Quinazoline compounds, compositions and applications of quinazoline compounds

Abstract

Quinazoline compounds, compositions and applications of the quinazoline compounds are provided, in particular the compound of formula (I), its stereoisomers, its pharma- ceutically acceptable salts or its deuterated derivatives, compositions and applications thereof in the preparation of medicaments acting as tyrosine kinase inhibitors, which have good inhibitory activity against EGFR, HER2 kinase, and their exon 20 mutations and EGFRviii mutations. [C1] TIFF2024510312000129.tif37156

Description

[Technical field]

[0001] The present disclosure is in the field of pharmaceutical technology and relates to quinazoline compounds, their compositions and applications. [Background technology]

[0002] Epidermal growth factor receptor (ErbB) tyrosine kinase can regulate cell proliferation, migration, differentiation, apoptosis, and cell motility through multiple pathways. ErbB family members and some of their ligands are commonly overexpressed, amplified, or mutated in many forms of malignant tumors, making them important therapeutic targets. This protein kinase family includes ErbB1 / EGFR / HER1, ErbB2 / HER2, ErbB3 / HER3, and ErbB4 / HER4, among which EGFR and HER2 are important targets for the development of drugs against non-small cell lung cancer and breast cancer (Non-Patent Document 1, Non-Patent Document 2). Currently, several generations of EGFR and HER2 kinase inhibitors are also commercially available.

[0003] However, the expression of EGFR and HER2 is not stable, and gene amplification and rearrangement occur frequently, which leads to changes in the antigen phenotype on the surface of tumor cells. The effectiveness of existing targeted drugs against various mutations of EGFR and HER2 varies greatly, with the weakest inhibitory ability against Ins20, which leads to drug-resistant mutations against which existing multi-generation targeted drugs are largely ineffective. Although the exon 20 mutations of the EGFR gene and the HER2 gene occur at similar positions, there are many types of EGFR exon 20 insertion mutations, of which 122 types have been found. In contrast, there are fewer types of exon 20 insertion mutations in the HER2 gene, the most common of which is the A775_G776insYVMA site, accounting for nearly 70% of the total number of mutations. Statistics also show that about 3% of NSCLC patients have HER2 mutations, and about 90% are patients with exon 20 mutation types of the HER2 gene. In these EGFR / HER2 exon 20 mutation patients, the effectiveness of existing targeted TKI drugs is very limited.

[0004] Meanwhile, there are a few research projects targeting EGFR / HER2 Ins20 mutations. Poziotinib is a broad-spectrum HER inhibitor developed by Hanmi. Clinical data shows that poziotinib has some efficacy against EGFR / HER2 exon 20 mutations, but has a high incidence of side effects. At the same time, the commercially available pyrotinib is also undergoing clinical studies for the relevant exon 20 mutations.

[0005] In addition, EGFRvIII, a mutant class of epidermal growth factor receptor EGFR that is expressed only on the surface of tumor cells and not on the cell surface of normal tissues, has also been identified in recent years, and is also a very common EGFR mutant. In contrast to the intact structure of EGFR, exons 2-7 encoding the extracellular ligand-binding region of EGFRvIII are deleted, resulting in a deletion of 801 base pairs that joins exons 1 and 8, and creates a new glycine at this binding site, causing a deletion of amino acids 6-273, which results in a loss of the ability to bind the ligand EGF. In the absence of ligand binding, EGFRvIII constitutively activates tyrosine kinases in a disordered manner by dimerization and autophosphorylation, inducing downstream signaling and stimulating tumor cell proliferation. Therefore, the development of new molecular targeted therapeutics against EGFRvIII would provide more effective and cost-effective treatment options for tumor patients, and there is a huge unmet clinical need.

[0006] From the viewpoint of chemical structure, many TKI drugs on the market, as well as the above-mentioned poziotinib and pyrotinib, are all derived from the structure of quinazoline or quinoline. As shown in the figure below, when constructing a TKI inhibitor via quinazoline or quinoline, an aniline-based group is usually introduced at the 4th position, and the 6th and 7th positions are substituted at the same time. Pyrotinib, neratinib, and poziotinib shown in the figure below are all substituted with an alkoxy group at the 7th position, and also have a substituent at the 6th position. However, there have been few attempts to construct a TKI inhibitor by substitution at the 5th position. In this application, a series of quinazoline compounds are synthesized by introducing a substituent at the 5th position and removing the substituent at the 7th position, which show excellent inhibitory activity against HER2 and its exon 20 mutation, and are expected to be used for the treatment of HER2 exon 20 mutation.

[0007] Of particular note is that none of the currently available small molecule HER2 inhibitors can effectively cross the blood-brain barrier, and approximately 50% of HER2-positive breast cancer patients develop brain metastasis. Considering that some compounds of the present application can effectively cross the blood-brain barrier and have extremely strong inhibitory effects on HER2-positive tumors, it is expected that the compounds of the present application can also be used to treat patients with brain metastasis from HER2-positive breast cancer.

[0008] [ka] [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Dienstmann R.,et.al.,(2001)Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.ONCOTARGET.2(3),165 [Non-Patent Document 2] Mitri Z.,et.al.(2012)The HER2 Receptor in Breast Cancer: Pathophysiology,Clinical Use,and New Advances in Therapy.,Chemotherapy Research&Practice.,Volum 2012(23),743193 Summary of the Invention [Means for solving the problem]

[0010] One aspect of the present disclosure provides a compound represented by formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof. [ka]

[0011] In formula (I), Z is -NH- or -O-;

[0012] T1 is -(CH2) n [wherein n is an integer from 0 to 3];

[0013] R1 is hydrogen, hydroxy, a 4- to 7-membered heteroalicyclic group, or -NR a R b and

[0014] R a and R b are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, or C3-C6 cycloalkyl-substituted C1-C6 alkyl;

[0015] The 4-7 membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S, and the heteroalicyclic group is unsubstituted or substituted with one or two of C1-C3 alkyl, C1-C4 alkyl acyl, hydroxy, cyano, amino acyl, mono- or di-substituted C1-C3 amino acyl, C1-C3 alkoxy-substituted C1-C3 alkyl, and hydroxy-substituted C1-C3 alkyl;

[0016] L is -O-, -S-, or -NH-;

[0017] R2 is C1-C6 alkyl, C1-C6 haloalkyl, hydroxy-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, or -(CH2)m-R5;

[0018] R5 is a C3-C6 cycloalkyl or a 4-6 membered heteroalicyclic group, and m is an integer of 0 to 3;

[0019] The 4- to 6-membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S;

[0020] T2 is -M-(CH2)p-, where M is O, S, or NH, and p is an integer from 0 to 2;

[0021] R3 is an aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl, and pyrrolyl, wherein the aryl or heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C4 cycloalkyl, C2-C3 alkynyl, C2-C3 alkenyl, and -NR'R";

[0022] R', R" are each independently H or C1-C3 alkyl;

[0023] R4 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 alkoxy.

[0024] According to an alternative embodiment, Z is -NH-.

[0025] According to an alternative embodiment, T1 is -(CH2) n [wherein n is an integer from 0 to 2],

[0026] R1 is hydrogen, a 4- to 6-membered heteroalicyclic group, or -NR a R b and

[0027] R a and R b are each independently hydrogen, C1-C3 alkyl, C3-C4 cycloalkyl, hydroxy-substituted C1-C3 alkyl, C1-C3 alkoxy-substituted C1-C3 alkyl, or C3-C6 cycloalkyl-substituted C1-C3 alkyl;

[0028] The 4- to 6-membered heteroalicyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or thiomorpholinyl, and the group is unsubstituted or substituted with one or two of methyl, ethyl, propyl, isopropyl, an aldehyde group, acetyl, propionyl, hydroxy, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl.

[0029] Further alternatively, T1 is -(CH2) n -wherein n is 0 or 1;

[0030] R1 is dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino, ethylpropylamino, methylcyclopropylamino, ethylcyclopropylamino, propylcyclopropylamino, isopropylcyclopropylamino, methylcyclobutylamino, ethylcyclobutylamino, propylcyclobutylamino, isopropylcyclobutylamino, pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, lysin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, 1-(2-hydroxypropyl)pyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-propylpiperazin-4-yl, 1-isopropylpiperazin-4-yl, 1-(2-hydroxyethyl)piperazin-4-yl, morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, or thiomorpholinyl.

[0031] Further alternatively, R1 is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, or 1-(2-hydroxypropyl)pyrrolidin-2-yl.

[0032] According to another alternative embodiment, L is -O- or -NH-;

[0033] R2 is C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, or -(CH2)m-R5;

[0034] R5 is a C3-C6 cycloalkyl or a 4-6 membered heteroalicyclic group, and m is 0, 1, or 2;

[0035] The 4- to 6-membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O and S.

