Novel skeletal derivatives effective for HER2 mutations and pharmaceutical compositions comprising same

Abstract

Compounds as defined in Chemical Formula 1, stereoisomers thereof, tautomers thereof, and pharmaceutically acceptable salts thereof are provided. The compound provided by the invention can inhibit the activity of HER2 kinase. In Chemical Formula 1, R1 to R3, A1 to A4, L1, E, Z and n are the same as those defined in the specification. [Chemical Formula 1]

Description

Technical Field

[0001] This disclosure relates to novel compounds that effectively inhibit the kinase activity of tumors carrying HER2 gene mutations. This disclosure also relates to antitumor pharmaceutical compositions comprising said novel compounds. Background Technology

[0002] Epidermal growth factor receptor (EGFR) is a protein composed of a receptor domain and a tyrosine kinase domain, which plays a role in transducing extracellular signals across the cell membrane into the cell. The EGFR / ERBB protein family includes EGFR and other tyrosine kinases structurally homologous to EGFR; more specifically, it includes four members: EGFR (ERBB1), HER2 (Neu, ERBB2), HER3 (ERBB3), and HER4 (ERBB4). EGFR family kinases play important roles in the development of organisms, participating in various signal transduction processes, such as cell growth and angiogenesis, by forming heteromultimers among family members. EGFR family proteins have been reported to be overexpressed or undergo frequent mutations in most solid tumor cell types, which is associated with poor prognosis. Such HER2 gene variants or mutations, such as insertions in exon 20 of the tyrosine kinase domains of EGFR and HER2, can help EGFR or HER2 escape normal activation control. It is now known that the activation caused by this type of mutation is a major cause of various cancers, including non-small cell lung cancer. Exon 20 insertion is the third most common type of EGFR mutation in non-small cell lung cancer. A representative HER2 exon 20 insertion is A775_G776insYVMA, which accounts for approximately 85% of all HER2 mutations.

[0003] Because we know very little about cancers carrying these mutations and unresponsive to EGFR inhibitors, effective targeted chemotherapy for these cancers remains to be achieved. There is still a need to develop a targeted chemotherapeutic agent that possesses strong anti-tumor activity against EGFR gene mutations with minimal side effects.

[0004] Related existing technologies

[0005] Yu et al., Clinical cancer research ( Clinical Cancer Research ), 19(8), 2013, pp. 2240-2247

[0006] Technical issues

[0007] The technical objective of this invention is to provide novel compounds capable of inhibiting the activity of HER2 kinase with genetic mutations. Furthermore, the technical objective of this invention is to provide selective inhibitory compounds that more strongly inhibit HER2 with genetic mutations than wild-type EGFR. Summary of the Invention

[0008] This article provides a compound defined by Formula 1, or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0009] [Chemical Formula 1]

[0010] In chemical formula 1, A 1 With A 3 Each is independently N or CH, and A 2 With A 4 Each is independent of the other as N or CR a , where R a For H, CN, C 1-4 Alkyl or C 1-4 Alkyl group. R 1 C 1-4 Alkyl, C 1-4 Alkyl groups, CF3, or halogens. R 2 It is a six- to five-membered fused bicyclic heteroaryl or a six- to six-membered fused bicyclic heteroaryl. Optionally, in the six- to five-membered fused bicyclic heteroaryl or the six- to six-membered fused bicyclic heteroaryl, one or more hydrogen atoms can be independently selected from halogens, carbon atoms ... 1-4 Alkyl and C 1-4 Functional group substitution in alkoxy groups. In a specific embodiment, R 2 It is selected from the group consisting of fused bicyclic heteroaryl substituents:

[0011] Where T is H or C 1-4 Alkyl group. Each R 3 Halogen and C are independent of each other. 1-4 Alkoxy or C 1-4 Alkyl group, where n is an integer from 0 to 3. L 1 for

[0012] -CH=CH-M、-CH=CHQ 1 M、-NR b Q 1 M、-OQ 1 M、-S(=O)2Q 1 M、-N(Q 2 )C(=O)Q1 M、-C(=O)N(Q 2 )Q 1 M, -C≡CM or -C≡CQ 1 M, where Q 1 C 1-3 Alkylene, Q 2 For H or C 1-3 Alkyl, R b For H or C 1-3 Alkyl group, where M is a single bond attached to the functional group E. E is... or -NR c -, J represents a single bond attached to the carbonyl group in formula 1 –C(=O)CH=CHZ. R in this text... c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, where Z is H or C 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e Independently H or C 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is wherein one or more hydrogen atoms in the corresponding unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

[0013] In embodiments herein, compounds having a structure as defined in Formula 2, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof are provided.

[0014] [Chemical Formula 2]

[0015] Where R 4 for Each R 5 They are halogens or C independently of each other. 1-4 Alkoxy group, n is an integer from 0 to 3, and R a For H, C 1-4 Alkyl or C 1-4 Alkoxy group. L 2 for -CH=CH-M、-CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M. A3 E, Z, T, Q 1 and R b The definition is the same as that in the aforementioned chemical formula 1, where M represents the carbon group to which the corresponding carbon is attached via a single bond to C(=O)CH=CHZ.

[0016] In specific embodiments herein, compounds having the structure as defined in Formula 3, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, are provided: [Chemical Formula 3]

[0017] Where A 3 R 4 R 5 The definition of Z is the same as that in the aforementioned chemical formula 2, and L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, and G is -NR c -、 The R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein J is a single bond attached to a carbonyl group of –C(=O)CH=CHZ.

[0018] In another specific embodiment of this document, compounds having the structure as defined in Formula 4, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, are provided: [Chemical Formula 4]

[0019] Where L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, M is connected to the functional group CH2=CHC(=O)NR c The single bond, and R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl. R 6 With R 7 H or F, Q, independent of each other. 1 and R b The definition is the same as that in the aforementioned chemical formula 1.

[0020] In another aspect of this document, a pharmaceutical composition for treating cancer is provided, the pharmaceutical composition comprising a therapeutically effective amount of the above-described compound or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0021] In another aspect of this document, a method for treating cancer is provided. This method includes administering to a subject a therapeutically effective amount of a compound of the present invention (e.g., a compound defined by Chemical Formula 1) or a pharmaceutical composition comprising a compound of the present invention.

[0022] [Beneficial Effects]

[0023] The compounds of the present invention can inhibit the kinase activity of HER2, particularly those HER2 carrying gene mutations. In a specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying gene mutations in exon 20. In a more specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying exon 20 insertions. In the most specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying exon 20 insertions more strongly than wild-type EGFR. Detailed Implementation

[0024] Examples of certain embodiments will now be shown in detail herein with reference to certain embodiments. First, it should be noted that the meanings of the terms or phrases used in this disclosure and / or the claims are not limited to their ordinary or dictionary meanings, but should be interpreted in accordance with the technical concept of the invention, with the principle that the inventor can act as his own lexicographer.

[0025] Although working examples will be described herein, it should be understood that these working examples are intended to provide a better understanding of the invention. Since these working examples are not intended to constitute or represent the entirety of the technical concept of the invention, those skilled in the art will recognize that many equivalent or modified forms can be made to the working examples, and that such equivalent or modified forms also fall within the scope of the invention.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. This disclosure describes exemplary methods and / or materials, but similar or equivalent methods and / or materials are also fully covered by this invention. Even if the term "about" is not present, any numerical value used herein should be understood to be preceded by the term "about". Any numerical range used herein includes both a starting value and an ending value, serving as the minimum and maximum values ​​defining the boundaries of the numerical range, respectively.

[0027] Mutations in HER2 and its exon 20

[0028] HER2 (also known as ERBB2) is an abbreviation for Human Epidermal Growth Factor Receptor Protein 2. HER2 is a member of the EGFR / ErbB protein family and possesses tyrosine kinase activity. The wild-type messenger RNA sequence of HER2 has the GenBank accession number NM_004448.2. HER2 gene variations can be broadly classified into gene amplification, protein overexpression, and gene mutation. HER2 gene amplification refers to a state in which the HER2 gene has more copies than normal, leading to HER2 protein overexpression. HER2 protein overexpression is a phenomenon caused by factors such as HER2 gene amplification, in which abnormally large copies of the HER2 protein are present on the cell surface, which can lead to abnormal growth and metastasis of tumor cells. HER2 gene mutation refers to variations occurring in the DNA sequence of the HER2 gene itself, which can modify the function of the HER2 protein. HER2 gene mutations have been found in breast cancer, lung cancer, bladder cancer, and ovarian cancer. Among the mutations in HER2, there is one called exon 20 insertion, in which a nucleotide is added to the wild-type sequence at exon 20 of HER2.

[0029] As used in this article, the term "gene variation" or simply "variation" encompasses gene mutations in which the base sequence of the corresponding gene deviates from that of the wild-type gene, and in which the gene deviates from the wild-type regulatory control, such as overexpression of the corresponding gene and gene amplification.

[0030] As used herein, the terms “insertion mutation,” “insertion,” or “insertion mutant” refer to the addition of one or more nucleotide pairs to a DNA sequence or a resulting sequence. For example, an insertion into exon 20 of HER2 refers to any mutation in HER2 DNA that involves the addition of at least one nucleotide of a length ranging from 3 to 18 nucleotides at the region corresponding to residues numbered 770 to 785 in the amino acid sequence.

[0031] HER2 exon 20 mutations and HER2 exon 20 mutants can include one or more mutations such as point mutations between residues 770 and 785 in the amino acid sequence of HER2, additions of 3 to 18 nucleotides, and / or deletions. Such one or more HER2 exon 20 mutations can occur at residues Ala775, Gly776, Ser779, and / or Pro780. These one or more HER2 exon 20 mutations can be A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776CV777insC, G776del insVV, G776del insVC, and / or P780insGSP.

[0032] As used herein, the terms "selective inhibition" or "selectively inhibited" mean that the compounds of the present invention cause a greater decrease in the signaling activity of a kinase (the biological target of the compounds of the present invention) than in the signaling activity of a non-target kinase, and this decrease is achieved through direct or indirect interaction with the target. For example, compounds that selectively inhibit exon 20 mutant HER2 relative to wild-type EGFR have at least about two times (or at least about three times, about five times, about ten times, or about fifty times) greater activity against exon 20 mutant isotypes than against wild-type EGFR isotypes.

