Aryl phosphate compounds and uses thereof

Abstract

The present invention provides aryl phosphorylated compounds having kinase inhibitory activity. The compounds inhibit various types of EGFR drug-resistant mutants (EGFR del19 , EGFR del19 / T790M , EGFR del19 / C797S , EGFR T790M / L858R , EGFR L858R / C797S , EGFR del19 / T790M / C797S , and EGFR L858R / T790M / C797S It can effectively inhibit the activity of ALK fusion genes and mutants (such as L1196M), and also has a significant inhibitory effect on ALK fusion genes and mutants (such as L1196M), and can be used for the treatment, co-treatment, or prevention of various types of cancer.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of medicine, and in particular to aryl phosphorylated compounds that are used as protein kinase inhibitors.

[0002] 〔background〕 Protein kinases represent a large family of proteins that play an important role in the regulation of multiple cellular processes and in the maintenance and control of cellular functions, including proliferation, apoptosis, cytoskeletal rearrangement, differentiation, development, immune response, nervous system function and conduction. In addition, many diseases and / or dysfunctions are associated with the abnormal, abnormal or unregulated activity of one or more kinases.

[0003] Lung cancer is one of the most common malignant tumors and is generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Lung cancer ranks first in China and the world. NSCLC accounts for more than 80% of all lung cancers and is a serious threat to human health (Chinese Journal of Lung Cancer [J], 2012 Feb 20; 15(2): 106-111).

[0004] EGFR, with the formal name epidermal growth factor receptor, is a transmembrane glycoprotein with tyrosine kinase activity, widely distributed on the cell membrane of various human tissues. Mutations and abnormal activation of EGFR are closely associated with the occurrence and development, malignancy, and metastasis with various tumors, such as non-small cell lung cancer, breast cancer, and esophageal cancer. Most patients with non-small cell lung cancer (NSCLC) have EGFR overexpression, and about 40-50% of non-small cell lung cancer patients in Asia (especially China) belong to EGFR mutations. Therefore, EGFR inhibition can significantly improve the survival time of NSCLC patients. Common mutations of EGFR can be divided into two categories. One category refers to drug-sensitive mutations, i.e., anti-tumor targeted agents can be used after mutations such as deletions in exon 19 and L858R mutations in exon 21. Meanwhile, the other category refers to drug-resistant mutations, i.e., resistant to certain anti-tumor targeted agents after mutations such as T790M mutations and C797S mutations. The first generation EGFR small molecule inhibitors gefitinib, erlotinib and icotinib achieve remarkable clinical therapeutic effects and prolong survival in patients with EGFR-sensitive mutations. However, most patients who benefit from these drugs develop drug resistance after taking the drugs for several months. More than 50% of drug-resistant patients develop drug resistance due to T790M mutations in EGFR. The second generation EGFR irreversible inhibitors afatinib and neratinib achieve better results in preclinical studies, but lack selectivity for wild-type EGFR (EGFRWT) and have significant side effects such as skin toxicity. The third generation irreversible inhibitor osimertinib (AZD9291) overcomes the drug resistance of EGFR T790M and can effectively treat advanced non-small cell lung cancer patients with epidermal growth factor receptor T790M mutations or drug resistance to other EGFR inhibitors in clinical practice.Although osimertinib has been largely successful in clinically treating non-small cell lung cancer harboring the EGFR T790M mutation, some patients who benefit from osimertinib develop drug resistance after 9 to 14 months of treatment (Nature Medicine 2015, 21(6), 560-562). In up to 40% of drug-resistant patients, osimertinib resistance was found to be due to a point mutation at (EGFR)C797S. Further mechanistic studies showed that the point mutation at (EGFR)C797S converts the cysteine ​​at position 797 to serine, preventing osimertinib from forming a covalent bond with the target protein, ultimately resulting in drug resistance. Currently, there are no clinically available EGFR inhibitors that are effective against the new mutation (C797S). Therefore, novel EGFR inhibitors with high selectivity are urgently needed to solve the problem of drug resistance caused by the point mutation at (EGFR)C797S.

[0005] Anaplastic lymphoma kinase (ALK), also known as ALK tyrosine kinase receptor or CD246, is an active enzyme encoded by the ALK gene in the human body. Fusion genes formed by ALK are closely related to the occurrence and development of various tumors, such as non-small cell lung cancer. In non-small cell lung cancer patients, fusion oncogenes such as EML4-ALK (fusion gene of echinoderm microtubule-associated protein 4 and anaplastic lymphoma kinase) account for approximately 3-7%. Therefore, developing protein kinase inhibitors against positive ALK fusion genes is of great clinical value. Meanwhile, in recent years, with the increase in non-small cell lung cancer patients and the widespread use of second-generation sequencing technology (deep sequencing), researchers have found that EGFR mutations and ALK gene fusions may occur simultaneously in some non-small cell lung cancer patients. Therefore, novel protein kinase inhibitors with high selectivity are urgently needed to solve the problem of drug resistance caused by the (EGFR) C797S point mutation and at the same time solve the fusion and mutation of the ALK gene.

[0006] 〔overview〕 One or more embodiments of the present application provide an aryl phosphorylation compound represented by the following formula (I) or a pharma- ceutically acceptable salt thereof for use as a protein kinase inhibitor. The aryl phosphorylation compound is capable of inhibiting various EGFR drug resistance mutants (e.g., EGFR del19 , EGFR del19 / T790M , EGFR del19 / C797S , EGFR T790M / L858R , EGFR L858R / C797S , EGFR del19 / T790M / C797S , and EGFR L858R / T790M / C797S ), and also has a significant inhibitory effect on ALK fusion genes and mutants (e.g., L1196M), and can be used for the treatment, combination treatment or prevention of various cancers.

[0007] [ka]

[0008] wherein R1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl, the C1-C6 alkyl and the C3-C6 cycloalkyl being optionally substituted with 0-6 R'; R2 is hydrogen, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, phenyl, 5-6 membered heteroaryl,

[0009] [ka]

[0010] the amino, the C1-C6 alkyl, the C3-C6 cycloalkyl, the phenyl and the 5- to 6-membered heteroaryl are optionally selected from 0 to 3 R a is substituted with a group; X is selected from CH, S, N or O; n is 0, 1 or 2; If X is O, then R a does not include;

[0011] [ka]

[0012] represents a C—C saturated bond or a C═C olefinic bond; R3 is C1-C6 alkyl, C3-C6 cycloalkyl, -NR b R c and halogen; the C1-C6 alkyl, the C3-C6 cycloalkyl and -NR b R c is optionally substituted with 0-3 R'; R4 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and halogen, wherein the C1-C6 alkyl and the C3-C6 cycloalkyl are optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl and halogen, wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R a and R aa each independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, halogen, amino, hydroxyl, cyano, nitro, -NR b C(O)R c , -NR b R c , and

[0013] [ka]

[0014] wherein said C1-C6 alkyl, said C3-C6 cycloalkyl, said phenyl, said 5-6 membered heteroaryl, said amino and said hydroxyl are optionally substituted with 0-3 R'; Y is selected from N or O, Z is selected from CH or N; when Y is O, R' is absent; R b and R c are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, and amino; the C1-C6 alkyl, the C3-C6 cycloalkyl, the C2-C6 alkenyl, and the C2-C6 alkynyl are optionally substituted with 0-3 R'; R' is selected from hydrogen, F, Cl, Br, I, hydroxyl, acyl, carboxyl, amino, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl; the C1-C6 alkyl, the C3-C6 cycloalkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the amino, and the hydroxyl are optionally substituted with 0-3 hydrogen, hydroxyl, carboxyl, carbonyl, F, Cl, Br, I, amino, nitro, cyano, methyl, trifluoroethyl, difluoromethyl, and monofluoromethyl.

[0015] In one or more embodiments of the present application, R1 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R2 is hydrogen, C1-C6 alkyl, amino,

[0016] [ka]

[0017] wherein said amino and said C1-C6 alkyl are selected from 1 to 3 R a is replaced by; R a and R aa are each independently hydrogen, NR b R c , C1-C6 alkyl, or

[0018] [ka]

[0019] Selected from; R3 is C1-C6 alkyl, C3-C6 cycloalkyl, halogen and -NR b R c said C1-C6 alkyl and said C3-C6 cycloalkyl are optionally substituted with 0-3 R'; R4 is selected from halogen, C1-C6 alkyl, and C3-C6 cycloalkyl; said C1-C6 alkyl and said C3-C6 cycloalkyl are optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl and halogen; the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is selected from hydrogen or methyl; R b and R c are each independently selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl; said C1-C6 alkyl and said C2-C6 alkenyl are optionally substituted with 0-3 R'.

[0020] In one or more embodiments of the present application, the compound or a pharma- ceutically acceptable salt thereof is: R3 is selected from C1-C6 alkyl and C3-C6 cycloalkyl; said C1-C6 alkyl and said C3-C6 cycloalkyl are optionally substituted with 0-3 R'; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is hydrogen.

[0021] In one or more embodiments of the present application, the compound or a pharma- ceutically acceptable salt thereof is: R2 is amino, and

[0022] [ka]

[0023] wherein the amino is optionally selected from 0 to 3 R a where X is selected from CH, N or O; R a teeth,

[0024] [ka]

[0025] , C1-C3 alkyl or NR b R c Selected from; wherein Y is selected from N or O, and Z is selected from CH or N; R b and R c are each independently selected from hydrogen and C1-C3 alkyl; R3 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R4 is selected from Cl, Br, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with 0-3 R'; R' is selected from hydrogen, C1-C6 alkyl, F, Cl, Br, I, hydroxyl and amino.

[0026] In one or more embodiments of the present application, R2 is amino, and

[0027] [ka]

[0028] wherein the amino is optionally selected from 0 to 3 Ra where X is selected from CH, N or O; R a teeth,

[0029] [ka]

[0030] , C1-C3 alkyl or NR b R c Selected from; wherein Y is selected from N or O, and Z is selected from CH or N; R b and R c are each independently selected from hydrogen and C1-C3 alkyl; R3 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R4 is selected from Cl, Br and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl, the C1-C6 alkyl being optionally substituted with 0-3 R'; R' is selected from F, Cl, Br, I, hydroxyl and amino.

[0031] In one or more embodiments of the present application, R1 is selected from methyl, ethyl, isopropyl, CF2H and CH2CF3; R2 is

[0032] [ka]

[0033] Selected from; R3 is selected from methyl, ethyl and isopropyl; R4 is selected from Cl, Br, CH3, CF3, and CH2CF3; R5 is selected from methyl, ethyl and isopropyl.

[0034] In one or more embodiments of the present application, R1 is selected from methyl, ethyl, isopropyl, CF2H and CH2CF3; R2 is

[0035] [ka]

[0036] Selected from; R3 is selected from methyl and ethyl; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from methyl and ethyl.

[0037] In one or more embodiments of the present application, the compound or a pharma- ceutically acceptable salt thereof is: R3 is a halogen; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is hydrogen; R' is selected from hydrogen, C1-C6 alkyl, F, Cl, Br, I, hydroxyl and amino.

[0038] In one or more embodiments of the present application, R3 is a halogen; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is hydrogen; R' is selected from F, Cl, Br, I, hydroxyl and amino.

[0039] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0040] [ka]

[0041] Selected from; R3 is selected from Cl and Br; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from methyl, ethyl and isopropyl.

[0042] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0043] [ka]

[0044] Selected from; R3 is selected from Cl and Br; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from methyl and ethyl.

[0045] In one or more embodiments of the present application, R3 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from halogen; R6 is hydrogen; R' is selected from hydrogen, C1-C6 alkyl, F, Cl, Br, I, hydroxyl and amino.

[0046] In one or more embodiments of the present application, R3 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from halogen; R6 is hydrogen; R' is selected from F, Cl, Br, I, hydroxyl and amino.

[0047] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0048] [ka]

[0049] Selected from; R3 is selected from methyl, ethyl and isopropyl; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from F and Cl.

[0050] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0051] [ka]

[0052] Selected from; R3 is selected from methyl and ethyl; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from F and Cl.

[0053] In one or more embodiments of the present application, R3 is -NR b R c and; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is hydrogen; R b and R c are each independently selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl; said C1-C6 alkyl and said C2-C6 alkenyl are optionally substituted with 0-3 R'; R' is selected from hydrogen, C1-C6 alkyl, F, Cl, Br, I, hydroxyl and amino.

[0054] In one or more embodiments of the present application, R3 is -NR b R c and; R4 is selected from halogen and C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with 0-3 R'; R5 is selected from C1-C6 alkyl; the C1-C6 alkyl is optionally substituted with 0-3 R'; R6 is hydrogen; R b and R c are each independently selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl; said C1-C6 alkyl and said C2-C6 alkenyl are optionally substituted with 0-3 R'; R' is selected from F, Cl, Br, I, hydroxyl and amino.

[0055] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0056] [ka]

[0057] Selected from; R3 is NHCH3; R4 is selected from Cl, Br, CF3, and CH2CF3; R5 is selected from methyl and ethyl.

[0058] In one or more embodiments of the present application, R1 is selected from methyl, ethyl, isopropyl, and -CF2H; R2 is

[0059] [ka]

[0060] Selected from; R3 is selected from methyl, ethyl and isopropyl; R4 is selected from Br; R5 is selected from methyl, ethyl and isopropyl.

[0061] In one or more embodiments of the present application, R1 is selected from methyl, ethyl and isopropyl; R2 is

[0062] [ka]

[0063] Selected from; R3 is selected from methyl, ethyl and isopropyl; R4 is selected from Br; R5 is selected from F and Cl.

[0064] The present invention provides the following compound or a pharma- ceutically acceptable salt thereof:

[0065] [ka] JPEG0007602630000021.jpg243169JPEG0007602630000022.jpg212169JPEG0007602630000023.jpg236169

[0066] One or more embodiments of the present application provide a pharmaceutical composition comprising a compound according to the present application, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0067] One or more embodiments of the present application provide a pharmaceutical preparation comprising a compound according to the present application, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable adjuvant.

[0068] One or more embodiments of the present application include: EGFR or ALK or EGFR and the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for preventing and / or treating a disease associated with ALK.

[0069] In one or more embodiments, EGFR or ALK or EGFR and the disease associated with ALK is cancer.

[0070] One or more embodiments of the present application provide for the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation or a pharmaceutical composition according to the present application in the manufacture of a medicament for preventing and / or treating cancer.

[0071] One or more embodiments of the present application provide a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, for use as a medicament.

[0072] One or more embodiments of the present application provide a method of using a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, for preventing and / or treating cancer.

[0073] One or more embodiments of the present application include: EGFR or ALK or EGFR and the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above for the prophylaxis and / or treatment of a disease associated with ALK.

[0074] One or more embodiments of the present application include: EGFR inhibitors, or ALK inhibitors, or EGFR and the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, as an inhibitor of ALK or a protein kinase inhibitor. EGFR There is provided the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, in the manufacture of an inhibitor.

[0075] One or more embodiments of the present application provide for the use of a compound of the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, in the manufacture of an ALK inhibitor.

[0076] One or more embodiments of the present application include: EGFR and the use of a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, in the manufacture of an inhibitor of ALK.

[0077] In one or more embodiments of the present application, the medicaments for treating cancer are aryl phosphorylated compounds having protein kinase inhibitory activity, including medicaments for preventing and / or treating lung cancer, e.g., medicaments for preventing and / or treating multiple myeloma; medicaments for preventing and / or treating lymphoma, e.g., medicaments for preventing and / or treating non-Hodgkin's lymphoma, mantle cell lymphoma and follicular lymphoma; medicaments for preventing and / or treating leukemia; and medicaments for preventing and treating mantle cell tumor, breast cancer, liver cancer, colon cancer, cervical cancer, lung cancer, plasmacytoma, lymphoma, ovarian cancer, renal cancer, gastric cancer, nasopharyngeal carcinoma, leukemia, melanoma, thyroid cancer, pancreatic cancer, adenocarcinoma or squamous cell carcinoma.

[0078] In one or more embodiments of the present application, the compounds of the present application can be used to treat lung cancer, plasmacytoma, mantle cell tumor, multiple myeloma, melanoma, breast cancer, liver cancer, cervical cancer, lymphoma, leukemia, ovarian cancer, renal cancer, gastric cancer, nasopharyngeal cancer, thyroid cancer, pancreatic cancer, prostate cancer, adenocarcinoma, oral cancer, esophageal cancer, squamous cell carcinoma, or colon cancer.

[0079] One or more embodiments of the present application include: EGFR or ALK or EGFR Further provided is a method for treating and / or preventing a disease associated with ALK, comprising administering to a subject in need thereof a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation or composition according to the present application.

[0080] One or more embodiments of the present application further provide a method for treating and / or preventing cancer or tumors, the method comprising administering to a subject in need thereof a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation or composition according to the present application.

[0081] One or more embodiments of the present application further provide for the use of a compound of the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation as described above, or a pharmaceutical composition as described above, in the manufacture of a protein kinase inhibitor.

[0082] One or more embodiments of the present application include: EGFR Further provided are inhibitors, and / or ALK inhibitors, or methods for inhibiting protein kinases in vivo or in vitro, comprising administering to a subject or a subject in need thereof a compound according to the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical preparation or composition according to the present application.

[0083] The terms used in the technical solutions of this application are described below. When used in this specification and the appended claims, unless otherwise specified, the terms of this application have the meanings set forth below.

[0084] The term "compound" includes all stereoisomers, geometric isomers and tautomers. The "compound" described herein may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers, e.g., individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof, are included. Compounds containing asymmetric carbon atoms herein may be isolated in optically pure form or as racemates. Optically active and pure forms may be separated from racemic mixtures or synthesized by using chiral materials or chiral reagents. The term "compound" as used herein also includes geometric isomeric forms. Geometric isomeric forms refer to compounds that have different cis-trans isomerism and no chirality at double bonds or ring substituents. The term "compound" as used herein also includes tautomeric forms. Tautomeric forms may result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.

[0085] The compounds of the present invention, whether intermediates or compounds of formula (I), may be isotopically labeled by replacing one or more atoms therein with atoms having different atomic mass or mass number.Such isotopically labeled (i.e., radiolabeled) compounds are considered to be within the scope of the present invention.Examples of isotopes in the compounds of the present invention include isotopes of carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, each of which has the same number of protons but different mass numbers.

[0086] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0087] The term "amino" refers to --NH.sub.2.

[0088] The term "cyano" refers to --CN.

[0089] The term "nitro" refers to --NO.

[0090] The term "hydroxyl" refers to --OH.

[0091] The term "carboxyl" refers to --COOH.

[0092] The term "alkyl" refers to saturated aliphatic hydrocarbyl groups. The term includes straight and branched chain hydrocarbyls, such as C1-C6 20 Alkyl, preferably C1-C6 alkyl. 20 Alkyl refers to alkyl having 1 to 20 carbon atoms, such as alkyl having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like. Alkyl may be unsubstituted or substituted with one or more substituents. The one or more substituents include, but are not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, amide, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.

[0093] The term "cycloalkyl" refers to cyclic alkyls having single or multiple rings (including fused, bridged, and spiro ring systems) and includes cyclic alkyls composed of 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms) and hydrogen atoms. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.4]octyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, and the like.

