Compounds capable of inhibiting the activity of HER2 kinase and pharmaceutical preparations containing these compounds.

Abstract

The invention relates to a compound with the chemical formula 1 or its tautomeric, stereoisomeric or pharmaceutical salts, in which R1 to R3, A1 to A4, L1, E, Z and n are defined as in this description. The compounds expressed in this description are capable of inhibiting the activity of the HER2 kinase. Chemical formula 1

Description

Novel skeletal derivatives effective against HER2 mutations and pharmaceutical compositions containing the same

[0001] The present invention relates to a novel compound that has the effect of inhibiting kinase activity in cancers harboring HER2 mutations. The present invention also relates to an anticancer pharmaceutical composition containing this novel compound.

[0002] The epidermal growth factor receptor (EGFR) is a protein composed of a receptor portion and a tyrosine kinase portion. It functions to transmit signals from outside the cell to inside the cell by passing through the cell membrane. The EGFR / ERBB protein family includes EGFR and tyrosine kinases that are structurally similar to EGFR, and specifically, there are four members: EGFR (ERBB1), HER2 (Neu, ERBB2), HER3 (ERBB3), and HER4 (ERBB4). EGFR family kinases perform essential functions during the development of an organism, and are involved in various signaling processes such as cell growth and angiogenesis by forming heteromultimers among family members. It has been reported that EGFR family proteins are abnormally overexpressed or frequently mutated in most solid cancer cells, and this is associated with a poor prognosis. Mutations such as these HER2 mutations or exon 20 insertions in the EGFR and HER2 tyrosine kinase domains cause EGFR and HER2 to escape normal activity control, leading to constitutive activation, which is known to be a major cause of various cancers, including non-small cell lung cancer. Exon 20 insertion mutations are the third most common group of epidermal growth factor receptor mutations found in non-small cell lung cancer. The representative HER2 exon 20 insertion mutation is A775_G776insYVMA, which accounts for approximately 85% of HER2 mutations.

[0003] Because cancers harboring these mutations are largely unknown and do not respond to epidermal growth factor receptor tyrosine kinase inhibitors, effective targeted therapy remains challenging. Therefore, there is a need to develop targeted anticancer agents with superior anticancer effects against epidermal growth factor receptor mutations, possessing antitumor activity and no side effects.

[0004] The technical task of the present invention is to provide a novel compound capable of inhibiting the activity of a mutated HER2 kinase. More preferably, the technical task of the present invention is to provide a selective inhibitor compound that inhibits a HER2 mutant more potently than a wild-type EGFR.

[0005] In one aspect of the present invention, a compound defined by chemical formula 1 or a totoisomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[0006] [Chemical Formula 1]

[0007]

[0008] In the chemical formula above, A 1 and A 3 are independently N or CH, and A 2 Wow A 4 are independently N or CR a and here R a is H, CN, C 1~4 Alkyl or C 1~4 Alkoxy, R 1 Silver C 1~4 Alkyl, C 1~4 Alkoxy, CF3 or halogen, and R 2 is a six-membered-five-membered fused bicyclic heteroaryl group or a six-membered-six-membered fused bicyclic heteroaryl group, and optionally, the six-membered-five-membered fused bicyclic heteroaryl group or the six-membered-six-membered fused bicyclic heteroaryl group has one or more hydrogen atoms substituted with halogen, C 1~4Alkyl and C 1~4 Each of which may be independently substituted with a functional group selected from among alkoxy. In one specific embodiment, R 2 is selected from the following fused bicyclic heteroaryl substituents:

[0009]

[0010] At this time T is H or C 1~4 It is alkyl. Each R 3 are independently halogens, C 1~4 Alkoxy or C 1~4 alkyl, n is an integer from 0 to 3, and L 1 silver -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, but at this time Q 1 Silver C 1~3 Alkylene, Q 2 is hydrogen or C 1~3 Alkyl, R b is H or C 1~3 Alkyl, M is a single bond connecting to the E functional group in the above chemical formula. E is or -NR c - and here, J is a single bond connected to the carbonyl group of -C(=O)CH=CHZ. At this time, R c is H, C 1~4 Alkyl or C 3~6 Cycloalkyl, Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and Rd Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0011] In one embodiment of the present invention, the compound of the present invention or its isomer, its stereoisomer and its pharmaceutically acceptable salt have a structure represented by Chemical Formula 2.

[0012] [Chemical Formula 2]

[0013]

[0014] In the chemical formula above, R 4 Is , and each R 5 are independently halogen or C 1~4 Alkoxy, n is an integer from 0 to 3, and R a is H, C 1~4 Alkyl or C 1~4 It is alkoxy. L 2 Is -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 It's M. A 3 , E, Z, T, Q 1 and R b The meaning is the same as explained above in chemical formula 1, and M indicates that the corresponding carbon is connected to the carbonyl group of C(=O)CH=CHZ by a single bond.

[0015] In one specific embodiment of the present invention, the compound of the present invention or its isomer, its stereoisomer and its pharmaceutically acceptable salt have a structure represented by Chemical Formula 3.

[0016] [Chemical Formula 3]

[0017]

[0018] A in the compound of chemical formula 3 3 , R 4 , R 5 The meaning of Z is the same as that explained in chemical formula 2 above, and L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M is and G is -NR c -, and here R c is H, C 1~4 Alkyl or C 3~6 It is cycloalkyl, and J is a single bond connected to a carbonyl group of -C(=O)CH=CHZ.

[0019] In another specific embodiment of the present invention, the compound of the present invention or its isomer, its stereoisomer and its pharmaceutically acceptable salt have a structure represented by chemical formula 4.

[0020] [Chemical Formula 4]

[0021]

[0022] In the chemical formula above, L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, where M is CH2=CHC(=O)NR c It is a single bond that connects to a functional group, R c is H, C 1~4 Alkyl or C 3~6 It is cycloalkyl. R 6 and R 7 are independently H or F and Q 1 and R b The meaning is as described above in chemical formula 1.

[0023] In another aspect of the present invention, a pharmaceutical composition for the treatment of cancer is provided, comprising a therapeutically effective amount of the compound described above, a stereoisomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0024] In another aspect of the present invention, a method for treating cancer is provided. The method comprises administering to a patient a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1, or a pharmaceutical composition comprising such a compound of the present invention.

[0025] The compounds of the present invention can inhibit the kinase activity of HER2 kinase, particularly HER2 having a mutation. In one specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 having an exon 20 mutation. In a more specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 having an exon 20 insertion mutation. In the most specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 having an exon 20 insertion mutation more potently than wild-type EGFR kinase.

[0026] Hereinafter, embodiments of the present invention will be described in detail. Prior to this, it should be noted that the terms and words used in this specification and claims should not be construed as limited to their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

[0027] Therefore, the embodiments described in this specification are merely examples presented for the purpose of helping to understand the present invention and do not represent all of the technical ideas of the present invention. Therefore, it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0028] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The numerical range indicated using the term "to" herein includes the ranges that include the values ​​described before and after the term "to" as the lower and upper limits, respectively.

[0029] HER2 and HER2 exon 20 mutations

[0030] HER2 stands for human epidermal growth factor receptor 2, also known by its other abbreviation, ERBB2. HER2 is a member of the EGFR / ErbB protein family and has tyrosine kinase activity. The wild-type messenger RNA sequence of HER2 is given as GenBank accession number NM_004448.2. HER2 mutations can be broadly categorized into gene amplification, protein overexpression, and gene mutation. HER2 gene amplification occurs when the HER2 gene has more copies than normal, resulting in overexpression of the HER2 protein. HER2 protein overexpression occurs when the HER2 protein is excessively expressed on the cell surface due to the amplification of the HER2 gene, promoting abnormal growth and metastasis of cancer cells. HER2 gene mutations are mutations that occur in the HER2 gene itself and can alter the function of the protein. They are found in breast cancer, lung cancer, bladder cancer, ovarian cancer, and other cancers. Among HER2 mutations, there is an exon 20 insertion type in which a nucleotide sequence is inserted into exon 20 of the wild-type sequence.

[0031] In this specification, the term “gene alteration” or “mutation” encompasses both a mutation in which the base sequence is different from the wild-type sequence of the gene, and a state in which the gene deviates from the state in which it is regulated in the wild type, such as overexpression or gene amplification of the gene.