[0036] Yet alternatively, L is -O-;

[0037] R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2 -trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, tetrahydrofuran-2-yl, and tetrahydrofuran-3-yl.

[0038] In another alternative embodiment, T2 is -O-(CH2)p-, where p is 0 or 1;

[0039] R3 is phenyl, pyridyl, or pyrimidyl, and the phenyl, pyridyl, and pyrimidyl are each independently selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyano, hydroxy, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 2,2,2 -trifluoroethyl, and 2,2-difluoroethyl, or is unsubstituted.

[0040] In yet another alternative, T2 is -O-(CH2)p-, where p is 1;

[0041] R3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 5-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 3-methylpyridin-2-yl, 3-methoxypyridin-2-yl, 6-fluoropyridin-2-yl, or 6-chloropyridin-2-yl.

[0042] According to an alternative embodiment, R4 is hydrogen, fluorine, chlorine, methyl, methoxy, and further alternatively, hydrogen, fluorine, chlorine.

[0043] According to an alternative embodiment, the present application provides a compound represented by the following formula, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [ka]

[0044] wherein R1 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or thiomorpholinyl, which is unsubstituted or substituted with one or two of methyl, ethyl, propyl, isopropyl, an aldehyde group, acetyl, propionyl, hydroxy, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl;

[0045] R2 is C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-substituted C1-C4 alkyl, C1-C3 alkoxy-substituted C1-C4 alkyl, or -(CH2)m-R5;

[0046] R5 is a C3-C6 cycloalkyl or a 4-6 membered heteroalicyclic group, and m is 0, 1, or 2;

[0047] The 4- to 6-membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S;

[0048] R3 is phenyl, pyridyl, or pyrimidyl, and the phenyl, pyridyl, and pyrimidyl are each independently selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyano, hydroxy, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 2,2,2 -unsubstituted or substituted with 1 to 2 substituents selected from trifluoroethyl, and 2,2-difluoroethyl;

[0049] R4 is hydrogen, fluorine, chlorine, methyl, or methoxy.

[0050] Further alternatively, R1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, or 1-(2-hydroxypropyl)pyrrolidin-2-yl;

[0051] R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2 -trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, or ethoxybutyl;

[0052] R3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 5-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 3-methylpyridin-2-yl, 3-methoxypyridin-2-yl, 6-fluoropyridin-2-yl, or 6-chloropyridin-2-yl;

[0053] R4 is fluorine or chlorine.

[0054] Further alternatively, R1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, or 1-(2-hydroxypropyl)pyrrolidin-2-yl;

[0055] R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2 -trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, or ethoxybutyl;

[0056] R3 is pyridin-2-yl;

[0057] R4 is chlorine.

[0058] Further alternatively, R1 is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl;

[0059] R2 is methyl, ethyl, propyl, methoxyethyl, methoxypropyl, 2,2-difluoroethyl;

[0060] R3 is pyridin-2-yl;

[0061] R4 is chlorine.

[0062] Exemplary compounds according to the present application are listed below. [Table 1-1] [Table 1-2] [Table 1-3]

[0063] Another aspect of the present application provides pharmaceutical compositions containing a compound described herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, and one or more pharma- ceutically acceptable carriers or excipients.

[0064] The pharmaceutical compositions of the present application may further contain one or more other therapeutic agents.

[0065] The present application further relates to the use of said compounds, their stereoisomers, their pharma- ceutically acceptable salts or their deuterated derivatives in the manufacture of a medicament for the treatment of diseases associated with the tyrosine kinase HER2, in particular diseases associated with exon 20 mutations of the tyrosine kinase HER2.

[0066] The disease may alternatively be cancer or an autoimmune disease, in particular ocular fundus diseases, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphomas, multiple myeloma, bile duct carcinosarcoma, or cholangiocarcinoma.

[0067] The present disclosure further relates to a method for treating a disease or condition mediated by a kinase such as HER2, comprising administering a therapeutically effective amount of a compound described in the present application or a salt thereof to a patient (a human or other mammal, particularly a human) in need thereof, the disease or condition mediated by a kinase such as HER2 including those mentioned above.

[0068] The foregoing and other objects, features, and advantages of the present disclosure will be more clearly understood from the following detailed description taken in conjunction with the drawings. [Brief description of the drawings]

[0069] [Figure 1] FIG. 1 shows the effect of neratinib on the T / C value of tumor-bearing mice over time. [Diagram 2] FIG. 1 shows the effect of pyrotinib on the T / C value of tumor-bearing mice over time. [Diagram 3] FIG. 2 shows the effect of the compound of Example 4 of the present application on the T / C value of tumor-bearing mice over time. [Figure 4] FIG. 2 shows the effect of the compound of Example 8 of the present application on the T / C value of tumor-bearing mice over time. [Diagram 5] FIG. 2 shows the effect of the compound of Example 9 of the present application on the T / C value of tumor-bearing mice over time. [Figure 6]FIG. 2 shows the effect of the compound of Example 11 of the present application on the T / C value of tumor-bearing mice over time. [Figure 7] FIG. 2 shows the effect of the compound of Example 24 of the present application on the T / C value of tumor-bearing mice over time. [Figure 8] FIG. 2 shows the effect of the compound of Example 29 of the present application on the T / C value of tumor-bearing mice over time. [Figure 9] FIG. 2 shows the effect of the compound of Example 33 of the present application on the T / C value of tumor-bearing mice over time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions set forth below. In this application, the use of "or" or "and" means "and / or" unless otherwise stated. In addition, the use of the term "comprises" and other forms such as "containing" and "having" is not limiting. Subheadings used herein are for organizational purposes only and should not be construed as limiting the topics described.

[0071] Unless otherwise specified, alkyl group refers to saturated straight and branched hydrocarbon groups having a specified number of carbon atoms, and the term C1-C6 alkyl refers to an alkyl moiety containing 1 to 6 carbon atoms. Similarly, C1-C3 alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms. For example, C1-C6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.

[0072] When a substituent term such as "alkyl" is used in combination with another substituent term, such as the term "C1-C3 alkoxy C1-C6 alkylthio" or "hydroxy-substituted C1-C6 alkyl", the linking substituent term (e.g., alkyl or alkylthio) is intended to include a divalent moiety whose point of attachment is through the linking substituent. Examples of "C1-C3 alkoxy C1-C6 alkylthio" include, but are not limited to, methoxymethylthio, methoxyethylthio, and ethoxypropylthio. Examples of "hydroxy-substituted C1-C6 alkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.

[0073] Alkoxy groups are alkyl-O- groups formed by a linear or branched alkyl group as described above and -O-, such as methoxy, ethoxy, etc. Similarly, alkylthio groups are alkyl-S- groups formed by a linear or branched alkyl group as described above and -S-, such as methylthio, ethylthio, etc.

[0074] Alkenyl and alkynyl groups include straight-chain or branched alkenyl or alkynyl groups, and the terms C2-C6 alkenyl or C2-C6 alkynyl refer to straight-chain or branched hydrocarbon groups having at least one alkenyl or alkynyl group.

[0075] The term "haloalkyl" such as "C1-C6 haloalkyl" refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of the alkyl portion containing 1 to 6 carbon atoms. Examples of "C1-C6 haloalkyl" include, but are not limited to, -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl. Similarly, the term "C1-C6 haloalkoxy" refers to a haloalkyl-O- group formed by the above C1-C6 haloalkyl and -O-, which may be, for example, trifluoromethoxy, trichloromethoxy, etc.

[0076] The term "cycloalkyl" refers to a non-aromatic saturated cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term "(C3-C6)cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having 3 to 6 ring carbon atoms. Exemplary "(C3-C6)cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "aryl" refers to a group or moiety that includes an aromatic monocyclic or bicyclic hydrocarbon radical containing 6 to 12 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" include phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Typically, in the compounds of this disclosure, aryl is phenyl.

[0078] Unless otherwise indicated, the term "heteroalicyclic group," as used herein, refers to an unsubstituted or substituted, stable, 4- to 7-membered, non-aromatic, monocyclic, saturated ring system consisting of carbon atoms and one to three heteroatoms selected from N, O, and S (wherein the N or S heteroatoms may optionally be oxidized and the N heteroatom may further optionally be quaternized). Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl.

[0079] The term "heteroaryl" as used herein refers to a group or moiety containing an aromatic monocyclic or bicyclic radical (containing 5-10 ring atoms) containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term also includes bicyclic heterocyclic aryls containing an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise indicated, it refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and may also refer to an unsubstituted or substituted benzene-fused heteroaromatic ring system or bicyclic heteroaromatic ring system containing 9 or 10 ring atoms, composed of 1-3 heteroatoms selected from N, O, and S (wherein the N and S heteroatoms may be oxidized and the N heteroatom may be further quaternized) and carbon atoms. The heteroaryl group may be attached to any heteroatom or carbon atom to form a stable structure. Representative examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indazinyl, indolyl, isoindolyl, and indolinyl. , benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, benzotriazolyl, triazolopyridyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridyl.

