EGFR inhibitors

Abstract

The present invention provides a therapeutic agent for EGFR-related diseases, comprising as an active ingredient a compound having EGFR inhibitory activity and brain metastasis. The present invention relates to a compound represented by the general formula (I) [wherein R1, R2, R3, R4, and R5 have the same meanings as those defined in the specification] or a salt thereof, as well as a therapeutic agent for EGFR-related diseases comprising as an active ingredient a compound represented by the following general formula (I) or a salt thereof. #imgabs0#

Description

Technical Field

[0001] The present invention relates to an EGFR inhibitor using a pyrimidine compound or a salt thereof. Background Art

[0002] EGFR (also known as "ErbB1") is a receptor-type tyrosine kinase belonging to the ErbB family. In normal tissues, it binds to epidermal growth factor (also known as "EGF"), mainly in epithelial tissues, and contributes to cell proliferation or apoptosis inhibition (Non-Patent Document 1).

[0003] EGFR is considered an oncogene, and gene amplification, overexpression, and mutation of EGFR have been reported in various cancers. According to non-clinical and clinical research data, it is believed that in cancer cells with these EGFR gene abnormalities and overexpression, the activation of EGFR and downstream signals plays an important role in the survival and proliferation of cancer cells. For example, the mutation of the 746th to 750th amino acid deletion in the exon 19 region of EGFR (also known as the "exon 19 deletion mutation") and the 858th amino acid mutation in the exon 21 region of EGFR from leucine to arginine (also known as the "L858R mutation") are believed to induce kinase activity by EGF-independent autophosphorylation of EGFR, thereby contributing to the survival and proliferation of cancer cells (non-patent document 2). Regarding these mutations, there are reports that they are present in approximately 30% to 50% of non-small cell lung cancers in East Asia and in approximately 10% of non-small cell lung cancers in Europe and the United States (non-patent document 3).

[0004] Therefore, inhibitors that can control the kinase activity of EGFR are believed to exert anti-tumor effects by inhibiting EGFR and downstream signaling in cancer cells with gene amplification, overexpression and / or mutation of EGFR, and are therefore useful for treating cancer patients, extending their lifespan and improving their quality of life (QOL).

[0005] Therefore, a lot of research and development of EGFR inhibitors as anticancer agents has been carried out for the treatment of EGFR mutation-positive tumors. For example, drugs such as afatinib, gefitinib, and erlotinib have been approved as therapeutic agents for EGFR mutation-positive lung cancer with exon 19 deletion mutation or L858R mutation. In addition, regarding osimertinib, it has been approved as a therapeutic agent for EGFR mutation-positive lung cancer with a mutation in the 790th amino acid of the exon 20 region from threonine to methionine (also known as "T790M mutation") in addition to exon 19 deletion mutation or L858R mutation.

[0006] Regarding the mutation of one or more amino acids inserted in the exon 20 region (also referred to as "exon 20 insertion mutation"), it is considered to be an activating mutation in lung cancer, etc. (non-patent literature 4), but there is a trend of low sensitivity reported for cancers with these mutations in a variety of existing EGFR inhibitors. For example, regarding afatinib, the report has the following tendency: as a clinical effect on EGFR mutation-positive lung cancer, the effect on exon 20 insertion mutation is significantly lower than that on exon 19 deletion mutation or L858R mutation (non-patent literature 5). Multiple clinical trials have been implemented for lung cancer with exon 20 insertion mutation of EGFR, but a treatment method has not yet been established. Therefore, there is a need for an EGFR inhibitor with inhibitory activity on exon 20 insertion mutation.

[0007] Furthermore, it has been reported that approximately 25-40% of lung cancers and 15-30% of breast cancers develop brain metastases, and that brain metastases also occur in a certain proportion in many other cancers (Non-Patent Documents 6 and 7).

[0008] From the perspective of disease control including brain metastases, an EGFR inhibitor that has inhibitory activity against EGFR mutations and also has brain metastasis is desired.

[0009] Prior art literature

[0010] Non-patent literature

[0011] Non-patent document 1: Nat. Rev. Cancer, vol. 6, pp 803-812 (2006)

[0012] Non-patent document 2: Nature Medicine, vol. 19, pp. 1389-1400 (2013)

[0013] Non-patent document 3: Nat. Rev. Cancer, vol. 7, pp. 169-181 (2007)

[0014] Non-patent document 4: Signal Transduct Target Ther. 4:5pp.1-10 (2019)

[0015] Non-patent document 5: Lancet Oncol. vol. 16, pp. 830-838 (2015)

[0016] Non-patent document 6: Current Oncology, 25, pp. S103-S114 (2018)

[0017] Non-patent document 7: Breast Cancer Research, 18(1), 8, pp. 1-9 (2016) Summary of the Invention

[0018] Technical problem to be solved by the invention

[0019] The present invention provides a therapeutic agent for EGFR-related diseases, comprising a compound having EGFR inhibitory activity and brain migration as an active ingredient.

[0020] Technical solutions to technical problems

[0021] The inventors of the present invention conducted intensive research and found that the compound represented by the following formula (I) or its salt, which has a pyrimidine as the basic skeleton, has EGFR inhibitory activity and brain migration, and can be used as a therapeutic agent for EGFR-related diseases (especially malignant tumors) by inhibiting EGFR, thereby completing the present invention.

[0022] That is, one embodiment of the present invention includes the following aspects.

[0023] [1] A therapeutic agent for EGFR-related diseases, comprising a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient,

[0024]

[0025] (Where,

[0026] R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent;

[0027] R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents;

[0028] R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents;

[0029] R4 represents a hydrogen atom or a C1-C4 alkyl group;

[0030] R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms. )

[0031] [2] The therapeutic agent according to [1], wherein the pyrimidine compound is a compound represented by the following general formula (II):

[0032]

[0033] (Where,

[0034] R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent;

[0035] R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents;

[0036] R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents;

[0037] R4 represents a hydrogen atom or a C1-C4 alkyl group;

[0038] R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms. )

[0039] [3] The therapeutic agent according to [1] or [2], wherein the pyrimidine compound is a compound in which R2 in the general formula (I) or (II) is a C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups as substituents.

[0040] [4] The therapeutic agent according to any one of [1] to [3], wherein the pyrimidine compound is a compound in which R3 in the general formula (I) or (II) is a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents.

[0041] [5] The therapeutic agent according to any one of [1] to [4], wherein the pyrimidine compound is a compound in which R5 in the general formula (I) or (II) is a phenyl group which may have 1 or 2 substituents selected from fluorine atoms and chlorine atoms.

[0042] [6] The therapeutic agent according to any one of [1] to [5], wherein the pyrimidine compound is a compound in which R1 in the general formula (I) or (II) is a methyl group, a tert-butyl group or a cyclopropyl group.

[0043] [7] The therapeutic agent according to any one of [1] to [6], wherein the pyrimidine compound is a compound in which R2 in the general formula (I) or (II) is a methyl group, an ethyl group, a methoxymethyl group or an ethoxymethyl group.

[0044] [8] The therapeutic agent according to any one of [1] to [7], wherein the pyrimidine compound is a compound in which R3 in the general formula (I) or (II) is a methyl group.

[0045] [9] The therapeutic agent according to any one of [1] to [8], wherein the pyrimidine compound is a compound in which R4 in the general formula (I) or (II) is a hydrogen atom.

[0046]

[10] The therapeutic agent according to any one of [1] to [9], wherein the pyrimidine compound is a compound wherein R5 in the general formula (I) or (II) is a phenyl group.

[0047]

[11] The therapeutic agent according to any one of [1] to

[10] , wherein the pyrimidine compound is a compound selected from the following (1) to (3).

[0048] (1) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0049] (2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0050] (3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(3,3-dimethylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0051]

[12] The therapeutic agent according to any one of [1] to

[11] , wherein the pyrimidine compound is 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

[0052]

[13] The therapeutic agent according to any one of [1] to

[12] , wherein the EGFR-related disease is a malignant tumor with EGFR overexpression, EGFR gene amplification, or EGFR mutation.

[0053]

[14] An EGFR inhibitor comprising a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient,

[0054]

[0055] (Where,

[0056] R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent;

[0057] R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents;

[0058] R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents;

[0059] R4 represents a hydrogen atom or a C1-C4 alkyl group;

[0060] R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms. )

[0061]

[15] A therapeutic agent for EGFR-positive tumors, comprising a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient,

[0062]

[0063] (Where,

[0064] R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent;

[0065] R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents;

[0066] R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents;

[0067] R4 represents a hydrogen atom or a C1-C4 alkyl group;

[0068] R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms. )

[0069]

[16] A pharmaceutical composition for treating EGFR-related diseases, comprising a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,

[0070]

[0071] (Where,

[0072] R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent;

[0073] R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents;

[0074] R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents;

[0075] R4 represents a hydrogen atom or a C1-C4 alkyl group;

[0076] R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms. )

[0077]

[17] The pharmaceutical composition according to

[16] , wherein the EGFR-related disease is a malignant tumor with EGFR overexpression, EGFR gene amplification or EGFR mutation.

[0078] The present invention also relates to the following solutions.

[0079] The compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating EGFR-related diseases.

[0080] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating EGFR-related diseases.

[0081] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for EGFR-related diseases.

[0082] The compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating EGFR-positive tumors.

[0083] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating EGFR-positive tumors.

[0084] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for EGFR-positive tumors.

[0085] A method for treating EGFR-related diseases, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0086] A method for treating EGFR-positive tumors, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0087] A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating a malignant tumor having an exon 18 mutant EGFR.

[0088] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating malignant tumors having exon 18 mutant EGFR.

[0089] Use of the compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for malignant tumors having exon 18 mutant EGFR.

[0090] A method for treating a malignant tumor having an exon 18 mutant EGFR, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0091] A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating a malignant tumor having exon 19 mutant EGFR.

[0092] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating malignant tumors having exon 19 mutant EGFR.

[0093] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for malignant tumors having exon 19 mutant EGFR.

[0094] A method for treating a malignant tumor having an exon 19 mutant EGFR, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0095] A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating a malignant tumor having an exon 20 mutant EGFR.

[0096] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating malignant tumors having exon 20 mutant EGFR.

[0097] Use of the compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for malignant tumors having exon 20 mutant EGFR.

[0098] A method for treating a malignant tumor having an exon 20 mutant EGFR, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0099] A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating a malignant tumor having exon 21 mutant EGFR.

[0100] Use of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for treating malignant tumors having exon 21 mutant EGFR.

[0101] Use of the compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for malignant tumors having exon 21 mutant EGFR.

