59(s,1H),6.30(dd,J=9.0,2.2Hz ,1H),4.32-4.23(m,2H),4.11-3.99(m,2H),3.90-3.81(m,2H),3.39-3.28(m,4H),3. 00(t,J=4.6Hz,4H),2.54(s,3H),2.45-2.37(m,2H),2.32(s,3H),1.97-1.91(m,3H).

[0218] Example 15

[0219] 1 1 -ethylsulfonyl-4 6 -methyl-4 4 -(4-methylpiperazin-1-yl)-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC950)

[0220] The synthesis method refers to Example 1, except that the intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine.

[0221] 1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),8.45(d,J=5.2Hz,1H),8.35(d,J=2.4Hz,1H),8. 32(t,J=4.4Hz,2H),8.03(s,1H),7.84(s,1H),7.40(d,J=5.2Hz,1H),7.28(d,J=2.2Hz ,1H),7.13-7.03(m,2H),5.78(dd,J=9.1,2.3Hz,1H),4.44-4.30(m,2H),4.10-4.00(m ,2H),3.78-3.62(m,6H),2.86-2.73(m,4H),2.21-2.11(m,2H),1.13(t,J=7.3Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ160.8,160.5,158.9,156.4,145.0,138.9,136.8,136.5,130.1,128.2,127.5,124.4,121.9,121 .8,120.7,119.7,119.7,119.3,110.2,108.5,101.8,66.8(2C),64.8,52.2(2C),48.8,48.1,30.3,8.3.HRMS(m / z):[M+H] + calculated for C 30 H 32 N7O4S,586.2231; found,586.2221.HPLC purity:97.67%.

[0222] Example 16

[0223] (Z)-1 1 -ethylsulfonyl-4 6 -methyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)pyrazole-4(1,3)-phenylcyclononaphthalene (HC950M)

[0224] The synthesis method refers to Example 1, except that the intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine, and the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methyl-5-nitrobenzene.

[0225] 1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.49(s,1H),8.40(d,J=5.2Hz,1H),8.30-8.22(m,2H) ,7.91(s,1H),7.89(s,1H),7.33(d,J=5.2Hz,1H),7.15(d,J=2.3Hz,1H),6.92(s,1H),5.39( dd,J=9.2,2.4Hz,1H),4.34(t,J=7.1Hz,2H),4.29-4.21(m,2H),3.90-3.70(m,4H),3.63(q, J=7.3Hz,2H),2.90-2.72(m,4H),2.30(s,3H),2.08(q,J=7.8Hz,2H),1.07(t,J=7.3Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ161.7,160.6,158.8,156.1,146.3,138.4,136.6,133.4,130.4,130.1,127.8,127.5,124 .7,124.6,121.8,121.2,120.6,119.0,109.0,108.4,101.0,66.6,65.4,52.1,48.7,48.6,31.0,18.4,8.2.[M+H] + calculated for C 31 H 34 N7O4S,600.2387; found,600.2378.HPLC purity:99.40%.

[0226] Example 17

[0227] (Z)-1 1 -ethylsulfonyl-4 6 -Methoxy-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)pyrazole-4(1,3)-phenylcyclononaphthalene (HC9591)

[0228] The synthesis method refers to Example 1, except that the intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine, and the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene.

[0229] 1H NMR(500MHz, CDCl3)δ8.79(s,1H),8.44(d,J=5.1Hz,1H),8.42(s,1H),8.35(d,J=8.9Hz,1H),7 .90(s,1H),7.83(s,1H),7.53(d,J=2.2Hz,1H),7.01(d,J=5.1Hz,1H),6.83(s,1H),6.75(s,1H ),6.21(dd,J=9.0,2.3Hz,1H),4.44(t,J=5.5Hz,2H),3.98(s,3H),3.95-3.89(m,2H),3.87-3. 76(m,4H),3.42(q,J=7.4Hz,2H),2.98-2.84(m,4H),2.51-2.43(m,2H),1.34(t,J=7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ160.5,159.9,158.5,157.5,146.9,144.2,139.4,136.9,129.4,126.1,125.7,124.3,122.2,12 0.7,120.3,119.6,118.6,110.9,108.2,102.2,102.0,67.3(2C),64.1,56.0,52.2(2C),48.8,47.2,30.0,8.1.[M+H] + calculated for C 31 H 34 N7O4S,616.2337; found,616.2340.HPLC purity:98.31%.

[0230] Example 18

[0231] (Z)-1 1 -ethylsulfonyl-4 6 -Methoxy-4 4 -(4-methylpiperazin-1-yl)-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)pyrazole-4(1,3)-phenylcyclononaphthalene (HC9592)

[0232] The synthesis method refers to Example 1, except that intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine, intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and intermediate 7 is replaced by N-methylpiperazine.

[0233] 1 H NMR (500MHz, DMSO) δ10.40 (s, 1H), 9.69 (s, 1H), 8.35 (d, J = 4.5Hz, 2H), 8.26 (s, 1H), 8.21-8.1 0(m,2H),7.94(s,1H),7.84(s,1H),7.36(d,J=5.3Hz,1H),7.27(d,J=2.2Hz,1H),6.81(s,1H), 6.53(s,1H),4.26(t,J=6.6Hz,2H),3.85(s,3H),3.69-3.62(m,2H),3.59(t,J=6.3Hz,2H),3. 34(s,3H),3.21-3.03(m,4H),2.93-2.61(m,4H),2.23(p,J=6.6Hz,2H),1.09(t,J=7.2Hz,3H).