[0032] As used herein, an insertion or insertional mutation or insertional variant refers to the addition of one or more nucleotide base pairs in a DNA sequence. For example, an insertional variant in HER2 exon 20 encompasses one or more insertions of 3 to 18 nucleotides in length in the DNA sequence of HER2 corresponding to amino acid residues 770 to 785 of the HER2 sequence.

[0033] HER2 exon 20 mutations may include one or more point mutations, insertions and / or deletions of 3 to 18 nucleotides between residues 770 and 785 of the HER2 amino acid sequence. The one or more HER2 exon 20 mutations may occur in residues Ala775, Gly776, Ser779 and / or Pro780. The one or more HER2 exon 20 mutations may be A775insV G776C, A775insYVMA, G776V, G776C V777insV, G776C V777insC, G776del insVV, G776del insVC and / or P780insGSP.

[0034] As used herein, the term "selective inhibition" or "selectively inhibits" means that a compound of the invention can inhibit the signal transduction activity of a biological target kinase to a greater extent, either through direct interaction with the target or through indirect interaction, than it can inhibit the signal transduction activity of a non-target kinase. For example, a compound that selectively inhibits exon 20 mutant HER2 over wild-type EGFR has at least about two-fold (or at least about three-fold, or about five-fold, or about ten-fold, or about fifty-fold) the activity against the exon 20 mutant isoform relative to its activity against the wild-type EGFR isoform.

[0035] Definition of terms

[0036] In this specification, the prefix "C x~y " or "C x ~C y "(where x and y are natural numbers) is used in front of a functional group to indicate the number of carbon atoms that the functional group has in its backbone. For example, C 1~4 An alkyl group has 1 to 4 carbon atoms, C 1~3 An alkyl group refers to an alkyl group having 1 to 3 carbon atoms. For example, C1~C4 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and t-butoxy. For example, C3~C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. In addition, when the number of elements constituting the ring is indicated and limited in front of a ring functional group or compound (including both a carbon ring and a heterocycle) in the present specification, the ring is a ring composed of that number of elements, that is, carbon and / or heteroatoms. For example, a six-membered ring heteroaryl refers to a heteroaryl group that contains one or more heteroatoms and is formed together with carbon, and the number of elements constituting the ring is 6.

[0037] Unless otherwise specified herein, when a functional group is linked to another part of a compound by a bond, the linkage may be via any atom of that functional group, provided that it is a suitable atom. For example, when referring to a propyl group, both prop-1-yl and prop-2-yl are included.

[0038] As used herein, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine and iodine.

[0039] In this specification, "C 1~4 The term "alkyl" refers to a group whose chemical formula is C when n is a natural number from 1 to 4. n H 2n+1 It refers to a saturated hydrocarbon group of 1-valent. C 1~4 Alkyl groups include all straight-chain or branched saturated hydrocarbons having 1 to 4 carbon atoms, such as n-propyl, i-propyl, sec-butyl, tert-butyl, etc.

[0040] In this specification, "C 1~3 The term "alkylene" refers to a group whose chemical formula is C when n is a natural number from 1 to 3. n H 2n Refers to a saturated hydrocarbon group of two atoms. In this specification, C 1~3 The functional group called alkylene includes both straight-chain and branched functional groups, and in this case, the two bonds mentioned above may all be on the same carbon atom, or may be divided into two different carbon atoms. C 1~3 Examples of alkylenes include methylene, ethylenes (-CH2CH2- or -CH(CH3)-), and propylenes (-CH2CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, or -C(CH3)2-).

[0041] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon having a ring structure and the chemical formula C n H 2n-1 It refers to a group of atoms of the first group. C3~6 Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] In this specification, the term "bicyclic" compound refers to a carbon ring compound or heterocyclic compound composed of two rings, which is composed of one or more ring atoms shared between the two constituent rings. In a bicyclic compound, the atom shared between the two rings is called a bridgehead atom. Bicyclic compounds are divided into three types depending on the number of bridgehead atoms and whether or not the bridgehead atoms are directly connected. A fused bicyclic compound has two bridgehead atoms that are directly connected to each other by a bond. Examples of fused bicyclic compounds include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. A ring compound with only one bridgehead atom is a spirocyclic compound. A bridged ring compound has two bridgehead atoms that are not directly connected to each other by a bond, but rather have one or more ring atoms interposed between the two bridgehead atoms. Examples of bridged ring compounds include norbornane, 7-oxabicyclo[2.2.1]heptane, and adamantane.

[0043] In this specification, fused bicyclic compounds can be expressed by specifying the number of ring atoms in each of the two rings that make up the compound. For example, thienopyridine, benzofuran, indole, etc. can be referred to as five- or six-membered fused bicyclic compounds. Similarly, purine, naphthalene, chromane, tetrahydroquinoline, quinoline, quinoxaline, pteridine, etc. can be referred to as six- or six-membered fused bicyclic compounds.

[0044] The term "aryl" in this specification refers to an aromatic C6~C 14It refers to a monovalent hydrocarbon functional group that can have one to three aromatic rings as a functional group. For example, aryl has C6, C 10 , C 13 and C 14 Aromatic hydrocarbon ring atoms are included, such as phenyl, naphthyl, anthracenyl, and fluorenyl.

[0045] The term "heteroaryl" as used herein refers to a monovalent aromatic ring composed of an unsaturated ring and one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The ring system of a heteroaryl can be a single ring, a double ring in the form of a fused ring, or a tricyclic ring. The term heteroaryl excludes rings containing a direct linkage between oxygen and sulfur atoms, such as ―O―O―, ―O―S―, or ―S―S―. Some examples of heteroaryl include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, quinazolinyl, 2-furyl, 3-furyl, benzofuryl, 2-thienyl, oxazolyl, isothiazolyl, thiadiazolyl, etc. Heteroaryl can also be defined by specifying its heteroatom. For example, heteroaryl in which the heteroatom is nitrogen includes pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, etc., but excludes furyl, oxazolyl, thienyl, etc.

[0046] Fused bicyclic heteroaryl groups include six-membered-five-membered fused bicyclic heteroaryl groups such as benzimidazolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrimidinyl, triazolopyrimidinyl, furyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, anthranilyl, benzisoxazolyl, benzopyrazolyl, benzothiadiazolyl, etc., and six-membered-six-membered fused bicyclic heteroaryl groups such as benzopyridinyl, benzopyrimidinyl, quinolinyl, These include isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolizinyl, and cinnolinyl.

[0047] The term "heterocycloalkyl" as used herein refers to a monovalent atomic group in which at least one carbon atom forming a ring in a cycloalkyl group is independently replaced in each instance by a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, and thiazolidinyl.

[0048] In this specification, the term "substituted" or "substituted" in front of a functional group refers to a structure in which at least one of the hydrogens of the functional group is replaced with a designated functional group other than hydrogen, unless otherwise stated in the specification, provided that the substituted functional group maintains its normal valence and yields a chemically stable functional group. In typical cases, the substituent is a halogen, CN, OH, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~14 Heteroaryl, C 1~6 Choose between alkoxy and CF3.

[0049] In this specification, a specific atom of a substituent forming part of a compound is " " indicates that the substituent is directly chemically bonded to the rest of the compound through that atom.

[0050] In this specification, if a dotted line such as "---" is shown on a bond line, it indicates that the bond line is an optional element that may or may not be present. For example, A notation like this indicates that this structural formula encompasses benzene and 1,3-cyclohexadiene.

[0051] As used herein, the term "pharmaceutically acceptable salt" for a compound refers to a salt that does not impair the desired biological activity of the compound and does not cause inappropriate toxicity, irritation, or allergic reactions when used in contact with human or animal tissues. Pharmaceutically acceptable salts are well known in the art. For example, reference may be made to prior literature, such as the paper by Berge et al., J. Pharmaceutical Sciences (1977), Vol. 66, pp. 1-19. Some examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, and hydrosulfide, and base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium (N + (C 1~4 There are alkyl)4), and examples of alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.

[0052] Those skilled in the art will appreciate that some of the compounds of the present invention may exist in more than one isomeric form. Since a chemical structural formula can only represent one isomeric form, it is well understood that when a compound is referred to by a single structural formula for convenience, the structural formula also encompasses the isomeric variations of that compound. Depending on the compound, one of several isomeric forms may exist primarily, a mixture of multiple isomeric forms may exist at room temperature, or only one isomeric form may be isolated. Examples of isomeric forms include those between the pyridone and hydroxypyridine forms, and those between the keto and enol forms.