[0094] The term "cycloalkenyl" refers to a cyclic or polycyclic hydrocarbyl containing one or more double bonds and having 3 to 13 carbon atoms, preferably 5 to 8 carbon atoms. Cycloalkenyl groups can be substituted or unsubstituted. Cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cyclooctenyl.

[0095] The term "alkenyl" refers to a hydrocarbyl containing one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl may be unsubstituted or substituted. Alkenyl may have 1 to 20 carbon atoms, and numerical ranges such as "1 to 20" refer to each integer within the given range. For example, "1 to 20 carbon atoms" refers to the alkenyl may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.

[0096] The term "alkynyl" refers to a hydrocarbyl containing one or more triple bonds in a straight or branched hydrocarbon chain. Alkynyl may be unsubstituted or substituted. Alkynyl may have 1 to 20 carbon atoms, and numerical ranges such as "1 to 20" refer to each integer within the given range. For example, "1 to 20 carbon atoms" refers to the alkynyl may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.

[0097] The term "heteroaryl" refers to a single or fused ring system having 5-12 ring atoms (e.g., 5, 6, 10, 12, 14 ring atoms) containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, with the remaining ring atoms being C, and having a fully conjugated pi-electron system. Fully conjugated pi-electron systems include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, benzimidazole, benzotriazole, and the like. Heteroaryls can be unsubstituted or substituted. Substituents include, but are not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, aralkyl, amide, halogen, sulfonyl, sulfinyl, phosphonyl, and the like. The term "substituted" as used herein means that any group is mono- or polysubstituted with a particular substituent, such mono- or polysubstitution (including multiple substitutions at the same moiety) to the extent that such substitution is chemically permitted, and each substituent may be located at any available position on the group and may be bonded via any available atom on the substituent. "Any available position" refers to any position on the group that is chemically permitted by methods known in the art or described herein and does not result in an overly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent, and therefore may be the same or different.

[0098] The term "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, or aryl as a substituent attached through a carbonyl. Examples include formyl, acetyl, propionyl, benzoyl, and acryloyl. Acyl may be substituted or unsubstituted.

[0099] The term "substituted" as used herein means that any group is mono- or polysubstituted with a particular substituent, such mono- or polysubstitution (including multiple substitutions at the same moiety) to the extent that such substitution is chemically permitted, and each substituent may be located at any available position on the group and may be bonded via any available atom on the substituent. "Any available position" refers to any position on the group that is chemically accessible by methods known in the art or described herein and does not result in an overly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent, and therefore may be the same or different.

[0100] When a group is described as "optionally substituted with 0-6 R'", it means that the group may be optionally substituted with 1, 2, 3, 4, 5, or 6 R', or may be substituted with no R' (i.e., corresponding to 0 R'). When a group is described as "optionally substituted with 0-3 R'", it means that the group may be optionally substituted with 1, 2, or 3 ... a When "substituted with" is described, the group may optionally be substituted with 1, 2 or 3 R a or R a It may not be replaced by (i.e., 0 R a corresponds to

[0101] Where a group is described as being "optionally substituted," that group may be unsubstituted or substituted with one or more of the following substituents: hydrogen, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, acyl, alkoxy, heterocycloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclic, aralkyl, heteroaralkyl, (heterocyclic)alkyl, hydroxy, aryl ... Aryl, aryloxy, sulfhydryl, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-thioformamyl, N-thioformamyl, C-acyamino, N-acyamino, S-sulfonylamino, N-sulfonylamino, carboxyl, isocyanate, thiocyanate, isothiocyanate, silyl, alkylthio, sulfinyl, sulfonyl, haloalkyl, haloalkoxy and amino.

[0102] The term "pharmaceutical acceptable" means that the compound must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or with the mammal being treated therewith.

[0103] The "pharmaceutical preparation" referred to in this application may be a pharmaceutical composition, either directly or in combination with other active ingredients, together with pharma- ceutically acceptable adjuvants or carriers. The preparations include tablets, pills, capsules, granules, suspensions, emulsions, and the like. Pharmaceutically acceptable adjuvants or carriers include: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint oil, methyl salicylate or orange flavoring; non-aqueous solvents such as dimethyl sulfoxide, alcohol, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate; aqueous carriers such as mixtures of alcohol and water, buffered media and saline; and preservatives, antibacterial agents, antioxidants, chelating agents, dyes, pigments or flavorings.

[0104] The cancer in one or more embodiments of the present application is, in particular, any one or more of plasmacytoma, mantle cell tumor, multiple myeloma, melanoma, breast cancer, liver cancer, cervical cancer, lung cancer, lymphoma, leukemia, ovarian cancer, renal cancer, gastric cancer, nasopharyngeal cancer, thyroid cancer, pancreatic cancer, prostate cancer, adenocarcinoma, oral cancer, esophageal cancer, squamous cell carcinoma, or colon cancer.

[0105] Other anti-tumor agents which can be combined with the compounds of the present application to form pharmaceutical compositions include cytotoxic agents, hormonal agents, antimetabolites, tumor-targeting agents, adjuvant therapeutic agents, and the like. Cytotoxic agents include, for example, carboplatin, cisplatin, irinotecan, paclitaxel, fluorouracil, cytarabine, lenalidomide, and retinoic acid; hormonal agents include, for example, dexamethasone, fulvestrant, tamoxifen, and the like; antimetabolites include, for example, fluorouracil, methotrexate, furanfluorouracil, and cytarabine; molecular targeted agents include, for example, the tinib drugs imatinib, erlotinib, lapatinib, and the like; PARP inhibitors include, for example, Olaparib, Rubraca, Zejula, and the like; adjuvant therapeutics include, for example, recombinant human granulocyte colony-stimulating factor, erythropoietin, pamidronate disodium, zoledronic acid, and the like. Additionally, anti-tumor biologic agents such as Keytruda, Opdiv, Tecentriq, Imfinzi, and Bavencio are also included.

[0106] [Technical effect] In one or more embodiments of the present invention, the compounds are capable of inhibiting various EGFR drug resistance mutations (EGFR del19 , EGFR del19 / T790M , EGFR del19 / C797S , EGFR T790M / L858R , EGFR L858R / C797S , EGFR del19 / T790M / C797S , and EGFR L858R / T790M / C797S etc.), and the compounds in one or more embodiments of the present invention have good inhibitory effects on the ALK fusion gene and its mutations. The compounds in one or more embodiments of the present invention have inhibitory activity on both EGFR drug resistance mutations and the ALK fusion gene and its mutations.

[0107] In one or more embodiments, for multiple EGFR drug resistance mutations characterized by the T790M mutation, the compounds of the present invention have a significantly lower IC than the compounds disclosed in the prior art.50 Value and / or GI 50 value and exhibit better inhibitory activity; multiple EGFR drug resistance mutations characterized by T790M mutation include EGFR-T790M / Del19, EGFR-T790M / L858R, EGFR-C797S / T790M / L858R, EGFR-C797S / T790M / Del19, etc.

[0108] In one or more embodiments, for multiple EGFR drug resistance mutations characterized by the C797S mutation, the compounds of the present invention have a significantly lower IC than the compounds disclosed in the prior art. 50 Value and / or GI 50 value and exhibit better inhibitory activity; multiple EGFR drug resistance mutations characterized by C797S mutation include EGFR-C797S / Del19, EGFR-C797S / L858R, EGFR-C797S / T790M / L858R, EGFR-C797S / T790M / Del19, etc.

[0109] In one or more embodiments, for multiple EGFR drug resistance mutations characterized by the L858R mutation, the compounds of the present invention have a significantly lower IC than the compounds disclosed in the prior art. 50 Value and / or GI 50 For multiple EGFR drug resistance mutations characterized by Del19 mutations, the compounds of the present invention have significantly lower IC values ​​than the compounds disclosed in the prior art. 50 Value and / or GI 50 values, indicating better inhibitory activity.

[0110] In one or more embodiments, the compounds of one or more embodiments of the present invention also exhibit greater selectivity for mutant and wild-type EGFR than compounds disclosed in the prior art.

[0111] In one or more embodiments, the compounds of one or more embodiments of the present invention have a significantly lower IC for ALK mutant genes, such as EML4-ALK, EML4-ALK-L1196M, than compounds disclosed in the prior art. 50 Value and / or GI 50 values, indicating better inhibitory activity.

[0112] In one or more embodiments, the compounds of the present application exhibit unexpected activity in EGFR drug resistance mutation inhibitory activity assays compared to comparative compounds, while also exhibiting significant and unexpected inhibitory activity against ALK fusion genes and mutants.

[0113] In one or more embodiments, the compounds of the present application exhibit greater safety and have significantly improved tolerability compared to comparative compounds.

[0114] The compounds of one or more embodiments of the present application have good physicochemical properties and high stability.

[0115] [Example] This application will be further described below in conjunction with the following examples, which are described to provide further illustration of the implementation of this application.However, it should be noted that the examples described below are illustrative and are used only to illustrate this application, but should not be interpreted as limiting this application.The variations and substitutions thereof by those skilled in the art are also within the scope of this application, which is determined by the scope of the appended claims.The reagents used in the examples of this application are all commercially available.

[0116] Example 1 Compound 1A:

[0117] [ka]

[0118] 2-Iodo-4-methylaniline (10g, 42.9mmol), K3PO4 (10.9g, 51.5mmol), Xantphos (2.48g, 4.3mmol), Pd(OAc)2 (0.96g, 4.3mmol), dimethylphosphine oxide (5g, 64.4mmol) and 100mL of DMF were added to a 500mL three-neck flask, and the reaction solution was heated to 120°C and reacted for about 3 hours until the reaction was completed by TLC test. The reaction solution was cooled to room temperature, suction filtered, and 600mL of H2O was added to precipitate a large amount of yellow solid, which was then suction filtered. The filtrate was extracted three times with 500mL of ethyl acetate, the organic phases were combined, washed twice with 250mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain compound 1A, which was continuously put into the next reaction without purification. 1 H NMR (400MHz, DMSO-d6) δ=9.21(brs,2H),7.57(d,J=13.6,1H),7.43(d,J=8.4,1H),7.26-7.23(m,1H),2.33(s,3H),1.85(s,3H),1.82(s,3H).

[0119] Compound 1B:

[0120] [ka]

[0121] Compound 1A obtained in the above step, 2,4,5-trichloropyrimidine (11.80 g, 64.3 mmol), K2CO3 (7.76 g, 128.73 mmol), nBu4NHSO4 (1.45 g, 4.29 mmol) and 100 mL of DMF were added to a 500 mL three-neck flask, and the reaction solution was heated to 65°C and reacted for about 4.5 hours until the TLC test showed that the reaction was complete. The reaction solution was cooled to room temperature, and 200 mL of H2O was added to precipitate a large amount of yellow solid, which was stirred continuously for about 0.5 hours and then filtered by suction. The filter cake was washed with 100 mL of H2O and dried to obtain compound 1B (8.57 g, the total yield of the two steps was 60.5%). 1H NMR (400MHz, DMSO) δ=11.62(s,1H),8.40(s,1H),8.27(dd,J=8.4,4.4Hz,1H),7.44(m,2H),2.33(s,3H),1.81(s,3H),1.77(s,3H).

[0122] Compound 1C:

[0123] [ka]

[0124] 3-Fluoro-4-methylphenol (10 g, 79.28 mmol) and benzyltriethylammonium chloride (1.77 g, 7.93 mmol) were weighed and added to a 250 mL three-neck flask, then dissolved by adding 80 mL of dichloromethane with stirring. Nitric acid (14.7 g, 158.57 mmol) was slowly added dropwise to the above reaction solution at 0-10 °C. After the addition was completed, the reaction mixture was continuously stirred for about 0.5 hours until the TLC test showed that the reaction was complete. Then, 120 mL of saturated aqueous sodium bicarbonate was slowly added, after which the reaction solution was separated, and then the organic phase was washed successively with 40 mL of H2O, and 40 mL of saturated sodium chloride.

[0125] After washing the aqueous solution, the organic phase was concentrated, separated and purified by column chromatography isolation (PE / EA=8 / 1) to obtain compound 1C (8 g, yield 59.2%). 1 H NMR (400MHz, CDCl3) δ=10.66(d,J=0.8Hz,1H),8.02(d,J=7.6Hz,1H),6.83(d,J=10.0Hz,1H),2.28(d,J=0.8Hz,3H).

[0126] Compound 1D:

[0127] [ka]

[0128] Compound 1C (2 g, 11.68 mmol), K2CO3 (2.42 g, 17.54 mmol), methyl iodide (1.08 mL, 17.54 mmol) and 30 mL of DMF were weighed and added to a 100 mL three-neck flask and stirred at room temperature overnight until TLC test showed that the reaction was complete. Then, 60 mL of water was added to the reaction solution to precipitate a large amount of off-white solid, which was stirred continuously for about 0.5 hours and then filtered by suction. The filter cake was filtered, washed with water and dried to give compound 1D (1.59 g, 73.6% yield). 1 H NMR (400MHz, CDCl3) δ=7.85(d,J=7.6Hz,1H),6.79(d,J=11.2Hz,1H),3.05(s,3H),2.27(d,J=1.6Hz,3H).

[0129] Compound 1E:

[0130] [ka]

[0131] Compound 1D (4.5 g, 24.3 mmol), K2CO3 (6.71 g, 48.6 mmol), 1-methyl-4-(4-piperidinyl)piperazine (6.67 g, 36.4 mmol) and 67.5 mL of DMF were weighed and added to a 250 mL three-neck flask, and then the reaction solution was heated to 120° C. and reacted for 4 hours with stirring until the TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 130 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours, and then suction filtered. The filter cake was filtered, washed with water and dried to obtain compound 1E (4.82 g, 56.8% yield). MS-ESI (m / z): 349.2248 (M+H) + .

[0132] Compound 1F:

[0133] [ka]

[0134] Compound 1E (4.5 g, 12.91 mmol), 0.45 g of 5% Pd / C, and 90 mL of methanol were weighed and added to a 250 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until the TLC test showed that the reaction was complete. After filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography (DCM / MeOH=8 / 1) to obtain compound 1F (4.02 g, 97.8% yield). MS-ESI (m / z): 319.2509 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=6.57(d,J=4.2Hz,2H),3.83(s,3H),3.08(d,J=8.4Hz,2H),2.81-2.45( m, 10H), 2.32 (s, 4H), 2.17 (s, 3H), 2.01-1.87 (m, 2H), 1.70-1.68 (m, 2H). MS-ESI(m / z):319.2509(M+H) + .

[0135] Compound 1:

[0136] [ka]

[0137] Compound 1B (500 mg, 1.51 mmol), compound 1F (667 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 9 mL of mixed solvent (EtOH / H2O=1 / 2) and purified to obtain compound 1 (707 mg, yield 76.3%). 1H NMR(400MHz, CDCl3) δ=10.57(s,1H),8.45(dd,J=8.4,4.8Hz,1H),8.05(m,2H),7.33(m,2H), 7.08(dd,J=14.4,1.2Hz,1H),6.62(s,1H),3.86(s,3H),3.15(d,J=11.6H z,2H),2.81-2.59(m,6H),2.51(m,2H),2.37(s,3H),2.31(s,3H),2.18( s,3H),2.12(s,3H),1.96(m,2H),1.85(s,3H),1.82(s,3H),1.72(m,2H). MS-ESI(m / z):612.3098(M+H) + .

[0138] Example 2 Compound 2B:

[0139] [ka]

[0140] Compound 1A (3.00 g, 16.38 mmol), 5-bromo-2,4-dichloropyrimidine (5.6 g, 24.57 mmol), K2CO3 (6.79 g, 49.14 mmol), nBu4NHSO4 (0.56 g, 1.638 mmol) and 60 mL of DMF were added to a 250 mL three-neck flask, heated to 65 °C, and reacted for about 4.5 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 200 mL of H2O was added to precipitate a large amount of yellow solid, which was stirred continuously for about 0.5 hours, and then filtered by suction. The filter cake was washed with 100 mL of H2O and dried to obtain compound 2B (4.5 g, 73.4% yield). 1 H NMR(400MHz, CDCl3) δ=11.19(s,1H),8.43(dd,J=8.4,4.8Hz,1H),8.32(s,1H),7.41(d,J=8.8Hz,1H),7.08(m,1H),2.38(s,3H),1.86(s,3H),1.83(s,3H). MS-ESI(m / z):395.9642(M+Na) + .

[0141] Compound 2:

[0142] [ka]

[0143] Compound 2B (375 mg, 1.00 mmol), compound 1F (414 mg, 1.30 mmol), 15% hydrogen chloride ethanol solution (730 mg, 3.00 mmol), and 4.0 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 hours. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 50 mL of 3% K2CO3 aqueous solution and 50 mL of dichloromethane were added, and after stirring for 10 minutes, the system was allowed to stand and separate. The upper aqueous phase was washed once with 50 mL of dichloromethane in succession, and the two dichloromethane phases were combined. The dichloromethane phase was then washed with 50 mL of saturated salt solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 2 (360 mg, yield 54.83%). 1 H NMR(400MHz, CDCl3) δ=10.29(s,1H),8.32(dd,J=8.8,4.8Hz,1H),8.18(s,1H),8.01(s,1H),7 .44-7.30(m,2H),7.11(d,J=14.0Hz,1H),6.61(s,1H),3.85(s,3H),3.15( d,J=11.6Hz,2H),2.80-2.52(m,11H),2.38(s,3H),2.35(s,3H),2.14(s, 3H), 1.96 (d, J=11.0Hz, 2H), 1.85 (s, 3H), 1.82 (s, 3H), 1.78-1.68 (m, 2H). MS-ESI(m / z):656.2459(M+H) + .

[0144] Example 3 Compound 3B:

[0145] [ka]

[0146] Compound 1A (420 mg, 2.29 mmol), 5-trifluoromethyl-2,4-dichloropyrimidine (745 mg, 3.43 mmol), K2CO3 (949 mg, 6.87 mmol), nBu4NHSO4 (78 mg, 0.23 mmol) and 8.5 mL of DMF were added to a 50 mL three-neck flask, and the reaction solution was heated to 65° C. and reacted for about 4.5 hours until TLC test showed that the reaction was complete. The reaction solution was cooled to room temperature, and 18.5 mL of H2O was added to precipitate a large amount of yellow solid, which was stirred continuously for about 0.5 hours and then filtered by suction. The filter cake was washed with 20 mL of H2O and dried to obtain compound 3B (466 mg, 56.0% yield). 1 H NMR(400MHz, CDCl3) δ=11.49(s,1H),8.58(s,1H),8.50-8.47(dd,J=8.4Hz,4.4Hz,1H),7.39(d,J=8.4Hz ,1H),7.08-7.04(dd,J=14.4Hz,1.2Hz,1H),2.37(s,3H),1.87(s,3H),1.84(s,3H). MS-ESI(m / z):364.0593(M+H) + ;386.0413(M+Na) + .