[0234] Example 19

[0235] (Z)-1 1 -ethylsulfonyl-4 6 -Methoxy-4 4 -(4-methylpiperazin-1-yl)piperidin-1-yl)-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazolol-4(1,3)-phenylcyclononaphthalene (HC9594)

[0236] The synthesis method refers to Example 1, except that intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine, intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and intermediate 7 is replaced by 1-methyl-4-piperidin-4-ylpiperazine.

[0237] 1H NMR (500MHz, CDCl3) δ8.75(s,1H),8.44(d,J=5.1Hz,1H),8.35(d,J=8.9Hz,1H),7.89(s, 1H),7.53(d,J=2.2Hz,1H),7.01(d,J=5.1Hz,1H),6.89(s,1H),6.72(s,1H),6.22(s,1H) ,4.43(t,J=5.6Hz,2H),3.96(s,3H),3.42(q,J=7.3Hz,2H),3.29-3.18(m,2H),3.16-2.7 4(m,6H),2.70-2.55(m,3H),2.50-2.38(m,2H),2.12-1.67(m,7H),1.34(t,J=7.4Hz,3H).

[0238] Example 20

[0239] (Z)-4 6 -ethoxy-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (HC9596)

[0240] The synthesis method refers to Example 1, except that the intermediate 1 in step 1 is replaced by 2,4-dichloropyrimidine, and the intermediate 6 in step 4 is replaced by 1-bromo-2-fluoro-4-ethoxy-5-nitrobenzene.

[0241] 1 H NMR (500MHz, CDCl3) δ8.81(s,1H),8.44(d,J=5.1Hz,1H),8.42(s,1H),8.35(d,J=8.9Hz,1H),7.92(s,1 H),7.84(s,1H),7.54(d,J=2.2Hz,1H),7.01(d,J=5.1Hz,1H),6.82(s,1H),6.74(s,1H),6.23(dd,J=8.9 ,2.3Hz,1H),4.43(t,J=5.5Hz,2H),4.21(q,J=7.0Hz,2H),3.94-3.87(m,2H),3.86-3.72(m,4H),3.42( q,J=7.4Hz,2H),2.99-2.81(m,4H),2.47(p,J=5.7Hz,2H),1.55(t,J=6.9Hz,3H),1.34(t,J=7.4Hz,3H).13 C NMR (126MHz, CDCl3) δ160.5,159.8,158.5,157.5,146.2,144.1,139.4,136.9,129.4,126.1,125.8,124.3,122.2,120. 7,120.3,119.5,118.6,110.9,108.2,103.1,102.0,67.3(2C),64.6,64.1,52.2(2C),48.8,47.2,30.0,15.0,8.1.[M+H] + calculated for C 31 H 34 N7O4S,630.2493; found,630.2492.HPLC purity:98.87%.

[0242] Example 21

[0243] 2 5 -Chloro-1 1 -ethylsulfonyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-10-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclodecane (HC8714)

[0244] The synthesis method is similar to that of Example 1, except that the intermediate 11 in step 6 is replaced by 4-bromo-1-butanol.

[0245] 1 H NMR (500MHz, CDCl3) δ8.43-8.37(m,2H),8.18(d,J=8.8Hz,1H),8.06(s,1H),7.62-7.57(m,1H),7.5 1-7.48(m,1H),7.08(d,J=8.5Hz,1H),6.89(dd,J=8.5,2.7Hz,1H),6.38(dd,J=8.8,2.3Hz,1H),5.40 -5.33(m,1H),4.23(t,J=6.3Hz,2H),4.19(t,J=5.8Hz,2H),3.79(t,J=4.4Hz,4H),3.40(q,J=7.4Hz ,2H),2.89(t,J=4.5Hz,4H),2.08-2.02(m,2H),1.66(dt,J=15.2,6.8Hz,2H),1.31(t,J=6.3Hz,3H).

[0246] Example 22

[0247] (Z)-1 1 -(ethylsulfonyl)-4- 6 -methoxy-7-methyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzazepinenonane (WQX-1-80)

[0248] The synthesis method refers to Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and in step 6, intermediate 11 is replaced by 3-bromo-2-methylpropanol.

[0249] 1 H NMR (600MHz, CDCl3) δ8.70(s,1H),8.42(d,J=5.1Hz,1H),8.37(d,J=8.9Hz,1H),8.34(s,1H),7.86(s, 1H),7.82(s,1H),7.51(d,J=2.2Hz,1H),7.00(d,J=5.0Hz,1H),6.89(s,1H),6.73(s,1H),6.16(dd,J=9 .0,2.3Hz,1H),4.42-4.25(m,2H),3.96(s,3H),3.93-3.86(m,1H),3.78(m,4H),3.62(m,1H),3.39(q, J=7.3Hz,2H),2.96(m,2H),2.84(m,2H),2.02(m,1H),1.32(t,J=7.4Hz,3H),1.27(d,3H).MS(ESI):m / z 630[M+H] +

[0250] Example 23

[0251] (Z)-1 1 -(ethylsulfonyl)-4- 6 -Methoxy-8-methyl-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzazepinenonane (WQX-1-86)

[0252] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine. In step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene. In step 6, intermediate 11 is replaced by 4-bromobutan-2-ol.

[0253] 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.41(d,J=5.1Hz,1H),8.33(t,J=4.4Hz,2H),7.86(s,1H),7.82(s,1H), 7.48(d,J=2.1Hz,1H),7.00(d,J=5.1Hz,1H),6.92(s,1H),6.73(s,1H),6.10(dd,J=9.2,2.2Hz,1H),4.79(q ,J=6.1Hz,1H),4.04(m,J=14.0,6.7,3.4Hz,1H),3.96(s,3H),3.91(m,1H),3.85-3.75(m,4H),3.39(q,J=7. 4Hz,2H),3.02(m,2H),2.80(m,2H),2.03(m,2H),1.52(d,J=6.1Hz,3H),1.31(t,J=7.4Hz,3H).MS(ESI):m / z 630[M+H] +

[0254] Example 24

[0255] Preparation of (Z)-1'-(ethylsulfonyl)-6'-methoxy-4'-morpholinospiro[cyclopropane-7'-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzocyclononane] (WQX-1-87)

[0256] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and in step 6, intermediate 11 is replaced by (1-(bromomethyl)cyclopropyl)methanol.