[0102] A method for treating a malignant tumor having an exon 21 mutant EGFR, comprising administering an effective amount of a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0103] A compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for use in treating malignant tumors resistant to existing EGFR inhibitors.

[0104] Use of the compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof for treating malignant tumors resistant to existing EGFR inhibitors.

[0105] Use of the compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for malignant tumors resistant to existing EGFR inhibitors.

[0106] A conventional method for treating EGFR inhibitor-resistant malignant tumors comprises administering an effective amount of a compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0107] Effects of the Invention

[0108] The therapeutic agent for EGFR-related diseases according to the present invention can provide a new therapeutic method for treating EGFR-related diseases or EGFR-positive tumors.

[0109] The compound of the present invention or a salt thereof has excellent inhibitory activity against wild-type EGFR and mutant EGFR, has excellent brain metastasis, and has an anti-tumor effect on malignant tumors and a survival-prolonging effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Figure 1 The anti-tumor effects of the compounds of Examples 2, 11 and 12 on the subcutaneous transplantation model of the H1975-EGFRinsSVD cell line are shown.

[0111] Figure 2 The graph shows the body weight change rate of mice when the compounds of Examples 2, 11, and 12 were administered to the subcutaneous transplantation model of the H1975-EGFRinsSVD cell line.

[0112] Figure 3The antitumor effect of the compound of Example 11 is shown in a brain direct transplantation model of a luciferase gene-transferred exon 20 insertion mutant EGFR-expressing cell line (H1975-EGFRinsSVD-Luc).

[0113] Figure 4 The graph shows the survival rate of mice when the compound of Example 11 was administered to a brain direct transplantation model of an EGFR-expressing cell line into which the luciferase gene was introduced and into which an exon 20 insertion mutant was inserted (H1975-EGFRinsSVD-Luc). DETAILED DESCRIPTION

[0114] One embodiment of the present invention relates to a compound represented by the following general formula (I) or a salt thereof.

[0115]

[0116] (In the formula, R1 to R5 are as defined above.)

[0117] A preferred embodiment of the present invention is a pyrimidine compound represented by the following general formula (II) or a salt thereof.

[0118]

[0119] (In the formula, R1 to R5 are as defined above.)

[0120] The compound represented by the general formula (I) or (II) of the present invention is a compound having pyrrolo[2,3-d]pyrimidine as a basic structure, and is a novel compound not described in any of the above-mentioned prior art documents.

[0121] In the present specification, specific examples of the "halogen atom" include a chlorine atom, an iodine atom, a fluorine atom, and an iodine atom. A chlorine atom and a fluorine atom are preferred, and a fluorine atom is more preferred.

[0122] In this specification, "alkyl" refers to a linear or branched saturated hydrocarbon group, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferably a linear or branched alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or tert-butyl group.

[0123] In the present specification, the term "haloalkyl" refers to a group in which one to all hydrogen atoms in a linear or branched saturated hydrocarbon group are substituted with the aforementioned halogen atoms. Specific examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, and 1,1-dichloroethyl. Preferably, the group is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms in which one to three hydrogen atoms are substituted with the aforementioned halogen atoms, and more preferably, the group is a monofluoromethyl group.

[0124] In the present specification, "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, with cyclopropyl and cyclobutyl being preferred.

[0125] In this specification, the "aromatic hydrocarbon group" refers to a cyclic substituent containing carbon and hydrogen and having an unsaturated bond, and a substituent containing 4e+2 (e is an integer of 1 or greater) electrons in the cyclic π electron system.

[0126] In the present specification, the "C6-C14 aromatic hydrocarbon group" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and specific examples thereof include phenyl, naphthyl, tetrahydronaphthyl, and anthracenyl, with phenyl being preferred.

[0127] In the present specification, "aralkyl" means the above-mentioned alkyl group substituted with the above-mentioned aromatic hydrocarbon group. Specific examples include C7-C16 aralkyl groups such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl. Benzyl is preferred.

[0128] In this specification, the "unsaturated hydrocarbon group" means a linear or branched hydrocarbon group having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond or triple bond. Specifically, the unsaturated hydrocarbon group includes vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl, 2-propynyl, etc., and vinyl, allyl, and 1-propenyl are preferred.

[0129] In the present specification, the term "alkenyl" refers to a linear or branched hydrocarbon group having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond. Specifically, examples include C2-C6 alkenyl groups such as vinyl, allyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl and 5-hexenyl, and preferably vinyl, allyl, 1-propenyl and 2-methyl-2-propenyl.

[0130] In this specification, the term "alkynyl" refers to a linear or branched unsaturated hydrocarbon group having at least one (e.g., 1 to 2, preferably 1) triple bond. Specifically, examples include C2-C6 alkynyl groups such as ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butyne, and 1-methyl-2-propynyl, with ethynyl and 2-propynyl being preferred.

[0131] In the present specification, "C3-C10 cyclic unsaturated hydrocarbon group" means a monocyclic or polycyclic hydrocarbon group having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. Specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc. are mentioned. Preferably, it is a monocyclic or polycyclic hydrocarbon group having 3 to 7 carbon atoms containing at least one carbon-carbon double bond, and more preferably a cyclopropenyl group.

[0132] In the present specification, the term "alkoxy" refers to an oxy group having the above-mentioned alkyl group. Specifically, examples include C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy. Preferred are methoxy and ethoxy, and more preferred are methoxy.

[0133] In this specification, the term "halogenated alkoxy" refers to the above-mentioned alkoxy group having at least one (preferably 1 to 13, more preferably 1 to 3) halogen atom, and specifically includes C1-C6 haloalkoxy groups such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoroisopropoxy.

[0134] In the present specification, "cycloalkoxy" refers to an oxy group having the above-mentioned cycloalkyl group. Specific examples include C3-C7 cycloalkoxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy. Preferred are cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0135] In the present specification, the term "aralkyloxy group" refers to an oxy group having the above-mentioned aralkyl group. Specific examples include C7-C20 aralkyloxy groups such as benzyloxy, phenethoxy, naphthylmethoxy, and fluorenylmethoxy, with benzyloxy being preferred.

[0136] In the present specification, the term "alkylthio" refers to a thioxy group having the above-mentioned alkyl group. Specifically, C1-C6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio can be mentioned, and methylthio, ethylthio, and n-propylthio are preferred.

[0137] In the present specification, the term "alkoxyalkyl group" refers to the above-mentioned alkyl group having at least one alkoxy group, and specific examples thereof include C1-C6 alkoxy-C1-C6 alkyl groups such as methoxymethyl, ethoxyethyl, methoxyethyl, and methoxypropyl.

[0138] In this specification, "alkylamino" means an amino group in which one or two hydrogen atoms are substituted by a linear or branched hydrocarbon group having 1 to 6 carbon atoms. Specifically, methylamino, ethylamino, dimethylamino, diethylamino, ethylmethylamino, etc. can be mentioned. Preferably, it is an amino group in which one or two hydrogen atoms are substituted by a linear or branched hydrocarbon group having 1 to 3 carbon atoms.

[0139] In this specification, the term "monoalkylamino" refers to an amino group in which one hydrogen atom is replaced by a linear or branched hydrocarbon group. Specifically, the group includes methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, and hexylamino. Preferably, the group includes an amino group in which one hydrogen atom is replaced by a linear or branched hydrocarbon group having 1 to 3 carbon atoms.

[0140] In this specification, "dialkylamino" means an amino group in which two hydrogen atoms are substituted by a linear or branched hydrocarbon group having 1 to 6 carbon atoms. Specific examples include dimethylamino, diethylamino, and ethylmethylamino. Preferably, it is an amino group in which two hydrogen atoms are substituted by a linear or branched hydrocarbon group having 1 to 3 carbon atoms, and more preferably, it is a dimethylamino group.

[0141] In this specification, "acyl" means a formyl group in which a hydrogen atom is replaced by a straight-chain or branched hydrocarbon group. Specifically, acetyl, n-propionyl, isopropionyl, n-butyryl, tert-butyryl, etc. are mentioned. Preferably, the hydrogen atom of the formyl group is replaced by a straight-chain or branched hydrocarbon group having 1 to 3 carbon atoms, and more preferably, an acetyl group.

[0142] In the present specification, "acyloxy" means an oxy group having the above-mentioned acyl group, and specifically, an alkylcarbonyloxy group or an arylcarbonyloxy group can be mentioned. Preferably, the hydrogen atom of the formyl group is substituted with a linear or branched hydrocarbon group having 1 to 3 carbon atoms, and preferably an alkylcarbonyloxy group.

[0143] In the present specification, the term "alkoxycarbonyl" refers to a carbonyl group having the above-mentioned alkoxy group. Specifically, examples include (C1-C6 alkoxy)carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl and hexyloxycarbonyl, and preferably tert-butoxycarbonyl.

[0144] In the present specification, the term "aralkyloxycarbonyl" refers to a carbonyl group having the above-mentioned aralkyloxy group. Specific examples include (C6-C20 aralkyl)oxycarbonyl groups such as benzyloxycarbonyl, phenethoxycarbonyl, naphthylmethoxycarbonyl, and fluorenylmethoxycarbonyl. Benzyloxycarbonyl is preferred.

[0145] In the present specification, the term "saturated heterocyclic group" refers to a monocyclic or polycyclic saturated heterocyclic group having at least one (preferably 1 to 5, more preferably 1 to 3) heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. Specifically, the group includes aziridinyl, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, thiazolinyl, and oxazolidinyl. Preferred groups include azetidinyl, pyrrolidinyl, and piperidinyl, and more preferred groups include azetidinyl and pyrrolidinyl.

[0146] In the present specification, the term "unsaturated heterocyclic group" refers to a monocyclic or polycyclic fully unsaturated or partially unsaturated heterocyclic group having at least one (preferably 1 to 5, more preferably 1 to 3) heteroatom selected from nitrogen, oxygen and sulfur atoms. Specific examples thereof include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimid ... 1-Hydroxy-1-pyrazol-1-ol, 1-d ...

[0147] In the present specification, the term "saturated heterocyclic oxy group" refers to an oxy group having the above-mentioned saturated heterocyclic group. Specific examples thereof include morpholinyloxy, 1-pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, tetrahydrothienyloxy, thiazolidinyloxy, and oxazolidinyloxy groups, with 1-pyrrolidinyloxy, piperidinyloxy, and piperazinyloxy groups being preferred.

[0148] In the compound represented by the general formula (I) or (II) of the present invention, R1 is a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent.

[0149] The "C1-C4 alkoxy group" in the "C1-C4 alkyl group optionally having a C1-C4 alkoxy group as a substituent" represented by R1 is preferably a methoxy group or an ethoxy group, with a methoxy group being most preferred. The number of substituents is preferably 1 to 3, with a single group being most preferred. When there are two or more substituents, the substituents may be the same or different.