[0053] compound

[0054] In one aspect of the present invention, a compound defined by chemical formula 1, its isomers, its stereoisomers, and pharmaceutically acceptable salts thereof are provided.

[0055]

[0056] In the above chemical formula 1, A 1 and A 3 are independently N or CH. In chemical formula 1, A 2 Wow A 4 are independently N or CR a And, at this time R a is H, CN, C 1~4 Alkyl or C 1~4 It is alkoxy.

[0057] R in chemical formula 1 1 Silver C 1~4 Alkyl, C 1~4 Alkoxy, CF3 or halogen.

[0058] R in chemical formula 1 2is a six-membered-five-membered fused bicyclic heteroaryl group or a six-membered-six-membered fused bicyclic heteroaryl group, and optionally, the six-membered-five-membered fused bicyclic heteroaryl group or the six-membered-six-membered fused bicyclic heteroaryl group has one or more hydrogen atoms substituted with halogen, C 1~4 Alkyl and C 1~4 Each can be independently substituted with a functional group selected from among alkoxy.

[0059] In the compound of chemical formula 1, each R 3 are independently halogens, C 1~4 Alkoxy or C 1~4 alkyl, and n is an integer from 0 to 3.

[0060] L in the compound of chemical formula 1 1 silver -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 and -C(=O)N(Q 2 )Q 1 M, C≡CM and -C≡CQ 1 The substituent of the ligand chosen from M, at this time Q 1 Silver C 1~3 Alkylene, Q 2 is hydrogen or C 1~3 Alkyl, R b is H or C 1~3 is alkyl, and M is a single bond connecting to the E functional group. In short, L is a functional group 1 This -CH=CHQ 1 If M, then -CH=CHQ 1 Q among M's vinyl records 1The carbon bonded to is connected to the E functional group of chemical formula 1, and the "─" sign indicates that the remaining carbons in the vinyl group are directly connected to the fused double ring of chemical formula 1 in the opposite direction to the direction of the E functional group mentioned above. Similarly, L 1 this In this case, the corresponding L 1 The carbon of the ring marked M in the group is directly connected to the E functional group, " " The vinyl group carbon with the symbol is connected in the direction opposite to the direction of the E functional group in the compound of chemical formula 1, i.e., it is directly connected to the fused double ring of chemical formula 1.

[0061] In the compound of formula 1, E is selected from the following divalent functional groups:

[0062] Wow -NR c -.

[0063] At this time R c is H, C 1~4 Alkyl or C 3~6 It is cycloalkyl. In this functional group E, J and " " The sign is L, which is the functional group of the tooth 1 Similar to what was explained above, the carbon labeled J indicates that it is directly connected to the -C(=O)CH=CHZ functional group in formula 1 by a single bond, The ring carbon labeled with the symbol is in the opposite direction to the direction of connection to the -C(=O)CH=CHZ functional group in the compound of formula 1, i.e. L 1 It indicates that it is directly connected to .

[0064] In the compound of chemical formula 1, Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R eare independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0065] In one specific embodiment, the compound of formula 1 is A 1 Inland A 3 At least one of them is nitrogen (N). In another more specific embodiment, the compound of formula 1 is L 1 This -CH=CH-Q 1 M and Q 1 is CH2 or -CH(CH3)-, and E is -NR c -, Z is hydrogen (H). In another more specific embodiment, the compound of formula 1 is 1 This -C≡CQ 1 M and Q 1 is CH2, and E is -NR c am.

[0066] In another specific embodiment, R of chemical formula 1 2 You can select from the following fused double ring heteroaryl groups:

[0067]

[0068] At this time T is H or C 1~4 It's alkyl. Here The sign is The carbon atom to which it is connected is the remainder of the compound of formula 1, i.e. OR 2 This indicates that it is directly connected to the oxygen atom of the site by a single bond.

[0069] In a more specific embodiment, among the compounds of the chemical formula 1 of the present invention, Select the site from the functional groups below:

[0070]

[0071] Here The symbol indicates that the nitrogen atom of the corresponding -NH is in the remainder of the compound of formula 1, i.e. A 1 Inland A 3 This indicates that it is directly connected to the heterocyclic ring by a single bond.

[0072] In a specific embodiment of the compound of the present invention, L 1 -EC(=O)CH=CHZ moiety is selected from the following functional groups.

[0073]

[0074] Here The indication is similar to the previous one, the corresponding L 1 -EC(=O)CH=CHZ part The remainder of the compound of formula 1, i.e. A, to the atom labeled 1 Inland A 3 This indicates that the heterocyclic ring included in this is directly connected by a single bond.

[0075] In one embodiment, the compound of the present invention has a structure represented by chemical formula 2.

[0076]

[0077] R in the compound of chemical formula 2 4 is selected from the following heterocyclic substituents:

[0078] Here T is H or C 1~4 It's alkyl.

[0079] In the compound of chemical formula 2, each R 5 are independent halogens or C 1~4 Alkoxy, and n is an integer from 0 to 3.

[0080] A in the compound of chemical formula 2 3 is N or CH, and R a is H, C 1~4 Alkyl or C1~4 It is alkoxy.

[0081] L in chemical formula 2 2 Is -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M and -OQ 1 As a functional group of the tooth that selects from M, at this time Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 It's alkyl. L 2 In M and " " The sign is L, which is the functional group of the tooth 1 Similar to what was explained above, the carbon labeled M indicates that it is directly connected to the E functional group in chemical formula 2 by a single bond, The ring carbon labeled with the symbol is in the opposite direction to the direction of connection to the E functional group in the compound of formula 2, i.e. A 3 This indicates that it is directly connected to the heterocyclic ring by a single bond.

[0082] In chemical formula 2, E is a divalent functional group, the same as E in chemical formula 1. Wow -NR c - Choose from. At this time, R c is H, C 1~4 Alkyl or C 3~6 Cycloalkyl is defined as the same as in chemical formula 1. Here, J is a single bond connected to a carbonyl group of -C(=O)CH=CHZ.

[0083] In chemical formula 2, Z is H, C, the same as in chemical formula 1. 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0084] In one specific embodiment, the compound of formula 2 is A 3 This is nitrogen (N).

[0085] In another specific embodiment, the compound of formula 2 is R 5 is fluorine (F).

[0086] In another specific embodiment, the compound of formula 2 is a compound wherein Z is H, CH3, Or -CH2N(CH3)2.

[0087] In another embodiment, the compound of the present invention has a structure represented by chemical formula 3.

[0088]

[0089] In the chemical formula above, R 4 Is , where T is H or C 1~4 It's alkyl.

[0090] Each R 5 are independent halogens, and n is an integer from 0 to 3.

[0091] A 3 is N or CH.

[0092] L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, and here Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 Alkyl, M is a single bond connecting to the above G functional group.

[0093] G is -NR c -, and here R c is H, C 1~4 Alkyl or C 3~6 It is cycloalkyl, and J is a single bond connected to the carbonyl group of -C(=O)CH=CHZ,

[0094] Z is H, C 1~4 Alkyl, X,-C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0095] In a more specific embodiment, the compound of the present invention has a structure of chemical formula 3 wherein G is -NR c -, am.

[0096] In another embodiment, the compound of the present invention has a structure represented by chemical formula 4.

[0097]

[0098] In the chemical formula above, L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, and here Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 Alkyl, M is CH2=CHC(=O)NR c It is a single bond that is directly connected to a functional group.

[0099] R c is H, C 1~4 Alkyl or C 3~6 Cycloalkyl, and R 6 and R 7 are independently H or F.

[0100] In one specific embodiment of the compound of formula 4, R c is methyl.

[0101] In another embodiment, the compound of the present invention has a structure represented by chemical formula 5.

[0102]

[0103] In the above chemical formula 5, A 1 and A 3 are independently N or CH, and A 2 is N or CR a and here R a is H, C 1~4 Alkyl or C 1~4 It is alkoxy.

[0104] R in the compound of chemical formula 5 2a is selected from the following heterocyclic substituents:

[0105] Here T is H or C 1~4 It's alkyl.

[0106] In the compound of chemical formula 5, each R" is an independent halogen, and n is an integer from 0 to 3. In the compound of chemical formula 5, m is an integer from 1 to 3.