[0257] 1H NMR (600MHz, CDCl3) δ8.82(s,1H),8.49(d,J=0.7Hz,1H),8.43(d,J=5.0Hz,1H),8.36(d,J=8.9Hz,1H), 7.89(s,1H),7.83(s,1H),7.58(d,J=2.2Hz,1H),7.00(d,J=5.1Hz,1H),6.76(d,J=0.7Hz,1H),6.75(s, 1H), 6.33 (dd, J=8.9, 2.3Hz, 1H), 4.18 (s, 2H), 3.96 (s, 3H), 3.84-3.80 (m, 4H), 3.65 (s, 2H), 3.41 (q, J= 7.4Hz,2H),2.94-2.90(m,4H),1.33(t,J=7.3Hz,3H),0.88(d,2H),0.84(d,J=4.7Hz,2H).MS(ESI):m / z 642[M+H] +

[0258] Example 25

[0259] (Z)-1 1 -(ethylsulfonyl)-4- 6 -Methoxy-4 4 -(morpholinomethyl)-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzocyclononane (WQX-2-35)

[0260] The synthesis method refers to Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and intermediate 8 is replaced by intermediate 21. 1H NMR (600MHz, CDCl3) δ8.83(s,1H),8.44(d,J=5.1Hz,1H),8.31(d,J=8.9Hz,1H),8.03(s,2 H),7.80(s,1H),7.49(d,J=2.2Hz,1H),7.02(d,J=5.0Hz,1H),7.00-6.95(m,1H),6.91(s, 1H),6.13(d,J=8.9Hz,1H),4.50(t,J=5.9Hz,2H),3.98(m,5H),3.73(s,4H),3.43(s,2H), 3.39(q,J=7.4Hz,2H),2.50(s,4H),2.44-2.36(m,2H),1.33(d,J=7.4Hz,3H).MS(ESI):m / z 630[M+H] +

[0261] The preparation method of the intermediate 4-(2-bromo-5-methoxy-4-nitrobenzyl)morpholine (21) is as follows:

[0262] Preheat the oil bath to 85°C. Add 1.014g of 1-bromo-4-methoxy-2-methyl-5-nitrobenzene, 0.8233g of NBS, and 0.1479g of AIBN to a 50mL dry eggplant-shaped flask. Replace the Ar gas three times. Under Ar protection, add 15mL of anhydrous DCE and react at 85°C for one day. Remove from heat and allow to cool naturally to room temperature. Add saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, and wash twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. Combine the organic layers, add anhydrous sodium sulfate, and dry. After 2 hours, filter and spin dry. Replace the Ar gas of the spin-dried product three times. Under Ar protection, add 15mL of acetonitrile, 0.5mL of morpholine, and 1.8mL of triethylamine to the system and stir at room temperature. After 3 h, the reaction progress was monitored by TLC (developing solvent: petroleum ether: ethyl acetate = 5:1, v / v), the system was directly spin-dried and purified by column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to obtain intermediate 21. 1 H NMR (500MHz, CDCl3) δ8.06 (s, 1H), 7.39 (s, 1H), 3.97 (s, 3H), 3.78-3.74 (m, 4H), 3.59 (s, 2H), 2.55 (dd, J = 5.6, 3.7Hz, 4H).

[0263] Example 26

[0264] (Z)-1 1 -(ethylsulfonyl)-4- 6 -Methoxy-4 4-(2-methylmorpholinyl)-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzocyclononane (WQX-2-43)

[0265] The synthesis method refers to Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and intermediate 7 is replaced by 2-methylmorpholine.

[0266] 1 H NMR (600MHz, CDCl3) δ8.78(s,1H),8.42(d,J=5.1Hz,1H),8.38(d,J=0.7Hz,1H),8.34(d,J=8.9Hz,1H),7.89(s, 1H),7.82(s,1H),7.52(d,J=2.2Hz,1H),7.00(d,J=5.0Hz,1H),6.81(d,J=0.7Hz,1H),6.73(s,1H),6.21(dd,J= 9.0,2.3Hz,1H),4.41(m,J=5.9,4.3Hz,2H),3.97(s,3H),3.94-3.85(m,3H),3.82-3.76(m,2H),3.40(q,J=7.4H z,2H),2.97(m,2H),2.77(m,1H),2.51-2.42(m,3H),1.33(d,J=7.4Hz,3H),1.16(d,J=6.3Hz,3H).MS(ESI):m / z 630[M+H] + .

[0267] Example 27

[0268] (Z)-1 1 -(ethylsulfonyl)-2- 5 -Fluoro-4 6 -Methoxy-4 4 -morpholinyl-1 1 H, 5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-benzazepinenonane (WQX-2-79)

[0269] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloro-5-fluoropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene.

[0270] 1 H NMR (600MHz, CDCl3) δ8.66 (s, 1H), 8.40-8.38 (m, 2H), 8.35 (d, J = 2.8Hz, 1H), 8.07 (d, J = 2.3Hz ,1H),7.85(s,1H),7.55(d,J=2.4Hz,1H),6.88-6.85(m,1H),6.74(s,1H),6.16(dd,J=9.0,2. 3Hz,1H),4.42(t,J=5.6Hz,2H),3.97(s,3H),3.94-3.90(m,2H),3.80(t,J=4.6Hz,4H),3.41( q,J=7.4Hz,2H),2.94-2.90(m,4H),2.45(p,J=5.6Hz,2H),1.33(d,J=7.4Hz,3H).MS(ESI):m / z 634[M+H] + .