[0147] Compound 3:

[0148] [ka]

[0149] Compound 3B (181 mg, 0.50 mmol), compound 1F (207 mg, 0.65 mmol), 15% hydrogen chloride ethanol solution (365 mg, 1.50 mmol), and 3.0 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 hours. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 50 mL of 3% K2CO3 aqueous solution and 50 mL of dichloromethane were added, and after stirring for 10 minutes, the system was allowed to stand and separate. The upper aqueous phase was washed once with 50 mL of dichloromethane in succession, and the two dichloromethane phases were combined. The dichloromethane phase was then washed with 50 mL of saturated salt solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by column chromatography to obtain compound 3 (70 mg, 21.68% yield). 1 H NMR(400MHz, CDCl3) δ=10.51(s,1H),8.30(s,2H),8.10(s,1H),7.50(s,1H),7.22(d,J=8.4Hz,1H),7.07(d,J=14.0Hz,1H),6. 64(s,1H),3.87(s,3H),3.19(d,J=10.4Hz,2H),3.08-2.12(m,20H),1.99(d,J=10.8Hz,2H),1.79(m,8H). MS-ESI(m / z):646.3213(M+H) + .

[0150] Example 4 Compound 4B:

[0151] [ka]

[0152] A mixed solvent of DMF / DMSO (15mL / 1.5mL) was added to a 50mL one-neck flask, cooled in an ice bath, and then NaH (0.66g, 16.38mmol) was added in batches to the above mixed solvent, stirred for 5-10 minutes, and then a mixed solution of DMF / DMSO (9mL / 1mL) of compound 1A (1.0g, 5.46mmol) of Example 1 was added dropwise, and after the addition was completed, the mixture was stirred at low temperature for 30 minutes, and then a mixed solution of DMF / DMSO (9mL / 1mL) of 5-methyl-2,4-dichloropyrimidine (1.33g, 8.16mmol) was added dropwise, and after the addition was completed, the mixture was slowly heated to room temperature and reacted at room temperature overnight. After TLC test showed that the reaction was completed, 90mL of H2O was added, followed by extraction with 25mL of ethyl acetate. The aqueous phase was then extracted twice with 25mL of ethyl acetate, the organic phase was combined, washed twice with 50mL of water, washed twice with 50mL of saturated saline, and the organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and purified by column chromatography to obtain compound 4B (1.2g, yield 70.59%). 1 H NMR(400MHz, CDCl3) δ=10.85(s,1H),8.62(dd,J=8.8,4.8Hz,1H),7.99(s,1H),7.39(d,J=8.8 Hz, 1H), 7.03 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 1.85 (s, 3H), 1.82 (s, 3H). MS-ESI(m / z):310.0874(M+H) + .

[0153] Compound 4:

[0154] [ka]

[0155] Compound 4B (500 mg, 1.61 mmol), compound 1F (461 mg, 1.45 mmol), 15% hydrogen chloride ethanol solution (1.18 g, 4.83 mmol), and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 100 ° C for 5 hours. After TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution and 10 mL of water were added, and then 10 mL of dichloromethane was added and stirred for extraction. The aqueous phase was then extracted twice with dichloromethane, and the organic phase was combined and washed twice with 15 mL of water, followed by washing twice with 15 mL of saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain an oily substance, which was then pulped and purified with a mixed solvent (EA / PE=3 / 2) to obtain compound 4 (120 mg, yield 14.0%). 1 H NMR(400MHz, CDCl3) δ=10.17(s,1H),8.59(dd,J=8.4,4.8Hz,1H),8.14(s,1H),7.91(s,1H), 7.32(d,J=8.8Hz,1H),7.26(s,1H),7.04(d,J=13.4Hz,1H),6.63(s,1H), 3.86(s,3H),3.16(d,J=12.0Hz,2H),2.67(m,9H),2.36(m,8H),2.20(d, J=6.4Hz,6H),1.97(m,2H),1.84(s,3H),1.81(s,3H),1.79-1.69(m,2H). MS-ESI(m / z):592.3526(M+H) + .

[0156] Example 5 Compound 5E:

[0157] [ka]

[0158] Compound 1D (1.5 g, 8.10 mmol), K2CO3 (2.24 g, 16.20 mmol), 4-dimethylaminopiperidine (1.56 g, 12.15 mmol) and 30 mL of DMF were weighed and added to a 100 mL one-neck flask, and then the reaction solution was heated to 120° C. and reacted for about 4 hours with stirring until TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 60 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours, and then suction filtered. The filter cake was filtered, washed with water and dried to obtain compound 5E (1.46 g, 61.3% yield). MS-ESI (m / z): 294.1825 (M+H) + .

[0159] Compound 5F:

[0160] [ka]

[0161] Compound 5E (1.4 g, 4.77 mmol), 0.52 g of 5% Pd / C, and 28 mL of methanol were weighed and added to a 250 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until a TLC test showed that the reaction was complete. After filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography (DCM / MeOH=8 / 1) to obtain compound 5F (918 mg, 73.0% yield). MS-ESI (m / z): 264.2065 (M+H) + .

[0162] Compound 5:

[0163] [ka]

[0164] Compound 1B (400 mg, 1.21 mmol), compound 5F (383 mg, 1.45 mmol), 15% hydrogen chloride ethanol solution (884 mg, 3.63 mmol), and 6.0 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 15 mL of saturated aqueous NaHCO3 and 10 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 h and then subjected to suction filtration. The filter cake was washed with water, then pulped with 6 mL of mixed solvent (PE / EA=5 / 1) and purified to obtain compound 5 (410 mg, yield 61.5%). 1 H NMR(400MHz, CDCl3) δ=10.58(s,1H),8.45(dd,J=8.4,4.8Hz,1H),8.06(m,2H),7.33(m,2H),7.09(d,J=14.4Hz,1H),6.64(s,1H),3.86(s,3H),3.1 5(d,J=12.0Hz,2H),2.65(m,2H),2.37(m,9H),2.27(m,1H),2.19(s,3H),1.93(m,2H),1.85(s,3H),1.82(s,3H),1.70(m,2H). MS-ESI(m / z):557.2571(M+H) + .

[0165] Example 6 compound 6

[0166] [ka]

[0167] Compound 2B (400 mg, 1.07 mmol), compound 5F (422 mg, 1.60 mmol), 15% hydrogen chloride ethanol solution (779 mg, 3.20 mmol), and 6.0 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 15 mL of saturated aqueous NaHCO3 and 10 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 h and then subjected to suction filtration. The filter cake was washed with water and dried, then separated and purified by column chromatography (DCM / MeOH=8 / 1), and then pulped with 5 mL of mixed solvent (PE / EA=4 / 1) to obtain compound 6 (276 mg, yield 43.0%). 1 H NMR(400MHz, CDCl3) δ=10.30(s,1H),8.33(dd,J=8.4,4.4Hz,1H),8.18(s,1H),8.03(s,1H),7.43-7.30(m,2H),7.11(d,J=14.0Hz,1H),6.62(s,1H),3.8 6(s,3H),3.16(d,J=11.8Hz,2H),2.65(m,2H),2.40(m,10H),2.14(s,3H),2.03-1.94(m,2H),1.85(s,3H),1.82(s,3H),1.73(m,2H). MS-ESI(m / z):601.2015(M+H) + .

[0168] Example 7 Compound 7:

[0169] [ka]

[0170] Referring to the synthesis method of compound 5, compound 1B was simply replaced with compound 3B to obtain compound 7. MS-ESI (m / z): 591.2856 (M+H) + . 1H NMR (400MHz, CDCl3) δ=10.55(s,1H),8.36(s,2H),8.12(s,1H),7.52(s,1H),7.25(d,J=8.4Hz,1H),7.10(d,J=14.0Hz,1H),6.65(s,1H),3.82(s ,3H),3.13(d,J=12.0Hz,2H),2.65(m,2H),2.38(m,10H),2.17(s,3H),1.95(m,2H),1.86(s,3H),1.83(s,3H),1.71(m,2H).

[0171] Example 8 Compound 8:

[0172]

change

[0173] The synthesis method of compound 5 was as follows, the replacement of compound 1B and compound 4B was carried out, and compound 8 was obtained. MS-ESI(m / z):537.3169(M+H) + . 1 H NMR (400MHz, CDCl3) δ=10.25(s,1H),8.45(dd,J=8.4,4.8Hz,1H),8.12(s,1H),7.89(s,1H),7.35(m,2H),7.04(d,J=14.0Hz,1H),6.60(s,1H),3.8 3(s,3H),3.15(d,J=12.0Hz,2H),2.68(m,2H),2.40(m,10H),2.18(m,6H),1.93(m,2H),1.85(s,3H),1.82(s,3H),1.74(m,2H).

[0174] Example 9 Compound 9A:

[0175]

change

[0176] 2-Iodo-5-methylaniline (2.0 g, 8.58 mmol), K3PO4 (2.91 g, 13.73 mmol), Xantphos (0.546 g, 0.944 mmol), Pd(OAc)2 (0.212 g, 0.944 mmol), dimethylphosphine oxide (1.34 g, 17.16 mmol), 36 mL of DMF and 4.8 mL of water were added to a 100 mL one-neck flask, purged with nitrogen 3-4 times, and reacted at 120 °C for approximately 4-5 hours until a TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature and filtered. 72 mL of H2O was added to the filtrate to precipitate a large amount of solid, which was filtered. The filtrate was extracted three times with 50 mL of dichloromethane, the organic phases were combined, washed twice with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated to give compound 9A (1.0 g, yield 64.0%). 1 H NMR(400MHz, CDCl3) δ=6.96(dd,J=13.6,8.0Hz,1H),6.52(d,J=8.0Hz,1H),6.47(d,J=4.0Hz,1H),5.29(s,2H),2.26(s,3H),1.76(s,3H),1.73(s,3H).

[0177] Compound 9B:

[0178] [ka]

[0179] Compound 9A (500 mg, 2.73 mmol), 5-bromo-2,4-dichloropyrimidine (808 mg, 3.55 mmol), K2CO3 (1.5 g, 10.92 mmol), nBu4NHSO4 (92.69 mg, 0.273 mmol) and 10 mL of DMF were added to a 50 mL three-neck flask and heated to 65° C. for about 4.5 hours until TLC test showed the reaction was complete. The reaction solution was then cooled to room temperature, 50 mL of H2O was added, and extracted with 20 mL of ethyl acetate. The aqueous phase was extracted twice with 10 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed twice with 20 mL of water, washed twice with 20 mL of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 9B (466 mg, 45.7% yield).

[0180] Compound 9:

[0181] [ka]

[0182] Compound 9B (500 mg, 1.33 mmol), compound 1F (383 mg, 1.2 mmol), 15% hydrogen chloride ethanol solution (974 mg, 4.0 mmol), and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 100° C. for 5 hours until TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 15 mL of saturated aqueous NaHCO3 and 10 mL of H2O were added to precipitate a large amount of solid, and the mixture was stirred continuously for about 0.5 hours, after which suction filtration was performed. The filter cake was washed with water, and then pulped with 5 mL of mixed solvent (PE / EA=2 / 3) and purified to obtain compound 9 (340 mg, yield 43.15%). 1H NMR(400MHz, CDCl3) δ=10.38(s,1H),8.25(d,J=4.0Hz,1H),8.20(s,1H),7.99(s,1H),7.32(s,1H),7 .21(dd,J=14.0,8.0Hz,1H),6.95(d,J=7.8Hz,1H),6.62(s,1H),3.86(s,3H),3.1 3(d,J=12.0Hz,2H),2.81-2.42(m,9H),2.34(s,3H),2.30(s,3H),2.07(s,3H),1 .95(d,J=12.0Hz,2H),1.86(m,2H),1.84(s,3H),1.81(s,3H),1.77-1.66(m,2H). MS-ESI(m / z):656.2456(M+H) + .

[0183] Example 10 Compound 10A:

[0184] [ka]

[0185] 2-Iodo-3-methylaniline (1.0 g, 4.29 mmol), K3PO4 (1.09 g, 5.15 mmol), Xantphos (0.25 g, 0.429 mmol), Pd(OAc)2 (0.096 g, 0.429 mmol), dimethylphosphine oxide (0.5 g, 6.44 mmol) and 10 mL of DMF were added to a 250 mL three-neck flask and heated to 120 °C until the TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature and suction filtered. The filtrate was added with 30 mL of H2O, extracted three times with 30 mL of dichloromethane, and the organic phases were combined. The organic phase was washed once with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 10A (440.0 mg, 56.0% yield). MS-ESI(m / z):184.0921(M+H) + .

[0186] Compound 10B:

[0187] [ka]

[0188] Compound 10A (3.93 g, 21.45 mmol), 5-bromo-2,4-dichloropyrimidine (7.33 g, 32.2 mmol), K2CO3 (8.89 g, 64.35 mmol), nBu4NHSO4 (0.73 g, 2.15 mmol) and 20 mL of DMF were added to a 250 mL three-neck flask and heated to 65 °C until TLC test showed the reaction was complete. The reaction solution was cooled to room temperature and 50 mL of H2O was added to precipitate a yellow solid, which was stirred continuously for about 0.5 h and then filtered by suction. The filtrate cake was washed with 100 mL of H2O and then dried to give compound 10B (3.88 g, 48.5% overall yield for two steps). MS-ESI (m / z): 373.9770 (M+H) + .

[0189] Compound 10:

[0190] [ka]

[0191] Compound 1F (500 mg, 1.57 mmol), compound 10B (588.12 mg, 1.57 mmol), 15% hydrogen chloride ethanol solution (917 mg, 3.77 mmol) and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed and reacted at 120° C. until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 50 mL of 3% K2CO3 aqueous solution and 30 mL of dichloromethane were added and stirred for 10 minutes. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, separated and purified by column chromatography to give compound 10 (551 mg, 53.5% yield). MS-ESI (m / z): 656.2486 (M+H) + .

[0192] Example 11 Compound 11A:

[0193] [ka]

[0194] 2-Iodo-4-fluoroaniline (5.0 g, 21.1 mmol), K3PO4 (5.37 g, 25.32 mmol), Xantphos (1.22 g, 2.11 mmol), Pd(OAc)2 (0.474 g, 2.11 mmol), dimethylphosphine oxide (2.47 g, 31.65 mmol) and 50 mL of DMF were added to a 100 mL three-neck flask and heated to 120 °C for about 4 hours until the TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature and suction filtered. 100 mL of H2O was added to the filtrate to precipitate a large amount of yellow solid, which was then suction filtered. The filtrate was extracted four times with 50 mL of dichloromethane, and the organic phases were combined. The organic phase was washed twice with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give oily compound 11A, and then 4 mL of ethyl acetate and 8 mL of petroleum ether were added to precipitate solid 11A (1.2 g, 30% yield). 1 H NMR (400MHz, CDCl3) δ=6.98(m,1H),6.78(m,1H),6.61(m,1H),5.23(s,2H),1.79(s,3H),1.75(s,3H). MS-ESI(m / z):188.0639(M+H) + .

[0195] Compound 11B:

[0196] [ka]

[0197] Compound 11A (500 mg, 2.67 mmol), 5-bromo-2,4-dichloropyrimidine (790.94 mg, 3.47 mmol), K2CO3 (1.11 g, 8.01 mmol), nBu4NHSO4 (0.09 g, 0.267 mmol) and 10 mL of DMF were added to a 50 mL three-neck flask and heated to 65 °C until the TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, 50 mL of H2O was added, and extracted with 20 mL of ethyl acetate. The aqueous phase was extracted twice with 10 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed twice with water, washed twice in turn with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 11B (700 mg, 69.3% yield).

[0198] Compound 11:

[0199] [ka]

[0200] Compound 11B (300 mg, 0.79 mmol), compound 1F (303 mg, 0.95 mmol), 15% hydrogen chloride ethanol solution (578 mg, 2.38 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 °C for 5-6 h until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 4.5 mL of saturated aqueous NaHCO3 and 13.5 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 h, and then subjected to suction filtration. The filter cake was washed with water and dried, then separated and purified by column chromatography (DCM / MeOH=15 / 1-10 / 1), and then pulped with 6 mL of mixed solvent (PE / EA=5 / 1) to obtain compound 11 (90 mg, yield 17.2%). 1H NMR(400MHz, CDCl3) δ=10.25(s,1H),8.46(m,1H),8.20(s,1H),7.95(s,1H),7.34(s,1H),7.21(m,1H),7.10-6.92(m,1H),6.62(s,1H),3.86(s,3H),3.16 (d,J=11.2Hz,2H),2.84-2.47(m,9H),2.37(m,5H),2.16(s,3H),1.97(d,J=11.4Hz,2H),1.87(s,3H),1.84(s,3H),1.79-1.67(m,2H). MS-ESI(m / z):660.2227(M+H) + .

[0201] Example 12 Compound 12B:

[0202] [ka]

[0203] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (2.0 g, 8.0 mmol), Pd(dppf)Cl2 (0.59 g, 0.8 mmol), triphenylphosphine (0.63 g, 2.4 mmol), cuprous bromide (0.34 g, 2.4 mmol), triethyl(vinyl)tin (3.8 g, 12.0 mmol) and 80 mL of toluene were added to a 250 mL three-neck flask and heated to 110° C. under nitrogen protection for about 4 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature and 80 mL of saturated aqueous potassium fluoride solution was added to quench the reaction, followed by extraction with 80 mL of ethyl acetate three times. The organic phases were combined, washed with 80 mL of saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, separated, and then purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain compound 12B (1.41 g, yield 89.2%). 1H NMR(400MHz,DMSO-d6) δ=8.24(d,J=7.9Hz,1H),7.33(d,J=12.6Hz,1H),6.75(dd,J=17.7,11.3Hz,1H),5.95(d,J=17.7Hz,1H),5.44(d,J=11.3Hz,1H),3.94(s,3H).

[0204] Compound 12C:

[0205] [ka]

[0206] 12B (1.20 g, 6.09 mmol), 1-methyl-4-(4-piperidinyl)piperazine (1.34 g, 7.30 mmol), potassium carbonate (1.69 g, 12.17 mmol) and 6 mL of DMF were added to a 50 mL round-bottom flask, heated to 120° C., and reacted for 4 hours. After TLC test showed that the reaction was complete, the reaction solution was cooled to room temperature and 20 mL of water was added to precipitate a large amount of yellow solid, which was stirred continuously for 1 hour, and then suction filtered. The filter cake was washed with water and dried to obtain compound 12C (1.87 g, 85.3% yield).

[0207] Compound 12A:

[0208] [ka]

[0209] Compound 12C (1.8 g, 5.0 mmol), 5% Pd / C 0.36 g, and methanol 36 mL were weighed and added to a 150 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until the TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography (DCM / MeOH=20 / 1) to obtain compound 12A (780 mg, 47.0% yield). 1H NMR(400MHz, CDCl3) δ=6.62(s,1H),6.58(s,1H),3.82(s,3H),3.04-2.99(m,2H),2.78-2.42(m,12H),2.31(s,4H),1.97-1.85(m,2H),1.69-1.64(m 2H),1.16(t,J=7.5Hz,3H).