[0107] In chemical formula 5, Z is the same as H, C in chemical formula 1. 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0108] In one specific embodiment, the compound of formula 5 is R 2a go am.

[0109] In another specific embodiment, the compound of formula 5 is A 1 This is CH, and A 3 is N.

[0110] In a most specific embodiment, the compound of the present invention is the following compound, a stereoisomer, a tert-butyl isomer or a pharmaceutically acceptable salt thereof:

[0111] (1)N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)-N-methylacrylamide,

[0112] (2)N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)ethyl)-N-methylacrylamide,

[0113] (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-methylacrylamide,

[0114] (4)N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)ethyl)-N-methylacrylamide,

[0115] (5)N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide,

[0116] (6)N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)acrylamide,

[0117] (7)N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)ethyl)acrylamide,

[0118] (8)N-methyl-N-(2-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)ethyl)acrylamide,

[0119] (9)N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)propyl)acrylamide,

[0120] (10)N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide,

[0121] (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-methylacrylamide,

[0122] (12)N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)-N-methylacrylamide,

[0123] (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-methylacrylamide,

[0124] (14)N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)ethyl)-N-methylacrylamide,

[0125] (15)N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)ethyl)acrylamide,

[0126] (16)N-methyl-N-(2-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)acrylamide,

[0127] (17)N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)propyl)acrylamide,

[0128] (18)N-methyl-N-(2-(methyl(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)ethyl)acrylamide,

[0129] (19)N-methyl-N-(2-(methyl(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)acrylamide,

[0130] (20)N-methyl-N-(3-(methyl(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)propyl)acrylamide,

[0131] (21)N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)-2-oxoethyl)acrylamide,

[0132] (22) (E)-N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide,

[0133] (23) (E)-N-methyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)aryl)acrylamide,

[0134] (24) (E)-N-methyl-N-(3-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)allyl)acrylamide,

[0135] (25) (E)-N-(3-(4-((3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0136] (26) (E)-N-methyl-N-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)but-4-en-1-yl)acrylamide,

[0137] (27) (E)-1-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)piperidin-1-yl)prop-2-en-1-one,

[0138] (28) (E)-1-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)azetidin-1-yl)prop-2-en-1-one,

[0139] (29) (E)-1-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0140] (30) (E)-N-methyl-N-(1-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)cyclopropyl)acrylamide,

[0141] (31) (E)-N-methyl-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,

[0142] (32) (E)-4-(dimethylamino)-N-methyl-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,

[0143] (33) (E)-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyridin-6-yl)allyl)acrylamide,

[0144] (34) (E)-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,

[0145] (35) (E)-N-(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)acrylamide,

[0146] (36) (E)-N-(3-(4-((2-chloro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)acrylamide,

[0147] (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,

[0148] (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,

[0149] (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,

[0150] (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,

[0151] (41) (E)-4-(dimethylamino)-N-((E)-3-(4-((2-fluoro-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,

[0152] (42) (E)-N-(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0153] (43) (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,

[0154] (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,

[0155] (45)(E)-N-(3-(4-((2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0156] (46) (E)-N-(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0157] (47) (E)-N-(3-(4-((2-fluoro-3-methyl-4-((3-methyl-3H-imidazolo[4,5-b]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0158] (48) (E)-1-(3-(2-(4-((3-methyl-4-((2-methyl-2H-indazol-6-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)azetidin-1-yl)prop-2-en-1-one,

[0159] (49) (E)-N-ethyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)acrylamide,

[0160] (50) (E)-N-methyl-N-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)but-3-en-2-yl)acrylamide,

[0161] (51) (S,E)-N-methyl-N-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)but-3-en-2-yl)acrylamide,

[0162] (52) (R,E)-N-methyl-N-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)but-3-en-2-yl)acrylamide,

[0163] (53) (E)-N-(tert-butyl)-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)acrylamide,

[0164] (54) (E)-N-(3-(4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0165] (55) (E)-N-(3-(4-((3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0166] (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-methylacrylamide,

[0167] (57) (E)-N-(3-(4-((4-(benzo[d]oxazol-5-yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide,

[0168] (58) (E)-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)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide,

[0169] (59) (E)-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)-4-(piperidin-1-yl)but-2-enamide,

[0170] (60) (E)-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)-4-morpholinobut-2-enamide,

[0171] (61) (E)-N-methyl-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)-4-(piperidin-1-yl)but-2-enamide,

[0172] (62) (E)-N-methyl-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)-4-morpholinobut-2-enamide,

[0173] (63) (E)-N-methyl-N-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)phenyl)acrylamide,

[0174] (64) (E)-N-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)phenyl)acrylamide,

[0175] (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-methylacrylamide,

[0176] (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-methylacrylamide,

[0177] (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-methylacrylamide,

[0178] (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-methylacrylamide,

[0179] (69)N-(3-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)prop-2-yn-1-yl)-N-methylacrylamide,

[0180] (70)N-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanoquinolin-6-yl)prop-2-yn-1-yl)-N-methylacrylamide,

[0181] (71)N-methyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)prop-2-yn-1-yl)acrylamide,

[0182] (72)N-methyl-N-(3-(8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[5,4-d]pyrimidin-2-yl)prop-2-yn-1-yl)acrylamide,

[0183] (73)N-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl) prop-2-yn-1-yl)-N-methylacrylamide,

[0184] (74) (R)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0185] (75) (S)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0186] (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,

[0187] (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,

[0188] (78) (R)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one,

[0189] (79) (S)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)azetidin-1-yl)prop-2-en-1-one,

[0190] (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)pyrrolidin-1-yl)prop-2-en-1-one,

[0191] (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)pyrrolidin-1-yl)prop-2-en-1-one,

[0192] (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,

[0193] (83) (R)-1-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0194] (84) (S)-1-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0195] (85) (R)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0196] (86) 1-((2R)-2-((4-((3-methyl-4-((1-methyl-3a,7a-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0197] (87) (S)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0198] (88) (R)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one,

[0199] (89) (S)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one,

[0200] (90) 1-((2R)-2-((8-((3-methyl-4-((1-methyl-3a,7a-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one,

[0201] (91) (R)-1-(2-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one or

[0202] (92) (S)-1-(2-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)piperidin-1-yl)prop-2-en-1-one.

[0203] 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 having a mutation in exon 20. In a specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 having a mutation in exon 20. In a further specific embodiment, the compounds of the present invention can inhibit the kinase activity of HER2 having an insertion mutation in exon 20.

[0204] pharmaceutical composition

[0205] In another aspect, the present invention discloses a pharmaceutical composition comprising the aforementioned compound and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used to inhibit the activity of HER2 in the body, for example, for the treatment of cancer. In particular, the pharmaceutical composition of the present invention can be used to treat cancer caused by HER2 having a genetic mutation or mutation in exon 20, such as an insertional mutation.

[0206] In the pharmaceutical composition of the present invention, the aforementioned compounds may be present as pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts may be formed with addition salts of metals or amines, such as alkali metal bases, alkaline earth metal bases, or organic amines. Pharmaceutically acceptable salts of the compounds may also be prepared using pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids.

[0207] In the present invention, a pharmaceutically acceptable excipient refers to an inactive ingredient approved by a relevant administrative agency (e.g., the Ministry of Food and Drug Safety of the Republic of Korea, the Federal Food and Drug Administration (FDA) of the United States) as being suitable for use together with an active pharmaceutical ingredient for the purpose of manufacturing a medicine for treating a disease in humans or livestock. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, fluidizing agents, disintegrating agents, sweeteners, diluents, preservatives, coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvent emulsifiers, and adjuvants.

[0208] The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release preparation, solution, or suspension; in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository.

[0209] The pharmaceutical composition according to the present invention can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coated tablet preparation, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The appropriate formulation will vary depending on the chosen route of administration.