[0080] The term "carbonyl" refers to the group -C(O)-. The terms "halogen" and "halo" refer to chlorine, fluorine, bromine, or iodine substituents. "Oxo" refers to an oxygen moiety containing a double bond, for example, "oxo" may be attached directly to a carbon atom to form a carbonyl moiety (C=O). "Hydroxy" is intended to refer to the radical -OH. As used herein, the term "cyano" refers to the group: -CN.

[0081] The term "deuterated derivatives" refers, in some cases, to derivatives obtained by deuteration of one or more hydrogen atoms in the compounds of the present application.

[0082] The term "independently" means that when multiple substituents are selected from a number of possible substituents, the substituents may be the same or different.

[0083] It is clear that the compound of formula I, or its stereoisomer, crystalline form, or prodrug, and its pharma- ceutically acceptable salt, may exist in solvated or non-solvated form.For example, the solvated form may be a water-soluble form.The present disclosure includes all solvated and non-solvated forms.

[0084] In this disclosure, the term "isomer" refers to different compounds having the same molecular formula and may include various isomeric forms such as stereoisomers and tautomers. "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms. Some compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R) or (S) forms based on absolute stereochemistry. The chemical compounds, pharmaceutical compositions, and methods disclosed herein are intended to include all of these possible isomers, including racemic mixtures, optically pure forms, and mixtures therebetween. Optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, to determine the predominance of one stereoisomer over the other.

[0085] Individual stereoisomers (or isomer-enriched mixtures) of the compounds of the present disclosure may be resolved using methods known to those of skill in the art. For example, such resolution may be carried out by (1) formation of a diastereoisomeric salt, complex, or other derivative; (2) selective reaction with a stereoisomer-specific reagent, such as by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support such as silica bound to a chiral ligand, or in the presence of a chiral solvent. Those skilled in the art will recognize that when the desired stereoisomer is converted to another chemical entity by one of the above-mentioned separation procedures, an additional step is required to liberate the desired form. Alternatively, a particular stereoisomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0086] When the compounds described herein contain olefinic double bonds, unless otherwise specified, the compounds are meant to include various cis and trans isomers.

[0087] "Tautomers" are structurally distinct isomers that are interconvertible by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic change tautomerization or proton transfer tautomerization, which can be considered part of acid-base chemistry. "Prototropic change tautomerization" or "proton transfer tautomerization" involves the migration of a proton with a change in bond level, often the exchange of a single bond with an adjacent double bond. When tautomerization is possible (e.g., in solution), the tautomers may reach chemical equilibrium. One example of tautomerization is keto-enol tautomerization.

[0088] The compounds of the present disclosure as active ingredients and their preparation methods are both included in the present disclosure.In addition, the crystalline forms of some compounds may exist as crystalline polymorphs, and such forms are also included in the present disclosure.In addition, some compounds may form solvates with water (i.e., hydrates) or with common organic solvents, and such solvates are also included in the scope of the present disclosure.

[0089] The compounds of the present disclosure may be used in therapy in free form or, where appropriate, as pharma- ceutically acceptable salts or other derivatives. As used herein, the term "pharma-ceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present disclosure that are suitable for use in humans and lower animals and have a reasonable benefit / risk ratio without undue toxicity, irritation, allergic reactions, etc. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. Salts may be formed by reacting the compounds of the present disclosure with a suitable free base or acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, and the like. Alternatively, salts may be obtained by methods well known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glyconate, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include the salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharma-ceutically acceptable salts include suitable non-toxic salts of ammonium, quaternary ammonium, and amine cations formed from the halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0090] Additionally, the term "prodrug" as used herein means a compound that can be converted in vivo to a compound of the present disclosure, said conversion being affected by hydrolysis of the prodrug in blood or by enzymatic conversion in blood or tissue to the parent compound.

[0091] The pharmaceutical compositions of the present disclosure contain a compound described herein or a pharma- ceutically acceptable salt thereof; an additional active agent selected from a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anti-cancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an antibiotic, and an anti-vascular hyperproliferation compound; and any pharma- ceutically acceptable carrier, adjuvant, or excipient.

[0092] The compounds of the present disclosure may be used alone or in combination with one or more other compounds of the present disclosure or one or more other drugs. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or sequential administration at different times, or may be administered as a single composition. "Combination therapy" refers to the use of a compound of the present disclosure with another drug, in a manner in which each drug is administered simultaneously or sequentially, in either case with the goal of achieving the optimal effect of the drug. Simultaneous administration includes separate dosage forms for each compound, as well as dosage forms for simultaneous delivery. Thus, administration of the compounds of the present disclosure may be combined with other therapies known in the art, such as radiation therapy, cytostatic agents, cytotoxic agents, and other anti-cancer agents, such as those used in the treatment of cancer, to improve the symptoms of cancer. The order of administration is not limited in the present disclosure. The compounds of the present disclosure may be administered before, simultaneously, or after the other anti-cancer or cytotoxic agent.

[0093] To prepare the pharmaceutical composition of the present disclosure, one or more compounds of formula (I) or its salts as active ingredients can be intimately mixed with pharmaceutical carriers, which is carried out according to conventional pharmaceutical preparation techniques.Carriers can be used in a wide variety of forms, depending on the formulations designed for various modes of administration (e.g., oral or parenteral administration).Suitable pharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers can be found in Handbook of Pharmaceutical Excipients, jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0094] The pharmaceutical composition of the present disclosure may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions, or suspensions; in a form for parenteral injection, such as clear solutions, suspensions, emulsions; or in a form for topical application, such as ointments, creams, or as a suppository for rectal administration. The pharmaceutical composition may also be provided in a unit dosage form for single administration with a precise dosage. The pharmaceutical composition includes a conventional pharmaceutical carrier or excipient, and a compound as an active ingredient prepared according to the present disclosure, and may also include other medicinal or pharmaceutical preparations, carriers, adjuvants, etc.

[0095] The therapeutic compound can also be administered to mammals other than humans. The dosage of the drug to the mammal depends on the species of the animal and its disease or disorder state. The therapeutic compound can be administered to the animal in the form of a capsule, bolus, tablet, or liquid. The therapeutic compound can also be introduced into the animal by injection or infusion. These drug forms are prepared in traditional ways that meet the standards of veterinary practice. Alternatively, the pharmaceutical compound can be mixed with the animal's feed to feed the animal, so that a concentrated feed additive or premix can be prepared by mixing with the normal animal feed.

[0096] It is a further object of the present disclosure to provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition containing a compound of the present disclosure.

[0097] The disclosure further includes the use of a compound of the disclosure, or a pharma- ceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of a disease associated with the tyrosine kinases EGFR and HER2, which may be cancer (including non-solid tumors, solid tumors, primary cancers, or metastatic cancers, as set forth elsewhere herein, and further including cancers that are resistant or refractory to one or more other therapies), in particular lung cancer or breast cancer. EXAMPLES

[0098] The present disclosure also provides methods for preparing the corresponding compounds. A variety of synthetic methods can be used to prepare the compounds described herein, including the following methods. The compounds of the present disclosure, or their pharma-ceutically acceptable salts, isomers, or hydrates, can be synthesized using the methods described below, synthetic methods known in the art of organic chemical synthesis, or modifications of these methods that will be understood by those skilled in the art. Alternative methods include, but are not limited to, the following methods.

[0099] In the following, the present disclosure will be described in more detail with specific examples to make the objectives, technical solutions and advantages of the present disclosure clearer. It should be understood that the specific examples described herein are only used to illustrate the present disclosure and are not intended to limit the present invention. If no specific techniques or conditions are shown in the examples, the techniques or conditions described in the literature or product specifications in the art shall be followed. If no manufacturer is shown for the reagents or equipment used, the reagents or equipment are all commercially available conventional products. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. Hereinafter, the examples are provided to better illustrate the present invention, and all temperatures refer to ° C unless otherwise specified. The names of some compounds in the present disclosure are generated and translated by Chemdraw.

[0100] Synthesis of intermediates Intermediate 1.

[0101] (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylic acid [ka]

[0102] Step 1): Synthesis of tert-butyl (R)-2-formylpyrrolidine-1-carboxylate

[0103] tert-Butyl (R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4 g, 20 mmol) and Dess-Martin reagent (8.5 g, 20 mmol) were added to dichloromethane (70 ml) in an ice-water bath, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, washed, dried, and concentrated to give 4 g of an oil, which was used directly in the next step.