[0033] definition

[0034] The prefix "C" placed before a functional group in this article x-y "or "C x To C y "" refers to the number of carbon atoms present in the main framework of the functional group. For example, C 1-4 Alkyl groups refer to alkyl groups having one to four carbon atoms, C 1-3 Alkyl refers to an alkyl group having one to three carbon atoms. For example, C1 to C4 alkoxy groups may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy. For example, C3 to C6 cycloalkyl groups may include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Furthermore, for cyclic functional groups or cyclic compounds (including both carbocyclic and heterocyclic groups) with a name preceding it that defines the number of atoms constituting the relevant ring, such cyclic functional groups or compounds are understood herein to have the defined number of atoms, i.e., carbon atoms and / or heteroatoms. For example, a 6-membered heteroaryl group refers to a heteroaryl ring containing one or more heteroatoms in addition to carbon atoms, giving it a six-atom ring constituting a heteroaryl ring.

[0035] Unless otherwise stated herein, when a functional group is referred to as being linked to another part of the compound via a bond, the link can be present at any suitable atom of the functional group. For example, propyl can refer to both propyl-1-yl and propyl-2-yl.

[0036] The term "halogen" as used in this article refers to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.

[0037] The term "C" as used in this article 1-4 "Alkyl" refers to a chemical formula of C n H 2n+1 A monovalent saturated hydrocarbon free radical, where n is a natural number from 1 to 4. C 1-4 Alkyl groups encompass every type of saturated hydrocarbon with a straight or branched chain having 1 to 4 carbon atoms, such as n-propyl, isopropyl, sec-butyl, and tert-butyl.

[0038] The term "C" as used in this article 1-3 "alkylene" refers to a chemical formula of C n H 2n A divalent saturated hydrocarbon free radical, where n is a natural number from 1 to 3. In this disclosure, it is referred to as C. 1-3 The functional groups of alkylene groups can be straight-chain or branched, and the two valence bonds mentioned above can be located at the same carbon atom or at different carbon atoms. C 1-3 Examples of alkylene groups include methylene, ethylene (-CH2CH2- and -CH(CH3)-), and propylene (-CH2CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, and -C(CH3)2-).

[0039] The term "cycloalkyl" as used in this article refers to a ring-shaped compound having the chemical formula C10. n H 2n-1 Monovalent saturated hydrocarbon free radicals. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0040] As used herein, the term "bicyclic" compound refers to a carbon ring or heterocycle in which two rings are formed, wherein the two constituent rings share one or more ring atoms between them. The shared atom between the two rings in a bicyclic compound is called a bridgehead atom. Based on the number of bridgehead atoms and whether there is a direct connection between them, there are three classes of bicyclic compounds. Fused bicyclic compounds have two bridgehead atoms directly connected to each other by bonds. Examples of fused bicyclic compounds include decahydronaphthalene, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. Bicyclic compounds having only a single bridgehead carbon are called spirobicyclic compounds. Bridged bicyclic compounds have two bridgehead atoms that are not directly connected to each other by bonds but have one or more intermediate ring atoms between them. Examples of bridged bicyclic compounds include norbornane, 7-oxabicyclo[2.2.1]heptane, and adamantane.

[0041] In this disclosure, fused bicyclic compounds can be designated by indicating the number of constituent ring atoms in each ring. For example, thienopyridine, benzofuran, and indole are six- to five-membered fused bicyclic compounds. Similarly, purine, naphthalene, dihydrobenzopiperanone (chromane), tetrahydroquinoline, quinoline, quinoxaline, and pteridine are six- to six-membered fused bicyclic compounds.

[0042] The term "aryl" as used in this article refers to an aromatic ring having one to three aromatic rings with a monovalent C24. 6-14 Hydrocarbon functional groups. For example, aryl groups are those with C6, C7, and C8 rings in aromatic hydrocarbons. 10 C 13 and C 14 Free radicals, such as phenyl, naphthyl, anthracene, and fluorene.

[0043] As used herein, the term "heteroaryl" refers to a monovalent unsaturated ring having carbon as a ring atom and one or more heteroatoms selected from nitrogen, oxygen, and sulfur, said monovalent unsaturated ring having aromatic properties. The ring system in a heteroaryl can be monocyclic, fused bicyclic, or tricyclic. In this disclosure, the term heterocyclic does not include rings in which the oxygen and sulfur atoms within the ring atoms are directly bonded (e.g., -OO-, -OS-, and -SS-). Limited examples of heteroaryl include pyrroleyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, triazolyl, quinazolinyl, 2-furanyl, 3-furanyl, benzofuranyl, 2-thienyl, oxazolyl, isothiazolyl, and thiadiazolyl. In this disclosure, heteroaryl can be referred to by specifying the heteroatom. For example, heteroaryl groups with nitrogen as a heteroatom include pyrrole, imidazolyl, pyrazolyl and 2-pyridyl, but do not include furanyl, oxazolyl and thiophene.

[0044] Fused bicyclic heteroaryl groups include: as (6+5) fused bicyclic heteroaryl groups, benzimidazolyl, benzofuranyl, benzothiophenyl, isoindolyl, inzolyl, imidazopyridyl, imidazopyrimidyl, imidazopyridyl, pyrazolylpyridyl, pyrrolopyrimidyl, pyrrolopyridyl, pyrrolopyrazinyl, triazolylpyridyl, triazolylpyrimidyl, furanyl, benzoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, anthranilyl, benzoisothiazolyl, benzopyrazolyl, and benzothiadiazolyl; as six-membered to six-membered fused bicyclic heteroaryl groups, benzopyridyl, benzopyrimidyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, quinazinyl, and cenolinyl.

[0045] As used herein, the term "heterocyclic alkyl" refers to a monovalent radical obtained by substituting at least one carbon atom on a cycloalkyl ring with a heteroatom selected from oxygen, nitrogen, and sulfur, each substitution example being independent of the others. Examples of heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, piperidinyl, piperazineyl, morpholinyl, and tetrahydrothiazolyl.

[0046] Unless otherwise stated, the term "substituted" as used herein, preceding a functional group, refers to a structure resulting from that functional group by substituting one or more hydrogen atoms with a specified non-hydrogen functional group, provided that such substitution produces a chemically stable functional group with a normal valence. Typically, the functional group used for substitution is selected from halogens, CN, OH, C... 1-6 Alkyl, C 3-6 cycloalkyl, C 3-14 heteroaryl, C 1-6 Alkyl groups and CF3.

[0047] In this disclosure, the label “…” is attached to an atom in a functional group that is part of a compound. "" indicates that the functional group is directly connected to the rest of the compound through a chemical bond with the atom.

[0048] In this disclosure, the dashed line "---" placed within the lines representing chemical bonds indicates that the specific line of the chemical bond is an optional element that may or may not be present. For example, such as The notation indicates that this structural formula can represent both benzene and 1,3-cyclohexadiene.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to salts suitable for contact with human or animal tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and without harmfully affecting the beneficial biological activity of the compound. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., in […], […]. medicine Learning impurities ( J. Pharmaceutical Sciences (1977) 66: Pages 1-19 elaborate on pharmaceutically acceptable salts. Non-limiting examples of pharmaceutically acceptable salts include acid addition salts formed from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, and hydrogen sulfate, as well as, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium [N] + (C 1-4 Alkali addition salts such as alkyl(4) salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.

[0050] Those skilled in the art will recognize that some compounds of the present invention can exist as tautomers. Since a structural formula can only depict one possible tautomer, it should be noted that even if a single structural formula is used to represent a compound for convenience, all tautomer forms of the compound are contemplated to be within the scope of the present invention. Depending on the compound, one of the many tautomer forms may be dominant, or the compound may exist at room temperature as a mixture of multiple tautomer forms from which a specific tautomer form can be isolated. Examples of tautomer forms include pyridone forms versus hydroxypyridine forms and ketone forms versus enol forms.

[0051] compound

[0052] In one aspect, the present invention provides compounds as defined by Formula 1, their tautomers, their stereoisomers, or their pharmaceutically acceptable salts.

[0053] [Chemical Formula 1]

[0054] In chemical formula 1, A 1 With A 3 They are either N or CH, independent of each other. In chemical formula 1, A 2 With A 4 Each is independent of the other as N or CR a , wherein R a For H, CN, C 1-4 Alkyl or C 1-4 Alkyl group.

[0055] In chemical formula 1, R 1 C 1-4 Alkyl, C 1-4 Alkyl groups, CF3, or halogens.

[0056] R in chemical formula 1 2It is a six- to five-membered fused bicyclic heteroaryl or a six- to six-membered fused bicyclic heteroaryl, wherein in the six- to five-membered fused bicyclic heteroaryl or the six- to six-membered fused bicyclic heteroaryl, one or more hydrogen atoms can be independently selected from halogens, C 1-4 Alkyl and C 1-4 Functional group substitution in alkoxy groups.

[0057] Each R in the compound of chemical formula 1 3 Independent of halogen, C 1-4 Alkoxy or C 1-4 Alkyl group, where n is an integer from 0 to 3.

[0058] In compounds of chemical formula 1, L 1 The substituents are selected from the following divalent substituents: -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M、-OQ 1 M、-S(=O)2Q 1 M,

[0059] -N(Q 2 )C(=O)Q 1 M、-C(=O)N(Q 2 )Q 1 M, -C≡CM and -C≡CQ 1 M, where Q 1 C 1-3 Alkylene, Q 2 For H or C 1-3 Alkyl, R b For H or C 1-3 Alkyl group, where M is a single bond attached to the functional group E. In other words, it represents the presence of a divalent substituent L. 1 -CH=CHQ 1 In the case of M, -CH=CHQ 1 M is bonded to Q 1 The carbon atom of the vinyl group is attached to the functional group E of Formula 1, and the "-" symbol indicates a direct attachment in the opposite direction to the functional group E, meaning that another carbon atom in the vinyl group is directly attached to the fused bicyclic ring of Formula 1. Similarly, it indicates that when L 1 for At that time, this specific L using the M tag 1 The carbon in the carbon atom is directly linked to the functional group E via a single bond, and utilizes " The labeled vinyl carbon is directly attached to the compound of Formula 1 in the opposite direction to the functional group E, that is, attached to the fused bicyclic ring of Formula 1.