[0210] Pharmaceutical compositions suitable for oral administration can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Using such excipients and carriers, the compounds disclosed herein can be formulated as tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and the like for oral ingestion by patients to be treated. Oral pharmaceutical preparations can be obtained by adding the compounds of the present invention together with solid excipients, grinding the resulting mixture if necessary, adding suitable auxiliaries if necessary, and then processing the granulated mixture to form tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

[0211] For pharmaceutical compositions for oral administration of a therapeutically effective amount of a compound of the present disclosure, the compositions are generally in the form of solid (e.g., tablets, capsules, pills, powders, or troches) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0212] When administered in tablet form, the composition may additionally contain functional solids and / or solid carriers such as gelatin or adjuvants. Compositions in the form of tablets, capsules, and powders may contain from about 1 to about 95 wt% of the compound of the present invention, preferably from about 15 to about 90 wt% of the compound of the present invention, based on the total weight of the composition. An example of a tablet composition may contain, for example, up to about 80 wt% of the active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of a binder, from about 0 wt% to about 85 wt% of a diluent, from about 2 wt% to about 10 wt% of a disintegrant, and from about 0.25 wt% to about 10 wt% of a lubricant.

[0213] When administered in liquid or suspension form, a functional liquid and / or liquid carrier such as water, petroleum, or animal or vegetable oil may be added. Liquid compositions may further contain saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5% to about 90% by weight of the compound of the present invention, preferably from about 1% to about 50% by weight of the compound of the present invention. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0214] When the pharmaceutical composition of the present invention is administered intravenously, transdermally, or subcutaneously, it is in the form of a parenteral aqueous solution that does not contain a pyrogen. The preparation of such parenteral solutions, taking into account pH, isotonicity, stability, etc., is within the skill of the art. Preferred compositions for intravenous, transdermal, or subcutaneous injection generally contain an isotonic vehicle. Such compositions can be prepared for administration as a solution of the free base or a pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as dispersions in oils, can also be prepared. Under normal storage and use conditions, such preparations may optionally contain a preservative to prevent the growth of microorganisms.

[0215] Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with various other ingredients, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In embodiments of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any additional required ingredients from a previously sterile-filtered solution thereof.

[0216] To achieve controlled release of the active compound upon contact with body fluids in the gastrointestinal tract and to provide substantially constant and effective levels of the active compound in the plasma, sustained-release or sustained-release formulations may be prepared. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, sustained-release approaches may enhance absorption through saturation or restriction pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix comprising a biodegradable polymer, a water-soluble polymer, or a mixture thereof, and optionally a suitable surfactant. Embedding in this context may mean incorporating microparticles into the polymer matrix. Controlled-release formulations may also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

[0217] The pharmaceutical composition of the present invention may be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion). The injectable formulation may be presented in unit dosage form (e.g., ampoules or multi-dose containers) with an added preservative. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0218] The pharmaceutical composition may be presented in unit dosage form suitable for single administration of precise dosages.

[0219] A pharmaceutical composition containing the compound of the present invention can be used according to the method described below.

[0220] Treatment methods

[0221] In another aspect, the present invention provides a method for treating cancer. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1. Alternatively, the present invention comprises administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient.

[0222] In a method for treating cancer, the compound of the present invention may be administered alone or in combination with at least one other drug. These other drugs and the compound of the present invention may be administered simultaneously or sequentially.

[0223] As used herein, unless specifically stated otherwise, a “therapeutically effective amount” of a compound refers to an amount of the compound sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or to provide a therapeutic effect for a disease, disorder, or condition. The term “therapeutically effective amount” encompasses an amount that improves overall healing, an amount that alleviates or avoids a symptom or cause of a disease or condition, and an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0224] The amount of compound administered may vary depending on the subject being treated, the subject's age, health, sex, and body weight, the type (if any) of concurrent treatment, the severity of the pain, the nature of the desired effect, the treatment regimen and frequency, and the prescribing physician's judgment. The frequency of administration may also vary depending on the pharmacodynamic effects on arterial oxygen pressure. However, the most desirable dosage can be tailored to the individual subject, as understood and determined by those skilled in the art without undue experimentation. This typically involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0225] While individual needs may vary, determining the optimal therapeutically effective dose of a compound is common knowledge in this field. When administered to humans for the therapeutic or preventative treatment of conditions and disorders using the compounds of the present invention, a typical dosage of the compounds of the present invention may range from about 0.01 mg / kg / day to about 50 mg / kg / day. This dosage may be administered as a single dose or divided into multiple doses.

[0226] In another aspect of the present invention, the use of a compound of the present invention as a medicament is provided. In one embodiment, the use of a compound of the present invention is provided for the treatment or prevention of cancer.

[0227] In another aspect of the present invention, a compound of the present invention is provided for use in the manufacture of a medicament. In one embodiment, a compound of the present invention is provided for use in the manufacture of a medicament for the treatment or prevention of cancer.

[0228] In another aspect of the present invention, a method for inhibiting intracellular HER2 kinase activity is provided. The method comprises contacting a cell in which HER2 kinase activity is to be inhibited with an effective amount of a compound of the present invention, e.g., a compound defined by Formula 1.

[0229] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way. Various changes and modifications may be made to the present examples, and such changes and modifications also fall within the scope of the appended claims.

[0230] [Example 1] Preparation of N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)-N-methylacrylamide

[0231]

[0232] Step 1) Preparation of 4-oxo-1H-quinazolin-6-yl acetate

[0233] 3 g (18.5 mmol) of 6-hydroxy-1H-quinazolin-4-one and 3.4 mL (42.5 mmol) of pyridine were diluted in 27.9 mL (296.0 mmol) of acetic anhydride and stirred at 100°C for 2 hours. After the reaction was completed, the resulting reaction mixture was slowly added dropwise to ice water and stirred. The resulting mixture was filtered under reduced pressure, and the obtained solid was washed with distilled water and dried in an oven at 50°C to obtain 4.4 g (yield 100%) of the title compound.

[0234] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0235] Step 2) Preparation of 4-chloroquinazolin-6-yl acetate

[0236] 2.2 g (10.7 mmol) of the compound prepared in the above step 1) was diluted in thionyl chloride (31 mL, 430.9 mmol), 0.3 mL of N,N-dimethylformamide was added, and the mixture was stirred at 90°C for 6 hours. The resulting mixture was distilled under reduced pressure to obtain 2 g (yield: 83%) of the title compound.

[0237] 1 H-NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 8.38 (d, 1H), 8.12 (s, 1H). 7.85 (d, 1H), 2.43 (s, 3H).

[0238] Step 3) Preparation of [4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]acetate

[0239] 1 g (4.49 mmol) of the compound prepared in the above step 2) and 1.1 g (4.49 mmol) of 3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline were diluted in a mixed solution of 12 mL of isopropyl alcohol and 12 mL of ethylene chloride, and stirred at 80°C for 4 hours. The resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to obtain 350 mg (yield: 18%) of the title compound.

[0240] 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).

[0241] Step 4) Preparation of 4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-ol

[0242] 350 mg (0.82 mmol) of the compound prepared in the above step 3) and 1.6 mL (0.82 mmol) of ammonium hydroxide were diluted in 6 mL of methanol and stirred at 80°C for 4 hours. The resulting mixture was distilled under reduced pressure and then crystallized with dichloromethane to obtain 305 mg (yield: 96%) of the title compound.

[0243] 1H-NMR (300 MHz, DMSO-d6) 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).

[0244] Step 5) Preparation of 3-tert-butylN-methyl-N-[2-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]oxyethyl]carbamate

[0245] 305 mg (0.79 mmol) of the compound prepared in the above step 4), 184 mg (0.95 mmol) of 3-tert-butyl N-(2-chloroethyl)-N-methyl-carbamate, and 438 mg (3.17 mmol) of potassium carbonate were diluted in 2 mL of N,N-dimethylformamide and stirred at 100°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 32 mg (yield: 7%) of the title compound.

[0246] 1 H-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, 2 H), 4.36-4.33 (m, 2H), 3.75-3.70 (m, 2H), 3.04 (s, 3H), 2.26 (s, 3H), 1.59 (s, 9H).

[0247] Step 6) Preparation of N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)-N-methylacrylamide

[0248] 32 mg (0.059 mmol) of the compound prepared in step 5) above was diluted in a mixed solution of 0.45 mL (5.9 mmol) of trifluoroacetic acid and 1 mL of dichloromethane, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure. 6.4 μL (0.09 mmol) of acrylic acid and 27 μL (0.09 mmol) of a propylphosphonic anhydride solution were diluted in 2 mL of N,N-dimethylformamide, and 75 μL (0.42 mmol) of N,N-diisopropylethylamine was added, and stirred at room temperature for 30 minutes. The mixed solution was added to the residue obtained by distillation under reduced pressure, and stirred at 0°C for 2 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, and then washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 4 mg of the title compound (yield: 12%).