[0210] Compound 12:

[0211] [ka]

[0212] Compound 2B (565 mg, 1.51 mmol), compound 12A (705 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, then pulped and purified to obtain compound 12 (673 mg, 66.5% yield). MS-ESI (m / z): 670.2642 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=10.23(s,1H),8.25(dd,J=8.4,4.8Hz,1H),8.19(s,1H),8.06(s,1H),7.44-7.29(m,2H),7.11(d,J=14.0Hz,1H),6.66(s,1H),3.85(s,3 H),3.08(d,J=11.6Hz,2H),2.93-2.21(m,19H),1.95(d,J=12.0Hz,2H),1.82(d,J=13.2Hz,6H),1.78-1.66(m,2H),1.00(t,J=7.6Hz,3H).

[0213] Example 13 Compound 13A:

[0214] [ka]

[0215] Compound 13A was obtained by referring to the synthesis of compound 12A and simply replacing compound triethyl(vinyl)tin with compound 2-(tributylstannyl)propene.

[0216] [ka]

[0217] Compound 2B (565 mg, 1.51 mmol), compound 13A (735 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 7.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, then pulped and purified to obtain compound 13 (622 mg, 60.2% yield). MS-ESI (m / z): 684.2756 (M+H) + .

[0218] Example 14 Compound 14A:

[0219] [ka]

[0220] 1-Chloro-2-fluoro-4-methoxy-5-nitrobenzene (500 mg, 2.43 mmol), 1-methyl-4-(4-piperidinyl)piperazine (490 mg, 2.68 mmol), potassium carbonate (507 mg, 3.65 mmol) and 10 mL of DMF were added to a 100 mL round-bottom flask, heated to 80° C., and reacted for 2.5 hours. After TLC test showed that the reaction was complete, the reaction solution was cooled to room temperature and 30 mL of water was added to precipitate a large amount of yellow solid, which was stirred continuously for 1 hour, and then suction filtered. The filter cake was washed with water and dried to obtain compound 14A (740 mg, 82.5% yield).

[0221] Compound 14B:

[0222] [ka]

[0223] Compound 14A (740 mg, 2.01 mmol), reduced iron powder (672 mg, 12.04 mmol), ammonium chloride (75 mg, 1.40 mmol) and 67 mL of mixed solution (ethanol / water = 3 / 1) were added to a 250 mL round bottom flask and heated to reflux for about 6.5 hours until the TLC test showed that the reaction was completed. The reaction solution was cooled to room temperature and the pH of the reaction solution was adjusted to about 8 with 2 mol / L aqueous sodium hydroxide. After concentrating the reaction solution to dryness, 110 mL of mixed solution (dichloromethane / methanol = 10 / 1) was added and stirred at room temperature for about 0.5 hours, followed by suction filtration. The filtrate was concentrated and separated by column chromatography (dichloromethane / methanol = 8 / 1) to obtain compound 14B (647 mg, yield 95.2%). MS-ESI (m / z): 339.1928 (M+H) + .

[0224] Compound 14:

[0225] [ka]

[0226] Compound 2B (253 mg, 0.67 mmol), compound 14B (243 mg, 1.01 mmol), 15% hydrogen chloride ethanol solution (493 mg, 2.02 mmol) and 4 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 °C for 5-6 hours until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 4 mL of saturated NaHCO3 aqueous solution and 12 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours and then filtered by suction. The filter cake was washed with water and dried, then separated and purified by column chromatography (DCM / MeOH=15 / 1-10 / 1), and then pulped with 6 mL of mixed solvent (PE / EA=5 / 1) to obtain compound 14 (120 mg, yield 26.3%). 1 H NMR(400MHz, CDCl3) δ=10.38(s,1H),8.39-8.24(m,2H),8.19(s,1H),7.47(d,J=8.8Hz,1H),7.41(s,1H),7.10(d,J=14.4Hz,1H),6.61(s,1H),3.88 (s,3H),3.40(d,J=11.2Hz,2H),2.83-2.46(m,9H),2.38(s,3H),2.33(s,3H),2.16(s,2H),1.95(d,J=11.4Hz,2H),1.81(m,8H). MS-ESI(m / z):676.1902(M+H) + .

[0227] Example 15 Compound 15A:

[0228] [ka]

[0229] 2-Chloro-4-fluoro-5-nitrotoluene (10.0 g, 52.4 mmol), cesium carbonate (83.2 g, 262 mmol), and 100 mL of isopropanol were added to a 250 mL one-neck flask and reacted at 60° C. for 4 hours until a TLC test showed that the raw materials had disappeared. The reaction solution was then cooled to room temperature, 100 mL of ethyl acetate was added, stirred for 10 minutes, and then filtered. The filter cake was washed with 50 mL of ethyl acetate and concentrated to dryness under reduced pressure. 100 mL of water and 150 mL of ethyl acetate were added to the residue, and the system was allowed to stand and stratify. The aqueous phase was extracted once with 100 mL of ethyl acetate, and the ethyl acetate phase was combined. The ethyl acetate phase was then washed twice with 100 mL of water, washed twice in turn with 100 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15A (11.45 g, 95.4% yield).

[0230] Compound 15B:

[0231] [ka]

[0232] Compound 15A (9.0 g, 39.2 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (13.33 g, 43.12 mmol), K2CO3 (16.25 g, 117.6 mmol), 82 mL of DME and 8 mL of water were added to a 250 mL one-neck flask. The mixture was subjected to nitrogen purge three times, then Pd(dppf)Cl2 (2.86 g, 3.92 mmol) was added, and after nitrogen purge three times again, the mixture was reacted at 120 °C for 5 h until the TLC test showed that the raw material had disappeared. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with 50 mL of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (PE:EA = 20:1 to 10:1) to obtain a pale yellow oily compound 15B (8.8 g, yield 60.0%). 1H NMR (400MHz, CDCl3) δ=7.62(s,1H),6.79(s,1H),5.62(s,1H),4.63(m,1H),4.06(d,J=2.0Hz,2H),3.6 4(t,J=5.6Hz,2H),2.33(s,2H),2.24(s,3H),1.51(s,9H),1.37(d,J=6.0Hz,6H). MS-ESI(m / z):399.1882(M+Na) + .

[0233] Compound 15C:

[0234] [ka]

[0235] Compound 15B (8.8 g, 23.4 mmol) and 20 mL of ethyl acetate were added to a 150 mL one-neck flask, stirred to dissolve, then 25 mL of 15% hydrogen chloride ethyl acetate solution was added, and stirred at room temperature overnight. TLC test showed that the raw material disappeared. 100 mL of water was added to the reaction solution, stirred for 10 minutes, and the system was allowed to stand and stratified. The ethyl acetate layer was then washed with 40 mL of water. The aqueous phases were combined, then the pH was adjusted to about 8 with saturated sodium bicarbonate solution. After adding 100 mL of ethyl acetate for extraction, the aqueous phase was extracted twice with 50 mL of ethyl acetate. The ethyl acetate phases were combined, then the ethyl acetate phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 15C (4.2 g, 65.01% yield). 1 H NMR(400MHz, CDCl3) δ=7.63(s,1H),6.84(s,1H),5.68(s,1H),4.64(m,1H),3.89(d,J=2.4Hz,2 H),3.48(t,J=6.0Hz,2H),2.71(m,2H),2.29(s,3H),1.38(d,J=6.0Hz,6H). MS-ESI(m / z):277.1547(M+H) + .

[0236] Compound 15D:

[0237] [ka]

[0238] Compound 15C (1.60 g, 5.79 mmol) and 64 mL of dichloromethane were added and dissolved in a 150 mL single-neck flask, then tetrahydro-4H-pyran-4-one (1.65 g, 17.37 mmol), acetic acid (1.32 g, 23.16 mmol) and sodium triacetoxyborohydride (4.66 g, 23.16 mmol) were added to the 150 mL single-neck flask and stirred at room temperature overnight. TLC test showed that the raw material had disappeared. Then, 120 mL of water was added to the reaction solution, stirred for 10 minutes, and the system was allowed to stand and stratify. The aqueous phase was then extracted with 20 mL of dichloromethane. The two dichloromethane phases were combined, and then the dichloromethane phase was washed with 40 mL of water and 40 mL of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give oily compound 15D (2.00 g, yield 95.80%).

[0239] Compound 15E:

[0240] [ka]

[0241] Compound 15D (0.99 g, 2.77 mmol) and 20 mL of ethanol were added and dissolved in a 50 mL one-neck flask, then 2.5 mL of 2N hydrogen chloride and iron powder (0.994 g, 17.76 mmol) were added and reacted at 60°C for 3 hours. TLC test showed that the raw materials had disappeared. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain oily substance 15E (779 mg, yield 85.0%). MS-ESI (m / z): 331.2381 (M+H) + .

[0242] Compound 15:

[0243] [ka]

[0244] Compound 2B (315 mg, 0.84 mmol), compound 15E (417 mg, 1.26 mmol), 15% hydrogen chloride ethanol solution (613 mg, 2.52 mmol) and 5.0 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 °C for 5-6 hours. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 50 mL of 3% K2CO3 aqueous solution and 50 mL of dichloromethane were added, stirred for 10 minutes, and then the system was allowed to stand for separation. The upper aqueous phase was washed once with 50 mL of dichloromethane in succession, and the two dichloromethane phases were combined. The dichloromethane phase was then washed with 50 mL of saturated salt solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 15 (310 mg, yield 55.20%). MS-ESI(m / z):668.2334(M+H) + .

[0245] Example 16 Compound 16D:

[0246] [ka]

[0247] Referring to the synthesis method of compound 15D, compound 15C (4.20 g, 15.20 mmol) and 160 mL of dichloromethane were added and dissolved in a 250 mL one-neck flask, then N-methyl-4-piperidone (5.16 g, 45.60 mmol), acetic acid (3.66 g, 60.80 mmol) and sodium triacetoxyborohydride (12.88 g, 60.80 mmol) were added and stirred at room temperature overnight. TLC test showed that the raw material had disappeared. Then, 60 mL of water was added to the reaction solution, stirred for 10 minutes, and the system was allowed to stand and stratify. Then, the aqueous phase was extracted with 60 mL of dichloromethane. The two dichloromethane phases were combined, and then the dichloromethane phase was washed with 40 mL of water and 40 mL of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give oily compound 16D (4.51 g, 79.4% yield). MS-ESI (m / z): 374.2443 (M+H).+ .

[0248] Compound 16E:

[0249] [ka]

[0250] Referring to the synthesis method of compound 15E, compound 16D (1.0 g, 2.68 mmol) and 20 mL of ethanol were added to a 50 mL one-neck flask and dissolved, then 2.5 mL of 2N hydrogen chloride solution and iron powder (0.960 g, 17.15 mmol) were added, and the mixture was reacted at 60 ° C for 3 hours. TLC test showed that the raw material had disappeared. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain oily substance 16E (736 mg, yield 80.0%).

[0251] Compound 16:

[0252] [ka]

[0253] Compound 2B (400 mg, 1.07 mmol), compound 16E (333 mg, 0.97 mmol), 15% hydrogen chloride ethanol solution (708 mg, 2.91 mmol) and 6 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 °C for 5-6 hours until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 6 mL of saturated aqueous NaHCO3 and 6 mL of H2O were added, followed by extraction with 30 mL of dichloromethane three times. The organic phases were combined, washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by column chromatography (DCM / MeOH=10 / 1) to obtain compound 16 (120 mg, 16.5% yield). MS-ESI (m / z): 681.2644 (M+H) + .

[0254] Example 17 Compound 17A:

[0255] [ka]

[0256] Compound 15D (1.8 g, 5.0 mmol), 0.27 g of 5% Pd / C, and 30 mL of methanol were weighed and added to a 100 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to obtain compound 17A (1.51 g, 90.8% yield). MS-ESI (m / z): 333.2572 (M+H) + .

[0257] Compound 17:

[0258] [ka]

[0259] Compound 2B (566 mg, 1.51 mmol), compound 17A (706 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 20 mL of mixed solvent (EA / PET=1 / 5) and purified to obtain compound 17 (558 mg, yield 55.2%). MS-ESI (m / z): 670.2554 (M+H) + .

[0260] Example 18 Compound 18A:

[0261] [ka]

[0262] Compound 16D (1.60 g, 4.28 mmol), 5% Pd / C 1.0 g, and methanol 10 mL were weighed and added to a 100 mL one-neck flask, purged with hydrogen 2-3 times, and stirred at room temperature for 48 hours under hydrogen atmosphere until TLC test showed the reaction was complete. After filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to give compound 18A (1.3 g, 87.8% yield).

[0263] Compound 18:

[0264] [ka]

[0265] Compound 2B (570 mg, 1.52 mmol), compound 18A (500 mg, 1.45 mmol), 15% hydrogen chloride ethanol solution (1.06 g, 4.35 mmol) and 7.5 mL ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 ° C for 4 hours until TLC test showed that the reaction was completed. After the reaction solution was cooled to room temperature, 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a solid, which was stirred continuously for about 0.5 hours, and then suction filtered. The filter cake was dissolved in methanol and concentrated under reduced pressure to obtain an oily substance, which was dissolved by adding 3 mL of ethyl acetate, and then 2 mL of petroleum ether was added dropwise, pulped, and purified to obtain compound 18 (241 mg, 23.21% yield). 1H NMR(400MHz, CDCl3) δ=10.30(s,1H),8.35(dd,J=8.4,4.4Hz,1H),8.19(s,1H),8.05(s,1H),7.51(s,1H),7. 33(d,J=8.4Hz,1H),7.12(d,J=14.0Hz,1H),6.82(s,1H),4.52(m,1H),3.06(d,J=11.2H) z,2H),2.96(d,J=11.2Hz,2H),2.71-2.60(m,1H),2.38(s,3H),2.34(m,2H),2.29(s,3H) ),2.16(s,3H),2.01-1.91(m,4H),1.84(m,8H),1.72(m,5H),1.37(s,3H),1.35(s,3H). MS-ESI(m / z):683.2800(M+H) + .

[0266] Example 19 Compound 19B:

[0267] [ka]

[0268] Compound 5-bromo-4-methyl-2-nitroanisole (9.65 g, 39.2 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (13.33 g, 43.12 mmol), K2CO3 (16.25 g, 117.6 mmol), 82 mL of DME and 8 mL of water were added to a 250 mL one-neck flask. The mixture was subjected to nitrogen purge three times, after which Pd(dppf)Cl2 (2.86 g, 3.92 mmol) was added, and then subjected to nitrogen purge again three times, followed by reaction at 120 °C for 5 hours until TLC test showed that the raw material had disappeared. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with 50 mL of ethyl acetate, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain pale yellow oily compound 19B (7.65 g, 56.0% yield). MS-ESI(m / z):349.1801(M+H) + .

[0269] Compound 19C:

[0270] [ka]

[0271] Compound 19C was obtained by referring to the synthesis of compound 15C and simply replacing compound 15B with compound 19B.

[0272] Compound 19D:

[0273] [ka]

[0274] Referring to the synthesis of compound 15D, compound 15C was simply replaced with compound 19C to obtain compound 19D. MS-ESI (m / z): 333.1875 (M+H) + .

[0275] Compound 19E:

[0276] [ka]

[0277] Referring to the synthesis of compound 17A, compound 15D was simply replaced with compound 19D to obtain compound 19E. MS-ESI (m / z): 305.2285 (M+H). + .

[0278] Compound 19:

[0279] [ka]

[0280] Referring to the synthesis of compound 17, compound 17A was simply replaced with compound 19E to obtain compound 19. MS-ESI (m / z): 642.2173 (M+H) + .

[0281] Example 20 Compound 20D:

[0282] [ka]

[0283] Compound 20D was obtained by referring to the synthesis of compound 16D and simply replacing compound 15C with compound 19C.

[0284] Compound 20E:

[0285] [ka]

[0286] Referring to the synthesis of compound 17A, compound 20E was obtained by simply replacing compound 15D with compound 20D. MS-ESI (m / z): 318.2512 (M+H). + .

[0287] Compound 20:

[0288] [ka]

[0289] Referring to the synthesis of compound 17, compound 20 was obtained by simply replacing compound 17A with compound 20E. MS-ESI (m / z): 655.2553 (M+H) + .

[0290] Example 21 Compound 21A:

[0291] [ka]

[0292] Compound 15C (4.20 g, 15.20 mmol) and 160 mL of dichloromethane were added and dissolved in a 250 mL single-neck flask, then paraformaldehyde (1.37 g, 45.60 mmol), acetic acid (3.66 g, 60.80 mmol) and sodium triacetoxyborohydride (12.88 g, 60.80 mmol) were added and stirred at room temperature overnight. TLC test showed that the raw material had disappeared. Then, 60 mL of water was added to the reaction solution, stirred for 10 minutes, and the system was allowed to stand and stratify. The aqueous phase was then extracted with 60 mL of dichloromethane. The two dichloromethane phases were combined, and then the dichloromethane phase was washed with 40 mL of water and 40 mL of saturated sodium chloride solution in turn, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give oily compound 21A (3.58 g, 81.2% yield).

[0293] Compound 21B:

[0294] [ka]

[0295] Referring to the synthesis of compound 17A, compound 21B was obtained by simply replacing compound 15D with compound 21A. MS-ESI (m / z): 263.2182 (M+H) + .

[0296] Compound 21:

[0297] [ka]

[0298] Referring to the synthesis of compound 17, compound 21 was obtained by simply replacing compound 17A with compound 21B. MS-ESI (m / z): 600.2165 (M+H) + .

[0299] Example 22 Compound 22A:

[0300] [ka]

[0301] Compound 15C (1.38 g, 5.00 mmol), 0.21 g of 5% Pd / C and 30 mL of methanol were weighed into a 100 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature under hydrogen atmosphere until TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to obtain compound 22A (1.07 g, 85.8% yield). MS-ESI (m / z): 249.1987 (M+H) + .

[0302] Compound 22:

[0303] [ka]

[0304] Referring to the synthesis of compound 17, compound 22 was obtained by simply replacing compound 17A with compound 22A. MS-ESI (m / z): 586.1975 (M+H) + .

[0305] Example 23 Compound 23A:

[0306] [ka]

[0307] Compound 5-fluoro-4-methyl-2-nitrophenol (2.57 g, 15.00 mmol), 60% sodium hydride (2.40 g, 60.00 mmol) and 30 mL of DMF were added to a 100 mL three-neck flask, stirred at 0° C. for 30 minutes, then 2-iodo-1,1,1-trifluoroethane (4.73 g, 22.50 mmol) was added in batches, and the mixture was then allowed to warm to room temperature and stirred overnight until TLC test showed that the reaction was complete. Then, 60 mL of water and 100 mL of ethyl acetate were added to the reaction solution, stirred for 10 minutes, and the system was allowed to stand for separation. The aqueous phase was washed once with 50 mL of ethyl acetate in succession. The two ethyl acetate phases were combined, and then the organic phase was washed once with saturated salt solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 23A (2.68 g, 70.5% yield) after column chromatography.

[0308] Compound 23B:

[0309] [ka]

[0310] Compound 23A (2.53 g, 10.00 mmol), K2CO3 (4.14 g, 30.00 mmol), 1-methyl-4-(4-piperidinyl)piperazine (2.75 g, 15.00 mmol), and 30 mL of DMF were added to a 250 mL three-neck flask, heated to 120° C., and stirred for about 4 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 60 mL of water and 100 mL of ethyl acetate were added, stirred for 10 minutes, and the system was allowed to stand for separation. The aqueous phase was washed once with 50 mL of ethyl acetate in succession. The two ethyl acetate phases were combined, and then the organic phase was washed once with saturated salt solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 23B (2.47 g, 59.2% yield) after column chromatography. MS-ESI(m / z):417.2175(M+H) + .