[0060] In chemical formula 1, E is selected from the following divalent functional groups: and -NRc-; Where R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl groups. J and " in the divalent functional group E "Compared with the above for the divalent functional group L..." 1 The similarity refers to the J-labeled carbon in Formula 1 being directly bonded to the functional group –C(=O)CH=CHZ via a single bond, while the use of " The labeled cyclic carbon is directly attached to the compound of formula 1 in the opposite direction to the functional group –C(=O)CH=CHZ, i.e., it is attached to L. 1 .

[0061] In compounds of chemical formula 1, Z represents H or C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e Independently H or C 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

[0062] In a specific embodiment of the compound of chemical formula 1, A 1 To A 4 At least one of them is nitrogen. In another specific embodiment of the compound of formula 1, L 1 -CH=CH-Q 1 Q 1 It is CH2 or -CH(CH3)-, and E is -NR. c - and Z is H. In yet another specific embodiment, L 1 -CH≡CH-Q 1 Q 1 It is CH2, and E is -NR c -

[0063] In yet another specific embodiment, R of chemical formula 1 2 Selected from the group consisting of fused bicyclic heteroaryl groups: Where T is H or C 1-4 Alkyl group. The marking here is " "" indicates that the carbon atom marked with it is directly connected to the rest of the compound via a single bond, i.e., connected to part of the OR. 2 Oxygen atoms.

[0064] In a more specific embodiment, the compounds of the present invention according to Chemical Formula 1 Selected from the following functional groups: The mark here is " "" indicates that the corresponding nitrogen atom is directly connected to the rest of the compound through a single bond, that is, connected to the part containing A. 1 To A 3 A mixed double ring.

[0065] In yet another specific embodiment, L in the compound of the present invention according to chemical formula 1 1 The -EC(=O)CH=CHZ part is selected from the following functional groups:

[0066] Similar to the above, the marker here is " "Indicates in the relevant L" 1 The -EC(=O)CH=CHZ part utilizes The labeled atoms are directly bonded to the rest of the compound of formula 1 via single bonds, that is, to the part containing A. 1 To A 3 A mixed double ring.

[0067] In the embodiments, the compounds of the present invention have the structure shown in Chemical Formula 2.

[0068] [Chemical Formula 2]

[0069] R in the compound of chemical formula 2 4 Selected from the following heterobicyclic substituents: .

[0070] Here, T is either H or C. 1-4 alkyl.

[0071] Each R in the compound of chemical formula 2 5 They are halogens or C independently of each other. 1-4 Alkoxy group, and n is an integer from 0 to 3.

[0072] A in compound with chemical formula 2 3 It is N or CH, and R a For H, C 1-4 Alkyl or C 1-4 Alkyl group.

[0073] L in chemical formula 2 2 The following are selected from divalent functional groups: CH=CH-M、-CH=CHQ 1 M、-NR b Q 1 M and -OQ 1 M, where Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group. L 2 M and " "Compared with the above for the divalent functional group L..." 1 Similarly, in Formula 2, the carbon labeled with M is directly linked to the functional group E via a single bond, while the carbon labeled with " The labeled ring carbon is directly attached to the compound of formula 2 in the opposite direction to the functional group E, that is, it is connected to the compound containing A through a single bond. 3 A mixed double ring.

[0074] Similar to E in Formula 1, E in Formula 2 is a divalent functional group selected from the following:

[0075] and -NR c -, where R c Same as the definition in Chemical Formula 1, consisting of H and C. 1-4 Alkyl or C 3-6 Cycloalkyl, and J is a single bond attached to a carbonyl group of –C(=O)CH=CHZ.

[0076] Similar to Z in chemical formula 1, Z in chemical formula 2 is H or C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e Independently H or C 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

[0077] In the specific embodiment of the compound of chemical formula 2, A 3 Let N be the number of elements in the array.

[0078] In another specific embodiment of the compound of chemical formula 2, R 5 It is fluorine (F).

[0079] In yet another specific embodiment, Z is H, CH3, Or -CH2N(CH3)2.

[0080] In another embodiment, the compound of the present invention has the structure of chemical formula 3: [Chemical Formula 3]

[0081] Where R 4 for The T is H or C 1-4 alkyl.

[0082] Each R 5 Each element is a halogen, and n is an integer from 0 to 3.

[0083] A 3 It can be N or CH.

[0084] L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, where Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group, and M is a single bond attached to the functional group G.

[0085] G is -NR c -、 The R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein J is a single bond attached to a carbonyl group of –C(=O)CH=CHZ.

[0086] Z represents H and C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e Independently H or C 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

[0087] In a more specific embodiment, the compound of the present invention has -NR c -、 As G in chemical formula 3.

[0088] In another embodiment, the compound of the present invention has the structure of chemical formula 4: [Chemical Formula 4]

[0089] Where L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, the Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group, and M is attached to the functional group CH2=CHC(=O)NR c A single key.

[0090] R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, and R 6 With R 7 They are H or F, independent of each other.

[0091] In a more specific embodiment, the compound of formula 4 has a methyl group as R. c .

[0092] In another embodiment, the compound of the present invention has the structure shown in Chemical Formula 5: [Chemical Formula 5]

[0093] Where A 1 With A 3 Each is independently N or CH, and A 2 For N or CR a The R a For H, C 1-4 Alkyl or C 1-4 Alkyl group.

[0094] R in compounds with chemical formula 5 2a Selected from the following heterobicyclic substituents: Where T is H or C 1-4 alkyl.

[0095] In compounds of formula 5, each R'' is independently a halogen, and n is an integer from 0 to 3. In compounds of formula 5, m is an integer from 1 to 3.

[0096] Similar to Z in chemical formula 1, Z in chemical formula 5 is H or C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e Independently H or C 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is a corresponding unsubstituted 5- to 6-membered heterocyclic alkyl ring in which one or more hydrogen atoms are independently selected from C1 and C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

[0097] In a specific embodiment, the compound of chemical formula 5 has As R 2a .

[0098] In another specific embodiment, the compound of formula 5 has CH as an A 1 And has N as A 3 .

[0099] In the most specific embodiment, the compounds of the present invention are selected from the following compounds or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof: (1) N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)- N -Methacrylamide, (2) N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)ethyl)- N -Methacrylamide, (3) N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)oxy)ethyl)-N -Methacrylamide, (4) N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)oxy)ethyl)- N -Methacrylamide, (5) N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide, (6) N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)ethyl)acrylamide, (7) N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)ethyl)acrylamide, (8) N -methyl- N -(2-((8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)oxy)ethyl)acrylamide, (9) N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)propyl)acrylamide, (10) N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide, (11) N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)amino)ethyl)- N -Methacrylamide, (12) N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)amino)ethyl)- N -Methacrylamide, (13) N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)(methyl)amino)ethyl)- N -Methacrylamide, (14) N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)(methyl)amino)ethyl)- N -Methacrylamide, (15) N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)ethyl)acrylamide, (16) N -methyl- N -(2-((8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)amino)ethyl)acrylamide, (17) N-methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)propyl)acrylamide, (18) N -methyl- N -(2-(methyl(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)ethyl)acrylamide, (19) N -methyl- N -(2-(methyl(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)amino)ethyl)acrylamide, (20) N -methyl- N -(3-(methyl(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)propyl)acrylamide, (twenty one) N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)-2-oxoethyl)acrylamide, (twenty two)( E )- N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide, (twenty three)( E )- N -methyl- N-(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)aryl)acrylamide, (twenty four)( E )- N -methyl- N -(3-(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)allyl)acrylamide, (25) E )- N -(3-(4-((3-chloro-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (26) E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-4-en-1-yl)acrylamide, (27) E )-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)piperidin-1-yl)prop-2-en-1-one, (28) E )-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)azacyclobutane-1-yl)prop-2-en-1-one, (29) E)-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)pyrrolidone-1-yl)prop-2-en-1-one, (30) E )- N -methyl- N -(1-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)cyclopropyl)acrylamide, (31) E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, (32) E )-4-(dimethylamino)- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, (33) E )- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyridin-6-yl)allyl)acrylamide, (34) E )- N -(3-(4-((3-methyl-4-((3-methyl-3) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- dPyrimidin-6-yl)allyl)acrylamide, (35) E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, (36) E )- N -(3-(4-((2-chloro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, (37) E )- N -(3-(4-((3-methyl-4-(pyrazolo[1,5-) a ]pyridin-5-yloxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (38) E )- N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (39) E )- N -(3-(4-((4-(imidazo[1,2- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (40) E )-4-(dimethylamino)- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1H-benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, (41) E )-4-(dimethylamino)- N -(( E)-3-(4-((2-fluoro-3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, (42) E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (43) E )- N -methyl- N -(3-(4-((3-methyl-4-((3-methyl-3) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (44) E )- N -methyl- N -(3-(4-((3-methyl-4-((3-methyl-3H-imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (45) E )- N -(3-(4-((2-fluoro-5-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (46) E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (47) E )- N -(3-(4-((2-fluoro-3-methyl-4-((3-methyl-3-) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (48) E )-1-(3-(2-(4-((3-methyl-4-((2-methyl-2) H -indazole-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)vinyl)azacyclobutane-1-yl)prop-2-en-1-one, (49) E )- N -Ethyl- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, (50) E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, (51) S , E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, (52) R , E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d[Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, (53) E )- N -(Terbutyric)- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, (54) E )- N -(3-(4-((2-methoxy-5-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (55) E )- N -(3-(4-((3-fluoro-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (56) E )- N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-ylmethyl)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (57) E )- N -(3-(4-((4-(benzo[ d [Oxazol-5-yloxy)-3-methylphenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, (58) E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)-3-(( R 1-Methylpyrrolidone-2-yl)acrylamide, (59) E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-(piperidin-1-yl)but-2-enamide, (60) E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-morpholinobut-2-enamide, (61) E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-(piperidin-1-yl)but-2-enamide, (62) E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-morpholinobut-2-enamide, (63) E )- N -methyl- N -(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d[Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)phenyl)acrylamide, (64) E )- N -(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)phenyl)acrylamide, (65) N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (66) N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[2,3- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (67) N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (68) N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (69) N -(3-(8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)prop-2-yn-1-yl)- N -Methacrylamide, (70) N-(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanoquinoline-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (71) N -methyl- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)prop-2-yn-1-yl)acrylamide, (72) N -methyl- N -(3-(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[5,4-] d Pyrimidin-2-yl)prop-2-yn-1-yl)acrylamide, (73) N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazoline-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, (74) R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (75) S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (76) R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, (77) S)-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, (78) R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azacyclobutane-1-yl)prop-2-en-1-one, (79) S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azacyclobutane-1-yl)prop-2-en-1-one, (80) R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (81) S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (82) R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, (83) R )-1-(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, (84) S )-1-(2-((8-((4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, (85) R )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, (86) 1-((2) R )-2-((4-((3-methyl-4-((1-methyl-3) a 7 a -dihydro-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (87) S )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, (88) R )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, (89) S )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, (90)1-((2) R )-2-((8-((3-methyl-4-((1-methyl-3) a 7 a -dihydro-1 H -benzo[ d[Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, (91) R )-1-(2-((8-((3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one and (92) S )-1-(2-((8-((3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d ]Pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one.