[0271] Example 28

[0272] (E)-1 1 -(ethylsulfonyl)-4- 6 -Methoxy-4 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(3,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-4-6)

[0273] The synthesis method refers to Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, and in step 5, intermediate 9 is replaced by 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0274] 1H NMR (600MHz, DMSO-d6) δ8.45-8.42(m,2H),8.27(d,J=1.9Hz,1H),7.92(d,J=2.2Hz,1H),7.62(ddt,J=6.5 ,2.9,1.3Hz,1H),7.57-7.54(m,1H),7.39(d,J=5.1Hz,1H),7.28(d,J=2.2Hz,1H),6.81-6.77(m,2H),5.7 9(dd,J=9.1,2.3Hz,1H),4.32(t,J=6.3Hz,2H),3.97(t,J=5.8Hz,2H),3.94(s,3H),3.67(d,J=7.3Hz,2H) ,3.62(t,J=4.5Hz,4H),2.83(t,J=4.5Hz,4H),2.21(d,J=5.6Hz,2H),1.12(t,J=7.2Hz,3H).MS(ESI):m / z 615.23[M+H]+.

[0275] Example 29

[0276] (Z)-4 6 -cyclopropyloxy-1 1 -(ethylsulfonyl)-4- 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-4-24)

[0277] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-cyclopropyloxy-5-nitrobenzene.

[0278] 1H NMR (600MHz, CDCl3) δ8.78(s,1H),8.41(s,1H),8.33(d,J=8.8Hz,1H),7.82(s,1H),7.74(s,1H),7.70-7.63(m,2H),7.52(d,J=2.2Hz, 1H),7.10(s,1H),6.99(d,J=5.0Hz,1H),6.81(s,1H),6.20(dd,J=8.9,2.3Hz,1H),4.42(t,J=5.6Hz,2H),3.94-3.88(m,2H),3.81(t,J =4.5Hz,4H),3.40(q,J=7.4Hz,2H),2.99-2.85(m,4H),2.52-2.39(m,2H),1.32(t,J=7.4Hz,3H),0.90(m,2H),0.87(t,J=4.4Hz,2H).MS(ESI):m / z 641.24[M+H] + .

[0279] Example 30

[0280] (Z)-1 1 -(ethylsulfonyl)-4- 4 -morpholinyl-4 6 -(trifluoromethoxy)-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-4-48)

[0281] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-trifluoromethoxy-5-nitrobenzene.

[0282] 1H NMR (600MHz, CDCl3) δ8.91 (s, 1H), 8.46 (d, J = 5.1Hz, 1H), 8.42-8.38 (m, 1H), 8.26 (d, J = 8.9Hz, 1H), 7. 84(s,1H),7.68-7.66(m,1H),7.53(d,J=2.1Hz,1H),7.46(d,J=3.0Hz,1H),7.07(d,J=5.1Hz,1H),7.0 3(t,J=1.6Hz,1H),6.87(s,1H),4.43(t,J=5.5Hz,2H),3.94-3.88(m,2H),3.79(t,J=4.5Hz,4H),3.41 (q,J=7.4Hz,2H),2.88(dd,J=5.7,3.3Hz,4H),2.49-2.44(m,2H),1.33(t,J=7.4Hz,3H).MS(ESI):m / z 669.20[M+H] + .

[0283] Example 31

[0284] (Z)-1 1 -(ethylsulfonyl)-4- 4 -morpholinyl-4 6 -(trifluoromethyl)-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-3-92)

[0285] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-trifluoromethyl-5-nitrobenzene.

[0286] 1H NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.48(s,1H),8.44(d,J=5.2Hz,1H),8.26(s,1H),8.13(s, 1H),8.07(s,1H),7.60(d,J=1.6Hz,1H),7.56(d,J=3.1Hz,1H),7.37(d,J=5.1Hz,1H),7.25(s, 1H),7.14(d,J=2.3Hz,1H),4.32(t,J=7.2Hz,2H),3.75(t,J=4.5Hz,4H),3.61(q,J=7.3Hz,2H) ,2.90(d,J=4.7Hz,4H),2.08(d,J=7.9Hz,2H),1.23(s,2H),1.06(t,J=7.2Hz,3H).MS(ESI):m / z 653.20[M+H] + .

[0287] Example 32

[0288] (Z)-1 1 -(ethylsulfonyl)-4- 6 -isopropoxy-4 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-3-84)

[0289] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-isopropoxy-5-nitrobenzene.

[0290] 1H NMR (600MHz, DMSO-d6) δ8.45(d,J=5.1Hz,1H),8.32(d,J=1.8Hz,2H),8.30(d,J=8.9Hz,1H),8.00(d,J=0.7H z,1H),7.81(s,1H),7.76(s,1H),7.44(d,J=5.1Hz,1H),7.27(d,J=2.3Hz,1H),6.82(s,1H),4.71(p,J=6.0H z,1H),4.36(t,J=6.5Hz,2H),4.07(dd,J=11.3,6.3Hz,2H),3.68(dd,J=6.0,3.3Hz,5H),2.82(t,J=4.6Hz,4 H),2.17(q,J=9.4,8.4Hz,2H),2.04-1.94(m,2H),1.34(d,J=6.1Hz,6H),1.12(t,J=7.3Hz,3H).MS(ESI):m / z 643.26[M+H] + .

[0291] Example 33

[0292] (Z)-4 6 -cyclopropyl-1 1 -(ethylsulfonyl)-4- 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-3-66)

[0293] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-cyclopropyl-5-nitrobenzene.