[0150] The "C1-C4 alkyl group" in the "C1-C4 alkyl group which may have a C1-C4 alkoxy group as a substituent" represented by R1 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, and most preferably a methyl group or a tert-butyl group.

[0151] The "C1-C4 alkyl group which may have a C1-C4 alkoxy group as a substituent" represented by R1 is preferably a C1-C4 alkyl group which may have 1 to 3 methoxy groups as substituents, more preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group or a 1-methyl-1-methoxyethyl group, and most preferably a methyl group or a tert-butyl group.

[0152] The "C3-C4 cycloalkyl group" represented by R1 is preferably a cyclopropyl group or a cyclobutyl group, and most preferably a cyclopropyl group.

[0153] R1 is preferably a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have 1 to 3 C1-C4 alkoxy groups as substituents.

[0154] R1 is more preferably a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have 1 to 3 methoxy groups as substituents.

[0155] R1 is more preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-methyl-1-methoxyethyl group or a cyclopropyl group.

[0156] Most preferably, R1 is methyl, tert-butyl or cyclopropyl.

[0157] In the compounds represented by general formula (I) or (II) of the present invention, R2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents.

[0158] The "halogen atom" represented by R2 is preferably a fluorine atom or a chlorine atom.

[0159] The "C1-C4 alkoxy group" of the "C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents" represented by R2 is preferably a methoxy group or an ethoxy group, and most preferably a methoxy group.

[0160] The "C1-C6 alkyl group" of the "C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents" represented by R2 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, and most preferably a methyl group.

[0161] The "C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents" represented by R2 is preferably a C1-C6 alkyl group which may have 1 to 5 methoxy groups, ethoxy groups or fluorine atoms as substituents (specifically, methyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.), more preferably a C1-C6 alkyl group, more preferably a methyl group, ethyl group, n-propyl group, isopropyl group or tert-butyl group, and most preferably a methyl group.

[0162] The "C1-C6 alkoxy group" represented by R2 is preferably a methoxy group or an ethoxy group, and most preferably a methoxy group.

[0163] R2 is preferably a C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents. In one embodiment, R2 is a C1-C6 alkyl group which may have 1 to 5 methoxy groups, ethoxy groups or fluorine atoms as substituents. In another embodiment, R2 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group (preferably a methyl group or an ethyl group, more preferably a methyl group) which may have 1 to 5 methoxy groups, ethoxy groups or fluorine atoms as substituents.

[0164] R2 is more preferably a C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups as substituents. In one embodiment, R2 is a C1-C6 alkyl group which may have 1 to 5 methoxy or ethoxy groups as substituents. In another embodiment, R2 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a tert-butyl group (preferably a methyl group or an ethyl group, more preferably a methyl group) which may have 1 to 5 methoxy or ethoxy groups as substituents. In another embodiment, R2 is a methyl group, an ethyl group, a methoxymethyl group, or an ethoxymethyl group.

[0165] R2 is more preferably a C1-C6 alkyl group.

[0166] R2 is more preferably methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0167] R2 is particularly preferably a methyl group or an ethyl group.

[0168] Most preferably, R2 is methyl.

[0169] In the compounds represented by general formula (I) or (II) of the present invention, R3 is a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents.

[0170] The "C1-C4 alkyl group" of the "C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents" represented by R3 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, and most preferably a methyl group.

[0171] The "C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents" represented by R3 is preferably methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl, more preferably methyl, trifluoromethyl or ethyl, and most preferably methyl.

[0172] R3 is preferably a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents.

[0173] More preferably, R3 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, fluoroethyl, difluoroethyl, trifluoroethyl, n-propyl, isopropyl or tert-butyl.

[0174] R3 is more preferably methyl, fluoromethyl, difluoromethyl, trifluoromethyl or ethyl.

[0175] More preferably, R3 is methyl, trifluoromethyl or ethyl.

[0176] R3 is particularly preferably a methyl group or an ethyl group.

[0177] Most preferably, R3 is methyl.

[0178] In the compound represented by the general formula (I) or (II) of the present invention, R4 is a hydrogen atom or a C1-C4 alkyl group.

[0179] The "C1-C4 alkyl group" represented by R4 is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, and most preferably a methyl group.

[0180] R4 is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group.

[0181] R4 is more preferably a hydrogen atom, a methyl group or an ethyl group.

[0182] More preferably, R4 is a hydrogen atom or a methyl group.

[0183] R4 is most preferably a hydrogen atom.

[0184] In the compound represented by general formula (I) or general formula (II) of the present invention, R5 is a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms.

[0185] R5 is preferably a phenyl group which may have 1 or 2 substituents selected from fluorine atoms and chlorine atoms.

[0186] More preferably, R5 is phenyl, 2-fluorophenyl, 3-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl or 3,5-difluorophenyl.

[0187] Most preferably, R5 is phenyl.

[0188] The compound of the present invention is preferably a compound or a salt thereof, wherein R1 in the general formula (I) or the general formula (II) is a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent, R2 is a C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups as substituents, R3 is a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents, R4 is a hydrogen atom or a C1-C4 alkyl group, and R5 is a phenyl group which may have 1 or 2 substituents selected from fluorine atoms and chlorine atoms.

[0189] More preferably, R1 in the general formula (I) or the general formula (II) is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a 1-methyl-1-methoxyethyl group, a cyclopropyl group or a cyclobutyl group, R2 is a methyl group, an ethyl group, an n-propyl group, a tert-butyl group, a methoxymethyl group or an ethoxymethyl group, R3 is a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, an ethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, R4 is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group or a tert-butyl group, and R5 is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 2,4-difluorophenyl group, a 2,3-difluorophenyl group, a 3,5-difluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 2,4-dichlorophenyl group or a 3,5-dichlorophenyl group, or a salt thereof.

[0190] More preferably, in the general formula (II), R1 is a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a 1-methyl-1-methoxyethyl group or a cyclopropyl group, R2 is a methyl group, an ethyl group, a methoxymethyl group or an ethoxymethyl group, R3 is a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or an ethyl group, R4 is a hydrogen atom, a methyl group or an ethyl group, and R5 is a phenyl group, a 2-fluorophenyl group, a 3-chlorophenyl group, a 2,3-difluorophenyl group, a 2,4-difluorophenyl group or a 3,5-difluorophenyl group, or a salt thereof.

[0191] More preferably, in the general formula (II), R1 is methyl, tert-butyl or cyclopropyl, R2 is methyl, ethyl, methoxymethyl or ethoxymethyl, R3 is methyl, trifluoromethyl or ethyl, R4 is a hydrogen atom or methyl, and R5 is a phenyl compound or a salt thereof.

[0192] More preferred are compounds or salts thereof in which, in the general formula (II), R1 is a methyl group, tert-butyl group or cyclopropyl group, R2 is a methyl group, ethyl group or methoxymethyl group, R3 is a methyl group, R4 is a hydrogen atom, and R5 is a phenyl group.

[0193] Particularly preferred are compounds or salts thereof in which, in the general formula (II), R1 is a methyl group, a tert-butyl group or a cyclopropyl group, R2 is a methyl group, R3 is a methyl group, R4 is a hydrogen atom, and R5 is a phenyl group.

[0194] Specific examples of the compound represented by the general formula (I) or (II) include compounds produced in the following examples, but are not limited thereto.

[0195] One embodiment of the present invention is a compound selected from the following (1) to (19) or a salt thereof. One embodiment of the present invention is a compound selected from the following (1) to (15) or a salt thereof.

[0196] (1) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0197] (2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0198] (3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(3,3-dimethylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0199] (4) 7-(R)-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-(3,5-difluorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0200] (5) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-(2-phenylpropan-2-yl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0201] (6) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylpropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0202] (7) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-(2-(2-fluorophenyl)propane-2-yl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0203] (8) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-(3-chlorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0204] (9) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-(2,4-difluorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0205] (10) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(prop-1-yn-1-yl)-N-((S)-2,2,2-trifluoro-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0206] (11) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0207] (12) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-(2,3-difluorophenyl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0208] (13) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(3-methoxy-3-methylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0209] (14) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(but-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0210] (15) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-(2-(2-fluorophenyl)propane-2-yl)-6-(3-methylbut-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0211] (16) 7-((3R,5S)-1-acryloyl-5-ethylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0212] (17) 7-((3R,5S)-1-acryloyl-5-ethylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0213] (18) 7-((3R,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0214] (19) 7-((3R,5R)-1-acryloyl-5-(ethoxymethyl)pyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0215] Preferred examples of the compound represented by the general formula (I) or (II) include compounds selected from the following (1) to (3) or salts thereof.

[0216] (1) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0217] (2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0218] (3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(3,3-dimethylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0219] The most preferred pyrimidine compound in the present invention is 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

[0220] <Method for producing the compound represented by formula (I)>

[0221] The compound of the present invention can be produced, for example, by the following production method or the method described in the Examples. However, the production method of the compound of the present invention is not limited to these examples.

[0222] The compounds (I) and (II) of the present invention can be produced, for example, by the following production method.

[0223] <Manufacturing method>

[0224]

[0225] [In the formula, L1, L2, and L3 are the same or different and represent leaving groups, P1 and P2 are the same or different and represent protecting groups, and other symbols have the same meanings as above.]

[0226] <Step 1>

[0227] This step is a method of reacting the compound represented by Formula 1 with a commercially available or commercially available compound represented by Formula 2, which can be prepared by a known method, to obtain a compound represented by Formula 3. The Mitsunobu reaction is usually carried out in the presence of a Mitsunobu reagent and a phosphine reagent.

[0228] The compound represented by Formula 2 (in Formula 2, P1 represents a protecting group for an amino group) can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 mol of the compound represented by Formula 1.

[0229] The "protective group for the amino group" is not particularly limited as long as it has the function, and examples thereof include: aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl, and cumyl; lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, pivaloyl, trifluoroacetyl, and trichloroacetyl; benzoyl; arylalkanoyl groups such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl; and p-nitrobenzyloxycarbonyl. , phenylethoxycarbonyl and other aralkyloxycarbonyl; lower alkylsilyl such as trimethylsilyl, tert-butyldimethylsilyl; for example, tetrahydropyranyl; for example, trimethylsilylethoxymethyl; lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl; lower alkylsulfinyl such as tert-butylsulfinyl; arylsulfonyl such as benzylsulfonyl, toluenesulfonyl, etc., imide such as phthalimide, particularly preferably trifluoroacetyl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, trimethylsilylethoxymethyl or isopropylphenyl.

[0230] As the Mitsunobu reagent, diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc. can be used. The amount of the Mitsunobu reagent used is usually about 1 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 1.