[0100] The compounds of the present invention can inhibit the kinase activity of HER2. In one embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying a gene mutation in exon 20. In a more specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying a mutation in exon 20. In a more specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 carrying an insertion mutation in exon 20.

[0101] Pharmaceutical Composition

[0102] In another aspect, the present invention provides a pharmaceutical composition comprising at least one of the above-described compounds and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used to inhibit the activity of HER2 in vivo, for example, for the treatment of cancer. Specifically, the pharmaceutical composition of the present invention can be used to treat cancers caused by gene variants or mutations (e.g., insertion mutations) in exon 20 of HER2.

[0103] The compounds of the present invention may be present in the pharmaceutical compositions of the present invention in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. Pharmaceutically acceptable base addition salts may be in the form of metal salts and amine salts, for example, salts derived from alkali metal or alkaline earth metal bases, or salts derived from organic amines. Pharmaceutically acceptable salts of the compounds may be prepared from pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include those formed from inorganic acids and organic acids.

[0104] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an inactive ingredient approved by a government regulatory agency (such as the Ministry of Food and Drug Safety of Korea and the U.S. Food and Drug Administration (FDA)) for use in combination with an active pharmaceutical ingredient in the preparation of a medicine for the treatment of diseases in humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, glidants, disintegrants, sweeteners, diluents, preservatives, colorants, flavorings, surfactants, humectants, dispersants, suspending agents, stabilizers, tension agents, solvents, emulsifiers, and adjuvants.

[0105] For example, the pharmaceutical compositions of the present invention may be in the following forms: suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, or solution suspensions; suitable for parenteral injection, such as sterile solutions, suspensions, or emulsions; suitable for topical administration, such as ointments or creams; or suitable for rectal administration, such as suppositories.

[0106] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulation, dressing-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Appropriate formulations depend on the chosen route of administration.

[0107] For oral administration, suitable compositions can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers, as known in the art. Such excipients and carriers enable the compounds of the present invention to be formulated into tablets, pills, tablets, capsules, liquids, gels, syrups, liquids, suspensions, etc., for oral ingestion by a patient to be treated. Orally administered pharmaceutical formulations can be obtained by adding the compounds disclosed herein together with a solid excipient, optionally grinding the resulting mixture, and treating the particulate mixture after adding suitable adjuvants (if desired) to obtain tablets or tablet cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants may be added if desired.

[0108] Typically, pharmaceutical compositions of the disclosed compounds for oral administration in therapeutically effective amounts are in the form of solids (e.g., tablets, capsules, pills, powders, or troche) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0109] When administered in tablet form, the pharmaceutical composition may additionally contain functional solids and / or solid carriers, such as gelatin or adjuvants. Pharmaceutical compositions in tablet, capsule, or powder form may contain about 1% to about 95% by weight of the compounds of the present invention, and preferably about 15% to about 90% by weight of the compounds. As an example, a tablet composition may contain, for example, about 80% or less of the active pharmaceutical ingredient, about 10% to about 90% by weight of a binder, about 0% to about 85% by weight of a diluent, about 2% to about 10% by weight of a disintegrant, and about 0.25% to about 10% by weight of a lubricant.

[0110] When administered in liquid or suspension form, a functional liquid and / or liquid carrier, such as water, petroleum, or oil of animal or plant origin, may be added. The liquid form of the pharmaceutical composition may also contain physiological saline solution, sugar alcohol solution, glucose or other sugar solution, or glycol. When administered in liquid or suspension form, the pharmaceutical composition may contain about 0.5% by weight to about 90% by weight of the compounds disclosed herein, and preferably about 1% by weight to about 50% by weight of the compounds disclosed herein. In one contemplated embodiment, the liquid carrier is anhydrous or substantially anhydrous. For liquid administration, the composition may be supplied in a rapidly dissolving solid dosage form for immediate dissolution or suspension prior to administration.

[0111] When the pharmaceutical compositions of the present invention are administered intravenously, subcutaneously, or subcutaneously, the compositions are in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions with appropriate consideration of pH, isotonicity, stability, etc., is within the scope of the art. Preferred compositions for intravenous, subcutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compounds disclosed herein. Such compositions can be prepared as an aqueous solution of a free base or pharmaceutically acceptable salt, appropriately mixed with a surfactant such as hydroxypropyl cellulose, before administration. Dispersants can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and oils. Under normal storage and use conditions, these formulations may optionally contain preservatives to prevent microbial growth.

[0112] Pharmaceutical compositions in injectable formulation may comprise sterile aqueous solutions, suspensions, or dispersants, as well as sterile powders for the provisional preparation of sterile injectable solutions, suspensions, or dispersants. Sterile injectable solutions are prepared by incorporating the desired amount of the active compound with various other ingredients listed above (if desired) into a suitable solvent, followed by filtration sterilization. Generally, dispersants are prepared by incorporating various sterilized active ingredients into a sterile excipient containing a basic dispersion medium and the other desired ingredients listed above. In embodiments for preparing sterile powders for sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution.

[0113] Sustained-release or sustained-release formulations can also be prepared to achieve controlled release of the active compound upon contact with bodily fluids in the gastrointestinal tract and to provide substantially constant effective levels of the active compound in the plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. Additionally, sustained-release methods can enhance absorption in the gastrointestinal tract through saturable or restrictive pathways. For example, for this purpose, the compound can be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, and optionally a suitable surfactant. In this context, embedding can refer to incorporating microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified droplets via known dispersion or emulsification coating techniques.

[0114] The pharmaceutical compositions of the present invention can be formulated for parenteral administration by injection (e.g., by a single rapid injection or continuous infusion). The injectable formulation may be in unit dosage form (e.g., in ampoules or multi-dose containers) and may contain preservatives. The compositions may be in the form of suspensions, solutions, or emulsions, for example, with oily or aqueous excipients, and may contain formulations such as suspending agents, stabilizers, and / or dispersants.

[0115] The pharmaceutical compositions of the present invention can be formulated into unit dosage forms suitable for precise administration of a single dose.

[0116] Pharmaceutical compositions containing compounds of the present invention can be used according to the methods described below.

[0117] Treatment

[0118] In another aspect, the present invention provides a method for treating cancer. This method includes administering a therapeutically effective amount of a compound of the present invention, such as a compound defined by chemical formula 1, to a subject requiring treatment. Alternatively, the present invention includes administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound and a pharmaceutically acceptable excipient.

[0119] In methods of treating cancer, the compounds of the present invention can be administered alone as a single agent or in combination with at least one other agent. Such co-administration of the compounds of the present invention with other agents can be performed simultaneously or sequentially.

[0120] Unless otherwise stated, the term "therapeuticly effective amount" as used herein refers to an amount of said compound sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to provide a therapeutic benefit to a disease, disorder, or condition. The term "therapeuticly effective amount" may also encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or disorder, or enhance the therapeutic efficacy of another therapeutic agent.

[0121] The amount of compound administered may depend on the subject being treated, the subject's age, health status, sex, weight, type of concomitant treatment (if present), severity of ailment, nature of the desired effect, mode and frequency of treatment, and the prescribing physician's judgment. The frequency of administration may also depend on the pharmacological effect on arterial oxygen pressure. However, as those skilled in the art will understand and determine, the optimal dose can be tailored to the individual subject without extensive experimentation. This typically involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0122] Although individual needs may vary, determining the optimal range of effective amounts of the compounds is within the scope of the art. For the administration of the compounds of the present invention to humans in the curative or preventative treatment of the conditions and disorders identified herein, a typical dose of the compounds of the present invention may be from about 0.01 mg / kg / day to about 50 mg / kg / day. Such doses may be administered as a single dose or may be divided into multiple doses.

[0123] In another aspect, the compounds of the present invention are provided for use as medicines. In one embodiment, the compounds of the present invention are provided for use as medicines for treating cancer.

[0124] In another aspect, the compounds of the present invention are provided for manufacturing a medicament. In one embodiment, the compounds of the present invention are provided for manufacturing a medicament for treating cancer.

[0125] In another aspect, the present invention provides a method for inhibiting the kinase activity of HER2 in cells. The method comprises contacting cells whose HER2 kinase activity needs to be inhibited with an effective amount of a compound as described in the present invention (e.g., a compound as defined in Formula 1).

[0126] Example

[0127] The invention will be further described in detail with reference to the following working examples and experimental examples. However, it should be understood that these working examples and experimental examples are by no means intended to limit the scope of the invention, but are provided merely for illustrative purposes. Those skilled in the art will readily understand that many modifications and alternatives are available for these embodiments. All such modifications and alternatives are intended to be covered within the scope of the appended claims.