[0311] Compound 23C:

[0312] [ka]

[0313] Compound 23B (2.47 g, 5.92 mmol), 0.25 g of 5% Pd / C, and 30 mL of methanol were added to a 100 mL single-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature under hydrogen atmosphere until TLC test showed the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to give compound 23C (1.93 g, 84.5% yield).

[0314] Compound 23:

[0315] [ka]

[0316] Referring to the synthesis of compound 17, compound 23 was obtained by simply replacing compound 17A with compound 23C. MS-ESI (m / z): 724.2315 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=10.56(s,1H),8.42(dd,J=8.8,4.8Hz,1H),8.23(s,1H),8.10(s,1H), 7.42(m,2H),7.16(d,J=14.4Hz,1H),6.82(s,1H),4.85(m,2H),3.10(d, J=11.6Hz,2H),2.80-2.48(m,11H),2.36(s,3H),2.32(s,3H),2.15(s,3 H),2.05(d,J=11.0Hz,2H),1.88(s,3H),1.84(s,3H),1.78-1.64(m,2H).

[0317] Example 24 Compound 24D:

[0318] [ka]

[0319] Compound 1C (2.00 g, 11.69 mmol), cesium carbonate (5.74 g, 17.52 mmol), 14 mL DMF and 0.34 mL H2O were added to a 50 mL one-neck flask and stirred evenly at room temperature, then sodium difluorochloroacetate (3.56 g, 23.38 mmol) was added in batches, and after the addition was completed, the mixture was heated to 100 °C and stirred for about 2 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, 56 mL H2O was added, and extracted twice with 28 mL petroleum ether. The organic phases were combined, washed with 20 mL saturated salt solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 24D (1.49 g, 57.64% yield).

[0320] Compound 24E:

[0321] [ka]

[0322] Compound 24D (1.21 g, 5.45 mmol) was added to a 50 mL one-neck flask, 22.35 mL of DMF was added, and the mixture was stirred to dissolve, then K2CO3 (1.51 g, 10.91 mmol), 1-methyl-4(4-piperidinyl)-piperazine (1.30 g, 7.09 mmol) were added, and the mixture was heated to 120° C. and reacted for about 2 hours until the TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, 40 mL of water was added, and the mixture was extracted twice with 120 mL of EA. After the organic phases were combined, the organic phase was washed three times with 30 mL of H2O, washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compound 24E (1.91 g, 91.3% yield).

[0323] Compound 24F:

[0324] [ka]

[0325] Compound 24E (1.91 g, 4.97 mmol), 0.24 g of 5% Pd / C, and 48 mL of methanol were added to a 100 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature under hydrogen atmosphere (normal pressure) until TLC test showed the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to give compound 24F (1.68 g, 95.5% yield). MS-ESI (m / z): 355.2302 (M+H) + .

[0326] Compound 24:

[0327] [ka]

[0328] Referring to the synthesis of compound 2, compound 1F was simply replaced with compound 24F to obtain compound 24. MS-ESI (m / z): 692.2234 (M+H) + . 1 H NMR (400MHz, CDCl3) δ=10.50(s,1H),8.42(m,1H),8.18(s,1H),8.06(s,1H),7.50-7.36(m,2H),7. 12(d,J=14.0Hz,1H),6.80(s,1H),6.66(s,0.25H),6.52(s,0.5H),6.40(s,0.2 5H),3.16(d,J=11.6Hz,2H),2.82-2.42(m,11H),2.36(s,3H),2.34(s,3H),2.1 6(s,3H),1.96(d,J=11.0Hz,2H),2.12(s,3H),1.96(s,3H),1.78-1.66(m,2H).

[0329] Example 25 Compound 25A:

[0330] [ka]

[0331] Compound 1B (2.13 g, 6.46 mmol), 4-fluoro-2-methoxy-5-nitroaniline (1.44 g, 7.75 mmol), 15% hydrogen chloride ethanol solution (4.71 g, 19.37 mmol) and 30 mL ethylene glycol monomethyl ether were added to a reaction flask, heated to 120° C., then sealed and reacted for about 5 hours until TLC test showed that the reaction was complete. The reaction solution was cooled to room temperature, and about 90 mL of 5% aqueous sodium bicarbonate solution was added to precipitate a large amount of tan solid, which was stirred continuously for about 0.5 hours, then suction filtered and washed with water. The filter cake was pulped and purified to obtain compound 25A (2.09 g, 67.4% yield).

[0332] Compound 25B:

[0333] [ka]

[0334] Compound 25A (1.57 g, 3.27 mmol), K2CO3 (0.91 g, 6.53 mmol), 1-methyl-4-(4-piperidinyl)piperazine (0.72 g, 3.92 mmol) and 30 mL of DMF were added to a 150 mL three-neck flask, heated to 120 °C, and stirred for about 3 h until TLC test showed that the reaction was complete. The reaction solution was cooled to room temperature and 60 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 h, then suction filtered and washed with water. The filter cake was dried to give compound 25B (1.69 g, 80.5% yield). MS-ESI (m / z): 643.2758 (M+H). + .

[0335] Compound 25C:

[0336] [ka]

[0337] Compound 25B (1.03 g, 1.61 mmol), reduced iron powder (0.54 g, 9.64 mmol) and ammonium chloride (0.06 g, 1.12 mmol) were added to a 100 mL one-neck flask, then 90 mL of mixed solvent (EtOH / H2O=3 / 1) was added, stirred uniformly and refluxed for about 2 hours until TLC test showed that the reaction was completed. The reaction solution was cooled to room temperature. After the reaction solution was concentrated, 330 mL of mixed solvent (DCM / MeOH=10 / 1) was added, stirred for about 15 minutes and then filtered. The filtrate was concentrated to obtain compound 25C (0.88 g, 89.7% yield). MS-ESI (m / z): 613.2968 (M+H) + .

[0338] Compound 25:

[0339] [ka]

[0340] Compound 25C (514 mg, 0.84 mmol) and DIPEA (120 mg, 0.93 mmol) were added to a 50 mL one-neck flask, dissolved in 7.5 mL of dichloromethane while stirring, cooled to 0-10 ° C, weighed and added acryloyl chloride (92 mg, 1.01 mmol), diluted with 2.5 mL of DCM, slowly added dropwise to the reaction solution, and after the addition was completed, the reaction was continued at 0-10 ° C for about 3 hours until the TLC test showed that the reaction was completed. Then, 20 mL of dichloromethane and 20 mL of H2O were added to the reaction solution to separate the phases, and the dichloromethane phase was washed with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, separated, and purified by column chromatography to obtain compound 25 (189 mg, 33.9% yield). MS-ESI (m / z): 667.3085 (M+H) + .

[0341] Example 26 Compound 26B:

[0342] [ka]

[0343] Following the synthesis method of compound 25B, compound 26B was obtained by simply replacing 1-methyl-4-(4-piperidinyl)piperazine with 4-dimethylaminopiperidine. MS-ESI (m / z): 588.2283 (M+H). + .

[0344] Compound 26C:

[0345] [ka]

[0346] Compound 26C was obtained by referring to the synthesis method of compound 25C. MS-ESI (m / z): 558.2412 (M+H) + .

[0347] Compound 26:

[0348] [ka]

[0349] Referring to the synthesis of compound 25, compound 25C was simply replaced with compound 26C to obtain compound 26. MS-ESI (m / z): 612.2684 (M+H) + .

[0350] Example 27 Compound 27B:

[0351] [ka]

[0352] Referring to the synthesis of compound 25B, compound 27B was obtained by simply replacing compound 1-methyl-4-(4-piperidinyl)piperazine with compound N,N,N'-trimethylethylenediamine. MS-ESI (m / z): 562.2127 (M+H). + .

[0353] Compound 27C:

[0354] [ka]

[0355] Compound 27C was obtained by referring to the synthesis method of compound 25C. MS-ESI (m / z): 532.2322 (M+H) + .

[0356] Compound 27:

[0357] [ka]

[0358] Referring to the synthesis of compound 25, compound 25C was simply replaced with compound 27C to obtain compound 27. MS-ESI (m / z): 586.2465 (M+H) + .

[0359] Example 28 Compound 28A:

[0360] [ka]

[0361] Compound 1D (4.5 g, 24.3 mmol), K2CO3 (6.71 g, 48.6 mmol), morpholine (3.17 g, 36.4 mmol) and 67.5 mL of DMF were weighed and added to a 250 mL three-neck flask, heated to 120 °C, and reacted with stirring for about 4 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 130 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours, and then suction filtered. The filter cake was filtered, washed with water, and dried to obtain compound 28A (3.26 g, 53.1% yield). MS-ESI (m / z): 253.1148 (M+H) + .

[0362] Compound 28B:

[0363] [ka]

[0364] Compound 28A (3.26 g, 12.94 mmol), 0.49 g of 5% Pd / C and 60 mL of methanol were weighed into a 250 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to obtain compound 28B (2.67 g, 92.8% yield). MS-ESI (m / z): 223.1475 (M+H) + .

[0365] Compound 28:

[0366] [ka]

[0367] Compound 2B (566 mg, 1.51 mmol), compound 28B (471 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 20 mL of mixed solvent (EA / PET=1 / 5) and purified to obtain compound 28 (387 mg, yield 45.7%). MS-ESI (m / z): 560.1402 (M+H) + .

[0368] Example 29 Compound 29A:

[0369] [ka]

[0370] Compound 1D (4.5 g, 24.3 mmol), K2CO3 (6.71 g, 48.6 mmol), N-methylpiperazine (3.64 g, 36.4 mmol) and 67.5 mL of DMF were weighed into a 250 mL three-neck flask and heated to 120° C. and reacted with stirring for about 4 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature and 130 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours and then filtered with suction. The filter cake was filtered, washed with water and dried to obtain compound 29A (3.38 g, 52.5% yield). MS-ESI (m / z): 266.1547 (M+H) + .

[0371] Compound 29B:

[0372] [ka]

[0373] Compound 29A (3.38 g, 12.71 mmol), 0.51 g of 5% Pd / C, and 60 mL of methanol were weighed and added to a 250 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to obtain compound 29B (2.80 g, 93.4% yield). MS-ESI (m / z): 236.1791 (M+H) + .

[0374] Compound 29:

[0375] [ka]

[0376] Compound 2B (566 mg, 1.51 mmol), compound 29B (500 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 20 mL of mixed solvent (EA / PET=1 / 5) and purified to obtain compound 29 (350 mg, yield 40.5%). MS-ESI (m / z): 573.1728 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=10.31(s,1H),8.34(dd,J=8.6,4.6Hz,1H),8.19(s,1H),8.05(s,1H),7.39-7.32(m,2H),7.15-7.08(m,1H),6.67( s,1H),3.87(s,3H),2.95(t,J=4.8Hz,4H),2.63(s,4H),2.40(d,J=5.0Hz,6H),2.17(s,3H),1.84(d,J=13.1Hz,6H). MS-ESI(m / z):573.1728(M+H) + .

[0377] Example 30 Compound 30A:

[0378] [ka]

[0379] Compound 1D (4.5 g, 24.3 mmol), K2CO3 (6.71 g, 48.6 mmol), 4-(4-piperidinyl)morpholine (6.20 g, 36.4 mmol) and 67.5 mL of DMF were weighed and added to a 250 mL three-neck flask, heated to 120 °C, and reacted for about 4 hours with stirring until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 130 mL of H2O was added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours, and then filtered by suction. The filter cake was filtered, washed with water, and dried to obtain compound 30A (5.54 g, 67.8% yield). MS-ESI (m / z): 336.1944 (M+H) + .

[0380] Compound 30B:

[0381] [ka]

[0382] Compound 30A (5.54 g, 16.48 mmol), 0.83 g of 5% Pd / C, and 60 mL of methanol were weighed and added to a 250 mL one-neck flask, purged with hydrogen 2-3 times, and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until TLC test showed the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated, and purified by column chromatography to obtain compound 30B (4.67 g, 92.7% yield). MS-ESI (m / z): 306.2152 (M+H) + .

[0383] Compound 30:

[0384] [ka]

[0385] Compound 2B (566 mg, 1.51 mmol), compound 30B (648 mg, 2.12 mmol), 15% hydrogen chloride ethanol solution (960 mg, 3.64 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 120 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was stirred continuously for 0.5 h, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 20 mL of mixed solvent (EA / PET=1 / 5) and purified to obtain compound 30 (455 mg, yield 46.9%). MS-ESI (m / z): 643.2160 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=10.38(s,1H),8.40(dd,J=8.8,4.8Hz,1H),8.22(s,1H),8.08(s,1H),7.48-7.32(m,2H),7.18(d,J=14.0Hz,1H),6.66(s,1H),3.95-3.7 8(m,7H),3.20(m,2H),2.88-2.49(m,7H),2.38(s,3H),2.35(s,3H),2.05(d,J=11.0Hz,2H),1.90(s,3H),1.86(s,3H),1.88-1.76(m,2H).

[0386] Example 31 Compound 31A:

[0387] [ka]

[0388] 260mL of DMSO was added to a 1.0L one-neck flask, and NaH (9.09g, 226mmol, 60%) was added in batches while stirring, followed by stirring for 10 minutes, then dimethyl malonate (26mL, 226mmol) was slowly added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 20 minutes, the reaction was kept at 100°C for 30-60 minutes, and then 5-fluoro-4-methyl-2-nitroanisole (14.0g, 75.4mmol) was added in batches, and the reaction was kept at 100°C for 60 minutes. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature. Then, 550mL of water was added dropwise, stirred at room temperature for 2 hours, and filtered. The filter cake was collected and forced air dried at 50°C to obtain compound 31A (10.5g, 46.8% yield). MS-ESI (m / z): 298.0956 (M+H) + .

[0389] Compound 31B:

[0390] [ka]

[0391] Compound 31A (10.5 g, 35.32 mmol) was dissolved in 300 mL of mixed solvent (EtOH / THF=1 / 1), stirred for 5 minutes, and 150 mL of 2N NaOH solution was added dropwise at room temperature. After the addition was completed, the reaction was kept at room temperature for 1-2 hours until the TLC test showed that the reactants had disappeared. The reaction solution was then concentrated under reduced pressure to half the remaining amount, and 6 mol / L hydrochloric acid solution was added dropwise until the pH of the reaction solution was 2-3. After stirring for 10 minutes, 180 mL of ethyl acetate was added for extraction, and the aqueous phase was extracted again with 100 mL of ethyl acetate. The two ethyl acetate phases were combined and washed with 100 mL of water, then washed twice with 100 mL of saturated sodium chloride solution, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then pulped, purified, and filtered. The filter cake was washed with mixed solvent (petroleum ether / ethyl acetate=5:1) and dried to obtain compound 31B (6.4 g, yield 80.5%). MS-ESI(m / z):226.0744(M+H) + .

[0392] Compound 31C:

[0393] [ka]

[0394] Compound 31B (5.3 g, 23.71 mmol) was suspended in 100 mL of dichloromethane and cooled to 0° C. in an ice bath, HOBT (3.53 g, 26.1 mmol) and EDCI (5.0 g, 26.1 mmol) were added, and after stirring at low temperature for 60 minutes, N-methylpiperazine (2.61 g, 26.1 mmol) was added, and DIPEA (3.67 g, 28.4 mmol) was further added dropwise, and after the addition was completed, the reaction was kept at low temperature for 2 hours, and then reacted at room temperature for 1 hour until the TLC test showed that the reactants had disappeared. After the reaction was completed, 100 mL of water was added to the reaction solution, and after stirring for 10 minutes, the system was allowed to stand and be layered. The aqueous phase was extracted once with 50 mL of dichloromethane, the two dichloromethane phases were combined, and then the dichloromethane phase was washed successively with 100 mL of water, 100 mL of 3% aqueous K2CO3 solution, and 150 mL of saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily material, which was purified by column chromatography to give compound 31C (5.9 g, 80.57% yield). MS-ESI (m / z): 308.1637 (M+H). + .

[0395] Compound 31D:

[0396] [ka]

[0397] Compound 31C (4.7 g, 15.33 mmol) was dissolved in 45 mL of anhydrous THF under nitrogen protection. After cooling to 0 °C in an ice bath, a solution of BH3 in THF (45 mL, 46.02 mmol) was added dropwise, and after the addition was completed, the ice bath was removed, and then the reaction solution was stirred at room temperature overnight until the reactants disappeared according to the TLC test. After the reaction was completed, 120 mL of methanol was added dropwise to quench the mixture, and then it was concentrated under reduced pressure. 120 mL of methanol and 100 mL of 2N HCl solution were added to the obtained solid, and the mixture was refluxed at 70 °C with stirring for 2 hours, and then it was concentrated under reduced pressure to about 120 mL. After the pH of the mixture solution was adjusted to 8-9 by adding 2N NaOH solution dropwise, it was extracted by adding 100 mL of ethyl acetate, and the aqueous phase was extracted once with 50 mL of ethyl acetate, and the two ethyl acetate phases were combined, and then the ethyl acetate phase was washed successively with 80 mL of water and 80 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily substance, which was then purified by column chromatography to give compound 31D (3.22 g, 71.50% yield). MS-ESI (m / z): 294.1815 (M+H). + .

[0398] Compound 31E:

[0399] [ka]

[0400] Compound 31D (3.15 g, 10.74 mol) was dissolved in 30 mL of methanol, and 0.30 g of Pd / C (5%) was added. The mixture was purged with hydrogen 2-3 times, and stirred overnight at room temperature under hydrogen atmosphere (normal pressure). TLC test showed that the reactants disappeared. After the reaction was completed, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated and purified by column chromatography to obtain compound 31E (2.55 g, 90.1% yield). MS-ESI (m / z): 264.2104 (M+H) + .

[0401] Compound 31:

[0402] [ka]

[0403] Referring to the synthesis of compound 2, compound 1F was simply replaced with compound 31E to obtain compound 31. MS-ESI (m / z): 601.2084 (M+H) + .

[0404] Example 32 Compound 32A:

[0405] [ka]

[0406] 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (608 mg, 2.43 mmol), 1-methyl-4-(4-piperidinyl)piperazine (490 mg, 2.68 mmol), potassium carbonate (507 mg, 3.65 mmol) and 10 mL of DMF were added to a 100 mL round-bottom flask, heated to 80° C., and reacted for 2.5 hours. After TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and 30mL of water was added to precipitate a large amount of yellow solid, which was continuously stirred for 1 hour, and then suction filtered. The filter cake was washed with water and dried to obtain compound 32A (743mg, yield 74.0%).