[0104] Step 2): Synthesis of tert-butyl (R,E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate;

[0105] Triethyl phosphonoacetate (3.6 mL, 18.1 mmol) was added dropwise to a solution of NaH (782 mg, 19.6 mmol) in THF (15 mL) at 25° C. After 0.5 h, the solution was cooled to 0° C. and a solution of Boc-L-proline (3 g, 15.1 mmol) in THF (60 mL) was added dropwise. The mixture was stirred at 0° C. for an additional 2 h and then quenched by the addition of water. The aqueous phase was back-extracted several times with DCM and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting yellow oil (4 g, quantitative) was used directly without further purification.

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[0106] Step 3): Synthesis of ethyl (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylate;

[0107] tert-Butyl (R,E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (0.27 g, 1 mmol) was added to a solution of trifluoroacetic acid (1 ml) in dichloromethane (4 ml), and the mixture was stirred at room temperature for 2 hours to react. The mixture was concentrated to give a yellow oil. The yellow oil was added to a solution of bromoethyl methyl ether (0.3 g, 2 mmol) and potassium carbonate (0.45 g, 3 mmol) in acetonitrile (10 ml), and the mixture was heated to 80° C. and reacted for 12 hours. The mixture was cooled, extracted with ethyl acetate, and washed with water three times. The organic phase was dried and concentrated to give 0.12 g of a pale yellow oil.

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[0108] Step 4): Synthesis of (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylic acid;

[0109] Ethyl (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylate (0.12 g, 0.5 mmol) and sodium hydroxide (0.04 g, 1 mmol) were added to a solution of methanol (1 ml) and water (1 ml) and the reaction was stirred at room temperature overnight. After the reaction was complete, the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, concentrated, washed with a mixture of dichloromethane and methanol, and filtered. The filtrate was concentrated and then slurried with acetonitrile to give the product as a white solid.

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[0110] Intermediate 2. (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acrylic acid [ka]

[0111] Step 1): Synthesis of ethyl (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acrylate

[0112] tert-Butyl (R,E)-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (0.27 g, 1 mmol) was added to a solution of trifluoroacetic acid (1 ml) in dichloromethane (3 ml). The mixture was stirred at room temperature for 2 hours to react and concentrated to obtain a yellow oil. Cyclobutyl-1-one (0.1 g, 1.5 mmol), a yellow oil, was added to 1,2-dichloroethane and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (0.13 g, 2 mmol) was then added to react. After completion of the reaction, the pH was adjusted to 8-9 and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, concentrated and purified by column chromatography to obtain the target product.

[0113] Step 2: Synthesis of (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acrylic acid

[0114] Ethyl (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acrylate (0.12 g, 0.5 mmol) and sodium hydroxide (0.04 g, 1 mmol) were added to a solution of methanol (1 ml) and water (1 ml), and the mixture was stirred at room temperature overnight to react. After the reaction was complete, the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to pH 4-5 with dilute hydrochloric acid, concentrated, washed with a mixture of dichloromethane and methanol, and filtered. The filtrate was concentrated and then slurried with acetonitrile to give the product as a white solid.

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[0115] Synthesis of Acryloyl Chloride Intermediate

[0116] The acryloyl chloride intermediates were synthesized by reacting the corresponding acrylic acid compounds in the presence of oxalyl chloride. The synthesis of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride is shown below as an example, and the remaining acryloyl chloride intermediates were synthesized by similar methods. [ka]

[0117] (R,E)-3-(1-methylpyrrolidin-2-yl)acrylic acid (150 mg, 1 mmol), oxalyl chloride (1.05 mmol), and DMF (1 drop) were added to anhydrous dichloromethane (2 ml) under ice-water bath conditions, and the mixture was stirred at room temperature for 2 hours to react. The mixture was concentrated to give a solid that could be used directly in the next step of the reaction.

[0118] The following acyl chloride intermediates were synthesized from the corresponding acids. [ka]

[0119] Example 1. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide [ka]

[0120] Step 1): Synthesis of 5-chloroquinazolin-4(3H)-one

[0121] 2-Amino-6-chlorobenzoic acid (17.2 g, 100 mmol) and formamidine acetate (15.6 g, 150 mmol) were added to a solution of ethanol (150 mL), and the mixture was heated to reflux and stirred for 24 hours to react. The mixture was cooled and filtered to give 14 g of a white solid in 78% yield.

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[0122] Step 2): Synthesis of 5-chloro-6-nitroquinazolin-4(3H)-one

[0123] 5-Chloroquinazolin-4(3H)-one (7.2 g, 40 mmol) was dissolved in concentrated sulfuric acid (40 mL) and potassium nitrate (4.2 g, 41.6 mmol) powder was added in portions at 0° C. The mixture was stirred at room temperature for 24 hours to react. The product was added in portions to crushed ice and the mixture was stirred for 1 hour. The mixture was filtered to give a pale yellow solid. The resulting solid was added to ethanol. The mixture was refluxed, then cooled and filtered to give 8.6 g of the product as a white solid in 95% yield.

[0124] Step 3): Synthesis of 4,5-dichloro-6-nitroquinazoline

[0125] 5-Chloro-6-nitroquinazolin-4(3H)-one (4.5 g, 20 mmol) was added to dichlorosulfoxide (45 mL) and DMF (2 mL) was added. The mixture was heated to 80° C. and reacted at reflux. When the product was completely dissolved, the mixture was reacted for an additional 2 hours and then concentrated. Toluene was added and the mixture was concentrated again to give 4.9 g of product as a white solid.

[0126] Step 4): Synthesis of 5-chloro-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine

[0127] 4,5-Dichloro-6-nitroquinazoline (4.9 g, 20 mmol) was added to anhydrous acetonitrile, and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (7 g, 30 mmol) and triethylamine (3 g, 30 mmol) were added at 0° C., respectively. The mixture was heated to 50° C. and reacted for 5 hours. The mixture was cooled, concentrated and washed with methanol to give 6.5 g of product as a white solid in 74% yield.

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[0128] Step 5): Synthesis of N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxy-6-nitroquinazolin-4-amine

[0129] 5-Chloro-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-nitroquinazolin-4-amine (4.4 g, 10 mmol) was added to a mixture of DMF (15 mL) and sodium methoxide solution (30% sodium methoxide in methanol, 15 mL) at 0° C. The mixture was stirred for 2 hours and quenched by adding ice. The mixture was filtered and dried to give 4.1 g of product as a yellow solid in 94% yield.

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[0130] Step 6):N 4 Synthesis of -(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine

[0131] N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxy-6-nitroquinazolin-4-amine (2.2 g, 5 mmol) was added to ethanol, followed by iron powder and aqueous ammonium chloride. The mixture was heated to 50° C. and reacted for 2 hours, then cooled, filtered, and rinsed with copious amounts of dichloromethane. The filtrate was washed with brine, dried, and concentrated to give 2 g of product as a pale purple solid in 98% yield.

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[0132] Step 7): Synthesis of (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide

[0133] N 4 -(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine (40 mg, 0.1 mmol) was added to a solution of NMP (1 mL) and a solution of (E)-4-(dimethylamino)but-2-enoyl chloride (24 mg, 0.15 mmol) in dichloromethane (1 mL) was added at 0° C. The mixture was stirred for 30 minutes to react and quenched by adding water. The mixture was adjusted to pH 9 with sodium bicarbonate and then extracted with dichloromethane. The organic phase was washed with saturated brine, dried and concentrated to give an oil. The oil was purified by column chromatography to give 18 mg of product as a white solid.

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[0134] Example 2. (E)-N-(4-((3-chloro-4 -( 3-Fluorobenzyloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide [ka]

[0135] The compound was synthesized in the same manner as in Example 1, except that in step 4) of Example 1, 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used in the reaction instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline.

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[0136] Example 3. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(cyclobutyl(methyl)amino)but-2-enamide [ka]

[0137] The compound was synthesized in the same manner as in Example 1, except that in step 7) of Example 1, (E)-4-(cyclobutyl(methyl)amino)but-2-enoyl chloride was used in the reaction instead of (E)-4-(dimethylamino)but-2-enoyl chloride.

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[0138] Example 4. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0139] Step 1) to Step 6): See Example 1.

[0140] Step 7):N 4 -(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-5-methoxyquinazoline-4,6-diamine (40 mg, 0.1 mmol) was added to the NMP solution, and a solution of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride (26 mg) in dichloromethane (1 mL) was added at 0° C. The mixture was stirred for 30 minutes to react, and then water was added to quench it. The mixture was adjusted to pH 9 with sodium bicarbonate, and then extracted with dichloromethane. The organic phase was washed with saturated brine, dried, and concentrated to give an oil. The oil was purified by column chromatography to give 24 mg of product as a white solid.

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[0141] Example 5. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-ethoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0142] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium ethoxide was used in the reaction instead of sodium methoxide.

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[0143] Example 6. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(2-hydroxyethoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0144] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 2-hydroxyethoxide was used in the reaction instead of sodium methoxide.

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[0145] Example 7. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(2-fluoroethoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0146] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 2-fluoroethoxide was used in the reaction instead of sodium methoxide.