[0128] Example 1: N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)- N Synthesis of methylacrylamide

[0129] Step (1): 4-Oxo-1 H Preparation of quinazoline-6-ylacetic acid ester

[0130] 3 grams of 6-hydroxy-1 H 18.5 mmol of quinazolin-4-one and 3.4 mL of pyridine (42.5 mmol) were diluted in 27.9 mL of acetic anhydride (296.0 mmol), and the mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was slowly added dropwise to ice water while stirring. The resulting mixture was filtered, and the solid obtained was washed with distilled water. The solid was dried in an oven at 50 °C to give 4.4 g of the title compound (100% yield).

[0131] 1 H-NMR (300 MHz, DMSO- d 6) δ 12.25 (s, 1H), 8.61 (s, 1H), 7.95 (d, 1H).7.71 (s, 1H), 7.66 (d, 1H), 2.75 (s, 3H).

[0132] Step (2): Preparation of 4-chloroquinazoline-6-ylacetic acid ester

[0133] 2.2 g (10.7 mmol) of the compound prepared in step (1) was diluted in thionyl chloride (31 mL, 430.9 mmol), and then 0.3 mL was added. N,N -Dimethylformamide. This mixture was stirred at 90°C for 6 hours. The resulting mixture was filtered to obtain 2 g of the title compound (83% yield).

[0134] 1 H-NMR (300 MHz, CDCl3) 9.15 (s, 1H), 8.38 (d, 1H), 8.12 (s, 1H). 7.85 (d, 1H), 2.43 (s, 3H).

[0135] Step (3): [4-[3-methyl-4-([1,2,4]triazolo[1,5- a Preparation of pyridine-7-yloxy)aniline]quinazolin-6-yl]acetate

[0136] 1 gram (4.49 mmol) of the compound prepared in step (2) and 1.1 gram (4.49 mmol) of 3-methyl-4-([1,2,4]triazolo[1,5- a Pyridin-7-yloxy)aniline was diluted in a solvent mixture of 12 mL isopropanol and 12 mL ethylene chloride, and the solution was stirred at 80 °C for 4 hours. The solution was diluted with ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 350 mg of the title compound (18% yield).

[0137] 1 H-NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.51 (d, 1H), 8.25 (s, 1H).7.97 (d, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.62-7.55 (m, 4 H), 7.11 (d, 1H), 6.92 (d, 1H), 6.85 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).

[0138] Step (4): 4-[3-methyl-4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)aniline]quinazolin- Preparation of 6-ol

[0139] 350 mg (0.82 mmol) of the compound prepared in step (3) and 1.6 mL (0.82 mmol) of ammonium hydroxide were diluted in 6 mL of methanol, and the mixture was stirred at 80 °C for 4 hours. The resulting mixture was subjected to vacuum distillation and recrystallized in dichloromethane to obtain 305 mg of the title compound (96% yield).

[0140] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 10.11 (s, 1H), 9.55 (s, 1H), 8.93 (d, 1H),8.47 (s, 1H), 8.38 (s, 1H), 7.92-7.81 (m, 3H), 7.68 (d, 1H), 7.43 (d, 1H),7.19 (d, 1H), 7.02 (d, 1H), 6.80 (s, 1H), 2.19 (s, 3H).

[0141] Step (5): 3-tert-butyl N -methyl- N -[2-[4-[3-methyl-4-([1,2,4]triazolo[1,5- a Preparation of pyridine-7-yloxy)aniline]quinazolin-6-yl]oxyethyl]carbamate

[0142] 305 mg (0.79 mmol) of the compound prepared in step (4) and 184 mg (0.95 mmol) of 3-tert-butyl N -(2-Chloroethyl)- N 2 mL of methyl carbamate and 438 mg (3.17 mmol) potassium carbonate were diluted. N, N The solution was stirred in dimethylformamide at 100°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 32 mg of the title compound (7% yield).

[0143] 1H-NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.51 (d, 1H), 8.24 (s, 1H).8.10 (d, 1H), 7.88-7.71 (m, 3H), 7.43-7.28 (m, 2H), 7.15-7.10 (m, 1H), 6.93-6.89 (m, 2H), 4.36-4.33 (m, 2H), 3.75-3.70 (m, 2H), 3.04 (s, 3H), 2.26 (s,3H), 1.59 (s, 9H).

[0144] Step (6): N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl) (amino)quinazolin-6-yl)oxy)ethyl)- N Preparation of 1-Methacrylamide

[0145] 32 mg (0.059 mmol) of the compound prepared in step (5) was diluted in 0.45 mL (5.9 mmol) of trifluoroacetic acid and 1 mL of dichloromethane, and the solution was stirred at ambient temperature for 2 hours. After the reaction was complete, the reaction mixture was vacuum distilled. 6.4 μL (0.09 mmol) of acrylic acid and 27 μL (0.09 mmol) of propylphosphonic anhydride were diluted in 2 mL of... N,N 75 μL (0.42 mmol) of dimethylformamide was then added. N,N The solution was reacted with diisopropylethylamine and stirred at ambient temperature for 30 minutes. This solution was transferred to the residue obtained from vacuum distillation, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 4 mg of the title compound (12% yield).

[0146] 1H-NMR (300 MHz, CDCl3) δ 8.75 (s, 2H), 8.50 (d, 1H), 8.40 (s, 1H).8.24 (s, 1H), 8.08-8.04 (m, 2H), 7.83 (d, 1H), 7.41 (d, 1H), 7.11 (d, 1H),6.92-6.90 (m, 2H), 6.69-6.66 (m, 1H), 6.53 (d, 1H), 5.84 (d, 1H), 4.44-4.39(m, 2H), 3.95-3.93 (m, 2H), 3.28 (s, 3H), 2.25 (s, 3H); MS (ESI+): m / z = 496.3 [M+H] + .

[0147] The compounds of Examples 2 to 10 shown in Table 1 below were prepared using the same or similar procedures as described in Example 1 above.

[0148] [Table 1]

[0149] Example 11: N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)amino)ethyl)- N Synthesis of methylacrylamide

[0150] Step (1): 4,6-Dichloropyrido[3,2- d Preparation of pyrimidine

[0151] 1.2 g of 6-chloropyridine[3,2- d Pyrimidine-4-ol (6.50 mmol) was diluted in 12 mL of thionyl chloride (165.22 mmol), and then 0.1 mL of [the solution] was added. N,N The reaction mixture was prepared with dimethylformamide and stirred at 120 °C for 12 hours. After the reaction was complete, the resulting mixture was cooled to room temperature and vacuum distilled to obtain 1.4 g of the title compound (100% yield).

[0152] 1H-NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.35 (d, 1H), 7.89 (d, 1H).

[0153] Step (2): N -(4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)-6-chloropyridine and [3,2- d Preparation of pyrimidine-4-amine

[0154] 1.4 g (0.7 mmol) of the compound prepared in step (1) and 1.5 g (6.3 mmol) of 4-([1,2,4]triazolo[1,5- a Pyridin-7-yloxy)-3-methylaniline was diluted in a solvent mixture of 15 mL isopropanol and 15 mL 1,2-dichloroethane. 1 mL of trifluoroacetic acid was added, and the solution was stirred at 80 °C for 5 hours. After the reaction was complete, the resulting mixture was cooled to room temperature and vacuum distilled. The residue was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The separated organic layer was dried over anhydrous sodium sulfate, then filtered and vacuum distilled. The residue was purified by column chromatography (hexane:ethyl acetate = 2:1 (v / v)) to give 1.5 g of the title compound (59% yield).

[0155] 1 H-NMR (300 MHz, DMSO- d 6) δ 10.16 (s, 1H), 8.94 (d, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.28 (d, 1H), 8.20-8.10 (m, 1H), 8.07-7.95 (m, 2H), 7.22 (d,1H), 7.03 (dd, 1H), 6.81 (d, 1H), 2.21 (s, 3H).

[0156] Step (3): 3-tert-butyl(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methyl phenyl)amino)pyrido[3,2- d Preparation of pyrimidin-6-yl)amino)ethyl)methyl)carbamate

[0157] 200 mg (0.5 mmol) of the compound prepared in step (2) and 863 mg (4.95 mmol) of 3-tert-butyl(2-aminoethyl)(methyl)carbamate were diluted in 1-butanol, and the solution was stirred at 110 °C for 12 h. After the reaction was complete, the resulting mixture was cooled to room temperature and vacuum distilled, then diluted in ethyl acetate and washed with water. The separated organic layer was dried with anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 278 mg of the title compound (100% yield).

[0158] 1 H-NMR (300 MHz, DMSO- d 6) δ 9.30 (d, 1H), 8.93 (d, 1H), 8.39 (d, 2H), 8.12-8.00 (m, 2H), 7.78 (d, 1H), 7.70-7.60 (m, 1H), 7.30-7.20 (m, 1H), 7.09(d, 1H), 7.03 (dd, 1H), 6.80-6.70 (m, 1H), 3.80-3.50 (m, 4H), 3.00-2.70 (m,3H), 2.20 (s, 3H), 1.39 (s, 9H).

[0159] Step (4): N -(4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)- N 6 -(2- (methylamino)ethyl)pyrido[3,2- d Preparation of pyrimidine-4-diamine

[0160] 278 mg (0.51 mmol) of the compound prepared in step (3) was diluted in 3 mL of dichloromethane and 1.5 mL (19.6 mmol) of trifluoroacetic acid was added. The mixture was stirred at ambient temperature for 2 hours. After the reaction was complete, the resulting mixture was vacuum distilled and slowly diluted with 2 N sodium hydroxide aqueous solution, followed by washing with a solvent mixture of chloroform:2-propanol (3:1 (v / v)). The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 1:99 (v / v)) to give 143 mg of the title compound (63% yield).

[0161] 1 H-NMR (300 MHz, DMSO- d 6) δ 9.20 (bs, 1H), 8.93 (d, 1H), 8.42-8.37 (m,2H), 8.02-7.96 (m, 2H), 7.76 (d, 1H), 7.51-7.40 (m, 1H), 7.21 (d, 1H), 7.14(d, 1H), 7.03 (dd, 1H), 6.79 (dd, 1H), 4.10 (bs, 1H), 3.64 (dd, 2H), 3.18 (s,3H), 2.76 (t, 2H), 2.20 (s, 3H).