[0231] The phosphine reagent may be triphenylphosphine, tributylphosphine, trifurylphosphine, etc. The amount of the phosphine reagent used is usually about 1 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 1.

[0232] Any solvent that does not adversely affect the reaction may be used, and examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), water, or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is from 0°C to the boiling point of the solvent, preferably from 0°C to 100°C.

[0233] The compound represented by Formula 3 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0234] <Step 2>

[0235] This step is a method of obtaining a compound represented by Formula 4 by reacting a compound represented by Formula 3 with ammonia or a salt thereof.

[0236] Ammonia or a salt thereof can be used in an amount of 1 to 1000 equivalents, preferably 1 to 100 equivalents, relative to 1 mol of the compound represented by Formula 3.

[0237] Any solvent that does not adversely affect the reaction may be used, and examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), water, or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 150°C.

[0238] The compound represented by Formula 4 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0239] <Step 3>

[0240] This step is a method of obtaining a compound represented by Formula 5 by reacting a compound represented by Formula 4 in a carbon monoxide atmosphere in the presence of, for example, a transition metal catalyst, a base, and an alcohol.

[0241] In this step, the pressure of carbon monoxide is usually 1 atmosphere to 20 atmospheres, preferably 1 atmosphere to 10 atmospheres.

[0242] Examples of the alcohol include methanol, ethanol, propanol, isopropanol, diethylaminoethanol, isobutanol, 4-(2-hydroxyethyl)morpholine, 3-morpholinopropanol, and diethylaminopropanol.

[0243] The amount of the alcohol used is usually 1 to 100 mol, preferably about 1 to 50 mol, relative to 1 mol of the compound represented by Formula 4.

[0244] As a transition metal catalyst, for example, a palladium catalyst (such as palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, palladium-carbon, etc.) can be used, and a ligand (such as triphenylphosphine, tri-tert-butylphosphine, etc.) can also be added and used as needed. The amount of the transition metal catalyst used varies depending on the type of catalyst, but is generally about 0.0001 to 1 mole relative to compound 4 (1 mole), preferably about 0.01 to 0.5 mole, and the amount of the ligand used is generally about 0.0001 to 4 moles relative to the compound represented by formula 4 (1 mole), preferably about 0.01 to 2 moles.

[0245] Examples of the base include organic amines (e.g., trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline, etc.), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), and alkali metal disilazide salts (e.g., lithium disilazide, sodium disilazide, potassium disilazide, etc.). Preferred among these are alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate; alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide; and organic amines such as triethylamine and diisopropylethylamine. The amount of the base used is usually 0.1 to 50 mol, preferably about 1 to 20 mol, relative to 1 mol of the compound represented by Formula 4.

[0246] As a solvent, any solvent that does not adversely affect the reaction may be used, and examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide, N-methylpyrrolidone), water, or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 150°C.

[0247] After this reaction, the ester corresponding to the alcohol used, or a mixture of the ester and the compound represented by Formula 5, may be subjected to a hydrolysis reaction to convert the compound represented by Formula 5.

[0248] As the base, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. are preferably used, and the amount used is usually 0.5 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 4.

[0249] Any solvent that does not adversely affect the reaction can be used, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, etc., either alone or in combination. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 100°C.

[0250] The compound represented by Formula 5 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0251] <Step 4>

[0252] This step is a method for introducing a protecting group into the carboxyl group of the compound represented by Formula 5 to obtain a compound represented by Formula 6 (in Formula 6, P2 represents a protecting group for the carboxyl group). The protection method can be carried out by a generally known method, for example, the method described in Protective Groups in Organic Synthesis 3rd edition, TW Greene and P.G.M. Wuts, John Wiley & Sons (1999), or a method based thereon.

[0253] The "protecting group for the carboxyl group" is not particularly limited as long as it has the function, and examples thereof include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and tert-butyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl; lower alkenyl groups such as allyl; trimethylsilylethoxymethyl; aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, and triphenylmethyl, among which methyl, ethyl, tert-butyl, allyl, benzyl, p-methoxybenzyl, and trimethylsilylethoxymethyl are particularly preferred.

[0254] In this reaction, it is preferred to introduce a protecting group such as tert-butyl ester, methyl ester, or ethyl ester.

[0255] Examples of protecting agents used in this reaction include 2-tert-butyl-1,3-diisopropylisourea, etc. The amount of these protecting agents used is usually 1 to 50 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 5.

[0256] As long as the solvent does not adversely affect the reaction, examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran, tert-butyl methyl ether), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), water, and mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 100°C.

[0257] The compound represented by Formula 6 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0258] <Step 5>

[0259] This step is a method for halogenating the compound represented by Formula 6 to obtain the compound represented by Formula 7 (where L3 represents a halogen atom). Halogenation can be performed, for example, by methods using fluorine, chlorine, bromine, iodine, or the like, or by methods using N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. In this reaction, methods using N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide are preferred.

[0260] N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 mol of the compound represented by Formula 6.

[0261] As a solvent, any solvent that does not adversely affect the reaction may be used, and examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), water, or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is from 0°C to the boiling temperature of the solvent, preferably 0°C to 100°C.

[0262] The compound represented by Formula 7 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0263] <Step 6>

[0264] This step is a method for deprotecting the amino protecting group (P1 in Formula 7) of the compound represented by Formula 7 to obtain the compound represented by Formula 8. The deprotection method can be carried out by a generally known method, for example, the method described in Protective Groups in Organic Synthesis, third edition, TW Greene and P.G.M. Wuts, John Wiley & Sons (1999), or a method based thereon.

[0265] Examples of the protecting group include tert-butyloxycarbonyl, etc. For example, when tert-butyloxycarbonyl is used as the protecting group, deprotection is preferably performed under acidic conditions, and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, and p-toluenesulfonic acid.

[0266] The amount of the acid used is preferably about 1 to 100 equivalents relative to 1 mol of the compound represented by Formula 7.

[0267] As the solvent used in the reaction, any solvent that does not adversely affect the reaction may be alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 to 100°C, preferably 0 to 50°C.

[0268] The compound represented by Formula 8 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0269] <Step 7>

[0270] This step is a method of obtaining a compound represented by Formula 9 by subjecting the amino group of the compound represented by Formula 8 to an amidation reaction with acrylic acid halide or acrylic anhydride.

[0271] When acrylic acid halide or acrylic anhydride is used, the amount thereof is usually 0.5 to 10 mol, preferably about 1 to 5 mol, relative to 1 mol of the compound represented by Formula 8. Commercially available products or acrylic acid anhydride can be used or produced by known methods.

[0272] In addition, a base can be added as needed. Examples of the base include organic amines (e.g., trimethylamine, triethylamine, isopropylethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline, etc.), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), and alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.). The amount of the base used is generally 1 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 8.

[0273] As the solvent used in the reaction, any solvent that does not adversely affect the reaction can be used, such as alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling temperature of the solvent, preferably 0°C to 100°C.

[0274] The compound represented by Formula 9 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0275] <Step 8>

[0276] This step is a method of obtaining a compound represented by Formula 10 by subjecting the compound represented by Formula 9 to a Sonogashira reaction with an acetylene derivative that is commercially available or can be produced by a known method.

[0277] The acetylene derivative can be used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, relative to 1 mol of the compound represented by Formula 9.

[0278] As the transition metal catalyst, for example, a palladium catalyst (e.g., palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)dipalladium, etc.), a nickel catalyst (e.g., nickel chloride, etc.) can be used. A ligand (e.g., triphenylphosphine, tri-tert-butylphosphine, etc.) can also be added as needed, and a copper catalyst (e.g., copper iodide, copper bromide, copper chloride) can be used as a co-catalyst. The amount of the transition metal catalyst used varies depending on the type of catalyst, but is generally about 0.0001 to 1 mol, preferably about 0.01 to 0.5 mol, relative to 1 mol of the compound represented by Formula 9. The amount of the ligand used is generally about 0.0001 to 4 mol, preferably about 0.01 to 2 mol, relative to 1 mol of the compound represented by Formula 9. The amount of the copper catalyst used is generally about 0.0001 to 4 mol, preferably about 0.010 to 2 mol, relative to 1 mol of the compound represented by Formula 9.

[0279] Examples of the base include organic amines (e.g., trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline, etc.), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), and disilazane alkali metal salts (e.g., lithium disilazide, sodium disilazide, potassium disilazide, etc.). Among these, preferred are alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide, and organic amines such as triethylamine and diisopropylethylamine. The amount of the base used is usually 0.1 to 10 mol, preferably about 1 to 5 mol, relative to 1 mol of the compound represented by Formula 9.

[0280] As long as the solvent does not adversely affect the reaction, examples include hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), alcohols (e.g., methanol, ethanol), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), water, or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling point of the solvent, preferably 0°C to 150°C.

[0281] The compound represented by Formula 10 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0282] <Step 9>

[0283] This step is a method for deprotecting the carboxyl protecting group (P2 in Formula 10) of the compound represented by Formula 10 to obtain the compound represented by Formula 11. The deprotection method can generally be carried out by a known method, for example, the method described in Protective Groups in Organic Synthesis, TW Greene and P.G.M. Wuts, John Wiley & Sons (1981), or a method based thereon.

[0284] Examples of the protecting group include tert-butyl ester, etc. For example, when a tert-butyl ester group is used as the protecting group, deprotection is preferably performed under acidic conditions, and examples of the acid include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, and p-toluenesulfonic acid.

[0285] The amount of the acid used is preferably about 1 to 100 equivalents relative to 1 mol of the compound represented by Formula 10.

[0286] As the solvent used in the reaction, any solvent that does not adversely affect the reaction may be alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0 to 100°C, preferably 0 to 50°C.

[0287] The compound represented by Formula 11 thus obtained can be isolated and purified by a known isolation and purification method, or can be supplied to the next step without isolation and purification.

[0288] <Step 10>

[0289] This step is a method of obtaining a compound represented by formula (I) by subjecting the carboxyl group of the compound represented by formula 11 to an amidation reaction with an amine which is commercially available or can be produced by a known method.

[0290] The amidation method can be carried out by a conventionally known method, and examples thereof include a method of reacting the compound in the presence of a condensing agent, or a method of activating the carboxylic acid moiety by a conventionally known method to prepare a reactive derivative, and then amidating the derivative with an amine (for any of the methods, refer to "Basics and Experiments of Peptide Synthesis" (Nobuo Izumiya et al., Maruzen Co., Ltd., 1983)).

[0291] Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC), diphenylphosphinate (DPPA), benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxytripyrrolidinylphosphonium phosphate (PyAOP), bromotripyrrolidinylphosphonium hexafluorophosphate (BroP), chlorotris(pyrrolidino)phosphonium hexafluorophosphate (CTP), and 1-aminobenzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate. The present invention also includes the following additives: 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and N-hydroxysuccinimide (HOSu). The amount of these additives used is generally 1 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 11.