[0407] Compound 32B:

[0408] [ka]

[0409] Compound 32A (740 mg, 1.79 mmol), reduced iron powder (600 mg, 10.74 mmol), ammonium chloride (75 mg, 1.40 mmol) and 67 mL of the mixed solution (ethanol / water = 3 / 1) were added to a 250 mL round bottom flask and heated to reflux for about 6.5 hours until the TLC test showed that the reaction was completed. The reaction solution was cooled to room temperature and the pH of the reaction solution was adjusted to about 8 with 2 mol / L aqueous sodium hydroxide. After concentrating the reaction solution to dryness, 110 mL of the mixed solution (dichloromethane / methanol = 10 / 1) was added and stirred at room temperature for about 0.5 hours, and then suction filtered. The filtrate was concentrated and separated by column chromatography (dichloromethane / methanol = 8 / 1) to obtain compound 32B (622 mg, yield 90.7%). MS-ESI (m / z): 383.1427 (M+H) + .

[0410] Compound 32:

[0411] [ka]

[0412] Compound 2B (253 mg, 0.67 mmol), compound 32B (387 mg, 1.01 mmol), 15% hydrogen chloride ethanol solution (439 mg, 2.02 mmol), and 4 mL of ethylene glycol monomethyl ether were added to the reaction flask, which was then sealed and reacted at 100 °C for 5-6 hours until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 4 mL of saturated NaHCO3 aqueous solution and 12 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 hours and then subjected to suction filtration. The filter cake was washed with water and dried, then separated and purified by column chromatography (DCM / MeOH=15 / 1-10 / 1), and then pulped with 6 mL of mixed solvent (PE / EA=5 / 1) to obtain compound 32 (173 mg, yield 35.7%). 1H NMR(400MHz, CDCl3) δ=10.47(s,1H),8.42-8.26(m,2H),8.21(s,1H),7.53(d,J=8.8Hz,1H),7.47(s,1H),7.15(m,1H),6.68(s,1H),3.95(s,3H) ),3.52(d,J=11.2Hz,2H),2.89-2.51(m,9H),2.41(s,3H),2.39(s,3H),2.21(s,2H),2.05(d,J=11.4Hz,2H),1.91(m,8H). MS-ESI(m / z):722.1459(M+H) + .

[0413] Example 33 Compound 33A:

[0414] [ka]

[0415] Referring to the synthesis of compound 11A, compound 2-iodo-4-fluoroaniline was simply replaced with compound 4-chloro-2-iodoaniline to obtain compound 33A. MS-ESI (m / z): 204.0367 (M+H). + .

[0416] Compound 33B:

[0417] [ka]

[0418] Referring to the synthesis of compound 11B, compound 33B was obtained by simply replacing compound 11A with compound 33A. MS-ESI (m / z): 393.9295 (M+H) + .

[0419] Compound 33:

[0420] [ka]

[0421] Compound 33 was obtained by referring to the synthesis of compound 11 and simply replacing compound 11B with compound 33B. 1 H NMR(400MHz, CDCl3) δ=10.38(s,1H),8.57-8.32(m,2H),8.05(s,1H),7.47(s,1H),7.32(m,1H),7.18-6.95(m,1H),6.69(s,1H),3.93(s,3H),3.2 5(m,2H),2.89-2.53(m,9H),2.42(m,5H),2.21(s,3H),2.05(d,J=11.4Hz,2H),1.92(s,3H),1.86(s,3H),1.81-1.69(m,2H). MS-ESI(m / z):676.1964(M+H) + .

[0422] Example 34 Compound 34:

[0423] [ka]

[0424] Compound 25C (305 mg, 0.50 mmol), K2CO3 (138 mg, 1.00 mmol), methyl iodide (142 mg, 1.00 mmol) and 10 mL of DMF were weighed and added to a 25 mL round bottom flask and stirred at room temperature overnight. After completion of the reaction, the reaction solution was purified by column chromatography to give compound 34 (65 mg, 20.5% yield). MS-ESI (m / z): 627.3125 (M+H). + .

[0425] Example 35 Compound 35:

[0426] [ka]

[0427] Compound 14B (403.27 mg, 1.19 mmol), compound 11B (500 mg, 1.32 mmol), 15% hydrogen chloride ethanol solution (963 mg, 3.96 mmol) and 7.5 mL ethylene glycol monomethyl ether were added to a reaction flask, sealed and reacted at 100° C. for 4 hours. After TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of water and saturated NaHCO3 aqueous solution were added to adjust the pH to about 8.0, causing a large amount of solid to precipitate, which was stirred continuously for about 0.5 hours, and then suction filtered. The filter cake was washed with water and then dried. The crude product was pulped with 6 mL of EA and purified to obtain compound 35 (380 mg, 38% yield). 1 H NMR(400MHz, CDCl3) δ=10.26(s,1H),8.38(m,1H),8.22(d,J=10.8Hz,2H),7.46-7.32(m,2H),7.03(m,1H),6. 62(s,1H),3.88(s,3H),3.41(d,J=11.6Hz,2H),2.81-2.22(m,14H),1.95-1.79(m,10H). MS-ESI(m / z):680.1686(M+H) + .

[0428] Example 36 Compound 36A:

[0429] [ka]

[0430] 2-Iodo-4-isopropylaniline (3.0 g, 11.5 mmol), K2CO3 (2.23 g, 16.1 mmol), Xantphos (0.174 g, 0.46 mmol), Pd(OAc)2 (0.103 g, 0.46 mmol), dimethylphosphine oxide (1.08 g, 13.8 mmol), and 18 mL of DMF were added to a 50 mL three-neck flask and heated to 100 °C for about 3 hours until the TLC test showed that the raw materials were completely reacted. The reaction solution was cooled to room temperature and subjected to suction filtration, and then 54 mL of H2O was added to precipitate a large amount of yellow solid, which was subjected to suction filtration. The filtrate was extracted with 25 mL of dichloromethane three times, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain oily compound 36A (2.60 g), which was used in the next reaction without purification.

[0431] Compound 36B:

[0432] [ka]

[0433] Compound 36A (2.60 g), 5-bromo-2,4-dichloropyrimidine (2.88 g, 12.6 mmol), K2CO3 (1.91 g, 13.8 mmol) and 15 mL of DMSO were added to a 50 mL one-neck flask and heated to 60 °C for about 3 hours until TLC test showed that compound 36A was completely reacted. The reaction solution was cooled to room temperature, 45 mL of H2O was added, and extracted twice with 50 mL of ethyl acetate. The organic phases were combined, washed twice with 50 mL of water, washed twice with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pink solid, which was added with a mixed solvent (PE:EA=3:1), pulped, and filtered to obtain a solid, which was dried to obtain compound 36B (2.5 g, Yield 54%).

[0434] Compound 36:

[0435] [ka]

[0436] Compound 36B (500 mg, 1.24 mmol), compound 1F hydrochloride (484.11 mg, 1.36 mmol) and 4 mL of ethylene glycol monomethyl ether were added to the reaction flask, and then reacted at 100 °C for 5-6 hours. After the TLC test showed that compound 36B was completely reacted, the reaction solution was cooled to room temperature, and then 4 mL of water was added, and the pH was adjusted to about 8.0 with saturated NaHCO3 aqueous solution to precipitate a solid, which was continuously stirred for 0.5 hours, and then suction filtered. The filter cake was washed with water and purified by column chromatography to obtain compound 36 (400 mg, yield 47.11%). 1 H NMR(400MHz, CDCl3) δ=10.39(s,1H),8.40(dd,J=8.6,4.6Hz,1H),8.18(s,1H),8.05(s,1H),7.47-7.33(m,2H),7.12(dd,J=14.4,1.6Hz,1H),6.62(s,1H),3.86 (s,3H),3.15(d,J=11.6Hz,2H),2.93(m,1H),2.78-2.13(m,17H),1.96(m,2H),1.85(d,J=13.2Hz,6H),1.73(m,2H),1.28(d,J=6.8Hz,6H). MS-ESI(m / z):706.2601(M+Na) + .

[0437] Example 37 Compound 37:

[0438] [ka]

[0439] Compound 36B (440 mg, 1.09 mmol), compound 12A (400 mg, 1.20 mmol), 15% hydrogen chloride ethanol solution (798 mg, 3.28 mmol) and 6.0 mL of ethylene glycol monomethyl ether were added to a reaction flask, sealed, and reacted at 100 °C for 5-6 h. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 6 mL of saturated NaHCO3 aqueous solution and 12 mL of H2O were added to precipitate a large amount of solid, which was stirred continuously for about 0.5 h, and then suction filtered. The filter cake was washed with water, separated, and purified to obtain compound 37 (228 mg, 29.8% yield). 1 H NMR (400MHz, CDCl3) δ=10.34(s,1H),8.35(dd,J=8.8,4.8Hz,1H),8.19(s,1H),8.08(s,1H),7.37 (m,2H),7.12(d,J=14.4Hz,1H),6.67(s,1H),3.86(s,3H),3.08(m,2H),2.92 (m,1H),2.80-2.44(m,11H),2.42-2.26(m,5H),1.95(d,J=11.2Hz,2H),1.84 (d,J=13.2Hz,6H),1.72(m,2H),1.28(d,J=6.8Hz,6H),1.03(t,J=7.4Hz,3H). MS-ESI(m / z):720.2757(M+Na) + .

[0440] Example 38 Compound 38:

[0441] [ka]

[0442] Compound 14B (309 mg, 0.91 mmol), compound 33B (300 mg, 0.76 mmol), 15% hydrogen chloride ethanol solution (554 mg, 2.28 mmol) and 4.5 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 100 °C for 5-6 hours. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, 5 mL of saturated NaHCO3 aqueous solution and 10 mL of H2O were added, and extracted with 30 mL of dichloromethane three times. The organic phases were combined and washed with 30 mL of saturated NaCl aqueous solution, and the organic phase was concentrated to dryness, then separated and purified to obtain compound 38 (154 mg, 29.1% yield). MS-ESI (m / z): 696.1377 (M+H) + . 1 H NMR(400MHz, CDCl3) δ=10.30(s,1H),8.35(m,1H),8.26(m,2H),7.48-7.30(m,2H),7.05(m,1H),6.68(s ,1H),3.89(s,3H),3.38(d,J=11.6Hz,2H),2.86-2.28(m,14H),2.05-1.72(m,10H).

[0443] Comparative Example 1: Preparation of Control Compound 1 Control compound 1B (intermediate):

[0444] [ka]

[0445] Reference compound 1B was obtained by simply replacing compound 5-bromo-2,4-dichloropyrimidine with compound 2,4,5-trichloropyrimidine with reference to the synthesis of compound 10B.

[0446] Control compound 1:

[0447] [ka]

[0448] Reference compound 1 was obtained by referring to the synthesis of compound 10 and simply replacing compound 10B with control compound 1B. 1 H NMR(400MHz,methanol-d4) δ=8.02(s,1H),7.93(dd,J=8.0,4.0Hz,1H),7.64(s,1H),7.42(t,J=8.0Hz,1H),7.15(dd,J=7.6,3.6Hz,1H),6.69(s,1H),3.84(s,3H) ,3.11(d,J=11.6Hz,2H),3.02-2.41(m,13H),2.32(m,4H),2.04(s,3H),2.00(d,J=12.6Hz,2H),1.94(s,3H),1.90(s,3H),1.68(m,2H). MS-ESI(m / z):612.2981(M+H)+.

[0449] Comparative Example 2: Preparation of Control Compound 2 Control compound 2A (intermediate):

[0450] [ka]

[0451] (2-aminophenyl)-dimethylphosphine oxide (2.5 g, 15.00 mmol), 2,4,5-trichloropyrimidine (2.70 g, 15.00 mmol), K2CO3 (2.45 g, 67.75 mmol), nBu4NHSO4 (0.5 g, 1.50 mmol), and 50 mL of DMF were added to a 100 mL three-neck flask, heated to 65 °C, and reacted for about 4.5 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, and 200 mL of H2O was added to precipitate a large amount of yellow solid, which was stirred continuously for about 0.5 hours, and then filtered by suction. The filter cake was washed with 100 mL of H2O and dried to obtain reference compound 2A (2.84 g, 60.0% yield). MS-ESI (m / z): 316.0178 (M+H) + .

[0452] Control compound 2:

[0453] [ka]

[0454] Control compound 2A (335 mg, 1.06 mmol), compound 1F (406 mg, 1.27 mmol), 15% hydrogen chloride ethanol solution (774 mg, 3.18 mmol), and 4.5 mL of ethylene glycol monomethyl ether were added to a reaction flask, which was then sealed and reacted at 120 °C for 5-6 hours. After the TLC test showed that the reaction was completed, the reaction solution was cooled to room temperature, and then 15 mL of saturated NaHCO3 aqueous solution was added to precipitate a large amount of solid, which was continuously stirred for 0.5 hours, and then suction filtered. The filter cake was washed with water, and the filter cake was pulped with 9 mL of mixed solvent (EtOH / H2O=1 / 2) and purified to obtain control compound 2 (320 mg, yield 50.5%). 1 H NMR(400MHz, CDCl3) δ=10.80(s,1H),8.63(dd,J=8.4,4.4Hz,1H),8.10(s,1H),8.04(s,1H),7.51(m,1H),7.38-7.26(m,2H),7.13(m,1H),6.63(s,1H),3.86( s,3H),3.16(d,J=12.0Hz,2H),2.61(m,9H),2.32(s,3H),2.18(s,3H),2.06(m,2H),1.96(m,2H),1.87(s,3H),1.83(s,3H),1.72(m,2H). MS-ESI(m / z):598.2826(M+H) + .

[0455] Comparative Example 3: Preparation of Control Compound 3 Control compound 3A (intermediate):

[0456] [ka]

[0457] 5-Fluoro-2-nitroanisole (2.0 g, 11.69 mmol), 1-methyl-4-(4-piperidinyl)piperazine (2.57 g, 14.02 mmol), potassium carbonate (3.25 g, 23.37 mmol) and 30 mL of DMF were added to a 100 mL round bottom flask and heated to 120° C. for about 3 hours until TLC test showed the reaction was complete. The reaction solution was cooled to room temperature, 30 mL of water was added, and extracted three times with 30 mL of ethyl acetate. The organic phases were combined, and the organic phase was washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give reference compound 3A (3.57 g, 91.3% yield).

[0458] Control compound 3B (intermediate):

[0459] [ka]

[0460] Reference compound 3A (3.57 g, 10.68 mmol), 0.36 g of 5% Pd / C and 72 mL of methanol were replaced with hydrogen 2-3 times and stirred overnight at room temperature in a hydrogen atmosphere (normal pressure) until TLC test showed that the reaction was complete. Then, after filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, separated and purified by column chromatography to obtain reference compound 3B (2.17 g, 66.8% yield). MS-ESI (m / z): 305.2315 (M+H) + .

[0461] Control compound 3:

[0462] [ka]

[0463] Compound 1B (400 mg, 1.21 mmol), control compound 3B (443 mg, 1.45 mmol), 15% hydrogen chloride ethanol solution (884 mg, 3.63 mmol) and 6 mL of ethylene glycol monomethyl ether were added to the reaction flask, sealed, and reacted at 120 °C for 5-6 hours until the TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 6 mL of saturated aqueous NaHCO3 and 6 mL of H2O were added, followed by extraction with 30 mL of dichloromethane three times. The organic phases were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, separated, and purified by column chromatography (DCM / MeOH=8 / 1), followed by pulping with 5 mL of mixed solvent (PE / EA=4 / 1) to obtain control compound 3 (257 mg, yield 35.4%). 1 H NMR(400MHz, CDCl3) δ=10.63(s,1H),8.49(dd,J=8.8,4.8Hz,1H),8.19-7.99(m,2H),7.31(d,J=8.8Hz,1H),7.25(s,1H),7.07(d,J=14.0Hz,1H),6.61-6.44(m,2H) ,3.87(s,3H),3.66(d,J=12.0Hz,2H),2.66(m,9H),2.38(s,3H),2.32(s ,3H),2.21(s,2H),1.97(m,2H),1.85(s,3H),1.81(s,3H),1.73(m,2H). MS-ESI(m / z):598.2804(M+H) + .

[0464] Comparative Example 4: Preparation of Control Compound 4 Control compound 4A (intermediate):

[0465] [ka]

[0466] 4-Bromo-2-iodoaniline (30 g, 100.7 mmol), K2CO3 (22.27 g, 161.1 mmol), Xantphos (5.83 g, 10.1 mmol), Pd(OAc)2 (1.12 g, 4.9 mmol), dimethylphosphine oxide (11.78 g, 150.9 mmol) and 450 mL of DMF were added to a 1 L three-neck flask under N2 protection, heated to 100 °C, and reacted for about 3 hours until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, 1350 mL of H2O was added dropwise, stirred, and then suction filtered. The filter cake was washed with water and extracted with 500 mL of dichloromethane three times. The organic phases were combined, and the organic phase was washed twice with 500 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give reference compound 4A (14 g, 56% yield).

[0467] Control compound 4B (intermediate):

[0468] [ka]

[0469] Compound 4A (12 g, 48.4 mmol), cyclopropylboronic acid (8.31 g, 96.7 mmol), K2CO3 (13.36 g, 96.7 mmol), Pd(dppf)Cl2 (1.77 g, 2.42 mmol), 1,4-dioxane (120 mL), and H2O (12 mL) were added to a 500 mL three-neck flask, heated to 100 °C, and reacted for about 8 hours under N2 protection until TLC test showed that the reaction was complete. The reaction solution was then cooled to room temperature, 150 mL of H2O was added, stirred, and then suction filtered. The filter cake was washed with dichloromethane, and the system was left to stand for separation. The aqueous phase was then extracted three times with 150 mL of dichloromethane. The organic phases were then combined, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated and purified by column chromatography to give reference compound 4B (7.5 g, 74% yield).

[0470] Control compound 4C (intermediate):

[0471] [ka]

[0472] Compound 4B (7.5 g, 35.8 mmol), K2CO3 (5.95 g, 43.1 mmol), 5-bromo-2,4-dichloropyrimidine (8.99 g, 39.5 mmol) and DMSO (45 mL) were added to a 100 mL reaction flask and heated to 60° C. for about 2.5 hours until TLC test showed the reaction was complete. The reaction solution was then cooled to room temperature and 135 mL of H2O was added dropwise to precipitate a large amount of tan solid, which was stirred continuously for 1 hour. The filter cake was washed with 100 mL of H2O and dried to give reference compound 4C (7.4 g, 51.6% yield).

[0473] Control compound 4:

[0474] [ka]

[0475] Compound 4C (1.7 g, 4.24 mmol), compound 12A (1.55 g, 4.66 mmol), trifluoroacetic acid (1.21 g, 10.6 mmol) and ethylene glycol monomethyl ether (27 mL) were added to a 100 mL reaction flask, heated to 100 °C, and reacted for about 7 hours until TLC test showed that the reaction was completed. The reaction solution was then cooled to room temperature, and 54 mL of H2O was added dropwise, followed by 27 mL of saturated aqueous NaHCO3 solution to precipitate a large amount of solid, which was stirred continuously for 1 hour and then filtered by suction. The filter cake was washed with water. The filter cake was pulped with 15 mL of ethyl acetate, purified, filtered and dried to obtain reference compound 4 (1.68 g, 56.8% yield). 1H NMR(400MHz,CD3OD) δ=8.13(s,1H),7.88(dd,J=8.8,4.8Hz,1H),7.66(s,1H),7.43(dd,J=14.0,2.2Hz,1H),7.19(m,1H),6.76(s,1H),3.85(s,3H), 3.04(m,2H),2.32-2.75(m,16H),2.01(m,3H),1.83(m,6H),1.74-1.65(m,2H),1.06(m,2H),0.96(t,J=7.6Hz,3H),0.76(m,2H). MS-ESI(m / z):696.2711(M+H) + .