[0294] 1H NMR(600MHz,DMF-d7)δ8.55(s,1H),8.42(d,J=5.1Hz,1H),8.33-8.29(m,1H),8.27(s,1H),8.00(s,1H),7.93(d, J=0.7Hz,1H),7.60(d,J=1.5Hz,1H),7.57-7.56(m,1H),7.35(d,J=5.1Hz,1H),7.17(d,J=2.3Hz,1H),6.68(s,1H ),5.43(dd,J=9.2,2.4Hz,1H),4.33(t,J=7.0Hz,2H),4.23-4.15(m,2H),3.70(t,J=4.5Hz,4H),3.63(q,J=7.3Hz ,2H),2.82(t,J=4.4Hz,4H),2.19-2.06(m,3H),1.23(s,2H),0.95-0.90(m,2H),0.61-0.57(m,2H).MS(ESI):m / z 625.25[M+H] + .

[0295] Example 34

[0296] (Z)-1 1 -(ethylsulfonyl)-4- 6 -isopropyl-4- 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-3-48)

[0297] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-isopropyl-5-nitrobenzene.

[0298] 1H NMR (600MHz, DMSO-d6) δ8.69(s,1H),8.56(s,1H),8.38(d,J=5.1Hz,1H),8.20(d,J=2.6Hz,1H),7.9 1(d,J=0.7Hz,1H),7.79(s,1H),7.64-7.61(m,2H),7.58-7.54(m,1H),7.25(d,J=5.1Hz,1H),7.12( d,J=2.3Hz,1H),6.92(s,1H),4.36-4.24(m,4H),3.72(t,J=4.5Hz,4H),3.60(q,J=7.2Hz,2H),2.86 (t,J=4.5Hz,4H),2.07(d,J=8.1Hz,2H),1.24(t,J=5.5Hz,3H),1.12(d,J=6.8Hz,6H).MS(ESI):m / z 627.26[M+H] + .

[0299] Example 35

[0300] (Z)-4 6 -ethyl-1 1 -(ethylsulfonyl)-4- 4 -morpholinyl-1 1 H,5 1 Preparation of H-9-oxa-3-aza-1(3,6)-indole-2(4,2)-pyrimidine-5(4,1)-pyrazole-4(1,3)-phenylcyclononaphthalene (FBH-3-47)

[0301] The synthesis method is as described in Example 1. In step 1, intermediate 1 is replaced by 2,4-dichloropyrimidine, and in step 4, intermediate 6 is replaced by 1-bromo-2-fluoro-4-ethyl-5-nitrobenzene.

[0302] 1H NMR (600MHz, DMSO-d6) δ8.64(s,1H),8.51(s,1H),8.39(d,J=5.1Hz,1H),8.23(s,1H),7.90(d,J= 0.7Hz,1H),7.84(s,1H),7.63(dtd,J=8.4,2.9,1.4Hz,1H),7.58-7.53(m,1H),7.28(d,J=5.1Hz, 1H),7.13(d,J=2.3Hz,1H),6.90(s,1H),4.29(m,4H),3.72(t,J=4.5Hz,4H),3.61(q,J=7.3Hz,2H ),2.85(d,J=5.2Hz,4H),2.71(q,J=7.5Hz,2H),2.07(d,J=8.1Hz,2H),1.05(m,6H).MS(ESI):m / z 613.25[M+H] + .

[0303] Example 36 Inhibitory Effect of Cyclic 2-Aminopyrimidine Compounds on Wild-Type EGFR and Mutant EGFR Kinase Activity

[0304] EGFR (WT) is the wild-type epidermal growth factor receptor. 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 amino acid position 790, and a mutation from cysteine ​​to serine at amino acid position 797.

[0305] The inhibitory effect of the compound on kinase activity was detected by enzyme-linked immunosorbent assay (ELISA). WT EGFR was purchased from Eurofins. 19del / T790M / C797S Kinase was purchased from BPS Bioscience.

[0306] The main experimental steps are as follows: Enzyme reaction substrate Poly (Glu, Tyr) 4:1Dilute the protein to 20 μg / mL in potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) and incubate at 37°C for 12-16 hours before coating the microplate. Add ATP (final concentration 5 μM) diluted in reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl2, 0.5 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) to each well. Add the test compound or solvent control, then initiate the kinase reaction and incubate at 37°C on a shaker for 1 hour. Wash the plate three times with T-PBS, add the PY99 antibody, and incubate at 37°C on a shaker for 0.5 hour. After washing with T-PBS, add horseradish peroxidase-conjugated IgG and incubate at 37°C on a shaker for 0.5 hour. Wash the plate again, then add 2 mg / mL OPD colorimetric solution and incubate at 25°C in the dark for 1-10 minutes. The reaction was terminated by adding 2M H2SO4 and detected with a wavelength-adjustable microplate reader SPECTRA MAX 190 at a wavelength of 492 nm. 50 The values ​​were obtained from inhibition curve analysis.

[0307] Table 1 lists the compound numbers (corresponding to the compound numbers in the above examples) and the test results of the compounds' inhibitory activities against various kinases.

[0308] Table 1 Test results of the inhibitory activity of cyclic 2-aminopyrimidine compounds on kinases Note: “ / ” in the table means the data has not been tested.

[0309] As shown in Table 1, the cyclic 2-aminopyrimidine compounds of the present invention can effectively and selectively inhibit the EGFR protein kinase drug-resistant mutant (EGFR L858R / T790M / C797S and EGFR 19del / T790M / C797S ) activity, which 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).