[0292] In addition, a base can be added as needed. Examples of the base include organic amines (e.g., trimethylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline, etc.), alkali metal salts (e.g., sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), and alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.). The amount of the base used is generally 1 to 100 mol, preferably about 1 to 10 mol, relative to 1 mol of the compound represented by Formula 11.

[0293] As the solvent used in the reaction, any solvent that does not adversely affect the reaction can be used, such as alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., dimethoxyethane, tetrahydrofuran), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphonamide), or mixtures thereof. The reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The reaction temperature is 0°C to the boiling temperature of the solvent, preferably 0°C to 100°C.

[0294] The compounds (I) and (II) thus obtained can be isolated and purified by known isolation and purification methods such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

[0295] In the above-described production method, "introduction of a protecting group to the carboxyl group of the compound represented by Formula 5" (Step 4) to "amidation reaction of the carboxyl group of the compound represented by Formula 11 with a commercially available amine or an amine that can be produced by a known method" (Step 10) are performed sequentially. However, this order may be reversed. Furthermore, "introduction of a protecting group to the carboxyl group of the compound represented by Formula 5" (Step 4) and "deprotection of the protecting group of the carboxyl group of the compound represented by Formula 10" (Step 9) may be omitted.

[0296] Specifically, the compounds represented by formula (I) and (II) can be derived by the following steps: "amidation reaction of the carboxyl group of the compound represented by formula 11 with a commercially available amine or an amine that can be produced by a known method" (step 10), "halogenation of the compound represented by formula 6" (step 5), "deprotection of the protective group of the amino group of the compound represented by formula 7" (step 6), "amidation reaction of the amino group of the compound represented by formula 8 with acryloyl halide or acrylic anhydride" (step 7), and "sonoshita reaction of an acetylene derivative that is commercially available or that can be produced by a known method, when L3 of the compound represented by formula 9 has a leaving group such as a halogen" (step 8). The conditions of each step are the same as those described above.

[0297] When the compounds of the present invention have isomers such as optical isomers, stereoisomers, rotamers, and tautomers, unless otherwise specified, any of the isomers and mixtures thereof are included in the compounds of the present invention. For example, when the compounds of the present invention have optical isomers, unless otherwise specified, racemates and optical isomers resolved from the racemates are also included in the compounds of the present invention.

[0298] The salt of the compound of the present invention refers to a pharmaceutically acceptable salt, and examples thereof include base addition salts and acid addition salts.

[0299] The pyrimidine compounds or salts thereof of the present invention also include prodrugs thereof. Prodrugs refer to compounds that are converted to compounds of the present invention or salts thereof under physiological conditions in vivo through reactions utilizing enzymes or gastric acid, i.e., compounds that are converted to compounds of the present invention or salts thereof through oxidation, reduction, hydrolysis, etc., by the action of enzymes, or compounds that are converted to compounds of the present invention or salts thereof through hydrolysis, etc., by gastric acid, etc. Alternatively, prodrugs may be substances that are converted to compounds of the present invention or salts thereof under physiological conditions, as described in "Development of Pharmaceuticals," Volume 7, Molecular Design, pp. 163-198, published by Hirokawa Shoten in 1990.

[0300] The pyrimidine compound or its salt of the present invention may be amorphous or crystalline, and the crystal form may be a single crystal or a polymorphic mixture, all of which are included in the compound or its salt of the present invention. Crystals can be produced by crystallization using a known crystallization method. The compound or its salt of the present invention may be a solvate (such as a hydrate) or a non-solvate, all of which are included in the compound or its salt of the present invention. 3 H. 14 C. 35 S. 125 Compounds labeled with SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3) or the like are also included in the compounds or salts thereof of the present invention.

[0301] The compounds of the present invention or their salts have excellent EGFR inhibitory activity. Therefore, the compounds of the present invention or their salts can be used as antitumor agents for malignant tumors characterized by EGFR overexpression, EGFR gene amplification, or EGFR mutation, and have the advantage of having fewer side effects because no significant weight loss is observed in mice.

[0302] In this specification, "EGFR" includes EGFR of humans or non-human mammals, preferably human EGFR. The NCBI Gene ID of human EGFR is 1956. In addition, the term "EGFR" includes isoforms.

[0303] The compound of the present invention or a salt thereof is useful as a medicine for preventing or treating EGFR-related diseases due to its excellent EGFR inhibitory activity.

[0304] "EGFR-related diseases" include diseases that can be reduced in incidence, alleviated, relieved, and / or cured by deleting, inhibiting, and / or suppressing the function of EGFR. Examples of such diseases include, but are not limited to, malignant tumors. Preferably, the disease is a malignant tumor with EGFR overexpression, EGFR gene amplification, or EGFR mutation.

[0305] One embodiment of the present invention provides a therapeutic agent for an EGFR-related disease comprising a compound of the present invention or a salt thereof. Another embodiment of the present invention provides an EGFR inhibitor comprising a compound of the present invention or a salt thereof. Another embodiment of the present invention provides a therapeutic agent for an EGFR-positive tumor comprising a compound of the present invention or a salt thereof. Another embodiment of the present invention provides a compound of the present invention or a salt thereof for treating an EGFR-related disease. Another embodiment of the present invention provides the use of a compound of the present invention or a salt thereof for treating an EGFR-related disease. Another embodiment of the present invention provides the use of a compound of the present invention or a salt thereof for manufacturing a therapeutic agent for an EGFR-related disease. Another embodiment of the present invention provides a method for treating an EGFR-related disease, comprising administering an effective amount of a compound of the present invention or a salt thereof to a subject in need of treatment. Another embodiment of the present invention provides a compound of the present invention or a salt thereof for treating an EGFR-positive tumor. Another embodiment of the present invention provides the use of a compound of the present invention or a salt thereof for treating an EGFR-positive tumor. Another embodiment of the present invention provides the use of a compound of the present invention or a salt thereof for manufacturing a therapeutic agent for an EGFR-positive tumor. Another embodiment of the present invention provides a method for treating an EGFR-positive tumor, comprising administering an effective amount of a compound of the present invention or a salt thereof to a subject in need of treatment.

[0306] The compound or salt thereof of one embodiment of the present invention inhibits wild-type EGFR and mutant EGFR having insertion mutations, point mutations or deletion mutations. One embodiment of the present invention provides a compound or salt thereof having inhibitory activity against wild-type EGFR and mutant EGFR, or a medicine or pharmaceutical composition comprising the compound or salt thereof. One embodiment of the present invention provides an inhibitor of wild-type EGFR and mutant EGFR comprising a compound or salt thereof of the present invention. In addition, one embodiment of the present invention provides a method for inhibiting wild-type EGFR and mutant EGFR, comprising the step of administering an effective amount of a compound or salt thereof of the present invention to a subject in need of inhibition. In addition, one embodiment of the present invention provides the use of a compound or salt thereof of the present invention for the manufacture of an inhibitor of wild-type EGFR and mutant EGFR. In addition, one embodiment of the present invention provides a compound or salt thereof of the present invention for use as an inhibitor of wild-type EGFR and mutant EGFR. In addition, one embodiment of the present invention provides the use of a compound or salt thereof of the present invention for inhibiting wild-type EGFR and mutant EGFR. In another embodiment of the present invention, the present invention provides the use of a compound or salt thereof of the present invention for preventing or treating diseases associated with wild-type EGFR and mutant EGFR.

[0307] The human wild-type EGFR gene is represented by, for example, SEQ ID NO: 1, and the human wild-type EGFR protein is composed of, for example, the amino acid sequence represented by SEQ ID NO: 2. The base sequence information of the human wild-type EGFR gene can be obtained through NCBI Reference Sequence: NM_005228, and the amino acid sequence information of the human wild-type EGFR protein can be obtained through NCBI Reference Sequence: NP_005219, etc.

[0308] In some embodiments, the pyrimidine compound or salt thereof of the present invention exhibits inhibitory activity against mutant EGFR. As used herein, "mutant EGFR" refers to EGFR having one or more activating mutations or resistance-acquiring mutations, such as insertion mutations, point mutations, or deletion mutations, in exon 18, exon 19, exon 20, or exon 21 of wild-type human EGFR.

[0309] In this specification, "exon 18" refers to the region from 688 to 728 in the amino acid sequence of the wild-type human EGFR protein (for example, the protein consisting of the amino acid sequence shown in SEQ ID NO: 2).

[0310] In the present invention, "exon 18 mutation" refers to a point mutation or deletion mutation of an amino acid in the exon 18 region of a human wild-type EGFR protein (e.g., a protein consisting of an amino acid sequence shown in SEQ ID NO: 2). As point mutations in exon 18, for example, glutamic acid at position 709 or glycine at position 719 in the exon 18 region is substituted with an arbitrary amino acid, i.e., E709X or G719X. As E709X, for example, glutamic acid at position 709 in the exon 18 region is substituted with lysine, i.e., E709K, or alanine, i.e., E709A. As G719X, for example, glycine at position 719 in the exon 18 region is substituted with alanine, i.e., G719A, or a serine, i.e., G719S, or a cysteine, i.e., G719C. Furthermore, deletion mutations in the exon 18 region include not only mutations resulting from the deletion of a portion of amino acids in the exon 18 region but also mutations resulting from the insertion of one or more arbitrary amino acids in addition to the amino acid deletion. Examples of deletion mutations in exon 18 include a mutation resulting from the deletion of glutamic acid at position 709 and threonine at position 710 in the exon 18 region and the insertion of aspartic acid (Del E709-T710insD).

[0311] In this specification, "exon 19" refers to the region from 729 to 761 in the amino acid sequence of the wild-type human EGFR protein (for example, the protein consisting of the amino acid sequence shown in SEQ ID NO: 2).

[0312] In this specification, "exon 19 mutation" refers to a mutation in which one or more amino acids are deleted in the exon 19 region of the human wild-type EGFR protein (e.g., a protein consisting of the amino acid sequence shown in SEQ ID NO: 2). Deletion mutations in the exon 19 region include not only mutations caused by the deletion of amino acids in part of the exon 19 region, but also mutations in which one or more arbitrary amino acids are inserted in addition to the deleted amino acids. Examples of exon 19 deletion mutations include a mutation in which five amino acids are deleted from glutamic acid at position 746 to alanine at position 750 in the exon 19 region (Del E746-A750 (also referred to as d746-750)), a mutation in which seven amino acids are deleted from leucine at position 747 to proline at position 753 in the exon 19 region, followed by an insertion of serine (Del L747-P753insS), a mutation in which five amino acids are deleted from leucine at position 747 to threonine at position 751 in the exon 19 region (Del L747-T751), and a mutation in which four amino acids are deleted from leucine at position 747 to alanine at position 750 in the exon 19 region, followed by an insertion of proline (DelL747-A750insP). In a preferred embodiment of the present invention, the exon 19 deletion mutation is a mutation in which five amino acids are deleted from glutamic acid at position 746 to alanine at position 750 in the exon 19 region (Del E746-A750).