[0249] 1 H-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, 2 H), 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);

[0250] MS (ESI+): m / z = 496.3 [M+H]+ .

[0251] The compounds of Examples 2 to 10 shown in Table 1 below were each prepared using the same or similar method as that of Example 1.

[0252]

[0253]

[0254]

[0255]

[0256] [Example 11]

[0257] Preparation of 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-methylacrylamide

[0258]

[0259] Step 1) Preparation of 4,6-dichloropyrido[3,2-d]pyrimidine

[0260] 1.2 g (6.50 mmol) of 6-chloropyrido[3,2-d]pyrimidin-4-ol was diluted in 12 mL (165.22 mmol) of thionyl chloride, 0.1 mL of N,N-dimethylformamide was added, and the mixture was stirred at 120°C for 12 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and distilled under reduced pressure to obtain 1.4 g (yield: 100%) of the title compound.

[0261] 1 H-NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 8.35 (d, 1H), 7.89 (d, 1H).

[0262] Step 2) Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-chloropyrido[3,2-d]pyrimidin-4-amine

[0263] 1.4 g (0.7 mmol) of the compound prepared in the above step 1) and 1.5 g (6.3 mmol) of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline were diluted in 15 mL of isopropanol and 15 mL of 1,2-dichloroethane. 1 mL of trifluoroacetic acid was added thereto, and the mixture was stirred at 80°C for 5 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and distilled under reduced pressure. The obtained residue was diluted with ethyl acetate solvent and washed with a saturated sodium bicarbonate aqueous solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2:1 (volume ratio)) to obtain 1.5 g (yield: 59%) of the title compound.

[0264] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0265] Step 3) Preparation of 3-tert-butyl (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)(methyl)carbamate

[0266] 200 mg (0.5 mmol) of the compound prepared in the above step 2) and 863 mg (4.95 mmol) of 3-tert-butyl (2-aminoethyl) (methyl) carbamate were diluted in 1-butanol and stirred at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the resulting reaction mixture was distilled under reduced pressure, diluted with ethyl acetate solvent, and washed with water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10: 1 (volume ratio)) to obtain 278 mg (yield: 100%) of the title compound.

[0267] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0268] Step 4) N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6 Preparation of -(2-(methylamino)ethyl)pyrido[3,2-d]pyrimidine-4-diamine

[0269] 278 mg (0.51 mmol) of the compound prepared in the above step 3) was diluted in 3 mL of dichloromethane, 1.5 mL (19.6 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure, and a 2N aqueous sodium hydroxide solution was slowly added dropwise, followed by washing with a diluted mixed solvent of chloroform: 2-propanol (3: 1 (volume ratio)). The organic layer thus separated was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 1: 99 (volume ratio)) to obtain 143 mg (yield: 63%) of the title compound.

[0270] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0271] Step 5) Preparation of 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-methylacrylamide

[0272] 0.03 mL (0.47 mmol) of acrylic acid and 0.17 mL (0.95 mmol) of N,N-diisopropylethylamine were diluted in 0.5 mL of N,N-dimethylformamide, and 0.14 mL (0.47 mmol) of propylphosphonic anhydride solution was added, and the mixture was stirred at room temperature for 30 minutes. The solution was added dropwise to a mixture of 140 mg (0.31 mmol) of the compound prepared in step 4) above and 0.08 mL (0.47 mmol) of N,N-diisopropylethylamine in 1 mL of N,N-dimethylformamide at 0°C, and the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 15.0 mg (yield: 10%) of the title compound.

[0273] 1 H-NMR (300 MHz, DMSO-d6) 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);

[0274] MS (ESI+): m / z = 517.2 [M+H] + .

[0275] The compounds of Examples 12 to 21 shown in Table 2 below were each prepared using a method identical or similar to that of Example 11.

[0276]

[0277]

[0278]

[0279]

[0280] [Example 22] Preparation of (E)-N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide

[0281]

[0282] Step 1) Preparation of 1-methyl-5-(2-methyl-4-nitro-phenoxy)benzimidazole

[0283] 1.05 g (7.0 mmol) of 1-methylbenzimidazol-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 were diluted with 30 mL of N,N-dimethylformamide and stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled water was added dropwise, and slowly stirred. The resulting solid was washed with distilled water, ethyl acetate, and hexane, and then filtered under reduced pressure to obtain 1.8 g (yield 89%) of the title compound.

[0284] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0285] Step 2) Preparation of 3-methyl-4-(1-methylbenzimidazol-5-yl)oxy-aniline

[0286] 1.8 g (6.3 mmol) of the compound prepared in the above step 1) was diluted in a mixed solution of 40 mL of ethyl acetate and 40 mL of methanol, 300 mg (15 wt%) of palladium / carbon was added, and the mixture was stirred at room temperature under hydrogen conditions for 16 hours. After the reaction was completed, the reaction mixture was washed with methanol and ethyl acetate through a filter filled with Celite, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 1.57 g (yield: 97%) of the title compound.

[0287] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0288] Step 3) Preparation of 6-iodo-N-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxy-phenyl]quinazolin-4-amine

[0289] 1.3 g (5.5 mmol) of the compound prepared in the above step 2) and 1.6 g (5.5 mmol) of 4-chloro-6-iodo-quinazoline were diluted with a mixed solution of 16 mL of isopropyl alcohol and 16 mL of ethylene chloride, 0.8 mL (11.0 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 80°C for 3 hours. After the reaction was completed, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to obtain 1.3 g (yield: 46%) of the title compound.

[0290] 1H-NMR (300 MHz, DMSO-d6) 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).

[0291] Step 4) Preparation of 3-tert-butyl N-methyl-N-[(E)-3-[4-[3-methyl-4-(1-methylbenzimidazol-5-yl)oxy-anilino]quinazolin-6-yl]allyl]carbamate

[0292] 1.3 g (2.5 mmol) of the compound prepared in the above 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) of tetrakis(triphenylphosphine)palladium(0) and 597 mg (5.6 mmol) of sodium carbonate were diluted with a mixed solution of 6 mL of 1,4-dioxane and 2 mL of distilled water, and stirred at 100°C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15:1 (volume ratio)) to obtain 720 mg (yield: 51%) of the title compound.

[0293] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0294] Step 5) Preparation of N-methyl-N-(1-methyl-4-nitro-1H-pyrazol-3-yl)methanesulfonamide

[0295] 130 mg (0.59 mmol) of the compound prepared in the above step 4) was diluted in 5 mL of N,N-dimethylformamide, and 28 mg (0.71 mmol) of sodium hydride (60%) was slowly added at 0°C, followed by stirring at room temperature for 30 minutes. 55 μL (0.89 mmol) of methyl iodide was slowly added to the reaction solution at 0°C, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the resulting mixture was diluted in ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: methanol = 15: 1 (volume ratio)) to obtain 88 mg (yield: 64%) of the title compound.

[0296] 1 H-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).

[0297] Step 6) Preparation of (E)-N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide

[0298] 6.4 μL (0.09 mmol) of acrylic acid and 27 μL (0.09 mmol) of propylphosphonic anhydride solution were diluted in 2 mL of dimethylformamide, and 75 μL (0.42 mmol) of N,N-diisopropylethylamine was added thereto and stirred at room temperature for 30 minutes. The mixed solution was added to 75 mg (0.16 mmol) of the compound obtained in step 5) above and stirred at 0°C for 2 hours. After the reaction was completed, 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, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 19 mg (yield: 21%) of the title compound.

[0299] 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);

[0300] MS (ESI+): m / z = 505.3 [M+H] + .

[0301] The compounds of Examples 23 to 64 shown in Table 3 below were each prepared using the same or similar method as that of Example 22 above.

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] [Example 65]

[0318] Preparation of 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-methylacrylamide

[0319]

[0320] Step 1) Preparation of 6-iodo-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine

[0321] 300 mg (1.03 mmol) of 4-chloro-6-iodo-quinazoline and 248 mg (1.03 mmol) of 3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)aniline were diluted in a mixed solution of 2.4 mL of isopropyl alcohol and 2.4 mL of 1,2-dichloroethane, and stirred at 80°C for 4 hours. The resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane: methanol = 15:1 (volume ratio)) to obtain 277 mg (yield: 54%) of the title compound.