[0476] Test Example 1 Enzyme Activity Test 1 1. Test objective: to detect the effect of the test compound on the activity of EGFR kinase.

[0477] 2.Exam Information: To evaluate the effect of compounds on the activity of wild-type and mutant EGFR kinase, kinase activity was tested by measuring ATP consumption in the enzyme reaction using ADP-Glo ​​(Promega Corporation) kit. The samples to be tested were dissolved in DMSO and diluted in gradient. In a microplate, EGFR kinase, reaction buffer (containing Tris-HCl at pH 7.5, MgCl2, DTT and BSA), kinase substrate Poly(Glu4, Tyr1) and samples (total amount of 20 μL per well) were added per well, while blank control (without enzyme and sample) and negative control (without sample) were set; incubated at 23 ° C for 15 minutes; ATP 5 μL was added and reacted at 23 ° C for 60 minutes; ADP-Glo ​​reagent was added and reacted continuously at room temperature for 40 minutes to inactivate excess ATP; then kinase detection reagent was added and reacted at room temperature for 30 minutes, after which the chemiluminescence intensity L of each well was measured. The inhibition rate of the compound was calculated according to the value of chemiluminescence L, inhibition rate = [1-(L サンプル -L ブランク ) / (L 陰性 -L ブランク )] × 100%. IC 50Values ​​were calculated using the 4-Parameter Logistic Model in XLfit software according to the calculations above.

[0478] 3. Test Results: The enzymatic activities of the compounds according to the examples of the present invention and the compounds of the comparative examples against EGFR-Del19, EGFR-C797S / Del19, EGFR-T790M / Del19, EGFR-T790M / L858R, EGFR-C797S / T790M / L858R, EGFR-C797S / T790M / Del19 and EGFR-WT are shown in Tables 1 and 2.

[0479] 4. Conclusion: As can be seen from Tables 1 and 2, the compounds according to the embodiments of the present invention have better selectivity against the enzyme activity of wild-type EGFR (EGFR-WT), and have better inhibitory effects against the enzyme activity of EGFR single, double and triple mutations (e.g., EGFR-Del19, EGFR-C797S / Del19, EGFR-T790M / Del19, EGFR-T790M / L858R, EGFR-C797S / T790M / L858R, and EGFR-C797S / T790M / Del19), all of which are much superior to the compounds according to the comparative examples.

[0480] [Table 1]

[0481] [Table 2]

[0482] Test Example 2 Enzyme Activity Test 2 1. Test objective: to detect the effect of the test compound on the activity of ALK kinase.

[0483] 2.Exam Information: To evaluate the effect of compounds on the activity of EML4-ALK kinase, the kinase activity was tested by measuring ATP consumption in the enzyme reaction using an ADP-Glo ​​(Promega Corporation) kit. The samples to be tested were dissolved in DMSO and diluted in a gradient. In a microplate, EML4-ALK kinase, reaction buffer (containing Tris-HCl at pH 7.5, MgCl2, DTT and BSA), kinase substrate IGF1 and samples (total amount of 20 μL per well) were added per well, while blank control (without enzyme and sample) and negative control (without sample) were set; ATP 5 μL was added and reacted at 23 ° C for 60 minutes; ADP-Glo ​​reagent was added and reacted continuously at room temperature for 40 minutes to inactivate excess ATP; then kinase detection reagent was added and reacted at room temperature for 30 minutes, after which the chemiluminescence intensity L of each well was measured. The inhibition rate of the compound was calculated according to the value of chemiluminescence L, inhibition rate = [1-(L サンプル -L ブランク ) / (L 陰性 -L ブランク )] × 100%. IC 50 Values ​​were calculated using the 4-Parameter Logistic Model in XLfit software according to the calculations above.

[0484] 3. Test results: IC of the compounds according to the examples of the present invention and the compounds of the comparative examples against ALK kinase 50 The values ​​are shown in Table 3.

[0485] 4. Conclusion: As can be seen from Table 3, the compounds according to the embodiments of the present invention have better inhibitory effects on the enzymatic activity of ALK kinase, and they are all much superior to the compounds according to the comparative examples.

[0486] [Table 3]

[0487] Test Example 3 Cell Antiproliferation Test 1 1. Test objective: To detect the effect of test compounds on the proliferation of cell lines containing EGFR mutations in BaF3 cells.

[0488] 2.Exam Information: 2.1. Cell information: The cell line containing the EGFR mutation in BaF3 was from WuXiAppTec: Cell lines expressing BaF3-EGFR mutations EGFR-T790M / Del19 EGFR-C797S / Del19 EGFR-T790M / L858R EGFR-C797S / L858R EGFR-C797S / T790M / L858R EGFR-C797S / T790M / Del19 EGFR-WT wild-type cell line.

[0489] 2.2. Test Method Day 0: Cells were seeded onto plates.

[0490] a. The UV lamp in the biological safety cabinet was turned on and a 30 minute countdown was started.

[0491] b. The medium was pre-warmed in a 37° C. water bath.

[0492] c. After UV irradiation was completed, the biological safety cabinet was opened. The pre-heated medium, PBS, etc. were wiped off with alcohol and placed in the biological safety cabinet.

[0493] d. Cells were removed from the incubator, blown into a homogenous cell suspension in a biosafety cabinet, and counted.

[0494] e. Based on the cell counting results, the cell suspension was adjusted to a density of 3,000 cells per well and 50 microliters per well and seeded into a 384-well plate.

[0495] f. After seeding, the cells were incubated in a 5% CO2 incubator at 37°C for 3 hours.

[0496] g. Compounds were added to the cell plates using a Tecan (liquid workstation).

[0497] Day 3: The cell plate containing the compound and CTG (CellTiter-Glo chemiluminescent cell activity assay reagent) was equilibrated at room temperature, 25 μl of CTG was added to each well, centrifuged at 1,000 rpm for 1 minute, and shaken for 1 to 2 minutes. Then, it was centrifuged again at 1,000 rpm for 1 minute, the cell plate was left to stand for 10 minutes, and the signal value was detected in Envision. The IC of each compound 50 was calculated by computer fitting using XL-Fit analysis software (IC of the compound for inhibiting cell activity 50 was obtained by reading the corresponding compound concentration at 50% inhibition. Inhibition %=(no drug control reading-sample reading) / no drug control reading×100.

[0498] 3. Test results: Activity inhibitory IC of compounds according to the examples of the present invention, compounds according to the comparative examples, and major drugs for the treatment of non-small cell lung cancer, such as brigatinib and osimertinib, against Ba / F3 cells expressing EGFR-T790M / Del19, EGFR-C797S / Del19, EGFR-T790M / L858R, EGFR-C797S / L858R, EGFR-C797S / T790M / L858R, EGFR-C797S / T790M / Del19, and EGFR-WT 50 The values ​​are shown in Tables 4 and 5. .

[0499] 4. Conclusion: As can be seen from Tables 4 and 5, the compounds according to the embodiments of the present invention have better selectivity for the activity of Ba / F3 cells expressing EGFR wild type (EGFR-WT), and are more selective for the activity of EGFR double and triple mutations (e.g., EGFR-T790M / Del19, EGFR-C797S / Del19, EGFR-T790M / L858R, EGFR-C797S / L858R, EGFR-C797S / T790M / L858R and EGFR-C797S / T790M / L858R). 90M / Del19), and in particular, the inhibitory activity of the compounds 1, 2, 4, 5, 6, 9, 11, 12, 14, 23, 24, 25, 28, 29, 30, 32, 33, 35, 36, 37 and 38 according to the examples against Ba / F3 cell lines expressing EGFR double mutation and triple mutation is much better than that of the control compounds 1, 2 and 3, and commercially available drugs such as brigatinib and osimertinib.

[0500] [Table 4]

[0501] [Table 5]

[0502] Test Example 4 Cell Antiproliferation Test 2 1. Study objective: To detect the effect of test compounds on the proliferation of cell lines containing EGFR mutations in PC9 cells.

[0503] 2.Exam Information: 2.1. Cell information: PC9 cells harbor EGFR Del19 mutation, and the remaining mutant cells were constructed from PC9 cells according to conventional stable cell line construction methods. Cell lines expressing PC9-EGFR mutations EGFR-Del19 EGFR-T790M / Del19 EGFR-C797S / T790M / Del19. 2.2. Test method: Test compounds were diluted 5-fold each time with appropriate concentration as initial concentration for testing, and diluted to 6 concentration gradients in total. Brigatinib (purchased from Selleck) was diluted 3-fold with 5μM as initial concentration for testing, and diluted to 6 concentration gradients in total. Test compounds and brigatinib were added to the cells respectively, and incubated at 37℃ and 5%CO2 for 72 hours. The optical density value of each well was read at 490nm wavelength by a microplate reader using SRB (sulphorhodamine B) detection method.

[0504] The optical density of cells with zero drug action was taken as the Tz value, which represents the value of cells at the time of drug addition. The optical density value of cells after 72 hours of exposure to the solvent control DMSO was taken as the C value. The optical density of cells exposed to the test compound for 72 hours was taken as the Ti value. The response of cells to drugs was calculated according to the method proposed by the US NIH-NCI (National Institutes of Health-National Institute of Cancer): when Ti was equal to or greater than Tz, the value was [(Ti-Tz) / (C-Tz)]×100; when Ti was less than Tz, the value was [(Ti-Tz) / Tz]×100. GI 50 Values ​​(concentration of test compound required for 50% cell growth inhibition) were calculated using the 4 Parameter Logistic Model in XLfit software according to the calculations above.

[0505] 3. Test results: GI of the compounds according to the examples of the present invention, the compounds according to the comparative examples, and brigatinib (a leading drug for the treatment of non-small cell lung cancer on the market) against PC9 cells expressing EGFR-Del19, EGFR-T790M / Del19, and EGFR-C797S / T790M / Del19. 50 The values ​​are shown in Table 6.

[0506] 4. Conclusion: As can be seen from Table 6, the compounds according to the embodiments of the present invention have better inhibitory effects on the proliferation activity of PC9 cells expressing EGFR single mutation, double mutation and triple mutation (e.g., EGFR-Del19, EGFR-T790M / Del19, and EGFR-C797S / T790M / Del19), and have superior inhibitory activity to that of the control compounds 1, 2 and 3, and the commercially available drug brigatinib.

[0507] [Table 6]

[0508] Test Example 5 Cell Antiproliferation Test 3 1. Study objective: To detect the effect of test compounds on the proliferation of cell lines containing ALK mutation in BaF3 cells.

[0509] 2.Exam Information: 2.1. Cell information: The cell line containing the ALK mutation in BaF3 was from WuXiAppTec: Ba / F3 cell lines expressing ALK gene fusions and mutations Ba / F3-EML-4-ALK-WT Ba / F3-EML-4-ALK-L1196M.

[0510] 2.2. Test Method Day 0: Cells were seeded onto plates.

[0511] a. The UV lamp in the biological safety cabinet was turned on and a 30 minute countdown was started.

[0512] b. The medium was pre-warmed in a 37° C. water bath.

[0513] c. After UV irradiation was completed, the biological safety cabinet was opened. The pre-heated medium, PBS, etc. were wiped off with alcohol and placed in the biological safety cabinet.

[0514] d. Cells were removed from the incubator, blown into a homogenous cell suspension in a biosafety cabinet, and counted.

[0515] e. Based on the cell counting results, the cell suspension was adjusted to a density of 3,000 cells per well and 50 microliters per well and seeded into a 384-well plate.

[0516] f. After seeding, the cells were incubated in a 5% CO2 incubator at 37°C for 3 hours.

[0517] g. Compounds were added to the cell plates using a Tecan (liquid workstation).

[0518] Day 3: The cell plate containing the compound and CTG was equilibrated at room temperature, 25 μl of CTG was added to each well, centrifuged at 1,000 rpm for 1 minute, and shaken for 1 to 2 minutes. Then, it was centrifuged again at 1,000 rpm for 1 minute, the cell plate was left to stand for 10 minutes, and the signal value was detected in Envision. The IC of each compound 50 was calculated by computer fitting using XL-Fit analysis software (IC of the compound for inhibiting cell activity 50 was obtained by reading the corresponding compound concentration at 50% inhibition. Inhibition %=(no drug control reading-sample reading) / no drug control reading×100.

[0519] 3. Test results: IC of the compounds according to the examples of the present invention and the compounds according to the comparative examples against BaF3 cells expressing EML-4-ALK-WT and EML-4-ALK-L1196M 50 The values ​​are shown in Table 7.

[0520] 4. Conclusion: As can be seen from Table 7, the compounds according to the examples of the present invention have very good inhibitory effects on the proliferation of BaF3 cells expressing EML-4-ALK-WT and EML-4-ALK-L1196M, and have better inhibitory activity than the control compounds 1, 2 and 3.

[0521] [Table 7]

[0522] Test Example 6: In vivo pharmacodynamics study of transplanted tumor model of artificial BaF3 EGFR-DTC (C797S / T790M / Del19) cells in nude mice The model used in this study was a subcutaneous implantation tumor model of artificial BaF3 EGFR-DTC (C797S / T790M / Del19) cells in BALB / c nude mice. Artificial BaF3 cells were cultured in in vitro suspension. BaF3 EGFR-DTC (C797S / T790M / Del19) were cultured in RPMI compound 140 medium with 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin and 10 μg / mL blasticidin at 37°C in a 5% CO2 incubator. Passage was performed twice a week. When the cell number reached the required amount, the cells were harvested, counted and inoculated. 0.2 mL (10 6 ) cells (added with Matrigel at a 1:1 volume ratio) were inoculated subcutaneously, resulting in a mean tumor volume of 109 mm 3 When the dose reached 100 mg / kg, the mice were divided into treatment groups, each consisting of 6 mice.

[0523] Method and frequency of administration: Oral administration was performed at a dose of 10 mL / kg, and the same amount of solvent was administered to the model group. Administration was once a day for 14 days. The doses of compound 2 and brigatinib were 25 mg / kg and 50 mg / kg, and the dose of compound 33 was 25 mg / kg.

[0524] The general condition of the mice, including their mental state, activity, and food intake, was observed every day, and their body weight was measured three times a week. The short diameter (a) and long diameter (b) of the tumor in each mouse were measured three times a week using a caliper with a vernier scale, and the mean diameter was calculated according to the formula (a 2 The tumor volume was calculated according to the following formula: RTV = V × b) / 2. The relative tumor volume (RTV) was calculated from the measured tumor volumes, RTV = V t / V0, where V0 is the tumor volume in the random group (i.e., d0), and V t are the measurements respectively (i.e., d n The relative tumor growth rate, an evaluation index of antitumor activity, was calculated according to the following formula: Relative tumor growth rate T / C (%):

[0525]

number

[0526] (Note: T RTV : Treatment group RTV; C RTV : Model control group RTV. According to the therapeutic effect evaluation criteria in the "Technical Guidelines for Nonclinical Trials of Cytotoxic Antitumor Agents" issued by the China National Medical Products Administration, the value (T / C%≦40%) was effective).

[0527] The effects of different test samples on the tumor status of the transplanted tumor model of BaF3 EGFR-DTC (C797S / T790M / Del19) cells in nude mice are shown in Tables 8-9.

[0528] [Table 8]

[0529] [Table 9]

[0530] The test results show that in the test, both compound 2 at a dose of 25 mg / kg and 50 mg / kg, and compound 33 at a dose of 25 mg / kg can obviously inhibit the tumor growth of implanted tumors of BaF3 EGFR-DTC (C797S / T790M / Del19) in nude mice. After 12 days of administration, the T / C% of compound 2 (25 mg / kg) and compound 2 (50 mg / kg) were 3.12% and 1.91%, respectively, and the T / C% of compound 33 (25 mg / kg) was 2.56%. Brigatinib did not significantly inhibit the tumor growth of implanted tumors of BaF3 EGFR-DTC (C797S / T790M / Del19) in nude mice. After 12 days of administration, the T / C% of brigatinib (25 mg / kg) and brigatinib (50 mg / kg) were 84.64% and 41.67%, respectively.

[0531] The effect of compound 2 in inhibiting tumor growth is significantly stronger than that of brigatinib, and on day 12 of administration, the T / C% of compound 2 and brigatinib (25 mg / kg: 3.12% and 84.64%; 50 mg / kg: 1.91% and 41.67%) are significantly different (p<0.01). Furthermore, the effect of compound 33 (25 mg / kg) on ​​inhibiting tumor growth is also significantly stronger than that of brigatinib, and the T / C% difference between compound 33 and brigatinib is significant on day 12 of administration (p<0.01).

[0532] The above results show that Compound 2 and Compound 33 have obviously stronger effects on inhibiting the growth of transplanted tumors of BaF3 EGFR-DTC (C797S / T790M / Del19) in nude mice than Brigatinib.

[0533] Test Example 7: In vivo pharmacodynamic study of transplanted tumor model of artificial BaF3 EML-4-ALK-L1196M cells in nude mice The model used in this study was a subcutaneously implanted tumor model of artificial BaF3 EML-4-ALK-L1196M cells in BALB / c nude mice. Artificial BaF3 cells were cultured in in vitro suspension. BaF3 EML-4-ALK-L1196M were cultured in RPMI compound 140 medium with 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin and 10 μg / mL blasticidin in a 5% CO2 incubator at 37°C. Passage was performed twice a week. When the cell number reached the required amount, the cells were harvested, counted and inoculated. Each mouse was injected with 0.2 mL (10 6 ) cells (added with Matrigel at a 1:1 volume ratio) were inoculated subcutaneously, resulting in a mean tumor volume of 128 mm 3 When the mice reached this age, they were divided into treatment groups, each with 6 mice.

[0534] Method and frequency of administration: forced oral administration was performed at a dose of 10mL / kg, and the same amount of solvent was administered to the model group. Administration was once a day for 14 days. The dose of compound 2 was 50mg / kg, the dose of compound 6 was 60mg / kg, and the dose of compound 14 was 80mg / kg.

[0535] The general condition of the mice, including their mental state, activity, and food intake, was observed every day, and their body weight was measured three times a week. The short diameter (a) and long diameter (b) of the tumor in each mouse were measured three times a week using a caliper with a vernier scale, and the mean diameter was calculated according to the formula (a 2 The tumor volume was calculated according to the following formula: RTV = V × b) / 2. The relative tumor volume (RTV) was calculated from the measured tumor volumes, RTV = V t / V0, where V0 is the tumor volume in the random group (i.e., d0), and V t are the measurements respectively (i.e., d n The relative tumor growth rate, an evaluation index of antitumor activity, was calculated according to the following formula: Relative tumor growth rate T / C (%):

[0536]

number

[0537] (Note: T RTV : Treatment group RTV; C RTV : Model control group RTV. According to the therapeutic effect evaluation criteria in the "Technical Guidelines for Nonclinical Trials of Cytotoxic Antitumor Agents" issued by the China National Medical Products Administration, the value (T / C%≦40%) was effective).