[0313] In this specification, "exon 20" refers to the region from 762 to 823 in the amino acid sequence of the wild-type human EGFR protein (for example, the protein consisting of the amino acid sequence shown in SEQ ID NO: 2).

[0314] In the present invention, "exon 20 mutation" refers to a point mutation, insertion mutation, deletion mutation, etc. of an amino acid in the exon 20 region of a human wild-type EGFR protein (e.g., a protein consisting of the amino acid sequence shown in SEQ ID NO: 2). Examples of exon 20 mutations include A763insFQEA, A767insASV, S768dupSVD, V769insASV, D770insNPG, D770insSVD, and D773insNPH (Nature medicine, 24, p638-646, 2018). In a preferred embodiment of the present invention, the exon 20 mutation is an insertion mutation or point mutation selected from one or more of V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, and T790M.

[0315] In this specification, "exon 21" refers to the region from 824 to 875 in the amino acid sequence of the wild-type human EGFR protein (for example, the protein consisting of the amino acid sequence shown in SEQ ID NO: 2).

[0316] In the present invention, "exon 21 mutation" refers to a point mutation in the amino acids of the exon 21 region of the human wild-type EGFR protein (e.g., a protein consisting of the amino acid sequence shown in sequence number 2). As a point mutation of exon 21, for example, a point mutation in which one amino acid in the exon 21 region is substituted can be cited, preferably a point mutation in which the leucine at position 858 or the leucine at position 861 in the exon 21 region is substituted with an arbitrary amino acid, i.e., L858X or L861X. As L858X, for example, a point mutation in which the leucine at position 858 in the exon 21 region is substituted with arginine, i.e., L858R, can be cited. As L861X, for example, a point mutation in which the leucine at position 861 in the exon 21 region is substituted with glutamine, i.e., L861Q, can be cited. In a preferred embodiment of the present invention, the point mutation of exon 21 is L858R.

[0317] Furthermore, in some embodiments, even if a mutation in a certain EGFR isoform differs from the amino acid position set forth in SEQ ID NO: 2 due to an amino acid deletion or insertion, it can be understood to be the same as a mutation at a position corresponding to the amino acid position set forth in SEQ ID NO: 2. Thus, for example, threonine at position 790 in the EGFR set forth in SEQ ID NO: 2 corresponds to threonine at position 745 in the EGFR consisting of the amino acid sequence set forth in SEQ ID NO: 4. Thus, for example, "T790M" means that threonine at position 790 in the EGFR set forth in SEQ ID NO: 2 is mutated to methionine, but since this is the position corresponding to amino acid position 745 in the EGFR consisting of the amino acid sequence set forth in SEQ ID NO: 4, "T745M" in the EGFR comprising the amino acid sequence set forth in SEQ ID NO: 4 corresponds to "T790M" in the EGFR set forth in SEQ ID NO: 2. Furthermore, for example, threonine at position 790 in the EGFR set forth in SEQ ID NO: 2 corresponds to threonine at position 523 in the EGFR consisting of the amino acid sequence set forth in SEQ ID NO: 6. Thus, for example, "T790M" means that the threonine at position 790 of the EGFR set forth in SEQ ID NO: 2 is mutated to methionine. However, in the EGFR consisting of the amino acid sequence set forth in SEQ ID NO: 6, this corresponds to the amino acid at position 523. Therefore, "T523M" in the EGFR consisting of the amino acid sequence set forth in SEQ ID NO: 6 corresponds to "T790M" in the EGFR set forth in SEQ ID NO: 2. Furthermore, the position of the amino acid corresponding to a certain amino acid in a certain EGFR isoform among the amino acids set forth in SEQ ID NO: 2 can be confirmed by, for example, BLAST Multiple Alignment.

[0318] Sequence numbers 1 to 6 are as follows.

[0319] EGFR mutant 1

[0320] Base sequence (SEQ ID NO: 1)

[0321]

[0322]

[0323] Amino acid sequence (SEQ ID NO: 2)

[0324]

[0325] EGFR mutant 5

[0326] Base sequence (SEQ ID NO: 3)

[0327]

[0328]

[0329] Amino acid sequence (SEQ ID NO: 4)

[0330]

[0331] EGFRvIII (del2-7EGFR)

[0332] Base sequence (SEQ ID NO: 5)

[0333]

[0334]

[0335] Amino acid sequence (SEQ ID NO: 6)

[0336]

[0337] In the present invention, "EGFR-positive tumors" are tumors in which EGFR protein or EGFR gene is detected. EGFR protein and EGFR gene also include mutant EGFR proteins and EGFR genes such as point mutations, insertion mutations, and deletion mutations.

[0338] EGFR protein detection methods include, for example, ELISA using an antibody that specifically binds to EGFR protein, Western blotting, immunostaining, and other commonly used detection methods. Antibodies that specifically bind to EGFR protein can be commercially available or prepared by commonly used methods.

[0339] In addition, the detection method of EGFR gene can be enumerated as follows, for example, Northern blotting, Southern blotting, RT-PCR, real-time PCR, digital PCR, DNA microarray, in situ hybridization, sequence analysis, etc., and commonly used detection methods. In addition, detection methods using commercially available EGFR gene mutation detection kits such as Cobas EGFR mutation detection kit (Roche Diagnostics) can also be enumerated.

[0340] In this specification, the term "effective amount" of the pyrimidine compound of the present invention refers to the amount of the compound of the present invention that causes a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease (therapeutically effective amount).

[0341] In this specification, the term "subject" includes mammals and non-mammals. Examples of mammals, without limitation, include humans, chimpanzees, apes, monkeys, horses, cattle, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles, wild boars, bears, tigers, lions, etc. Examples of non-mammals, without limitation, include birds, fish, insects, etc. In one embodiment, the subject is a human, which can be a person diagnosed as needing treatment for the symptoms, conditions, or diseases disclosed in this specification.

[0342] The compound of the present invention or its salt, when used as medicine, can be coordinated with a pharmaceutically acceptable carrier as needed, and various administration forms can be adopted according to prevention or treatment purpose, as this form, for example, can be any one of oral agent, injection, suppository, ointment, patch, etc., preferably oral agent. These administration forms can be respectively manufactured by the commonly used preparation method known to those skilled in the art.

[0343] One embodiment of the present invention provides an oral antitumor agent having a compound of the present invention or a salt thereof as an active ingredient. In addition, one embodiment of the present invention provides a method for preventing and / or treating a tumor, comprising orally administering an effective amount of a compound of the present invention or a salt thereof to a subject in need of prevention and / or treatment. In addition, one embodiment of the present invention provides the use of a compound of the present invention or a salt thereof for the manufacture of an antitumor agent for oral administration. In addition, one embodiment of the present invention provides a compound of the present invention or a salt thereof for oral administration to prevent and / or treat a tumor.

[0344] One embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a salt thereof. A pharmaceutical composition according to one embodiment of the present invention comprises a compound of the present invention or a salt thereof, and a pharmaceutically acceptable carrier. In addition, one embodiment of the present invention provides the use of a compound of the present invention or a salt thereof in the manufacture of a pharmaceutical composition. Another embodiment of the present invention provides a compound of the present invention or a salt thereof for use as a medicine.

[0345] As pharmaceutically acceptable carriers, various conventional organic or inorganic carrier substances can be used as formulation raw materials, and can be used as excipients, binders, disintegrants, lubricants, coating agents, colorants in solid preparations, and solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid preparations. In addition, formulation additives such as preservatives, antioxidants, sweeteners, stabilizers, etc. can also be used as needed.

[0346] When preparing a solid preparation for oral administration, an excipient can be added to the pyrimidine compound of the present invention, and a binder, disintegrant, lubricant, colorant, flavoring agent, etc. can be added as needed, and then tablets, coated tablets, granules, powders, capsules, etc. can be manufactured by conventional methods.

[0347] When preparing injections, a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. can be added to the pyrimidine compound of the present invention, and injections for subcutaneous, intramuscular, and intravenous use can be produced by conventional methods.

[0348] The amount of the pyrimidine compound of the present invention to be incorporated into each of the above-mentioned dosage unit forms is not fixed depending on the symptoms of the subject to whom the pyrimidine compound of the present invention is to be applied, the dosage form thereof, etc., but is generally preferably 0.05 to 1000 mg per dosage unit form for oral preparations, 0.01 to 500 mg for injections, and 1 to 1000 mg for suppositories.

[0349] The daily dosage of the drug having the above-mentioned dosage form varies depending on the subject's symptoms, body weight, age, sex, etc. and cannot be generalized. However, based on the compound of the present invention, it is generally 0.05 to 5000 mg, preferably 0.1 to 1000 mg per day for an adult (50 kg body weight).

[0350] The malignant tumors that are the subject of the present invention are not particularly limited, and examples thereof include brain tumors, head and neck cancer, digestive system cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder-choledochal cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, reproductive system cancers (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), urinary system cancers (renal cancer, bladder cancer, prostate cancer, testicular tumors, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone-soft tissue tumors, skin cancer, etc., preferably lung cancer, breast cancer, gastric cancer, head and neck cancer, brain tumor, colorectal cancer, bladder cancer, biliary tract cancer, or uterine cancer, and more preferably lung cancer, breast cancer, colorectal cancer, or brain tumor.

[0351] In one embodiment, the tumor that becomes the object of the present invention is a malignant tumor with EGFR overexpression, EGFR gene amplification or EGFR mutation. Specific malignant tumors include brain tumors, head and neck cancer, digestive system cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder-choledochal cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, reproductive system cancer (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), urinary system cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone-soft tissue tumors, skin cancer, etc., preferably lung cancer, breast cancer, gastric cancer, head and neck cancer, brain tumor, colorectal cancer, bladder cancer, biliary tract cancer or uterine cancer, more preferably lung cancer, breast cancer, colorectal cancer or brain tumor.

[0352] In one embodiment, the tumor that becomes the object of the present invention is an EGFR-positive tumor. Specific tumors include brain tumors, head and neck cancer, digestive system cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder-choledochal cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, reproductive system cancer (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), urinary system cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone-soft tissue tumors, skin cancer, etc., preferably lung cancer, breast cancer, gastric cancer, head and neck cancer, brain tumor, colorectal cancer, bladder cancer, biliary tract cancer or uterine cancer, more preferably lung cancer, breast cancer, colorectal cancer or brain tumor.