[0322] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0323] Step 2) Preparation of tert-butyl N-methyl-N-[3-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)anilino]quinazolin-6-yl]prop-2-ynyl]carbamate

[0324] 150 mg (0.30 mmol) of the compound prepared in the above step 1) and 102 mg (0.60 mmol) of tert-butyl N-methyl-N-prop-2-ynyl-carbamate, 11 mg (0.06 mmol) of cuprous iodide, 21 mg (0.03 mmol) of bis(triphenylphosphine)palladium(II) dichloride, and 0.17 mL (1.21 mmol) of triethylamine were diluted in 1.5 mL of N,N-dimethylformamide and stirred at 70°C for 16 hours. After completion of the reaction, 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, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 1:1 (volume ratio)) to obtain 100 mg of the title compound (yield: 61%).

[0325] 1 H-NMR (300 MHz, 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).

[0326] Step 3) Preparation of 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-methylacrylamide

[0327] 100 mg (0.18 mmol) of the compound prepared in step 2) above was diluted in a mixed solution of 0.34 mL (4.5 mmol) of trifluoroacetic acid and 1.2 mL of dichloromethane, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure. 18 μL (0.27 mmol) of acrylic acid and 81 μL (0.27 mmol) of a propylphosphonic anhydride solution were diluted in 2 mL of N,N-dimethylformamide, and 0.22 mL (1.26 mmol) of N,N-diisopropylethylamine was added, and stirred at room temperature for 30 minutes. The mixed solution was added to the residue obtained by distillation under reduced pressure, and stirred at 0°C for 2 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, and then washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 12 mg (yield: 13%) of the title compound.

[0328] 1 H-NMR (300MHz, DMSO-d6) 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);

[0329] MS (ESI+): m / z = 490.2 [M+H] + .

[0330] The compounds of Examples 66 to 73 shown in Table 4 below were each prepared using a method identical or similar to the method of Example 65 above.

[0331]

[0332]

[0333]

[0334] [Example 74] Preparation of (R)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0335]

[0336] Step 1) Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-amine

[0337] 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 were diluted in 8 mL of isopropyl alcohol and 8 mL of 1,2-dichloroethane, and stirred at 80°C for 12 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and distilled under reduced pressure. The obtained residue was washed with isopropyl alcohol and hexane to obtain 2.73 g (yield: 100%) of the title compound.

[0338] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0339] Step 2) Preparation of tert-butyl (R)-2-ethynylpyrrolidine-1-carboxylate

[0340] 500 mg (2.5 mmol) of tert-butyl (R)-2-formylpyrrolidine-1-carboxylate 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 and stirred at room temperature for 3 hours. After completion of the reaction, the resulting reaction mixture was distilled under reduced pressure, diluted with dichloromethane, and washed with a saturated aqueous sodium bicarbonate solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 476 mg (yield: 97%) of the title compound.

[0341] 1 H-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).

[0342] Step 3) Preparation of tert-butyl (R)-2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidine-1-carboxylate

[0343] 300 mg (0.6 mmol) of the compound prepared in step 1), 5.8 mg (0.03 mmol) of cuprous iodide, and 30 mg (0.04 mmol) of bis(triphenylphosphine)palladium(II) dichloride were diluted in 2 mL of N,N-dimethylformamide and stirred at room 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 N,N-dimethylformamide and added dropwise to the reaction mixture, followed by stirring at 65°C for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 15:1 (volume ratio)) to obtain 310 mg of the title compound (yield: 91%).

[0344] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0345] Step 4) Preparation of (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(pyrrolidin-2-ylethynyl)quinazolin-4-amine 2,2,2-trifluoroacetic acid

[0346] 305 mg (0.54 mmol) of the compound prepared in the above step 3) was diluted in 2 mL of dichloromethane, 1 mL (13.1 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the resulting reaction mixture was distilled under reduced pressure to obtain 400 mg of the mixture, which was used in the next reaction without purification.

[0347] Step 5) Preparation of (R)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one

[0348] 0.05 mL (0.75 mmol) of acrylic acid and 0.26 mL (1.5 mmol) of N,N-diisopropylethylamine were diluted in 1 mL of N,N-dimethylformamide, and 0.22 mL (0.75 mmol) of propylphosphonic anhydride solution was added, and the mixture was stirred at room temperature for 30 minutes. The solution was added dropwise to a mixture of 288 mg (0.5 mmol) of the compound prepared in step 4) and 0.39 mL (2.25 mmol) of N,N-diisopropylethylamine in 1 mL of N,N-dimethylformamide at 0°C, and the mixture was stirred for 3 hours. After the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 18.0 mg (yield: 7%) of the title compound.

[0349] 1H-NMR (300 MHz, DMSO-d6) 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);

[0350] MS (ESI+): m / z = 516.2 [M+H] + .

[0351] The compounds of Examples 75 to 92 shown in Table 5 below were each prepared using the same or similar method as that of Example 74.

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360] [Experimental Example 1] Growth inhibition test of Ba / F3 HER2 A775insYVMA and wild-type Ba / F3 cells

[0361] In this experimental example, the effect of the compounds obtained in Examples 1 to 92 on the activity of cells expressing the HER2 A775insYVMA mutant or EGFR wild type (WT) was examined. To this end, the cell growth inhibitory effect according to the addition of the compounds to Ba / F3 cells (ATCC) genetically engineered to overexpress the HER2 A775_G776insYVMA or wild type EGFR gene, respectively, was evaluated as follows.

[0362] Specifically, cells were suspended in RPMI 1640 medium containing 10% FBS and 1% penicillin / streptomycin (Gibco BRL), placed in culture flasks, and cultured in a cell incubator at 37°C and 5% carbon dioxide conditions to stabilize the cells in the logarithmic growth phase. After that, cells were taken from the flask, centrifuged to remove the culture medium, and 1 × 10 5 The solution was diluted to 10 cells / mL and dispensed into a 96-well plate at 100 μL per well. The compounds prepared in the above examples were each dissolved in 99.5% dimethyl sulfoxide (hereinafter referred to as DMSO, cell culture grade) to a concentration of 10 mM. For HER2 A775insYVMA Ba / F3 cells, the DMSO solution of each compound was diluted in the culture medium to obtain final concentrations of 1000, 200, 40, 8, 1.6, and 0.32 nM. For EGFR wild-type (WT) overexpressing Ba / F3 cells, the DMSO solution of the compound was diluted in the culture medium to obtain final concentrations of 10000, 5000, 1000, 200, 40, and 8 nM.

[0363] Each compound test solution was added to a 96-well plate seeded with cells at 50 μL each, to obtain a final concentration of 10 μM to 0.32 nM in 150 μL per well. The cells treated with the test solution were cultured for 72 hours at 37°C under 5% carbon dioxide conditions. For the Ba / F3 cell line, the 96-well plate containing the cultured cells was allowed to adapt to room temperature for 30 minutes, and then 50 μL of CellTiter-Glo® Luminescent Cell Assay Reagent (CTG, Promega) was dispensed per well. After stabilizing the luminescence signal for 10 minutes, the luminescence intensity was measured using a microplate reader. Based on the measured value, the half-maximal growth inhibition concentration (GI) of each compound was defined as the concentration that inhibited cell growth by 50% when the initial cell density value was subtracted from the final cell density value of the well not treated with the test substance and the resulting value was set to 100%. 50 The values ​​were calculated. The GI of each compound 50 The values ​​were calculated using GraphPad Prism's nonlinear regression; log[inhibitor] vs. normalized response analysis, and the results are shown in Table 6 below. GI in Table 6 below 50 If the value is less than 100 nM, it is graded as A, if it is 100 nM or more but less than 1,000 nM, it is graded as B, if it is 1,000 nM or more but less than 5,000 nM, it is graded as C, and if it is 5,000 nM or more, it is graded as D.

[0364]

[0365]

[0366] Although the present invention has been described through limited embodiments as described above, the technical idea and scope of the present invention are not limited to these embodiments, and the invention of the patent claims described below, as well as various modifications or variations of the invention described in the patent claims that are obvious to a person having ordinary skill in the technical field to which the present invention pertains, are also included in the scope of the present invention within the equivalent scope of the invention described in the patent claims.