[0162] Step (5): N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl) (amino)pyrido[3,2- d ]pyrimidin-6-yl)amino)ethyl)- N Preparation of 1-Methacrylamide

[0163] Mix 0.03 ml (0.47 mmol) of acrylic acid and 0.17 ml (0.95 mmol) N,N -Diisopropylethylamine diluted in 0.5 mL N,N - Dimethylformamide was added, followed by 0.14 mL (0.47 mmol) of propylphosphonic anhydride solution, and the mixture was stirred at ambient temperature for 30 minutes. This solution was then added dropwise at 0 °C to 1 mL containing 140 mg (0.31 mmol) of the compound prepared in step (4) and 0.08 mL (0.47 mmol). N,N -Diisopropylethylamine N,N The reaction mixture was stirred in a dimethylformamide solution for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water. The separated organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 15.0 mg of the title compound (10% yield).

[0164] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 9.45 (d, 1H), 8.93 (d, 1H), 8.43 (d, 1H), 8.37 (s, 1H), 8.30-7.90 (m, 3H), 7.82-7.73 (m, 1H), 7.70-7.60 (m, 1H), 7.30-7.20 (m, 1H), 7.15-7.10 (m, 1H), 7.10-7.00 (m, 1H), 6.80 (s, 1H), 6.27-5.98(m, 1H), 5.75-5.40 (m, 1H), 3.70-3.60 (m, 4H), 3.20 (s, 3H), 2.20 (s, 3H); MS (ESI+): m / z = 517.2 [M+H] + .

[0165] The compounds of Examples 12 to 21 shown in Table 2 below were prepared using the same or similar procedures as described in Example 11 above.

[0166] [Table 2]

[0167] Example 22: ( E )-N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d Synthesis of imidazole-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide

[0168] Step (1): Preparation of 1-methyl-5-(2-methyl-4-nitro-phenoxy)benzimidazole

[0169] Dilute 1.05 g (7.0 mmol) of 1-methylbenzimidazole-5-ol, 1.4 g (9.2 mmol) of 1-fluoro-2-methyl-4-nitrobenzene, and 2.4 g (17.7 mmol) of potassium carbonate in 30 mL. N,N The solution was stirred in dimethylformamide at 80°C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and distilled water was added dropwise while the mixture was slowly stirred. The obtained solid was washed with distilled water, ethyl acetate, and hexane and then filtered to give 1.8 mg of the title compound (89% yield).

[0170] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 8.25 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, 1H), 7.67 (d, 1H), 7.42 (s, 1H), 7.09 (d, 1H), 6.68 (d, 1H), 3.87 (s, 3H), 2.42(s, 3H).

[0171] Step (2): Preparation of 3-methyl-4-(1-methylbenzimidazol-5-yl)oxy-aniline

[0172] 1.8 g (6.3 mmol) of the compound prepared in step (1) was diluted in a solvent mixture of 40 mL ethyl acetate and 40 mL methanol. 300 mg palladium / carbon (15 wt%) was added, and the mixture was reacted at ambient temperature under a hydrogen atmosphere for 16 h. After the reaction was complete, the reaction mixture was transferred to a filter filled with diatomaceous earth® (Celite®), washed with methanol and ethyl acetate, and then filtered by suction. The filtrate was vacuum distilled to give 1.57 g of the title compound (97% yield).

[0173] 1 H-NMR (300 MHz, DMSO- d 6) δ 8.09 (s, 1H), 7.45 (d, 1H), 6.87-6.85 (m,2H), 6.64 (d, 1H), 6.50 (s, 1H), 6.41 (d, 1H), 4.87 (s, 2H), 3.79 (s, 3H),1.99 (s, 3H).

[0174] Step (3): 6-Iodine- N -[3-methyl-4-(1-methylbenzimidazol-5-yl)oxy-phenyl]quinazolin-4-amine preparation

[0175] 1.3 g (5.5 mmol) of the compound prepared in step (2) and 1.6 g (5.5 mmol) of 4-chloro-6-iodoquinazoline were diluted in a solvent mixture of 16 mL isopropanol and 16 mL 1,2-dichloroethane. Then, 0.8 mL (11.0 mmol) of trifluoroacetic acid was added, and the solution was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried with anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 1.3 g of the title compound (46% yield).

[0176] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 8.77 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.65 (d, 1H), 7.61 (s, 1H), 7.44 (d, 1H), 7.36(d, 1H), 7.31 (s, 1H), 7.10 (d, 1H), 6.88 (d, 1H), 3.88 (s, 3H), 2.34 (s,3H).

[0177] Step (4): 3-tert-butyl N -methyl- N -[( E )-3-[4-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxy Preparation of [-aniline]quinazolin-6-yl]allyl]carbamate

[0178] 1.3 g (2.5 mmol) of the compound prepared in step (3) and 1.1 g (3.8 mmol) of 3-tert-butyl N -methyl- N -[( E[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]carbamate, 296 mg (0.2 mmol) tetra(triphenylphosphine)palladium(O) and 579 mg (5.6 mmol) sodium carbonate were diluted in a solvent mixture of 6 mL 1,4-dioxane and 2 mL distilled water, and the mixture was stirred at 100 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with dichloromethane, then washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 720 mg of the title compound (51% yield).

[0179] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 8.25 (s, 1H), 8.23 ​​(s, 1H), 8.00 (d, 1H), 7.67 (d, 1H), 7.42 (s, 1H), 7.09 (d, 1H), 6.68 (d, 1H), 3.87 (s, 3H), 2.42(s, 3H).

[0180] Step (5): N -methyl- N -(1-Methyl-4-nitro-1 H Preparation of pyrazole-3-yl)methanesulfonamide

[0181] 130 mg (0.59 mmol) of the compound prepared in step (4) was diluted in 5 mL. N,N 28 mg (0.71 mmol) of sodium hydride was slowly added to dimethylformamide at 0 °C. The mixture was stirred at ambient temperature for 30 min. 55 μL (0.89 mmol) of iodomethane was slowly added to this solution at 0 °C, and the mixture was stirred at ambient temperature for 12 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 88 mg of the title compound (64% yield).

[0182] 1H-NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.88 (s. 1H), 7.64 (d, 1H), 7.46 (m, 1H), 7.37-7.31 (m, 2H), 7.11-7.08 (d,1H), 6.92-6.87 (m, 1H), 6.63 (d, 1H), 6.34-6.29 (m, 1H), 4.06 (d, 1H), 3.87(s, 3H), 2.92 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H).

[0183] Step (6): E )- N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl] Preparation of oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide

[0184] Dilute 6.4 μL (0.09 mmol) of acrylic acid and 27 μL (0.09 mmol) of propylphosphonic anhydride in 2 mL of water. N,N 75 μL (0.42 mmol) of dimethylformamide was then added. N,N -Diisopropylethylamine was added to the solution and stirred at ambient temperature for 30 minutes. 75 mg (0.16 mmol) of the compound prepared in step (5) was added to this solution, and the mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 19 mg of the title compound (21% yield).

[0185] 1 H-NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 7.88-7.84 (m, 4H), 7.64 (s.1H), 7.56-7.49 (m, 2H), 7.37-7.34 (m, 2H), 7.10 (d, 1H), 6.92 (d, 1H), 6.72-6.61 (m, 2H), 6.45-6.39 (m, 2H), 5.80-5.72 (m, 1H), 4.30-4.25 (m, 2H), 3.87(s, 3H), 3.14 (s, 3H), 2.36 (s, 3H); MS (ESI+): m / z = 505.3 [M+H] + .

[0186] The compounds of Examples 23 to 64 shown in Table 3 below were prepared using the same or similar procedures as described in Example 22 above.

[0187] [Table 3]

[0188] Example 65: N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)prop-2-yn-1-yl)- N Synthesis of methylacrylamide

[0189] Step (1): 6-Iodine- N -[3-methyl-4-([1,2,4]triazolo[1,5- a [Pyridine-7-yloxy)phenyl]quinazole Preparation of 4-line-amine

[0190] 300 mg (1.03 mmol) of 4-chloro-6-iodoquinazoline and 248 mg (1.03 mmol) of 3-methyl-4-([1,2,4]triazolo[1,5-) a Pyridin-7-yloxy)aniline was diluted in a solvent mixture of 2.4 mL isopropanol and 2.4 mL 1,2-dichloroethane, and the solution was stirred at 80 °C for 4 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 277 mg of the title compound (54% yield).

[0191] 1 H-NMR (300MHz, DMSO- d 6) δ 9.92 (s, 1H), 9.03 (s, 1H), 8.93 (d, 1H).8.65 (s, 1H), 8.38 (s, 1H), 8.13 (d, 1H), 7.88-7.85 (m, 2 H), 7.57 (d, 1H),7.22 (d, 1H), 7.03 (d, 1H), 6.81 (s, 1H), 2.20 (s, 3H).

[0192] Step (2): tert-butyl N -methyl- N -[3-[4-[3-methyl-4-([1,2,4]triazolo[1,5- a ]pyridin-7-yl Preparation of [oxy-phenylaniline]quinazolin-6-yl]prop-2-ynyl]carbamate

[0193] 150 mg (0.30 mmol) of the compound prepared in step (1) and 102 mg (0.60 mmol) of tert-butyl N -methyl- N 2-Propyl-2-ynyl-carbamate, 11 mg (0.06 mmol) cuprous iodide (I), 21 mg (0.03 mmol) bis(triphenylphosphine)palladium dichloride (II) and 0.17 mL (1.21 mmol) triethylamine were diluted in 1.5 mL N,N The mixture was stirred in dimethylformamide at 70°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate, then washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (hexane:ethyl acetate = 1:1 (v / v)) to give 100 mg of the title compound (61% yield).

[0194] 1 H-NMR (300MHz, CDCl3) δ 8.78 (s, 1H), 8.52 (d, 1H), 8.25 (s, 1H).8.10 (s, 1H), 7.88-7.69 (m, 4H), 7.12 (d, 1H), 6.92-6.87 (m, 2 H), 4.34 (s, 2H), 4.15-4.12 (m, 1H), 3.03 (s, 3H), 2.25 (s, 3H), 1.52 (s, 9H).