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[0147] Example 8. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(2-methoxyethoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0148] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 2-methoxyethoxide was used in the reaction instead of sodium methoxide.

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[0149] Example 9. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(3-methoxypropoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0150] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 3-methoxypropoxide was used in the reaction instead of sodium methoxide.

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[0151] Example 10. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(3-fluoropropoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0152] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 3-fluoropropoxide was used in the reaction instead of sodium methoxide.

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[0153] Example 11. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(2,2-difluoroethoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0154] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 2,2-difluoroethoxide was used in the reaction instead of sodium methoxide.

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[0155] Example 12. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(3,3,3-trifluoropropoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0156] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 3,3,3-trifluoropropoxide was used in the reaction instead of sodium methoxide.

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[0157] Example 13. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-propoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0158] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium propoxide was used in the reaction instead of sodium methoxide.

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[0159] Example 14. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-isobutoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0160] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium isobutoxide was used in the reaction instead of sodium methoxide.

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[0161] Example 15. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(2-hydroxy-2-methylpropoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0162] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 2-methyl-2-hydroxypropoxide was used in the reaction instead of sodium methoxide.

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[0163] Example 16. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(3-hydroxy-3-methylbutoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0164] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 3-methyl-3-hydroxybutoxide was used in the reaction instead of sodium methoxide.

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[0165] Example 17. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(3-hydroxypropoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0166] The compound was synthesized in the same manner as in Example 4, except that in step 5) of Example 4, sodium 3-hydroxypropoxide was used in the reaction instead of sodium methoxide.

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[0167] Example 18 (R,E)-N-(4-((3-chloro-4 -( 3-Fluorobenzyloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-isopropylpyrrolidin-2-yl)acrylamide [ka]

[0168] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used as a raw material instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline, and in step 7), (R,E)-3-(1-isopropylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0169] Example 19. (R,E)-N-(4-((3-chloro-4 -( 3-Fluorobenzyloxy)phenyl)amino)-5-ethoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)acrylamide [ka]

[0170] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline, in step 5) sodium ethoxide was used instead of sodium methoxide, and in step 7) (R,E)-3-(1-ethylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0171] Example 20. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-ethoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)acrylamide [ka]

[0172] The compound was synthesized using the same method as in Example 4, except that in step 5) sodium ethoxide was used instead of sodium methoxide, and in step 7) (R,E)-3-(1-ethylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0173] Example 21. (R,E)-N-(5-ethoxy-4-((3-fluoro-4-(pyridin-2-ylmethoxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0174] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-fluoro-4-(pyridin-2-ylmethoxy)aniline was used instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline, and in step 5) of Example 4, sodium ethoxide was used instead of sodium methoxide in the reaction.

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[0175] Example 22. (R,E)-N-(4-((3-chloro-4-((6-methylpyridin-2-yl)methoxy)phenyl)amino)-5-ethoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0176] The compound was synthesized in the same manner as in Example 4, except that 3-chloro-4-((6-methylpyridin-2-yl)methoxy)aniline was used instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline in step 4) of Example 4, and sodium ethoxide was used instead of sodium methoxide in the reaction in step 5).

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[0177] Example 23. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(4-methoxybutoxy)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0178] The compound was synthesized using the same method as in Example 4, except that in step 5), sodium 4-methoxybutoxide was used in the reaction instead of sodium methoxide.

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[0179] Example 24. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-isopropylpyrrolidin-2-yl)acrylamide [ka]

[0180] The compound was synthesized using the same method as in Example 4, except that in step 7), (R,E)-3-(1-isopropylpyrrolidin-2-yl)acryloyl chloride was used in the same reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0181] Example 25. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acrylamide [ka]

[0182] The compound was synthesized using the same method as in Example 4, except that in step 7), (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0183] Example 26 (R,E)-N-(4-((3-chloro-4-((3-fluorobenzene L) oxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-(2-methoxyethyl) L) Pyrrolidin-2-yl)acrylamide [ka]

[0184] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used as a raw material instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline, and in step 7), (R,E)-3-(1-(2-methoxyethyl)pyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0185] Example 27. (R,E)-N-(4-((3-chloro-4-((6-methoxypyridin-2-yl)methoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0186] The compound was synthesized in the same manner as in Example 4, except that in step 4) of Example 4, 3-chloro-4-((6-methoxypyridin-2-yl)methoxy)aniline was used as a raw material in the reaction instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline.

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[0187] Example 28 (R,E)-N-(4-((3-chloro-4 -( 3-Fluorobenzyloxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)acrylamide [ka]

[0188] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used as a raw material instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline, and in step 7), (R,E)-3-(1-ethylpyrrolidin-2-yl)acryloyl chloride was used in place of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0189] Example 29. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)acrylamide [ka]

[0190] The compound was synthesized using the same method as in Example 4, except that in step 7), (R,E)-3-(1-ethylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0191] Example 30. (R,E)-N-(4-((3-fluoro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0192] The compound was synthesized using the same method as in Example 4, except that in step 4) of Example 4, 3-fluoro-4-(pyridin-2-ylmethoxy)aniline was used in the reaction instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline.

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[0193] Example 31. (R,E)-N-(5-(2-hydroxyethoxy)-4-((4-phenyloxyphenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0194] The compound was synthesized using the same method as in Example 4, except that 4-phenyloxyaniline was used instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline in step 4) of Example 4, and sodium 2-hydroxyethoxide was used in place of sodium methoxide in the reaction in step 5).

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[0195] Example 32. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-((3-methoxypropyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0196] The compound was synthesized in the same manner as in Example 4, except that in step 5), 3-methoxypropylamine was used in the reaction instead of sodium methoxide.

[0197]

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[0198] Example 33. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(methoxy-d3)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0199] In step 5), sodium trideuterated oxide is used instead of sodium methoxide. Meth The compound was synthesized using the same method as in Example 4, except that an oxide was used in the reaction.

[0200]

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[0201] Example 34. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(methoxy-d3)quinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)acrylamide [ka]

[0202] In step 5), sodium trideuterated oxide is used instead of sodium methoxide. MethThe compound was synthesized using the same method as in Example 4, except that (R,E)-3-(1-ethylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride in step 7).

[0203]

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[0204] Example 35. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(methoxy-d3)quinazolin-6-yl)-3-(1-isopropylpyrrolidin-2-yl)acrylamide [ka]

[0205] In step 5), sodium trideuterated oxide is used instead of sodium methoxide. Meth The compound was synthesized using the same method as in Example 4, except that (R,E)-3-(1-isopropylpyrrolidin-2-yl)acryloyl chloride was used in the reaction in place of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride in step 7).

[0206]

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[0207] Example 36. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(methoxy-d3)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide [ka]

[0208] In step 5), sodium trideuterated oxide is used instead of sodium methoxide. Meth The compound was synthesized using the same method as in Example 1, except that an oxide was used in the reaction.

[0209]

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[0210] Example 37. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-cyclopropoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0211] The compound was synthesized using the same method as in Example 4, except that in step 5), sodium cyclopropoxide was used in the reaction instead of sodium methoxide.

[0212]

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[0213] Example 38. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-(cyclopropylmethoxy)quinazolin-6-yl)-3-(1-methylpyrrolidon-2-yl)acrylamide [ka]

[0214] The compound was synthesized in the same manner as in Example 4, except that in step 5), sodium cyclopropyl methoxide was used in the reaction instead of sodium methoxide.

[0215]

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[0216] Example 39. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-cyclobutoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide [ka]

[0217] The compound was synthesized using the same method as in Example 4, except that in step 5), sodium cyclobutoxide was used in the reaction instead of sodium methoxide.

[0218]

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[0219] Example 40. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide [ka]

[0220] The compound was synthesized using the same method as in Example 4, except that in step 5), sodium tetrahydrofuran-3-olate was used in the reaction instead of sodium methoxide.

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[0221] Example 41. (R,E)-N-(4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-5-cyclopropoxyquinazolin-6-yl)-3-(1-methylpyrrolidon-2-yl)acrylamide [ka]

[0222] The compound was synthesized in the same manner as in Example 4, except that 3-chloro-4-((3-fluorobenzyl)oxy)aniline was used instead of 3-chloro-4-(pyridin-2-ylmethoxy)aniline in step 4) of Example 4, and sodium cyclopropoxide was used instead of sodium methoxide in the reaction in step 5).