[0310] Example 37 Compound Inhibits Proliferation of EGFR Mutant Cells

[0311] Ba / F3 cells were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ). Stably expressing EGFR 19del / T790M / C797S or EGFR L858R / T790M / C797SBa / F3 cells were generated by infecting parental cells with the corresponding retrovirus. PC-9-OR was generated by using CRISPR technology to simultaneously knock in T790M and C797S mutations in PC-9 tumor cells that are dependent on 19del activation mutations. 19del / T790M / C797S Tumor cell models with drug-resistant mutations are used to evaluate the effects of compounds on EGFR 19del / T790M / C797S Inhibitory activity of drug-resistant mutants (Cancer Science. 2022; 113: 709-720). All cells in the study were verified by short tandem repeat (STR) analysis performed by Genesky.

[0312] Tumor cell viability was assessed using a CCK-8 cell counting kit (A311-01 / 02, Vazyme, Nanjing, China). Cells were seeded into 96-well plates at a density of 3,000 cells per well and cultured overnight. They were then treated with various concentrations of compounds and incubated for 72 hours. After 72 hours, CCK-8 solution (10 μL) was added to each well. The plate was then returned to the incubator and incubated at 37°C for 2 hours. The absorbance was measured at 450 nm using a microplate reader. A calibration curve was drawn using data obtained from wells containing a known number of viable cells.

[0313] The test results are shown in Table 2: The cyclic 2-aminopyrimidine compounds of the present invention can effectively and selectively inhibit the growth and proliferation of EGFR mutant cells.

[0314] Table 2 Results of the inhibitory activity of compounds on the proliferation of EGFR mutant cells Note: “ / ” in the table means the data has not been tested.

[0315] Example 38 Compound Inhibitory Experiment on EGFR Phosphorylation Level in Tumor Cells

[0316] After starvation overnight, cells were treated with test compounds for 2 hours and then stimulated with 50 ng / mL of EGF for 15 minutes. Subsequently, cells were collected with trypsin, lysed with SDS lysis buffer, and then centrifuged at 12,000 g for 30 minutes. Protein concentration was measured using a BCA protein assay kit (Cat. No. 23227, Thermo Fisher Scientific). After heating at 100° C. for 15 minutes, protein samples were separated on 8%-12% SDS-PAGE gels and then transferred to nitrocellulose membranes (Life Technologies). The membrane was blocked in 5% skim milk in TBST and incubated with primary antibodies against phosphorylated EGFR (Tyr1068; dilution, 1:500; catalog number 2234L, CST) and β-actin (dilution, 1:20,000; catalog number 60008-1-Ig, Proteintech) at 4°C overnight, followed by incubation with secondary antibodies (catalog number 111-035-003, Jackson) for one hour.

[0317] The experimental results are shown in Figure 1: The cyclic 2-aminopyrimidine compounds of the present invention can effectively inhibit EGFR 19del / T790M / C797S Mutant cells and EGFR L858R / T790M / C797S EGFR phosphorylation levels in mutant cells.

[0318] Example 39 Determination of pharmacokinetic parameters of the compound in rats

[0319] Sprague-Dawley rats (male, 3 per group), weighing 180-220 g, were administered the test compound at doses of 1 mg / kg and 5 mg / kg, respectively, by intravenous injection or oral gavage. The compound was dissolved in a mixed solvent (5% DMSO + 10% Solutol + 85% PBS) for intravenous injection. Oral administration was performed using a 0.5% CMC-Na solution (800-1200 cps) as a suspension. At the designated time points, 0.2 mL of blood was collected from the jugular vein, placed in a tube containing K2-EDTA, stored on ice, and then centrifuged. The time intervals for blood collection were 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the injection group and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours for the oral group. Blood samples were centrifuged at 6800 g for 6 minutes at 2-8°C within 1 hour of collection and stored frozen at approximately -80°C. Subsequently, 20 μL of plasma sample containing 100 ng / mL IS was precipitated with 200 μL of MeOH. The mixture was vortexed for 1 minute and then centrifuged at 18,000 g for 7 minutes. 200 μL of supernatant was transferred to a 96-well plate, and a 1 μL aliquot of the supernatant was injected for LC-MS / MS analysis. PK parameters were calculated using Phoenix WinNonlin 7.0 software.

[0320] Table 3 Pharmacokinetic parameters of the compounds in rats

[0321] As shown in Table 3, the pharmacokinetic properties of the cyclic 2-aminopyrimidine compounds of the present invention in rats are significantly better than those of the compounds reported in CN116102575A. The compounds of the present invention have higher oral bioavailability (F% = 39.6%), lower clearance (CL = 9.2 mL / min / kg) and longer half-life (T 1 / 2 =7.10h).