[0353] In one embodiment, the tumor is a brain tumor. The pyrimidine compound of the present invention can be used to treat brain symptoms that require passage through the blood-brain barrier. The pyrimidine compound of one embodiment has preferred permeability across the blood-brain barrier for delivery to the brain, i.e., excellent brain migration. Indicators of compound migration to the brain include the compound concentration in the brain and the Kp value (ratio of drug concentration in the brain to that in plasma).

[0354] The brain tumors treated by the pyrimidine compounds of the present invention include metastatic brain tumors and primary brain tumors.

[0355] Brain tumors are not particularly limited, and examples thereof include metastatic brain tumors (e.g., brain metastases of lung cancer, breast cancer, gastric cancer, colorectal cancer, bladder cancer, biliary tract cancer, uterine cancer, etc. (preferably lung cancer, breast cancer, or gastric cancer)), pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma-oligodendroglial astrocytoma, anaplastic astrocytoma-anaplastic oligodendroglial astrocytoma, anaplastic oligoastrocytoma, glioblastoma, ependymoma, anaplastic ependymoma, ganglioglioma, central nervous system tumor, medulloblastoma, germ cell tumor (germinoma), malignant lymphoma of the central nervous system, meningioma, schwannoma, GH (growth hormone) type pituitary adenoma, PRL (prolactin) type pituitary adenoma, ACTH (adrenocorticotropic hormone) type pituitary adenoma, non-functional pituitary adenoma, craniopharyngioma, chordoma, hemangioblastoma, epithelioid tumor, etc.

[0356] Example

[0357] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0358] In this specification, "room temperature" generally means about 10° C. to about 35° C. In the following examples of compounds, % represents weight percentage unless otherwise specified.

[0359] Unless otherwise specified, all reagents used in the Examples were commercially available products. For silica gel chromatography, Biotage SNAP Cartridge Ultra, manufactured by Biotage, was used, and for basic silica gel chromatography, Biotage SNAP Cartridge Isolute Flash-NH2, manufactured by Biotage, was used.

[0360] For preparative thin layer chromatography, Kieselgel™ 60F254, Art. 5744 manufactured by Merck or NH2 silicagel 60F254 Plate-Wako manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. was used.

[0361] 1 H-NMR was measured using a JEOL AL400 (400 MHz), a Varian Mercury (400 MHz), or a Varian Inova (400 MHz) using tetramethylsilane as a standard substance. Mass spectrometry was performed using a Waters Micromass ZQ or SQD using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Microwave reactions were performed using an Initiator manufactured by Biotage.

[0362] The meanings of the abbreviations are as follows.

[0363] s: single peak

[0364] d: Twin Peaks

[0365] t: triplet

[0366] q: quartet

[0367] dd: double peaks

[0368] dt: double triplet

[0369] td: triple double peaks

[0370] tt: triple triplet

[0371] ddd: double double peaks

[0372] DDT: Double Double Triple

[0373] DTD: Double Triple Peak

[0374] TDD: Triple Double Peaks

[0375] m: multiple peaks

[0376] br: broad peak

[0377] ATP: adenosine triphosphate

[0378] DMSO-d6: deuterated dimethyl sulfoxide

[0379] CDCl3: deuterated chloroform

[0380] EDTA: Ethylenediaminetetraacetic acid

[0381] THF: Tetrahydrofuran

[0382] DMF: N,N-dimethylformamide

[0383] DMSO: dimethyl sulfoxide

[0384] NMP: N-methylpyrrolidone

[0385] HATU: O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0386] HPMC: Hydroxypropyl methylcellulose

[0387] PdCl2(PPh3)2: Dichlorobis(triphenylphosphine)palladium(II)

[0388] Reference Example 1

[0389] Reference Example 1(1)(2S,4R)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7- tert-Butyl)-2-methylpyrrolidine-1-carboxylate

[0390] Dissolve tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (19.0 g) and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (13.1 g) in THF (190 mL). After cooling to 0°C, add triphenylphosphine (37.2 g) and diisopropyl azodicarboxylate (28.1 mL). Warm to room temperature and stir for 1 hour. The reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel chromatography (hexane:ethyl acetate) to obtain the corresponding coupled compound. The resulting compound is used in the next reaction without further purification.

[0391] The resulting coupled product, THF (114 mL), and aqueous ammonia (114 mL) were added to a pressure tube and stirred at 100°C for 14 hours. The reaction mixture was cooled to room temperature, and then water (285 mL) was added and stirred at room temperature for 5 hours. The precipitated solid was filtered, washed with water, and dried to obtain the desired product (34.5 g).

[0392] 1 HNMR (CDCl3) δ: 8.27 (s, 1H) 7.15 (s, 1H) 5.55-5.73 (m, 2H) 5.12-5.25 (m, 1H) 3.86-4.18 (m, 2H )3.43-3.57(m, 1H)2.59-2.69(m, 1H)1.92-2.03(m, 1H)1.48(s, 9H)1.30-1.40(m, 3H)ESI-MS m / z 444(MH+)

[0393] Reference Example 1(2) 4-amino-7-((3R,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3- yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

[0394] After adding the compound (28.0 g) of Reference Example 1 (1), 10% palladium carbon catalyst (720 mg), NMP (84 mL), methanol (26 mL), and triethylamine (17.6 mL) to a pressure tube, carbon monoxide substitution was performed and the mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, 2M sodium hydroxide aqueous solution (79 mL) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through celite, washed with methanol, and the methanol in the filtrate was concentrated under reduced pressure. After further addition of water, the aqueous layer was washed with tert-butyl methyl ether. 1M potassium hydrogen sulfate aqueous solution was added to the aqueous layer, the pH was adjusted to about 3, the precipitated solid was filtered, washed with water, and dried to obtain the target product (23.4 g).

[0395] 1HNMR (400MHz, DMSO-d6) δ: 8.14 (s, 1H) 8.08 (s, 1H) 5.16-4.93 (m, 1H) 4.07-3.79 (m, 2H) 3 .61-3.45 (m, 1H) 2.53 (m, 1H) 2.33-2.02 (m, 1H) 1.42 (s, 9H) 1.29 (d, J = 6.1Hz, 3H) ESI-MS m / z 362(MH+)

[0396] <Example>

[0397] Example 1

[0398] Example 1 (1) 4-amino-6-bromo-7-((3R,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrole tert-Butyl 7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

[0399] Under a nitrogen atmosphere, the compound of Reference Example 1 (2) (15.0 g) was dissolved in chloroform (150 mL), 2-tert-butyl-1,3-diisopropylisourea (25 mL) was added, the temperature was raised to 60°C, and the mixture was stirred for 2 hours. 2-tert-butyl-1,3-diisopropylisourea (25 mL) was further added and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Tert-butyl methyl ether was added to the obtained residue, the precipitated solid was filtered out, and washed with tert-butyl methyl ether. The filtrate was further concentrated under reduced pressure, tert-butyl methyl ether was added to the obtained residue, the precipitated solid was filtered out, and washed with tert-butyl methyl ether. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain a tert-butyl ester. The obtained compound was used in the subsequent halogenation reaction without further purification.

[0400] The resulting tert-butyl ester was dissolved in chloroform (140 mL), N-bromosuccinimide (11.8 g) was added, and the mixture was stirred at room temperature for 24 hours. Chloroform and 10% aqueous sodium bisulfite solution were added to the reaction mixture in sequence, followed by extraction with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the desired product (13.8 g).

[0401] 1 HNMR(CDCl3)δ:8.02(s,1H)5.74-5.13(m,2H)4.07-3.64(m,2H)2.43-2.29(m,1H)2.07-1.97(m,1H)1.63(s,9H)1.48(m,12H)

[0402] ESI-MS m / z 496, 498 (MH+)

[0403] Example 1(2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- tert-Butyl 6-bromo-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

[0404] The compound of Example 1 (1) (11.4 g) was dissolved in THF (57 mL), cooled to 0°C, and a 4 M solution of hydrogen chloride in 1,4-dioxane (114 mL) was added, followed by stirring at 0°C for 10 hours. 5 M aqueous sodium hydroxide solution (92 mL), acetonitrile (57 mL), diisopropylethylamine (20 mL), and acryloyl chloride (2.0 mL) were added to the reaction mixture, and stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain the target product (7.72 g).

[0405] 1 HNMR (CDCl3) δ: 8.26-8.16 (m, 1H) 6.62-6.30 (m, 2H) 5.81-5.64 (m, 1H) 5.33-5.14 (m, 1H) 4.81-3.75 (m, 3H) 3.07-2.86 (m, 1H) 2.67-2.33 (m, 1H)

[0406] 1.69-1.61(m,9H)1.60-1.51(m,3H)

[0407] ESI-MS m / z 450, 452 (MH+)

[0408] Example 1(3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- tert-Butyl 6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

[0409] To the compound of Example 1(2) (7.72 g), acetonitrile (154 mL), triethylamine (7.2 mL), PdCl2(PPh3)2 (1.2 g), and copper (I) iodide (330 mg) was added a 1.0 M propyne solution in DMF (85.7 mL), the atmosphere was purged with nitrogen, and the mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain the target product (4.06 g).

[0410] 1HNMR (CDCl3) δ: 8.29-8.17 (m, 1H) 6.63-6.30 (m, 2H) 5.81-5.63 (m, 1H) 5.42-5.15 (m, 1H) 4.66-3.8 1(m,3H)3.01-2.82(m,1H)2.65-2.32(m,1H)2.92-2.13(m,3H)1.65-1.59(m,9H)1.57-1.49(m,3H)

[0411] ESI-MS m / z 410 (MH+)

[0412] Example 1 (4) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-(Propan-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

[0413] The compound of Example 1 (3) (1.52 g) was dissolved in chloroform (5 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, and the mixture was concentrated under reduced pressure again. The residue was dried under reduced pressure to obtain the target compound (1.25 g).

[0414] ESI-MS m / z 354 (MH+)

[0415] Example 1(5) 7-(R)-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino N-((R)-1-(3,5-difluorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3- d]pyrimidine-5-carboxamide

[0416] To a solution of the compound (100 mg) of Example 1(4) in DMF (1.0 mL) were added (R)-1-(3,5-difluorophenyl)ethane-1-amine (89.0 mg), diisopropylethylamine (0.25 mL), and HATU (215 mg), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain the title compound (60 mg).