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[0223] Example 42. (R,E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-3-(1-cyclobutylpyrrolidin-2-yl)acrylamide [ka]

[0224] The compound was synthesized using the same method as in Example 4, except that in step 7) of Example 4, (R,E)-3-(1-cyclobutylpyrrolidin-2-yl)acryloyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0225] Example 43. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(pyrrolidin-1-yl)but-2-enamide [ka]

[0226] The compound was synthesized in the same manner as in Example 4, except that in step 7) of Example 4, (E)-4-(pyrrolidin-1-yl)but-2-enoyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0227] Example 44. (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-5-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide [ka]

[0228] The compound was synthesized in the same manner as in Example 4, except that in step 7) of Example 4, (E)-4-(piperidin-1-yl)but-2-enoyl chloride was used in the reaction instead of (R,E)-3-(1-methylpyrrolidin-2-yl)acryloyl chloride.

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[0229] In order to characterize the biochemical activity, pharmacological properties, etc. of the compounds of the present application, the compounds of the present application, as well as pyrotinib, neratinib, and control compounds 1 and 2, were assayed as follows: Among them, the synthesis of pyrotinib and control compound 2 is described in Chinese patent CN102471312, and control compound 1 is the stereoisomer of the R configuration of control compound 2. [ka]

[0230] Assay example 1. EGFR with small molecule compounds WT and assay for inhibition of HER2 kinase activity Reagents and consumables: ULightTM Labeled Ploy GT Peptide (Perkin Elmer, Cat.No.TRF-0100-M); ULight TM Labeled JAK-1 (Try1023) Peptide (Perkin Elmer, Cat. No. TRF-0121-M); Eu-W1024 labeled Anti-Phosphotyrosine Antibody (PT66) (Perkin Elmer, Cat. No. AD0068); 10× Detection Buffer (Perkin Elmer, Cat. No. CR97-100); Her2 kinase (Carna Biosciences, Cat. No. 08-016); EGFR kinase (Carna Biosciences, Cat. No. 08-115); HEPES (GIBCO, Cat. No. 15630-080); EGTA (Sigma, Cat. No. 03777-10G); EDTA (Sigma, Cat. No. EDS-100G); MgCl2 (Sigma, Cat. No. 63069-100ML); DTT (Sigma, Cat. No. 43816-10ML); Tween-20 (Sigma, Cat. No. P7949-100ML); DMSO (Life Science, Cat. No. 0231-500ML); 384-well plates (Perkin Elmer, Cat. No. 607290); multifunction plate reader (Perkin Elmer, Cat. No. Envision)

[0231] Preparation of compound solutions: Assay compounds were dissolved in DMSO to form a 10 mM stock solution. Prior to use, compounds were diluted to 0.25 mM in DMSO (100 times the final concentration in diluent) and then diluted 3-fold in a gradient to give a total of 11 concentrations. The solution was diluted with buffer to give a dilution 4 times the final concentration at which the compounds were added.

[0232] HER2 Kinase Assay: Prepare a buffer and use this buffer to add 40 nM 4× Her2 Kinase solution, 40 μM 4× ATP solution, and 400 nM 4× ULight TMA labeled Ploy GT Peptide substrate solution was prepared. After preparation was completed, the enzyme was mixed with various concentrations of the compounds previously prepared by dilution, and the mixture was left at room temperature for 5 minutes. Each concentration was performed in duplicate. The corresponding substrate and ATP were added, and the mixture was reacted at room temperature for 120 minutes (negative and positive controls were set). After completion of the reaction, PT66 detection antibody was added. The mixture was incubated at room temperature for 60 minutes, and then detected by Envision.

[0233] EGFR WT Kinase assay: Prepare a buffer and use this buffer to mix 3.48 nM of 4× EGFR kinase solution, 600 μM of 4× ATP solution, and 400 nM of 4× ULight. TM A labeled JAK-1 (Try1023) Peptide substrate solution was prepared. After preparation was completed, the enzyme was mixed with various concentrations of compounds previously prepared by dilution, and the mixture was left at room temperature for 5 minutes. Each concentration was performed in duplicate. The corresponding substrate and ATP were added, and the mixture was reacted at room temperature for 120 minutes (negative and positive controls were set). After completion of the reaction, PT66 detection antibody was added. The mixture was incubated at room temperature for 60 minutes, and then detected by Envision.

[0234] Data Calculation: Well readings and percent inhibition were calculated using Excel, where Well reading=10000*(Well EU665 value) / (Well EU615 value), percent inhibition=[(Positive control well reading-Assay well reading) / (Positive control well reading-Negative control well reading)]*100%. Compound concentrations and corresponding percent inhibition were entered into GraphPad Prism for processing to obtain IC 50 The value was calculated.

[0235] EGFR WT The results of the inhibitory activity assay of the compounds of the present application against HER2 tyrosine kinase are listed in Table 1. In the table, A is the IC 50 is 10 nM or less, and B is the IC 50 is more than 10 nM and less than 100 nM, and C is the IC50 indicates >100 nM to ≤1000 nM, and NT indicates no relevant results.

[0236] [Table 2]

[0237] As can be seen from the results in Table 1 above, all of the compounds of the present application can inhibit both HER2 and EGFR kinase. In particular, against HER2 kinase, the compounds of the present application as a whole exhibit very good inhibitory activity, and can be used for the treatment of tumors and other diseases mediated by HER2 kinase.

[0238] Assay Example 2. Assay for inhibition of cell proliferation by small molecule compounds In this application, the in vitro antiproliferative activity of the compounds of the present disclosure against BT474, NCI-N87, Ba / F3-EGFR-VIII, and Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD cell lines cultured in vitro was investigated by CTG method.

[0239] Reagents and consumables: RPMI1640 (ThermoFisher, Cat. No. C11875500BT); fetal bovine serum (Hyclone, Cat. No. SV30087.03); 0.25% trypsin-EDTA (ThermoFisher, Cat. No. 25200-072); penicillin-streptomycin (Hyclone, Cat. No. SV30010); DMSO (Amresco, Cat. No. 0231-500ML); CTG assay kit (Promega, Cat. No. G924C); 96-well plates (Corning, Cat. No. 3603); multifunction plate reader (Perkin Elmer, Cat. No. Envision)

[0240] Cell lines: BT474 (obtained from the Cell Bank of the Chinese Academy of Sciences), NCI-N87 (obtained from ATCC), Ba / F3-EGFR-VIII, Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD (all obtained from KYinno Biotechnology (Beijing) Co., Ltd.); all of the above cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin during the culture process.

[0241] Specific assay methods:

[0242] 1. Assay compounds were dissolved in DMSO to form stock solutions and gradient dilutions were performed followed by corresponding dilutions with medium to obtain solutions with 5x working concentrations.

[0243] 2. The cells in logarithmic growth phase were diluted with culture medium to a specific cell density, and 80 μL of the cell suspension was added to a 96-well plate, so that the seeding density of the cells of BT474, NCI-N87, Ba / F3-EGFR-VIII, Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD was all 3000 cells / well. The cells of Ba / F3-EGFR-VIII, Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD were used directly in the next step (treatment with compounds), while BT474 and NCI-N87 had to be cultured overnight in a 37°C, 5% carbon dioxide gas incubator to attach to the wall, and then treated with compounds.

[0244] 3. 20 μL of compound solution was added to each well of the 96-well plate inoculated with cells. The highest concentration of compound assayed was 10 μM, with 4-fold serial dilutions, a total of 9 concentrations, and duplicate wells. A compound-free control group was also set up.

[0245] 4. The cells were further cultured for 72 hours, and then the cell viability was detected by CTG assay kit. The signal value was read by a multifunction plate reader (Perkin Elmer). The dose-response curve was generated using GraphPad Prism software, and the IC 50 was calculated.

[0246] The results of the antiproliferative activity assay of representative compounds of the present disclosure against BT474, NCI-N87, Ba / F3-EGFR-VIII, Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD cells are listed in Table 2. In the table, A is IC 50 is 1 nM or less, and B is the IC 50 is greater than 1 nM and less than 5 nM, and C is the IC 50 is greater than 5 nM and less than 10 nM, and D is the IC 50 indicates >10 nM to ≤100 nM, and NT indicates no relevant results.

[0247] [Table 3]

[0248] From the results in Table 2, it can be seen that all the compounds of the present application exhibit excellent antitumor proliferation activity against various cell lines assayed above. In particular, against Ba / F3 HER2 A775-G776sYAMA cells, the compounds of the present application exhibit activity several times, even several tens of times, superior to that of the existing drugs neratinib and pyrotinib.

[0249] Assay Example 3. Pharmacokinetic Assay of Small Molecule Compounds In this assay, the pharmacokinetic properties of several compounds of the present application were assessed following administration to SD rats by single oral dose and intravenous injection.

[0250] (i) Reagents, equipment, and animals used [Table 4]

[0251] [Table 5]

[0252] [Table 6]

[0253] (ii) Preparation of sample formulations 1. Intravenous (IV) injection group: An appropriate amount of assay compound was weighed and completely dissolved in an appropriate amount of vehicle (DMSO / Solutol / H2O=5 / 10 / 85 v / v / v (the vehicle in Example 9 was DMSO / Solutol / H2O=5 / 10 / 85 v / v / v with 2 times molar maleic acid)). The mixture was stirred, vortexed, and / or sonicated. Once a solution was obtained, the vehicle was gradually added to the final volume to reach the target concentration. The solution was vortexed and sonicated to obtain a homogeneous solution. The solution was filtered through a 0.22 μm PVDF membrane.