Claims

1. A compound of chemical formula 1 or a stereoisomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the chemical formula above, A 1 and A 3 are independently N or CH, and A 2 Wow A 4 are independently N or CR a and here R a is H, CN, C 1~4 Alkyl or C 1~4 It is alkoxy; R 1 Silver C 1~4 Alkyl, C 1~4 alkoxy, CF3 or halogen; R 2 is a six-membered-five-membered fused bicyclic heteroaryl group or a six-membered-six-membered fused bicyclic heteroaryl group, and optionally, the six-membered-five-membered fused bicyclic heteroaryl group or the six-membered-six-membered fused bicyclic heteroaryl group has one or more hydrogen atoms substituted with halogen, C 1~4 Alkyl and C 1~4 Each of which can be independently substituted with a functional group selected from among alkoxy, Each R 3 are independently halogens, C 1~4 Alkoxy or C 1~4 alkyl, and n is an integer from 0 to 3; L 1 silver -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, and here Q 1 Silver C 1~3 Alkylene, Q 2 is hydrogen or C 1~3 Alkyl, R b is H or C 1~3 Alkyl, M is a single bond connecting to the above E functional group; E is or -NR c - and here R c is H, C 1~4 Alkyl or C 3~6 Cycloalkyl, and J is a single bond connected to a carbonyl group of -C(=O)CH=CHZ of chemical formula 1; Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

2. In paragraph 1, A 1 Inland A 4 A compound characterized in that at least one of them is N.

3. In the second paragraph, the L 1 Silver -CH=CH-Q 1 M and Q 1 is CH2 or -CH(CH3)-, and E is -NR c -, a compound characterized in that Z is H.

4. In paragraph 2, L 1 Silver -C≡CQ 1 M and Q 1 is CH2, and E is -NR c A compound characterized by:

5. In the first paragraph, the R 2 Is , where T is H or C 1~4 A compound characterized by being alkyl.

6. In the first paragraph, the compound is characterized by having a structure of chemical formula 2: [Chemical Formula 2] In the chemical formula above, R 4 Is , where T is H or C 1~4 It is alkyl; Each R 5 are independent halogens or C 1~4 alkoxy, and n is an integer from 0 to 3; A 3 is N or CH, and R a is H, C 1~4 Alkyl or C 1~4 It is alkoxy; L 2 Is -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, and here Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 Alkyl, M is a single bond connecting to the above E functional group; E is or -NR c - and here R c is H, C 1~4 Alkyl or C 3~6 Cycloalkyl, and J is a single bond connected to a carbonyl group of ZCH=CHC(=O); Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

7. In paragraph 6, the A 3 A compound characterized in that it is N.

8. In paragraph 6, the R 5 A compound characterized by being F.

9. In paragraph 6, Z is H, CH3, Or a compound characterized by being -CH2N(CH3)2.

10. In paragraph 6, the compound is characterized by having a structure of chemical formula 3: [Chemical Formula 3] In the chemical formula above, R 4 Is , where T is H or C 1~4 It is alkyl; Each R 5 are independent halogens, and n is an integer from 0 to 3; A 3 is N or CH; L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, where Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 Alkyl, M is a single bond connecting to the above G functional group; G is -NR c -, , where R c is H, C 1~4 Alkyl or C 3~6 It is cycloalkyl, and J is a single bond connected to a carbonyl group of -C(=O)CH=CHZ; Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

11. In the 10th paragraph, the compound is characterized by having a structure of chemical formula 4: [Chemical Formula 4] In the chemical formula above, L 3 Silver -CH=CH-M, -CH=CHQ 1 M, -NR b Q 1 M or -OQ 1 M, and here Q 1 Silver C 1~3 Alkylene, R b is H or C 1~3 Alkyl, M is CH2=CHC(=O)NR c It is a single bond that connects to a functional group; R c is H, C 1~4 Alkyl or C 3~6 is cycloalkyl; R 6 and R 7 are independently H or F.

12. In the first paragraph, the compound is characterized by having a structure of chemical formula 5: [Chemical Formula 5] In the chemical formula above, A 1 and A 3 are independently N or CH, and A 2 is N or CR a and here R a is H, C 1~4 Alkyl or C 1~4 It is alkoxy, R 2a Is , where T is H or C 1~4 It is alkyl; Each R" is independently a halogen, and n is an integer from 0 to 3; m is an integer from 1 to 3; Z is H, C 1~4 Alkyl, X, -C 1~3 Alkylene-X or -C 1~3 alkylene-NR d R e , wherein X is a substituted or unsubstituted 5-6 membered heterocycloalkyl, and R d Wow R e are independently H or C 1~3 Alkyl, and the substituted 5-6 membered heterocycloalkyl is C, wherein at least one hydrogen in the unsubstituted 5-6 membered heterocycloalkyl ring 1~4 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

13. In the 12th paragraph, the R 2a Is A compound characterized by:

14. In paragraph 13, A 1 is CH, and A 3 A compound characterized by being N.

15. Any one compound selected from the group consisting of the following compounds, a stereoisomer thereof, a tert-butyl isomer thereof, or a pharmaceutically acceptable salt thereof: N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)oxy)ethyl)-N-methylacrylamide, N-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)ethyl)-N-methylacrylamide, 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-methylacrylamide, N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)ethyl)-N-methylacrylamide, N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)ethyl)acrylamide, N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)ethyl)acrylamide, N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-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-1H-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-methylacrylamide, N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)-N-methylacrylamide, 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-methylacrylamide, N-(2-((8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)ethyl)-N-methylacrylamide, N-methyl-N-(2-((4-((3-methyl-4-((1-methyl-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)acrylamide, N-methyl-N-(3-((4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)ethyl)acrylamide, N-methyl-N-(3-(methyl(4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)aryl)acrylamide, (E)-N-methyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)allyl)acrylamide, (E)-N-(3-(4-((3-chloro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-N-methyl-N-(4-(4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)azetidin-1-yl)prop-2-en-1-one, (E)-1-(3-(2-(4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)pyrrolidin-1-yl)prop-2-en-1-one, (E)-N-methyl-N-(1-(2-(4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-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-1H-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-3H-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-1H-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-1H-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-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (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, (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, (E)-N-(3-(4-((2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-N-(3-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-N-(3-(4-((2-fluoro-3-methyl-4-((3-methyl-3H-imidazolo[4,5-b]pyridin-6-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-1-(3-(2-(4-((3-methyl-4-((2-methyl-2H-indazol-6-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)vinyl)azetidin-1-yl)prop-2-en-1-one, (E)-N-ethyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-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-1H-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-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)but-3-en-2-yl)acrylamide, (E)-N-(tert-butyl)-N-(3-(4-((3-methyl-4-((1-methyl-1H-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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-N-(3-(4-((3-fluoro-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (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-methylacrylamide, (E)-N-(3-(4-((4-(benzo[d]oxazol-5-yloxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)allyl)-N-methylacrylamide, (E)-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)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide, (E)-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)-4-(piperidin-1-yl)but-2-enamide, (E)-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)-4-morpholinobut-2-enamide, (E)-N-methyl-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)-4-(piperidin-1-yl)but-2-enamide, (E)-N-methyl-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)-4-morpholinobut-2-enamide, (E)-N-methyl-N-(3-(2-(4-((3-methyl-4-((1-methyl-1H-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-1H-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-methylacrylamide, 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-methylacrylamide, 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-methylacrylamide, 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-methylacrylamide, N-(3-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)prop-2-yn-1-yl)-N-methylacrylamide, N-(3-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)-3-cyanoquinolin-6-yl)prop-2-yn-1-yl)-N-methylacrylamide, N-methyl-N-(3-(4-((3-methyl-4-((1-methyl-1H-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-1H-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-methoxyquinazolin-6-yl) prop-2-yn-1-yl)-N-methylacrylamide, (R)-1-(2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-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)pyrrolidin-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)azetidin-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)azetidin-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)pyrrolidin-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)pyrrolidin-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)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-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)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one, (R)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one, 1-((2R)-2-((4-((3-methyl-4-((1-methyl-3a,7a-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one, (S)-1-(2-((4-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one, (R)-1-(2-((4-((3-methyl-4-((1-methyl-1H-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-1H-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-((2R)-2-((8-((3-methyl-4-((1-methyl-3a,7a-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)ethynyl)pyrrolidin-1-yl)prop-2-en-1-one, (R)-1-(2-((8-((3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[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-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)pyrimido[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, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.