[0195] Step (3): N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino (yl)quinazolin-6-yl)prop-2-yn-1-yl)- N Preparation of 1-Methacrylamide

[0196] 100 mg (0.18 mmol) of the compound prepared in step (2) was diluted in a mixture of 0.34 mL (4.5 mmol) trifluoroacetic acid and 1.2 mL dichloromethane, and the resulting solution was stirred at ambient temperature for 2 hours. After the reaction was complete, the reaction mixture was vacuum distilled. 18 μL (0.27 mmol) acrylic acid and 81 μL (0.27 mmol) propylphosphonic anhydride were diluted in 2 mL... N,N 0.22 mL (1.26 mmol) of dimethylformamide was then added. N, N -Diisopropylethylamine was added and stirred at room temperature for 30 minutes. This resulting solution was transferred to the residue obtained from vacuum distillation, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The organic layer thus separated was dried with anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The resulting residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 12 mg of the title compound (13% yield).

[0197] 1 H-NMR (300MHz, DMSO- d 6 ) δ 9.96 (s, 1H), 8.93 (d, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7.89-7.74 (m, 4H), 7.22 (d, 1H), 7.03 (d, 1H), 6.81 (d, 2H), 6.21 (d, 1H), 5.77 (d, 1H), 4.65 (s, 2H), 3.33 (s, 3H), 2.20 (s, 3H); MS (ESI+): m / z = 490.2 [M+H] + .

[0198] The compounds of Examples 66 to 73 shown in Table 4 below were prepared using the same or similar procedures as described in Example 65 above.

[0199] [Table 4]

[0200] Example 74: ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- aSynthesis of pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one

[0201] Step (1): N -(4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)-6-iodoquinazole Preparation of 4-line-amine

[0202] 1.5 g (5.16 mmol) of 4-chloro-6-iodoquinazoline and 1.24 g (5.16 mmol) of 4-([1,2,4]triazolo[1,5- a pyridin-7-yloxy)-3-methylaniline was diluted in a solvent mixture of 8 mL isopropanol and 8 mL 1,2-dichloroethane, and the resulting solution was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and vacuum distilled. The residue was washed with isopropanol and hexane to give 2.73 g of the title compound (100% yield).

[0203] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 11.4 (s, 1H), 9.29 (d, 1H), 8.99 (s, 1H), 8.97 (s, 1H), 8.43 (s, 1H), 8.37 (dd, 1H), 7.79 (d, 1H), 7.73 (d, 2H), 7.30(d, 1H), 7.06 (dd, 1H), 6.87 (d, 1H), 2.24 (s, 3H).

[0204] Step (2): tert-butyl ( R Preparation of 2-ethynylpyrrolidine-1-carboxylate

[0205] 500 mg (2.5 mmol) of tert-butyl ( R )-2-Formylpyrrolidine-1- First The ester and 694 mg (5.0 mmol) of potassium carbonate were diluted in 20 mL of methanol. 578 mg (3.0 mmol) of dimethyl (1-diazo-2-oxopropyl)phosphonate was added to this mixture, and the mixture was stirred at ambient temperature for 3 h. After the reaction was complete, the reaction mixture was vacuum distilled and diluted in dichloromethane, then washed with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation to give 476 mg of the title compound (97% yield).

[0206] 1H-NMR (300 MHz, CDCl3) δ 4.75-4.40 (m, 1H), 3.48 (bs, 1H), 3.35 (bs, 1H), 2.23 (s, 1H), 2.20-2.00 (m, 3H), 2.00-1.85 (m, 1H), 1.50 (s, 9H).

[0207] Step (3): tert-butyl ( R )-2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methyl Preparation of phenyl(amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-carboxylate

[0208] 300 mg (0.6 mmol) of the compound prepared in step (1), 5.8 mg (0.03 mmol) of cuprous iodide (I), and 30 mg (0.04 mmol) of bis(triphenylphosphine)palladium (II) dichloride were diluted in 2 mL of water. N,N - Dimethylformamide was added, and the mixture was stirred at ambient temperature. 178 mg (0.91 mmol) of the compound prepared in step (2) and 0.25 mL (1.82 mmol) of triethylamine were dissolved in 1 mL of [amount missing]. N,N The solution was added dropwise to the reactants in dimethylformamide, and the mixture was stirred at 65°C for 18 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate, then washed with distilled water and brine. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 310 mg of the title compound (91% yield).

[0209] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 9.94 (d, 1H), 8.94 (d, 1H), 8.71 (d, 2H), 8.39 (s, 1H), 8.07-7.95 (m, 2H), 7.70-7.55 (m, 1H), 7.25 (d, 2H), 7.03 (dd,1H), 6.82 (s, 1H), 4.09 (d, 4H), 2.21 (s, 3H), 2.10-1.85 (m, 3H), 1.44 (s, 9H).

[0210] Step (4): R )- N -(4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)-6- Preparation of (pyrrolidine-2-ylethynyl)quinazolin-4-amine 2,2,2-trifluoroacetic acid

[0211] 305 mg (0.54 mmol) of the compound prepared in step (3) was diluted in 2 mL of dichloromethane. 1 mL (13.1 mmol) of trifluoroacetic acid was added to this mixture, and the mixture was stirred at ambient temperature for 2 hours. After the reaction was complete, the reaction mixture was vacuum distilled to yield a 400 mg mixture of product that was not purified and used in the following steps.

[0212] Step (5): R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylbenzene Preparation of (-)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one

[0213] Mix 0.05 ml (0.75 mmol) of acrylic acid and 0.26 ml (1.5 mmol) of acrylic acid. N,N -Diisopropylethylamine diluted in 1 ml N,N The solution was then added to dimethylformamide, followed by the addition of 0.22 mL (0.75 mmol) of propylphosphonic anhydride, and stirred at ambient temperature for 30 minutes. This solution was then added dropwise at 0 °C to a volume containing 288 mg (0.5 mmol) of the compound prepared in step (4) and 0.39 mL (2.25 mmol). N,N 1 ml of diisopropylethylamine N,N The mixture was stirred in a dimethylformamide solution for 3 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to suction filtration and vacuum distillation. The residue was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to give 18.0 mg of the title compound (7% yield).

[0214] 1 H-NMR (300 MHz, DMSO- d 6 ) δ 10.0 (s, 1H), 8.95 (d, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 7.93-7.70 (m, 4H), 7.22 (d, 1H), 7.03 (dd, 1H),6.90-6.60 (m, 2H), 6.30-6.18 (m, 1H), 5.80-5.70 (m, 1H), 5.28-4.98 (m, 1H),3.77-3.50 (m, 2H), 2.40-2.00 (m, 7H); MS (ESI+): m / z = 516.2 [M+H] + .

[0215] The compounds of Examples 75 to 92 shown in Table 5 below were prepared using the same or similar procedures as described in Example 74 above.

[0216] [Table 5]

[0217] Experimental Example: Growth Inhibition of Ba / F3 HER2 A775insYVMA and Wild-type Ba / F3 Cells

[0218] In this experimental example, the ability of the compounds obtained in Examples 1 through 92 to inhibit the growth of cells carrying the HER2A775insYVMA mutation or wild-type EGFR was evaluated. For this purpose, Ba / F3 cells (American Type Culture Collection (ATCC), USA) were genetically engineered to overexpress HER2 A775_G776insYVMA or wild-type EGFR, and the growth of these engineered Ba / F3 cells was monitored in the presence of the compounds described in the examples to evaluate their growth-inhibiting effect.

[0219] Specifically, culture flasks containing engineered Ba / F3 cells suspended in RPMI 1640 medium (Gibco BRL, USA) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin were placed in a cell incubator and incubated at 37°C and 5% CO2 to achieve a stable logarithmic growth phase. Cells were then harvested by centrifugation to remove the old medium and then transferred to fresh medium at 1×10⁶ cells / mL. 5 A dilution of 1 cell / mL was aliquoted into 100 μL aliquots / wells, and the cells were placed in 96-well plates. Each of the compounds prepared in the foregoing examples was dissolved in 99.5% (cell culture grade) dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, which was then serially diluted in culture medium to final concentrations of 1000, 200, 40, 8, 1.6, and 0.32 nM for HER2 A775insYVMA Ba / F3 cells and 10000, 5000, 1000, 200, 40, and 8 nM for Ba / F3 cells overexpressing wild-type EGFR.

[0220] 50 μL of test solution containing one of the compounds was added to each aliquot of cells in a 96-well plate to make a cell volume of 150 μL per well, with the final concentration of the compound ranging from 10 µM to 0.32 nM. Ba / F3 cells treated with the test solution were incubated at 37°C and 5% CO2 for 72 hours and then acclimatized for 30 minutes by placing the cell-bearing 96-well plate at ambient temperature. Subsequently, 50 μL of CellTiter-Glo® luminescence assay reagent (CTG, Promega, USA) was added to each well. After 10 minutes of signal stabilization, the luminescence intensity was measured using a microplate reader. The half-maximal growth inhibition concentration (GIC) was calculated from the luminescence readings of the test compounds. 50 In this study, the difference between the initial and final cell densities of untreated wells was set as 100% growth. The glycemic index (GI) of each compound was calculated using nonlinear regression analysis of log[inhibitor] and normalized response patterns based on Graph Prism software. 50 The calculated GI values ​​are summarized in Table 6. 50 Values ​​are classified into four categories: A represents GI values ​​less than 100 nM. 50 Value, B is a GI value greater than 100 nM but less than 1,000 nM. 50 Value, C is the GI value greater than 1,000 nM but less than 5,000 nM. 50 Value, and D is a GI greater than 5,000 nM. 50 value.

[0221] [Table 6]

[0222] Although the invention has been described with reference to a limited number of examples, it should be understood that the technical concept and scope of the invention are not limited to the embodiments disclosed herein. The embodiments defined in the appended claims, as well as various modifications, alterations, and variations of these embodiments that will be apparent to those skilled in the art, are all covered within the scope of this invention.