[0254] 2. Oral (PO) group: An appropriate amount of assay compound was weighed and completely dissolved in an appropriate amount of vehicle (DMSO / Solutol / H2O=5 / 10 / 85 v / v / v (the vehicle in Example 9 was DMSO / Solutol / H2O=5 / 10 / 85 v / v / v with 2 times molar maleic acid)). The mixture was stirred, vortexed, and / or sonicated. Once a solution was obtained, the vehicle was gradually added to the final volume to reach the target concentration. The solution was vortexed and sonicated to obtain a homogenous solution.

[0255] (iii) Dosing and sampling of rats The animals were randomly divided into groups according to body weight, and the weight of the animals in each group after grouping was equivalent (not exceeding ±20% of the mean body weight). Meanwhile, the IV group was not fasted, and the PO group was fasted overnight (>12 hours) and fed 2 hours after drug administration. All animals were given water ad libitum. The dosing schedule and pharmacokinetic sampling schedule are shown in Tables 6 and 7 below, respectively.

[0256] [Table 7]

[0257] [Table 8]

[0258] Rats were dosed according to the above regimen and blood and brain tissue samples were taken and processed at the indicated time points (collection and processing were performed according to conventional methods in the art).

[0259] (iv) Analysis of samples Six volumes of acetonitrile were added to the whole blood samples, and the mixture was vortexed for 1 min and then centrifuged at 4500 rpm for 15 min at 4° C. The supernatant was diluted 2-fold with ultrapure water, and the samples were analyzed by LC / MS.

[0260] Brain tissues were weighed and homogenized by adding 4x homogenization solution (acetonitrile / water = 1 / 1 v / v). Six volumes of acetonitrile were added to each brain tissue homogenate, and the mixture was vortexed for 1 min, then centrifuged at 4500 rpm for 15 min at 4°C. The supernatant was diluted 2x with ultrapure water, and the samples were analyzed by LC / MS.

[0261] (v) Data Analysis: Pharmacokinetic parameters were calculated using WinNonlin software. The following pharmacokinetic parameters were calculated from plasma drug concentration-time data: CL (clearance); V d (apparent volume of distribution);T 1 / 2 (elimination half-life); Cmax (peak concentration); T max (time to peak); AUC (area under the plasma drug concentration-time curve); MRT (mean retention time); F% (bioavailability).

[0262] The results of the assay are shown in Tables 8 to 11 below. Tables 8 to 11 show the values ​​of each pharmacokinetic parameter of pyrotinib, neratinib, control compounds 1 and 2, and some compounds of the present application, both under intravenous injection and oral administration, respectively. The results show that control compounds 1 and 2 are hardly absorbed when orally administered, and effective pharmacokinetic data cannot be obtained because they are not measurable, but all of the compounds of the present application exhibit excellent pharmacokinetic properties and are superior to pyrotinib and neratinib in terms of bioavailability.

[0263] [Table 9]

[0264] [Table 10]

[0265] [Table 11]

[0266] [Table 12]

[0267] Meanwhile, as shown in Table 11-1 below, the compounds of the present application exhibit excellent ability to pass through the blood-brain barrier, and the brain / blood ratio is significantly increased compared with pyrotinib and neratinib. This further indicates that the compounds of the present application not only have excellent inhibitory activity against EGFR and HER2 kinase, but also have excellent ability to pass through the blood-brain barrier, and therefore the compounds of the present application are expected to be applied to related tumors mediated by EGFR and / or HER2 kinase, especially brain metastasis.

[0268] [Table 13]

[0269] Assay Example 4. Assaying the efficacy of small molecule compounds in tumor-bearing mice In this assay, several compounds of the present application were orally administered to a Ba / F3 ERBB2 A775_G776insYVMA tumor-bearing nude mouse model to examine the effect of the compounds of the present application on tumor growth.

[0270] [Table 14]

[0271] [Table 15]

[0272] Reagents: RPMI1640 (ThermoFisher, Cat. No. C11875500BT); Fetal Bovine Serum (Hyclone, Cat. No. SV30087.03); 0.25% Trypsin-EDTA (ThermoFisher, Cat. No. 25200072); Penicillin-Streptomycin (Hyclone, Cat. No. SV30010); DSMO (Life Science, Cat. No. 0231-500ML); Solutol (Sigma, 70142-34-6-1kg)

[0273] Preparation of assay compounds: An appropriate amount of the compound to be assayed was weighed out and completely dissolved in an appropriate amount of vehicle (DMSO). The mixture was vortexed or sonicated. An appropriate amount of Solutol was then added and mixed thoroughly. Finally, sterile drinking water was added and the mixture was mixed by stirring or vortexing to obtain a homogenous solution or suspension.

[0274] Methods: All assays were approved and agreed to by the Animal Welfare Committee. Exponentially growing Ba / F3 ERBB2 A775_G776insYVMA were inoculated into the right back of immunodeficient nude mice (BALB / c nude, female, 6-7 weeks old, weighing 18 ± 2 g) at 4 × 10 6 Cells were inoculated subcutaneously per rat. Tumors were 150–200 mm 3 After the animals had grown to 100 mm Hg, they were randomly divided into treatment and control groups. The treatment groups received a solution of each assay compound, and the control group received a vehicle solution without the assay compound. Both treatment and control groups were dosed once a day for approximately 2 weeks. The dose of each assay product was 30 mg / kg (calculated as the effective compound concentration), and all assay compounds were freshly prepared. During the assay, the diameter of the tumor was measured twice a week, and the body weight of the mice was also measured. Tumor volume (TV) was calculated according to the formula: TV=1 / 2×a×b 2 (wherein a and b refer to length and width, respectively). Based on the measurement results, the relative tumor volume (RTV) was calculated by the formula: RTV=Vt / V0 (wherein V0 is the tumor volume measured at the time of grouping and administration, and Vt is the tumor volume at each measurement). The evaluation index of antitumor activity is the relative tumor growth rate T / C(%) calculated by the formula: T / C(%)=(TRTV / CRTV)×100% (TRTV: RTV of the administration group; CRTV: RTV of the control group). T and C refer to the average tumor volume at a certain time point in the administration group and the control group, respectively.

[0275] The assay results are shown in Table 14 and Figures 1 to 9 below. As shown in the table and figures, neratinib and pyrotinib have a certain tumor inhibitory effect at a dose of 30 mg / kg, and the T / C values ​​on the 14th day are 45.9% and 38.3%, respectively. The compounds of Example 4, Example 8, Example 9, Example 11, Example 24, Example 29, and Example 33 of the present application have a remarkable tumor inhibitory effect at a dose of 30 mg / kg, and the T / C values ​​on the 14th day of the compounds of Example 4 and Example 24 are 2.6% and 12.4%, respectively, the T / C values ​​on the 15th day of the compounds of Example 8, Example 9, and Example 11 are 5.83%, 3.85%, and 5.71%, respectively, and the T / C values ​​on the 11th day of the compounds of Example 29 and Example 33 are 18.7% and 12.4%, respectively. Combined with the results of the above-mentioned Ba / F3 HER2 A775-G776sYAMA cell proliferation activity assay, the compounds of the present application not only have better in vitro antitumor cell proliferation activity against HER2 exon 20 insertion mutation (HER2 A775_G776insYVMA) than pyrotinib and neratinib, but also have much better antitumor activity than neratinib and pyrotinib in Ba / F3 ERBB2 A775_G776insYVMA tumor-bearing nude mouse model. All assayed compounds achieve significant tumor shrinkage, but the tumors in the neratinib group and pyrotinib group still maintain significant growth at the same dose (30mg / kg).

[0276] [Table 16]

[0277] Taking all the assay results together, it can be seen that the present application synthesizes a series of compounds by introducing a substituent at the 5-position of quinazoline and removing the substituent at the 7-position. The compounds of the present application exhibit good to excellent inhibitory activity against HER2 and EGFR kinase, as well as good to excellent inhibitory activity against the proliferation of BT474, NCI-N87, Ba / F3-EGFR-VIII, Ba / F3 HER2 A775_G776insYVMA, and Ba / F3 EGFR D770_N771insSVD cells. In particular, all the compounds of the present application exhibited excellent inhibitory activity against the proliferation of Ba / F3 HER2 A775_G776insYVMA cell model. Vitro Cell proliferation inhibition assay and Bibo In tumor-bearing model assay, the compound of the present application exhibits significantly better effect than neratinib and pyrotinib.In addition, the compound of the present application also shows excellent pharmacokinetic properties in pharmacokinetic assay.The overall performance of the compound of the present application is significantly better than neratinib, pyrotinib, and control compounds 1 and 2, and the compound of the present application can be applied in the treatment of related diseases mediated by HER2, EGFR kinase, or its exon 20 mutation, or other mutations.