[0538] The effects of different test samples on the tumor status of the transplanted tumor model of BaF3 EML-4-ALK-L1196M cells in nude mice are shown in Tables 10-11.

[0539] [Table 10]

[0540] [Table 11]

[0541] The test results show that in the test, compound 2 (50 mg / kg), compound 6 (60 mg / kg) and compound 14 (80 mg / kg) can all significantly inhibit the tumor growth of BaF3 EML-4-ALK-L1196M transplanted tumors in nude mice.

[0542] Test Example 8: Single-dose toxicity study of oral intragastric administration of Compound 2 and Brigatinib to SD rats Eight-week-old SD rats (10 per group, half male and half female) were purchased from Beijing SiPeiFu. The rats were acclimated in this laboratory for 3 days before testing. Oral administration was performed intragastrically at a dose of 10 mL / kg. The rats were fasted and allowed to drink water for 17 hours before administration. The rats in the control group were given the same volume of the vehicle by oral gavage. Feeding was resumed approximately 2 hours after the end of administration.

[0543] After administration, the subjects were observed twice a day. The first day of administration was defined as study day 1. The study was conducted for 14 consecutive days and ended on the 15th day.

[0544] Test doses and groups and animal mortality on day 15 post-dose are shown in Table 12:

[0545] [Table 12]

[0546] The test results showed that in a single-dose toxicity study of oral intragastric administration of compound 2 and brigatinib to SD rats, the maximum tolerated dose (MTD) of compound 2 was 125 mg / kg, while the MTD of brigatinib was less than 75 mg / kg. Under the conditions of this study, the single-dose toxicity of compound 2 in SD rats was much lower than that of brigatinib, indicating that compound 2 has better safety.

[0547] Test Example 9: In vivo pharmacodynamics study of tumor models in which NCI-H3122 and NCI-H1975 EGFR DTC (C797s / T790m / Del19) cells were subcutaneously implanted into both sides of BALB / c nude mice The model used in this study was a tumor model in which NCI-H3122 and NCI-H1975 EGFR DTC (C797s / T790m / Del19) cells were subcutaneously implanted into each side of the same BALB / c nude mouse (Note: NCI-H3122 was an EML4-ALK fusion gene positive cell line).

[0548] NCI-H3122 and NCI-H1975 EGFR DTCs (C797S / T790M / Del19) were cultured in RPMI compound 140 medium with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Passage was performed twice a week. When the cell number reached the required amount, the cells were harvested, counted, and inoculated.

[0549] Each mouse was injected with 0.2 mL (5 × 10 6 ) Inoculate NCI-H3122 cells (supplemented with Matrigel at a 1:1 volume) subcutaneously into the right lower flank of each mouse in 0.2 mL (5 × 10 6) NCI-H1975 EGFR DTC (C797S / T790M / Del19) cells (added with Matrigel at a 1:1 volume ratio) were inoculated subcutaneously. The mean tumor volume of NCI-H3122 subcutaneously implanted tumors was approximately 116 mm 3 The mean tumor volume of NCI-H1975 EGFR DTC (C797S / T790M / Del19) subcutaneously implanted tumors was approximately 110 mm 3 When the dose reached 10 mg / kg, the mice were divided into treatment groups with 8 mice per group.

[0550] Method and frequency of administration: oral administration was performed at a dose of 10mL / kg, and the same amount of solvent was administered to the model group. Administration was once a day for 16 days. The doses of compound 2 were 20mg / kg and 40mg / kg, and the dose of crizotinib was 50mg / kg.

[0551] The general condition of the mice, including their mental state, activity, and food intake, was observed every day, and their body weight was measured three times a week. The short diameter (a) and long diameter (b) of the tumor in each mouse were measured three times a week using a caliper with a vernier scale, and the mean diameter was calculated according to the formula (a 2 The tumor volume was calculated according to the following formula: RTV = V × b) / 2. The relative tumor volume (RTV) was calculated from the measured tumor volumes, RTV = V t / V0, where V0 is the tumor volume in the random group (i.e., d0), and V t are the measurements respectively (i.e., d n The relative tumor growth rate, an evaluation index of antitumor activity, was calculated according to the following formula: Relative tumor growth rate T / C (%):

[0552]

number

[0553] Note: T RTV : Treatment group RTV; C RTV Model control group RTV. According to the therapeutic effect evaluation criteria in the "Technical Guidelines for Nonclinical Trials of Cytotoxic Antitumor Agents" issued by the China National Medical Products Administration, the value (T / C%≦40%) was effective.

[0554] The effects of various test samples on the tumor status of subcutaneously implanted tumor models in which NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) cells were subcutaneously inoculated into both sides of the same BALB / c nude mice are shown in Tables 13 and 14.

[0555] [Table 13]

[0556] [Table 14]

[0557] The test results show that in this study, compound 2, at doses of 20mg / kg and 40mg / kg, can simultaneously and obviously inhibit the tumor growth of subcutaneously transplanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) cells in nude mice, and has a dose-effect relationship. After 16 days of administration, the T / C% of compound 2 (20mg / kg) for subcutaneously transplanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) was 8.16% and 37.95%, respectively, and the T / C% was less than 40%, meeting the therapeutic effect evaluation criteria in the technical guidelines for non-clinical trials of cytotoxic antitumor agents issued by the China National Medical Products Administration. The T / C% of compound 2 (40 mg / kg) against subcutaneously implanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) was 3.6% and 14.36%, respectively, showing a stronger inhibitory effect on tumor growth and a clear dose-effect relationship.

[0558] In this study, crizotinib (50mg / kg) did not significantly inhibit tumor growth of subcutaneously implanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) cells in nude mice. After 16 days of treatment, the T / C% of subcutaneously implanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) were 49.35% and 95.67%, respectively, which did not reach the efficacy criteria.

[0559] The above results show that compound 2 can simultaneously and significantly inhibit the tumor growth of subcutaneously transplanted tumors of NCI-H3122 and NCI-H1975 EGFR DTC (C797S / T790M / Del19) cells in nude mice, with a clear dose-effect relationship.

[0560] Test Example 10 Cell Antiproliferation Test 4 1. Study objective: To detect the effect of test compounds on the proliferation of cell lines containing ALK mutation in BaF3 cells.

[0561] 2. Test materials BaF3 EML-4-ALK-L1196M cell line, Brand: KYinno, Product code: KC-102 Cell Counting Kit-8 (CCK-8), Brand: Targetmol, Part Number: C0005 Multifunctional microplate reader POLARstar Omega, Brand: BMG LABTECH.

[0562] 3. Test Method Day 0: Cells were seeded onto plates.

[0563] a. Cells were removed from the incubator, blown into a homogenous cell suspension in a clean bench, and counted.

[0564] b. Based on the cell counting results, the cell suspension was adjusted to a density of 8,000 cells per well and 110 μL per well and seeded into a 96-well plate.

[0565] c. 10 μL of gradient diluted compounds were added to the cell plate to obtain final compound concentrations of 500, 166.67, 55.56, 18.52, 6.17, 2.06, 0.69, 0.23 and 0.08 nM.

[0566] d. The cell plates were incubated at 37° C. in a 5% CO2 incubator for 72 hours.

[0567] Day 3: After equilibrating CCK8 at room temperature, 10 μL of CCK8 was added to each well and incubated at 37°C for 2 hours in a 5% CO2 incubator, and then the signal value OD was measured using a multifunctional microplate reader POLARstar Omega. 450 The IC of each compound was detected. 50 was calculated by computer fitting using GraphPad Prism analysis software (IC of compounds for inhibition of cell activity 50 was obtained by reading the corresponding compound concentration at 50% inhibition. Inhibition %=(no drug control reading-sample reading) / (no drug control reading-medium only control reading)×100.

[0568] 4. Test results: IC of the compounds according to the examples of the present invention and the compounds according to the comparative examples against BaF3 cells expressing EML-4-ALKL1196M 50 The values ​​are shown in Table 15.

[0569] Conclusion: As can be seen from Table 15, the compounds according to the examples of the present invention have very good inhibitory effects on the proliferation of BaF3 cells expressing EML-4-ALK-L1196M, and have better inhibitory activity than the control compound 4.

[0570] [Table 15]

[0571] Test Example 11 Pharmacokinetic study Six SD rats were taken, all male, approximately 8-9 weeks old, weighing approximately 430 g / rat, and fasted but allowed to drink water for 18 hours.

[0572] The rats were divided into two groups, the rats in group 1 were administered compound 2, and the rats in group 2 were administered the control compound 4 at a dose of 20 mg / kg both orally and intragastrically. The lavage solution was prepared using 70 mM citrate buffer (pH 3.0) at a dose of 5 mL / kg.

[0573] 0.6 mL of blood (EDTA-2K anticoagulated) was collected from the rat orbit at 0.5, 1.5, 3, 4.5, 8, 12, 24, 36, 48 and 72 hours after administration, respectively. Plasma was separated and stored at -70°C, and plasma samples were analyzed using liquid chromatography tandem mass spectrometry (LC-MS / MS). The plasma concentration-time data of the individual rates were analyzed using the non-compartmental model of DAS3.3.1 software, and the pharmacokinetic parameters of the test compounds were calculated. The pharmacokinetic properties of the compounds in rats are shown in Table 16.

[0574] [Table 16]

[0575] As can be seen from Table 16, the systemic exposure of Compound 2 was higher than that of the control Compound 4 at the same dose administered orally once in rats.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 In the formula, R １ is C １ ~C ６ alkyl, １ ~C ６ The alkyl is optionally substituted with 0-6 R'; R ２ is hydrogen, amino, C １ ~C ６ Alkyl, 【Chemistry 2】 said amino, and said C １ ~C ６ Alkyl is optionally represented by 0 to 3 R ａ is substituted with a group; X is selected from CH, N or O; n is 0, 1 or 2; When X is O, R ａ does not include; 【Chemistry 3】 represents a C—C saturated bond or a C═C olefinic bond; R ３ is C １ ~C ６ Alkyl, -NR ｂ R ｃ , Cl and Br; R ４ and R ６ are each independently hydrogen, C １ ~C ６ alkyl, and halogen; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ selected from alkyl and halogen; R ａ and R ａａ are each independently hydrogen, C １ ~C ６ Alkyl, amino, and 【Chemistry 4】 wherein said C １ ~C ６ alkyl, and said amino is optionally substituted with 0-3 R'; Y is selected from N or O, Z is selected from CH or N; R ｂ and R ｃ are each independently hydrogen, and C １ ~C ６ alkyl; R′ is hydrogen, F, amino, and C １ ~C ６ alkyl; １ ~C ６ alkyl, and said amino is optionally substituted with 0 to 3 methyl; A compound or a pharma- ceutically acceptable salt thereof.

2. R １ is C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ２ is hydrogen, C １ ~C ６ Alkyl, amino, 【Chemistry 5】 wherein said amino and said C １ ~C ６ Alkyl is one to three R ａ is substituted with; R ａ and R ａａ are each independently hydrogen, C １ ~C ６ Alkyl, or 【Chemistry 6】 Selected from: R ３ is C １ ~C ６ Alkyl, Cl, Br and -NR ｂ R ｃ Selected from: R ４ is a halogen, and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ selected from alkyl and halogen; R ６ is selected from hydrogen or methyl; R ｂ and R ｃ are each independently hydrogen, C １ ~C ６ selected from alkyl, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. R ３ is C １ ~C ６ alkyl; R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ is alkyl; R ６ is hydrogen, 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

4. R ２ is amino, and 【Chemistry 7】 wherein the amino is optionally selected from 0 to 3 R ａ where X is selected from CH, N or O; R ａ teeth, 【Chemistry 8】 , and C １ ~C ３ alkyl; wherein Y is selected from N or O, and Z is selected from CH or N; R ｂ and R ｃ are each independently hydrogen and C １ ~C ３ alkyl; R ３ is C １ ~C ６ alkyl; R ４ is Cl, Br and C １ ~C ６ alkyl, １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R′ is hydrogen, C １ ~C ６ selected from alkyl, F, and amino; 4. The compound of claim 3 or a pharma- ceutically acceptable salt thereof.

5. R ２ is amino, and 【Chemistry 9】 wherein the amino is optionally selected from 0 to 3 R ａ where X is selected from CH, N or O; R ａ teeth, 【Chemistry 10】 , and C １ ~C ３ alkyl; wherein Y is selected from N or O, and Z is selected from CH or N; R ｂ and R ｃ are each independently hydrogen and C １ ~C ３ alkyl; R ３ is C １ ~C ６ alkyl; R ４ is Cl, Br and C １ ~C ６ alkyl, １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R' is selected from F and amino; 4. The compound of claim 3 or a pharma- ceutically acceptable salt thereof.

6. R １ is methyl, ethyl, isopropyl, CF ２ H and CH ２ CF ３ Selected from: R ２ teeth, 【Chemistry 11】 Selected from: R ３ is selected from methyl, ethyl and isopropyl; R ４ is Cl, Br, CH ３ , C.F. ３ and C.H. ２ CF ３ Selected from: R ５ is selected from methyl, ethyl and isopropyl; 5. The compound of claim 4 or a pharma- ceutically acceptable salt thereof.

7. R １ is methyl, ethyl, isopropyl, CF ２ H and CH ２ CF ３ Selected from: R ２ teeth, 【Chemistry 12】 Selected from: R ３ is selected from methyl and ethyl; R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from methyl and ethyl; 6. The compound of claim 5 or a pharma- ceutically acceptable salt thereof.

8. R ３ is selected from Cl and Br; R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R ６ is hydrogen; R′ is hydrogen, C １ ~C ６ selected from alkyl, F, and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

9. R ３ is selected from Cl and Br; R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R ６ is hydrogen; R' is selected from F and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

10. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 13】 Selected from: R ３ is selected from Cl and Br; R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from methyl, ethyl and isopropyl; 9. The compound of claim 8 or a pharma- ceutically acceptable salt thereof.

11. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 14】 Selected from: R ３ is selected from Cl and Br; R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from methyl and ethyl; 10. The compound of claim 9 or a pharma- ceutically acceptable salt thereof.

12. R ３ is C １ ~C ６ alkyl; R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is selected from halogens; R ６ is hydrogen; R′ is hydrogen, C １ ~C ６ selected from alkyl, F, and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

13. R ３ is C １ ~C ６ alkyl; R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is selected from halogens; R ６ is hydrogen; R' is selected from F and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

14. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 15】 Selected from: R ３ is selected from methyl, ethyl and isopropyl; R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from F and Cl; 13. The compound of claim 12 or a pharma- ceutically acceptable salt thereof.

15. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 16】 Selected from: R ３ is selected from methyl and ethyl; R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from F and Cl; 14. The compound of claim 13 or a pharma- ceutically acceptable salt thereof.

16. R ３ Ha-NR ｂ R ｃ and R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R ６ is hydrogen; R ｂ and R ｃ are each independently hydrogen, and C １ ~C ６ alkyl; R′ is hydrogen, C １ ~C ６ selected from alkyl, F, and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

17. R ３ Ha-NR ｂ R ｃ and R ４ is halogen and C １ ~C ６ alkyl; １ ~C ６ The alkyl is optionally substituted with 0-3 R'; R ５ is C １ ~C ６ alkyl; R ６ is hydrogen; R ｂ and R ｃ are each independently hydrogen, and C １ ~C ６ alkyl; R' is selected from F and amino; 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

18. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 17】 Selected from: R ３ is NHCH ３ and R ４ is Cl, Br, CF ３ and C.H. ２ CF ３ Selected from: R ５ is selected from methyl and ethyl; 17. The compound of claim 16 or a pharma- ceutically acceptable salt thereof.

19. R １ is methyl, ethyl, isopropyl and -CF ２ H; R ２ teeth, 【Chemistry 18】 Selected from: R ３ is selected from methyl, ethyl and isopropyl; R ４ is selected from Br; R ５ is selected from methyl, ethyl and isopropyl; 7. The compound of claim 6 or a pharma- ceutically acceptable salt thereof.

20. R １ is selected from methyl, ethyl and isopropyl; R ２ teeth, 【Chemistry 19】 Selected from: R ３ is selected from methyl, ethyl and isopropyl; R ４ is selected from Br; R ５ is selected from F and Cl; 15. The compound of claim 14 or a pharma- ceutically acceptable salt thereof.

21. 【Fig. 20】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt thereof.

22. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. Pharmaceutical compositions.

23. A compound according to any one of claims 1 to 21, comprising another anti-cancer or anti-tumor agent. Pharmaceutical compositions.

24. The anti-cancer or anti-tumor agent is one or more of a cytotoxic agent, a hormonal agent, an antimetabolite, a tumor-targeting agent, a PARP inhibitor, an adjuvant therapeutic agent, or an anti-tumor biologic agent; 24. The pharmaceutical composition of claim 23.

25. the cytotoxic agent is one or more of carboplatin, cisplatin, irinotecan, paclitaxel, fluorouracil, cytarabine, lenalidomide, and retinoic acid; the hormonal agent is one or more of dexamethasone, fulvestrant, and tamoxifen; the antimetabolite is one or more of fluorouracil, methotrexate, furanfluorouracil, and cytarabine; the tumor targeting agent is one or more of imatinib, erlotinib, and lapatinib; and the PARP inhibitor. is one or more of Olaparib, Rubraca, and Zejula; the adjuvant therapy is one or more of recombinant human granulocyte colony-stimulating factor, erythropoietin, pamidronate disodium, and zoledronic acid; the anti-tumor biologic agent is one or more of Keytruda, Opdiv, Tecentriq, Imfinzi, and Bavencio; 25. The pharmaceutical composition of claim 24.

26. A composition comprising a compound according to any one of claims 1 to 21 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable adjuvant. Pharmaceutical preparations.

27. Use in the manufacture of a medicament for preventing and / or treating cancer, comprising: Use of a compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22 or 25, or a pharmaceutical preparation according to claim 26.

28. The cancer is plasmacytoma, mantle cell tumor, multiple myeloma, melanoma, breast cancer, liver cancer, cervical cancer, lung cancer, lymphoma, leukemia, ovarian cancer, kidney cancer, gastric cancer, nasopharyngeal cancer, thyroid cancer, pancreatic cancer, prostate cancer, adenocarcinoma, oral cancer, esophageal cancer, squamous cell carcinoma or colon cancer; 28. The use according to claim 27.

29. In the manufacture of an EGFR inhibitor, or an ALK inhibitor, or an inhibitor of EGFR and ALK, or a protein kinase inhibitor, Use of a compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22 or 25, or a pharmaceutical preparation according to claim 26.

30. The EGFR inhibitor, or the ALK inhibitor, or the EGFR and ALK inhibitor, or the protein kinase inhibitor is applied to plasmacytoma, mantle cell tumor, multiple myeloma, melanoma, breast cancer, liver cancer, cervical cancer, lung cancer, lymphoma, leukemia, ovarian cancer, kidney cancer, gastric cancer, nasopharyngeal cancer, thyroid cancer, pancreatic cancer, prostate cancer, adenocarcinoma, oral cancer, esophageal cancer, squamous cell carcinoma or colon cancer; 30. The use according to claim 29.

Images