[0322] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A cyclic 2-aminopyrimidine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof: in: A is selected from: CR5, N; B is selected from: CR7, N; D, E, Q, and P are independently selected from: CR8, N; X is selected from: -O-, -O(=O)C-, -S-, -S(=O)2-, -S(=O)-, -C(=O)O-, -C(=O)NH-, -CH2-, -C=C-, -C≡C-, -NH-, -NH(C=O)-; R1 is selected from: hydrogen, hydroxyl, C6~C 10 Aryl, 5-10 membered heteroaryl, -C(=O)R9, -S(=O)2R9, -S(=O)R9, -P(=O)(R9)2, R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 3-8 membered heterocyclic group; each R9 is independently selected from: R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C1-C8 alkoxy, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted C3-C8 epoxyalkyl, amino, C1-C8 alkylamino, (C1-C8 alkyl)2amino; each R 10 are independently selected from: hydrogen, deuterium, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, 3-8 membered heterocyclic group, halogen, hydroxyl, cyano, amino, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 、C6~C 10 Aryl, 5-10 membered heteroaryl; each R 11 Each is independently selected from: C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl; R2, R3, R4, R5, R7, and R8 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, 5-10 membered heteroaryl, C6-C 10 Aryl, R 10 Substituted or unsubstituted C1-C8 alkyl, R 10 Substituted or unsubstituted C2-C8 alkenyl, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted C1-C8 alkoxy, R 10 Substituted or unsubstituted C3-C8 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R 12 )2; each R 12 Each independently selected from: hydrogen, C1-C8 alkyl; Alternatively, R2, R3 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 5-8 membered heterocyclic ring, R 10 a substituted or unsubstituted 5-10 membered heteroaromatic ring; Alternatively, R4, R7 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C3-C8 cycloalkyl, R 10 Substituted or unsubstituted 5-8 membered heterocyclic ring, R 10 a substituted or unsubstituted 5-10 membered heteroaromatic ring; R6 is selected from: -NR 13 R 14 , -CR 13 R 14 R 15 、-(CH2) n R 13 R 14 R 15 、-(CH2) n NR 13 R 14 ; Each R 13 and each R 14 are independently selected from: hydrogen, R 10 Substituted or unsubstituted C1-C8 alkyl, or R 13 , R 14 Together with the N or C to which it is connected, it forms a substituted or unsubstituted 3-12 membered heterocyclic group; R 15 Selected from: hydrogen, C1-C8 alkyl; n is selected from: 1, 2, 3; R is selected from: hydrogen, C1-C8 alkyl, -C(=O)R 11 、-C(=O)N(R 12 )2, or, R and the carbon to which it is connected together form -C(=O); L is selected from: R 16 Substituted or unsubstituted C1-C8 alkylene, R 16 Substituted or unsubstituted C2-C8 alkenyl; R 16 is selected from the group consisting of: hydrogen, deuterium, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C3-C8 cycloalkyl, amino, halogen, hydroxy, cyano, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, 3-8 membered heterocyclic group; or, two R connected to the same carbon atom 16 or two R connected to two adjacent carbon atoms 16 Connected to form a C3~C8 cycloalkyl group.

2. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1, characterized in that: The cyclic 2-aminopyrimidine compound has a structure as shown in the following formula (II):

3. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: A is selected from: CH, N.

4. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: B is selected from: CR7, N; R7 is selected from: hydrogen, C5-C6 cycloalkyl, C2-C6 alkenyl, C1-C5 alkyl.

5. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 4, characterized in that: B is selected from the group consisting of CR7 and N; and R7 is selected from the group consisting of hydrogen, cyclopentyl, methylvinyl, 2-methylpropenyl, isobutyl, 3,3-dimethylbutenyl and 3,3-dimethylbutyl.

6. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 2, characterized in that: E is CH; D is CH or N; Q is N.

7. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1, characterized in that: E is CH; D is CH or N; Q is N; P is CH; or, E is CH; D is CH or N; Q is N; P is N.

8. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R1 is selected from the group consisting of hydrogen, -C(=O)R9, -S(=O)2R9, -S(=O)R9, -P(=O)(R9)2, R 10 Substituted or unsubstituted C1-C4 alkyl; each R9 is independently selected from: C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkylamino, (C1-C4 alkyl)2amino, halogen-substituted C1-C4 alkyl; R in R1 10 Selected from: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, cyano, amino.

9. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 8, characterized in that: R1 is selected from: hydrogen, ethanesulfonyl, methylsulfonyl, propylsulfonyl, methyl, ethyl, propyl, acetyl, trifluoroformyl, aminoacyl, methylaminoacyl, dimethylaminoacyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, -P(=O)(OCH3)2, -P(=O)(CH3)2.

10. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R2 and R3 are independently selected from: hydrogen, halogen, cyano, nitro, amino, R 10 Substituted or unsubstituted C1-C4 alkyl, R 10 Substituted or unsubstituted C2-C4 alkenyl, R 10 Substituted or unsubstituted C3-C6 cycloalkyl, R 10 Substituted or unsubstituted C1-C4 alkoxy, R 10 Substituted or unsubstituted C3-C6 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R 12 )2; Each R in R2 and R3 10 are independently selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, cyano, and amino; Each R in R2 and R3 11 Each is independently selected from: C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl; Each R in R2 and R3 12 are independently selected from: hydrogen, C1-C4 alkyl; Alternatively, R2, R3 and the carbon atom to which they are attached together form: R 10 Substituted or unsubstituted benzene ring, R 10 Substituted or unsubstituted C5-C6 cycloalkyl, R 10 Substituted or unsubstituted 5-6 membered heterocyclic ring, R 10 A substituted or unsubstituted 5-6 membered heteroaromatic ring.

11. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 10, characterized in that: R2 is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, nitro, amino, trifluoromethyl, acetamide, acrylamide, isobutylamide, propionamide, and cyano; R3 is hydrogen; Alternatively, R2, R3 and the carbon atom to which they are connected together form: a benzene ring, a pyrrole ring, a thiophene ring, a pyrazole ring, a pyrazole ring, a pyridine ring, or a furan ring.

12. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: When R4 is selected from: hydrogen or methyl; R2 is not hydrogen.

13. The cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof according to claim 1 or 2, characterized in that: R4 is selected from the group consisting of: hydrogen, halogen, cyano, nitro, amino, R 10 Substituted or unsubstituted C1-C4 alkyl, R 10 Substituted or unsubstituted C2-C4 alkenyl, R 10 Substituted or unsubstituted C3-C6 cycloalkyl, R 10 Substituted or unsubstituted C1-C4 alkoxy, R 10 Substituted or unsubstituted C3-C6 cycloalkoxy, -NR 12 C(=O)R 11 、-C(=O)R 11 、-C(=O)N(R 12 )2; Each R in R4 10 are independently selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, cyano, and amino; Each R in R4 11 Each is independently selected from: C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl; Each R in R4 12 Each is independently selected from: hydrogen, C1-C4 alkyl.

14. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 13, characterized in that: R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, deuterated methoxy, trifluoromethoxy, cyclopropyloxy, trifluoromethyl, and cyclopropyl.

15. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R4 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, nitro, amino, trifluoromethyl, acetamide, acrylamide, isobutyramide, propionamide, and cyano; R3 is hydrogen.

16. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R4 is selected from the group consisting of methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, deuterated methoxy, trifluoromethoxy, cyclopropyloxy, trifluoromethyl, cyclopropyl, isopropyl, and ethyl; R2 is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, iodine, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, nitro, amino, trifluoromethyl, acetamide, acrylamide, isobutyramide, propionamide, and cyano; R3 is hydrogen.

17. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R1 is selected from the group consisting of ethylsulfonyl, methylsulfonyl and propylsulfonyl; one of R2 and R4 is hydrogen and the other is not hydrogen; R3 is hydrogen.

18. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R6 is selected from: -NR 13 R 14 , -CR 13 R 14 R 15 、-(CH2) n R 13 R 14 R 15 、-(CH2) n NR 13 R 14 ; Each R 13 and each R 14 are independently selected from: hydrogen, C1-C4 alkyl, C1-C4 alkyl substituted with dimethylamino, or R 13 , R 14 Together with the N or C to which it is connected, it forms R 17 Substituted or unsubstituted 3-12 membered heterocyclic group; R 15 Selected from: H, C1-C4 alkyl; Each R 17 are independently selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl, C1-C8 alkyl substituted with hydroxy, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 alkylamino, halogen, hydroxy, cyano, amino, R 18 Substituted or unsubstituted 3-8 membered heterocyclic group, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 , or R 17 Together with the carbon atom to which it is attached, it forms C(=O); R 18 Selected from: hydrogen, C1-C8 alkyl.

19. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 18, characterized in that: Each R 17 are independently selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, hydroxy-substituted C1-C4 alkyl, C5-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, dimethylamino, halogen, hydroxy, cyano, amino, R 18 Substituted or unsubstituted 3-8 membered heterocyclic group, -C(=O)R 11 、-S(=O)2R 11 、-S(=O)R 11 , or R 17 Together with the carbon atom to which it is attached, it forms C(=O); R 18 Selected from: hydrogen, C1-C4 alkyl; R 17 Each R in 11 Each is independently selected from: C1-C4 alkyl, C1-C4 alkoxy.

20. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 19, characterized in that: R6 is selected from:

21. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: R is selected from the group consisting of hydrogen, methoxycarbonyl, isopropyloxycarbonyl, carbamoyl, methyl, ethoxycarbonyl, or R together with the carbon atom to which it is attached forms C(=O).

22. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: L is selected from: R 16 Substituted or unsubstituted C2-C6 alkylene, R 16 Substituted or unsubstituted C2-C6 alkenyl; R 16 is selected from the group consisting of: hydrogen, deuterium, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, amino, halogen, hydroxy, cyano, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino; or, two R connected to the same carbon atom 16 Connected to form a cyclopropyl group.

23. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 22, characterized in that: L is selected from: -(CH2)2-, -(CH2)3-, -(CH2)4-, 24. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: Selected from the following compounds:

25. The cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule according to claim 1 or 2, characterized in that: Selected from the following compounds:

26. Use of the cyclic 2-aminopyrimidine compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof in the preparation of an EGFR inhibitor.

27. Use of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or stereoisomer or prodrug molecule according to any one of claims 1 to 25 in the preparation of a mutant EGFR inhibitor, characterized in that: The mutant EGFR is EGFR T790M , EGFR T790M / C797S , EGFR 19del / T790M / C797S , EGFR L858R / T790M , EGFR L858R / C797S , EGFR L858R / T790M / C797S .

28. Use of the cyclic 2-aminopyrimidine compound according to any one of claims 1 to 25 or its pharmaceutically acceptable salt or stereoisomer or its prodrug molecule in the preparation of a drug for preventing and / or treating tumors.

29. The use according to claim 28, characterized in that The tumor is a malignant tumor with EGFR gene mutation.

30. The use according to claim 29, characterized in that The tumor is EGFR 19del / T790M / C797S Mutation, EGFR T790M Mutation, EGFR T790M / C797S Mutation, EGFR L858R / T790M Mutation, EGFR L858R / C797S Mutation and / or EGFR L858R / T790M / C797S of malignant tumors.

31. The use according to claim 28, characterized in that 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 tumor, colon cancer, rectal cancer or glioma.

32. A pharmaceutical composition for preventing and / or treating tumors, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the cyclic 2-aminopyrimidine compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

33. A method for preventing and / or treating tumors, characterized in that: The method comprises: administering to the patient a safe and effective amount of any one of 1-25 cyclic 2-aminopyrimidine compounds or a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof; and / or, Administer a safe and effective amount of the pharmaceutical composition of claim 32.

34. The method according to claim 33, characterized in that 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 tumor, colon cancer, rectal cancer or glioma.

35. A method for selectively inhibiting mutant EGFR kinase activity, characterized in that: The method comprises: administering to the patient a safe and effective amount of any one of 1-25 cyclic 2-aminopyrimidine compounds or a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof; and / or, Administer a safe and effective amount of the pharmaceutical composition of claim 32.

36. The method according to claim 35, characterized in that The mutant EGFR is EGFR T790M , EGFR T790M / C797S , EGFR 19del / T790M / C797S , EGFR L858R / T790M , EGFR L858R / C797S , EGFR L858R / T790M / C797S .

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