[0278] The above embodiments are alternative embodiments of the present disclosure. It should be noted that those skilled in the art can make some improvements and modifications to the embodiments of the present disclosure without departing from the principles of the present disclosure, and these improvements and modifications should also be considered as within the protection scope of the present disclosure.

Claims

1. A compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, [Formula 1] In formula (I), Z is -NH- or -O-; T １ is -(CH ２ ) ｎ - where n is an integer from 0 to 3; R １ is hydrogen, hydroxy, a 4- to 7-membered heteroalicyclic group, or -NR ａ R ｂ and R ａ and R ｂ are each independently hydrogen, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, hydroxy-substituted C １ ~C ６ Alkyl, C １ ~C ３ Alkoxy-substituted C １ ~C ６ Alkyl, or C ３ ~C ６ Cycloalkyl-substituted C １ ~C ６ is alkyl; The 4-7 membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S, and the heteroalicyclic group is １ ~C ３ Alkyl, C １ ~C ４ Alkyl acyl, hydroxy, cyano, amino acyl, mono- or di-substituted C １ ~C ３ Aminoacyl, C １ ~C ３ Alkoxy-substituted C １ ~C ３ Alkyl and hydroxy substituted C １ ~C ３ is unsubstituted or substituted with one or two of alkyl; L is -O-, -S-, or -NH-; R ２ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, Hydroxy Substituted C １ ~C ６ Alkyl, C １ ~C ３ Alkoxy-substituted C １ ~C ６ Alkyl, or -(CH ２ ) m-R ５ and R ５ is C ３ ~C ６ cycloalkyl or a 4-6 membered heteroalicyclic group, m is an integer from 0 to 3; The 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S; T ２ is -M-(CH ２ )p-, wherein M is O, S, or NH, and p is an integer from 0 to 2; R ３ is an aryl or heteroaryl group selected from phenyl, pyridyl, pyrimidinyl, and pyrrolyl, said aryl or heteroaryl being selected from halogen, cyano, hydroxy, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C ３ ~C ４ Cycloalkyl, C ２ ~C ３ Alkynyl, C ２ ~C ３ substituted or unsubstituted with 1 to 3 substituents selected from alkenyl, and -NR'R"; R′ and R″ are each independently H or C １ ~C ３ is alkyl; R ４is hydrogen, halogen, C １ ~C ３ Alkyl, or C １ ~C ３ A compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, which is alkoxy.

2. The compound according to any one of the following claims i) to v): i) Z is -NH-; ii) T 1 is —(CH 2 ) n —, where n is an integer from 0 to 2; R 1 is hydrogen, a 4- to 6-membered heteroalicyclic group, or -NR a R b ; R a and R b are each independently hydrogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, hydroxy-substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl-substituted C 1 -C 3 alkyl; the 4-6 membered heteroalicyclic group is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or thiomorpholinyl, which is unsubstituted or substituted with one or two of methyl, ethyl, propyl, isopropyl, an aldehyde group, acetyl, propionyl, hydroxy, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl; Alternatively, T 1 is —(CH 2 ) n —, where n is 0 or 1; R 1 is dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino, ethylpropylamino, methylcyclopropylamino, ethylcyclopropylamino, propylcyclopropylamino, isopropylcyclopropylamino, methylcyclobutylamino, ethylcyclobutylamino, propylcyclobutylamino, isopropylcyclobutylamino, pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, 1-(2-hydroxypropyl)pyrrolidin-2-yl, piperidin-1-yl, 1-methylpiperazin-4-yl, 1-ethylpiperazin-4-yl, 1-propylpiperazin-4-yl, 1-isopropylpiperazin-4-yl, 1-(2-hydroxyethyl)piperazin-4-yl, morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, or thiomorpholinyl; iii) L is -O- or -NH-; R 2 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy-substituted C 1 -C 4 alkyl, C 1 -C 3 alkoxy-substituted C 1 -C 4 alkyl, or —(CH 2 ) m —R 5 ; R 5 is a C 3 -C 6 cycloalkyl or a 4-6 membered heteroalicyclic group; m is 0, 1, or 2; the 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S; Alternatively, L is -O-; R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, tetrahydrofuran-2-yl, or tetrahydrofuran-3-yl; iv) T 2 is —O—(CH 2 )p-, where p is 0 or 1; R 3 is phenyl, pyridyl, or pyrimidyl, said phenyl, pyridyl, and pyrimidyl being unsubstituted or substituted with 1 to 2 substituents selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyano, hydroxy, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 2,2-difluoroethyl; Alternatively, T 2 is —O—(CH 2 )p-, where p is 1; R 3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 5-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 3-methylpyridin-2-yl, 3-methoxypyridin-2-yl, 6-fluoropyridin-2-yl, or 6-chloropyridin-2-yl; v) R 4 is hydrogen, fluorine, chlorine, methyl, or methoxy; Alternatively, R 4 is hydrogen, fluorine, or chlorine.

2. The compound of claim 1, its stereoisomer, its pharma- ceutically acceptable salt, or its deuterated derivative, having one or more of:

3. The compound has the following structural formula: [Case 2] R １ is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or thiomorpholinyl, which is unsubstituted or substituted with one or two of methyl, ethyl, propyl, isopropyl, an aldehyde group, acetyl, propionyl, hydroxy, cyano, aminoacyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, isopropoxypropyl, hydroxymethyl, hydroxyethyl, and hydroxypropyl; R ２ But, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, Hydroxy Substituted C １ ~C ４ Alkyl, C １ ~C ３ Alkoxy-substituted C １ ~C ４ Alkyl, or -(CH ２ ) m-R ５ and R ５ But, C ３ ~C ６ cycloalkyl or a 4-6 membered heteroalicyclic group, m is 0, 1, or 2; the 4-6 membered heteroalicyclic group is a heteroalicyclic group containing 1 to 2 heteroatoms selected from N, O, and S; R ３ is phenyl, pyridyl, or pyrimidyl, said phenyl, pyridyl, and pyrimidyl being unsubstituted or substituted with 1 to 2 substituents selected from fluorine, chlorine, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyano, hydroxy, fluoromethyl, 2-fluoroethyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 2,2-difluoroethyl; R ４ is hydrogen, fluorine, chlorine, methyl, or methoxy; Alternatively, R 1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, or 1-(2-hydroxypropyl)pyrrolidin-2-yl; R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, or ethoxybutyl; R 3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-2-yl, 6-methoxypyridin-2-yl, 5-methylpyridin-2-yl, 5-methoxypyridin-2-yl, 4-methylpyridin-2-yl, 4-methoxypyridin-2-yl, 3-methylpyridin-2-yl, 3-methoxypyridin-2-yl, 6-fluoropyridin-2-yl, or 6-chloropyridin-2-yl; R 4 is fluorine or chlorine; Alternatively, R 1 is pyrrolidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, 1-propylpyrrolidin-2-yl, 1-isopropylpyrrolidin-2-yl, 1-(2-methoxyethyl)pyrrolidin-2-yl, 1-(2-methoxypropyl)pyrrolidin-2-yl, 1-(2-ethoxyethyl)pyrrolidin-2-yl, 1-(2-ethoxypropyl)pyrrolidin-2-yl, 1-(2-hydroxymethyl)pyrrolidin-2-yl, 1-(2-hydroxyethyl)pyrrolidin-2-yl, or 1-(2-hydroxypropyl)pyrrolidin-2-yl; R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 3,3-difluoropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, or ethoxybutyl; R 3 is pyridin-2-yl; R 4 is chlorine; Alternatively, R 1 is 1-methylpyrrolidin-2-yl, 1-ethylpyrrolidin-2-yl, or 1-isopropylpyrrolidin-2-yl; R 2 is methyl, ethyl, propyl, methoxyethyl, methoxypropyl, or 2,2-difluoroethyl; R 3 is pyridin-2-yl; 2. The compound of claim 1, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, wherein R4 is chlorine.

4. The compound is selected from the group consisting of: [C3] [C4] [C5] 2. The compound of claim 1 , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, selected from:

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, and one or more pharma- ceutically acceptable carriers or excipients, Optionally, the pharmaceutical composition further comprises one or more other therapeutic agents.

6. A pharmaceutical composition for the treatment of a disease, comprising a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, or a deuterated derivative thereof, the disease is a disease associated with the tyrosine kinase HER2; Alternatively, the disease is a disease associated with a mutation in exon 20 of the tyrosine kinase HER2; Alternatively, The pharmaceutical composition, wherein the disease is cancer or an autoimmune disease, in particular, ocular fundus disease, xerophthalmia, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, bile duct carcinosarcoma, or bile duct carcinoma.

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