Claims

1. A compound of Formula 1, or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula, A 1 With A 3 Each is independently N or CH, and A 2 With A 4 Each is independent of the other as N or CR a , where R a For H, CN, C 1-4 Alkyl or C 1-4 Alkoxy; R 1 is C 1-4 alkyl, C 1-4 alkoxy, CF3or halogen; R 2 It is a six- to five-membered fused bicyclic heteroaryl or a six- to six-membered fused bicyclic heteroaryl. Optionally, in the six- to five-membered fused bicyclic heteroaryl or the six- to six-membered fused bicyclic heteroaryl, one or more hydrogen atoms are independently selected from halogens, carbon atoms ... 1-4 Alkyl and C 1-4 Functional group substitution in alkoxy groups; Each R 3 Halogen and C are independent of each other. 1-4 Alkoxy or C 1-4 Alkyl groups, where n is an integer from 0 to 3; L 1 for -CH=CH-M、-CH=CHQ 1 M、-NR b Q 1 M、-OQ 1 M、-S(=O)2Q 1 M、-N(Q 2 )C(=O)Q 1 M、-C(=O)N(Q 2 )Q 1 M, -C≡CM or -C≡CQ 1 M, where Q 1 C 1-3 Alkylene, Q 2 For H or C 1-3 Alkyl, R b For H or C 1-3 Alkyl group, and M is a single bond attached to the functional group E; E is or -NR c -, where R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, and J is a single bond attached to a carbonyl group in Formula 1 (=O)CH=CHZ; and Z represents H and C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e H or C, independent of each other. 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

2. The compound according to claim 1, characterized in that, A 1 at least one of A 4 is N.

3. The compound according to claim 2, characterized in that, said L 1 is -CH=CH-Q 1 M, Q 1 is CH2or -CH(CH3)-, E is -NR c -, and Z is H.

4. The compound according to claim 2, characterized in that, L 1 is -C=C-Q 1 M, Q 1 is CH2, and E is -NR c .

5. The compound according to claim 1, characterized in that, The R 2 for Where T is H or C 1-4 alkyl.

6. The compound according to claim 1, characterized in that, The compound has the structure of chemical formula 2: [Chemical Formula 2] In the above chemical formula, R 4 for Where T is H or C 1-4 alkyl; each R is independently halogen, or C 5 independently halogen or C 1-4 alkoxy, and n is an integer from 0 to 3; A 3 It is N or CH, and R a For H, C 1-4 Alkyl or C 1-4 Alkoxy; L 2 for -CH=CH-M、-CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, where Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group, and M is a single bond attached to the functional group E; E is or -NR c -, where R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, and J is a single bond attached to a carbonyl group of ZCH=CHC(=O); and Z represents H and C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e H or C, independent of each other. 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

7. The compound according to claim 6, characterized in that, The A 3 Let N be the number of elements in the array.

8. The compound according to claim 6, characterized in that, The R 5 It is F.

9. The compound according to claim 6, characterized in that, Z is H, CH3, Or -CH2N(CH3)2.

10. The compound according to claim 6, characterized in that, The compound has the structure of chemical formula 3: [Chemical Formula 3] In the above chemical formula, R 4 for Where T is H or C 1-4 alkyl; Each R 5 Each element is a halogen, and n is an integer from 0 to 3. A 3 For N or CH; L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, where Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group, and M is a single bond attached to the functional group G; G is -NR c -、 , where R c For H, C 1-4 Alkyl or C 3-6 Cycloalkyl, and J is a single bond attached to a carbonyl group at –C(=O)CH=CHZ; and Z represents H and C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e H or C, independent of each other. 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

11. The compound according to claim 10, characterized in that, The compound has the structure of chemical formula 4: [Chemical Formula 4] In the above chemical formula, L 3 -CH=CH-M, -CH=CHQ 1 M、-NR b Q 1 M or -OQ 1 M, where Q 1 C 1-3 Alkylene, R b For H or C 1-3 Alkyl group, and M is attached to the functional group CH2=CHC(=O)NR c single key; R c For H, C 1-4 Alkyl or C 3-6 cycloalkyl; and R 6 With R 7 They are H or F, independent of each other.

12. The compound according to claim 1, characterized in that, The compound has the structure of chemical formula 5: [Chemical Formula 5] In the above chemical formula, A 1 With A 3 Each is independently N or CH, and A 2 For N or CR a , where R a For H, C 1-4 Alkyl or C 1-4 Alkoxy; R 2a for Where T is H or C 1-4 alkyl; Each R'' is a halogen independently of each other, and n is an integer from 0 to 3; m is an integer from 1 to 3; and Z represents H and C. 1-4 Alkyl, X, -C 1-3 Alkylene-X or -C 1-3 Alkylene-NR d R e In this case, X is a substituted or unsubstituted 5- or 6-membered heterocyclic alkyl group, and R d With R e H or C, independent of each other. 1-3 Alkyl group, wherein the substituted 5- to 6-membered heterocyclic alkyl group is in which one or more hydrogen atoms in the unsubstituted 5- to 6-membered heterocyclic alkyl ring are each independently selected from C1 to C2. 1-4 A ring substituted with a functional group in the group consisting of alkyl, halogen, CN, NO2 and CF3.

13. The compound according to claim 12, characterized in that, The R 2a for .

14. The compound according to claim 13, characterized in that, A 1 It is CH, and A 3 Let N be the number of elements in the array.

15. A compound selected from the group consisting of any of the following compounds, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof: N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)- N -Methacrylamide, N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridine-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)ethyl)- N -Methacrylamide, N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)oxy)ethyl)- N -Methacrylamide, N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)oxy)ethyl)- N -Methacrylamide, N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide, N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)ethyl)acrylamide, N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)ethyl)acrylamide, N -methyl- N -(2-((8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)oxy)ethyl)acrylamide, N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)oxy)propyl)acrylamide, N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide, N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)amino)ethyl)- N -Methacrylamide, N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)amino)ethyl)- N -Methacrylamide, N -(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)(methyl)amino)ethyl)- N -Methacrylamide, N -(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)(methyl)amino)ethyl)- N -Methacrylamide, N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)ethyl)acrylamide, N -methyl- N -(2-((8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)amino)ethyl)acrylamide, N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)propyl)acrylamide, N -methyl- N -(2-(methyl(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)ethyl)acrylamide, N -methyl- N -(2-(methyl(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)amino)ethyl)acrylamide, N -methyl- N -(3-(methyl(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)propyl)acrylamide, N -methyl- N -(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)amino)-2-oxoethyl)acrylamide, ( E )- N -methyl- N -(3-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide, ( E )- N -methyl- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)aryl)acrylamide, ( E )- N -methyl- N -(3-(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)allyl)acrylamide, ( E )- N -(3-(4-((3-chloro-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-4-en-1-yl)acrylamide, ( E )-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)piperidin-1-yl)prop-2-en-1-one, ( E )-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)azacyclobutane-1-yl)prop-2-en-1-one, ( E )-1-(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)pyrrolidone-1-yl)prop-2-en-1-one, ( E )- N -methyl- N -(1-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)cyclopropyl)acrylamide, ( E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, ( E )-4-(dimethylamino)- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, ( E )- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyridin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((3-methyl-4-((3-methyl-3) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((2-chloro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((3-methyl-4-(pyrazolo[1,5-) a ]pyridin-5-yloxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, (E )- N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((4-(imidazo[1,2- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, ( E )-4-(dimethylamino)- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, ( E )-4-(dimethylamino)- N -(( E )-3-(4-((2-fluoro-3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)but-2-enamide, ( E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -methyl- N -(3-(4-((3-methyl-4-((3-methyl-3) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -Methyl-N-(3-(4-((3-methyl-4-((3-methyl-3-) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((2-fluoro-5-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1-) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(3-(4-((2-fluoro-3-methyl-4-((3-methyl-3-) H -imidazo[4,5- b ]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )-1-(3-(2-(4-((3-methyl-4-((2-methyl-2) H -indazole-6-yl)oxy)phenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)vinyl)azacyclobutane-1-yl)prop-2-en-1-one, ( E )- N -Ethyl- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, ( S , E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, ( R , E )- N -methyl- N -(4-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)but-3-en-2-yl)acrylamide, ( E )- N -(Terbutyric)- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)acrylamide, ( E )- N -(3-(4-((2-methoxy-5-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(3-(4-((3-fluoro-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-ylmethyl)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(3-(4-((4-(benzo[ d [Oxazol-5-yloxy)-3-methylphenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)- N -Methacrylamide, ( E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d ]pyrimidin-6-yl)allyl)-3-(( R 1-Methylpyrrolidone-2-yl)acrylamide, ( E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-(piperidin-1-yl)but-2-enamide, ( E )- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-morpholinobut-2-enamide, ( E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-(piperidin-1-yl)but-2-enamide, ( E )- N -methyl- N -(( E )-3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)allyl)-4-morpholinobut-2-enamide, ( E )- N -methyl- N -(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)phenyl)acrylamide, ( E )- N -(3-(2-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)vinyl)phenyl)acrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[2,3- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,4- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d ]pyrimidin-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -(3-(8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d ]pyrimidin-2-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanoquinoline-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, N -methyl- N -(3-(4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)prop-2-yn-1-yl)acrylamide, N -methyl- N -(3-(8-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[5,4-] d Pyrimidin-2-yl)prop-2-yn-1-yl)acrylamide, N -(3-(4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazoline-6-yl)prop-2-yn-1-yl)- N -Methacrylamide, ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azacyclobutane-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azacyclobutane-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrido[3,2- d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, ( R )-1-(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, ( S )-1-(2-((8-((4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimidin[5,4- d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, 1-((2 R )-2-((4-((3-methyl-4-((1-methyl-3) a 7 a -dihydro-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)pyrrolidine-1-yl)prop-2-en-1-one, ( R )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, ( S )-1-(2-((4-((3-methyl-4-((1-methyl-1) H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-] d Pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one, 1-((2 R )-2-((8-((3-methyl-4-((1-methyl-3) a 7 a -dihydro-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)ethynyl)pyrrolidone-1-yl)prop-2-en-1-one, ( R )-1-(2-((8-((3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d Pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one and ( S )-1-(2-((8-((3-methyl-4-((1-methyl-1 H -benzo[ d [Imidazol-5-yl)oxy)phenyl)amino)pyrimidin[5,4-] d ]Pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one.

16. A pharmaceutical composition for the prevention or treatment of cancer, said composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable excipient.

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