[0417] 1 HNMR (DMSO-d6) δ: 8.51 (d, J=7.3Hz, 1H) 8.16 (s, 1H) 7.25-7.07 (m, 3H) 6.74-6.47 (m, 1H) 6.25-6.08 (m, 1H) 5.78-5.58 (m, 1H) 5.41-5.21 (m, 1H)

[0418] 5.21-5.06(m,1H)4.45-4.29(m,1H)4.24-3.91(m,2H)2.78-2.58(m,1H) 2.52-2.41 (m, 1H) 2.23 (s, 3H) 1.48 (d, J = 7.1Hz, 3H) 1.39 (d, J = 6.1Hz, 3H)

[0419] ESI-MS m / z 493 (MH+)

[0420] Example 27 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- ((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0421] The title compound was obtained in the same manner as in Example 1 (5), except that (R)-1-phenylethane-1-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0422] 1 HNMR (DMSO-d6) δ: 8.35 (d, J=7.8Hz, 1H) 8.17-8.13 (m, 1H) 7.48-7.23 (m, 5H) 6.76-6.46 (m, 1H) 6.28-6.06 (m, 1H) 5.81-5.58 (m, 1H) 5.43- 5.02 (m, 2H) 4.42-4.28 (m, 1H) 4.21-3.96 (m, 2H) 2.74-2.59 (m, 1H) 2.54-2.41 (m, 1H) 2.17 (s, 3H) 1.50 (d, J = 6.8Hz, 3H) 1.42-1.33 (m, 3H)

[0423] ESI-MS m / z 457 (MH+)

[0424] Example 37 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- (2-Phenylpropan-2-yl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate amine

[0425] The title compound was obtained in the same manner as in Example 1 (5), except that 2-phenylpropane-2-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0426] 1HNMR (DMSO-d6) δ: 8.26 (s, 1H) 8.16-8.08 (m, 1H) 7.44 (dd, J=8.8, 1.2Hz, 2H) 7.38-7.28 (m, 2H) 7.21 (tt, J=7.3, 1.27 Hz, 1H) 6.76-6.50 (m, 1H) 6.25-6.10 (m, 1H) 5.79-5.62 (m, 1H) 5.45-5.19 (m, 1H) 4.45-4.30 (m, 1H) 4.26-4.01 (m, 2H)

[0427] 2.79-2.42(m,2H)2.29-2.22(m,3H)1.71(s,6H)1.43-1.36(m,3H)

[0428] ESI-MS m / z 471 (MH+)

[0429] Example 47 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- ((R)-1-phenylpropyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0430] The title compound was obtained in the same manner as in Example 1 (5), except that (R)-1-phenylpropane-1-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0431] 1 HNMR (DMSO-d6) δ: 8.35 (brd, J=8.0Hz, 1H) 8.17-8.11 (m, 1H) 7.46-7.22 (m, 5H) 6.74-6.50 (m, 1H) 6.26-6.08 (m, 1H) 5.79-5.60 (m, 1H) 5. 40-5.21(m,1H)4.99-4.87(m,1H)4.43-4.30(m,1H)4.23-3.94(m,2H)2.76-2.42(m,2H)2.21(s,3H)1.95-1.74(m,2H)1.44-1.34(m,3H)

[0432] 0.91 (t, J = 7.3 Hz, 3H)

[0433] ESI-MS m / z 471 (MH+)

[0434] Example 57 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- (2-(2-fluorophenyl)propan-2-yl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-Formamide

[0435] The title compound was obtained in the same manner as in Example 1 (5), except that 2-(2-fluorophenyl)propane-2-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0436] 1 HNMR (CDCl3) δ: 8.28 (s, 1H) 8.11 (d, J = 4.4Hz, 1H) 8.02 (s, 1H) 7.47-7.42 (m, 1H) 7.29-7.23 (m, 1H) 7.15 (t , J=7.7Hz, 1H) 7.02 (ddd, J=12.5, 8.1, 1.1Hz, 1H) 6.58-6.35 (m, 2H) 5.79-5.70 (m, 1H) 5.30-5.19 (m, 1H) 4 .53 (t, J=10.1Hz, 0.7H) 4.38-4.25 (m, 1.6H) 3.92 (t, J=8.8Hz, 0.7H) 2.91-2.78 (m, 1H) 2.70-2.60 (m, 0.3 H) 2.54-2.43 (m, 0.7H) 2.28 (d, J = 7.0Hz, 3H) 1.88 (dt, J = 10.0, 5.0Hz, 6H) 1.53 (t, J = 6.2Hz, 3H) ESI-MSm / z 489(MH+)

[0437] Example 67 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- ((R)-1-(3-chlorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5- Formamide

[0438] The title compound was obtained in the same manner as in Example 1 (5), except that (R)-(+)-1-(3-chlorophenyl)ethylamine hydrochloride was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0439] 1 HNMR (CDCl3) δ: 8.22 (d, J = 5.9Hz, 1H) 7.75 (d, J = 7.0Hz, 1H) 7.38 (s, 1H) 7.35-7.27 (m, 3H) 6.58-6.33 (m, 2H) 5.78-5.66 (m, 1H) 5.29-5.19 (m, 2H) 4.56 (t, J = 10.3Hz, 0.7H) 4.3 9-4.20 (m, 1.6H) 3.89 (t, J = 8.8Hz, 0.7H) 2.94-2.82 (m, 1H) 2.66-2.58 (m, 0.3H) 2.46 (d t, J=14.5, 6.1Hz, 0.7H) 2.18 (d, J=11.0Hz, 3H) 1.60 (d, J=7.0Hz, 3H) 1.55-1.51 (m, 3H)

[0440] ESI-MS m / z 491, 493 (MH+)

[0441] Example 77 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- ((R)-1-(2,4-difluorophenyl)ethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine Pyridine-5-carboxamide

[0442] The title compound was obtained in the same manner as in Example 1 (5), except that (R)-(+)-1-(2,4-difluorophenyl)ethylamine hydrochloride was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0443] 1 HNMR (CDCl3) δ: 8.20 (d, J = 5.9Hz, 1H) 7.98 (d, J = 7.7Hz, 1H) 7.37-7.31 (m, 1H) 6.90-6.81 ( m, 2H) 6.58-6.35 (m, 2H) 5.78-5.65 (m, 1H) 5.44-5.37 (m, 1H) 5.30-5.19 (m, 1H) 4.56 (t, J= 10.1Hz, 0.7H) 4.38-4.23 (m, 1.6H) 3.88 (t, J = 8.8Hz, 0.7H) 2.94-2.83 (m, 1H) 2.66-2.57 ( m, 0.3H) 2.51-2.42 (m, 0.7H) 2.27 (d, J = 9.2Hz, 3H) 1.61 (d, J = 7.0Hz, 3H) 1.56 - 1.51 (m, 3H)

[0444] ESI-MS m / z 493 (MH+)

[0445] Example 87 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6- (Propan-1-yn-1-yl)-N-((S)-2,2,2-trifluoro-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine Pyridine-5-carboxamide

[0446] The title compound was obtained in the same manner as in Example 1 (5), except that (S)-2,2,2-trifluoro-1-phenylethane-1-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0447] 1 HNMR (CDCl3) δ: 8.40 (d, J=8.8Hz, 1H) 8.16 (s, 1H) 7.44 (s, 5H) 6.58-6.38 (m, 2H) 5.92-5.84 (m, 1H) 5.81-5.69 (m, 1H) 5.29-5.19 (m, 1H) 4.55 (t, J = 10.3Hz, 0.7H) 4.41-4.24 (m, 1.6H) 3.91 (t, J=8.6Hz, 0.7H) 2.92-2.80 (m, 1H) 2.70-2 .61 (m, 0.3H) 2.54-2.46 (m, 0.7H) 2.35 (d, J = 8.4Hz, 3H) 1.54 (t, J = 7.3Hz, 3H)

[0448] ESI-MS m / z 511 (MH+)

[0449] Example 97 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6- (cyclopropylethynyl)-N-(2-phenylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0450] The title compound was obtained in the same manner as in Example 1, except that cyclopropylacetylene was used instead of 1.0 M propyne solution in DMF in Example 1(3) and 2-phenylpropane-2-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine in Example 1(5).

[0451] 1 HNMR (CDCl3) δ: 8.15 (s, 1H) 8.00 (s, 1H) 7.44 (d, J = 7.7Hz, 2H) 7.37 (t, J = 7.7Hz, 2H) 7.32 - 7.27 (m, 1H) 6.66-6.30 (m, 2H) 5.81-5.69 (m, 1H) 5.38-5.24 (m, 1H) 4.48 (t, J = 9.9Hz, 0.7H)

[0452] 4.42-4.29(m,1.6H)4.22(t,J=10.4Hz,0.7H)

[0453] 2.77-2.68(m,1H)2.67-2.60(m,0.3H)2.59-2.52(m,0.7H)1.83(s,6H)1.60-1.52(m,4H)1.08-1.01(m,2H)0.92-0.88(m,2H)

[0454] ESI-MS m / z 497 (MH+)

[0455] Example 10 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-(cyclopropylethynyl)-N-((R)-1-(2,3-difluorophenyl)ethyl)-7H-pyrrolo[2,3-d]pyrimidine- 5-Formamide

[0456] The title compound was obtained by the same procedure as in Example 1, except that cyclopropylacetylene was used instead of a 1.0 M DMF solution of propyne in Example 1(3) and (R)-(+)-1-(2,3-difluorophenyl)ethylamine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine in Example 1(5).

[0457] 1HNMR (CDCl3) δ: 8.17 (d, J = 4.0Hz, 1H) 8.04 (d, J = 8.1Hz, 1H) 7.15-7.05 (m, 3H) 6.58-6.36 (m, 2H) 5.80-5.68 (m, 1H) 5.49-5.42 (m, 1H) 5.34-5.24 (m, 1H) 4.52 (t, J = 10.1Hz, 0.7H) 4. 37-4.23 (m, 1.6H) 3.92 (t, J = 8.8Hz, 0.7H) 2.86-2.76 (m, 1H) 2.69-2.63 (m, 0.3H) 2.52-2 .46(m,0.7H)1.73-1.63(m,4H)1.55(t,J=5.3Hz,3H)1.14-1.07(m,2H)1.01-0.92(m,2H)

[0458] ESI-MS m / z 519 (MH+)

[0459] Example 11

[0460] Example 11(1)(2S,4R)-4-(4-amino-6-bromo-5-(((R)-1-phenylethyl)amino) tert-Butyl 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpyrrolidine-1-carboxylate

[0461] The compound of Reference Example 1 (2) (1.00 g), (R)-(+)-1-phenylethylamine (0.503 g), diisopropylethylamine (1.79 g), and N,N-dimethylformamide (10 mL) were added, followed by HATU (1.58 g) and stirred at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain an amide (1.53 g). The resulting compound was used in the next reaction without further purification.

[0462] Chloroform (15 mL) was added to the amide (1.53 g), and the mixture was cooled to 0°C. N-bromosuccinimide (0.88 g) was then added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the target product (1.39 g).

[0463] 1HNMR (CDCl3) δ: 8.21 (s, 1H) 7.42-7.28 (m, 5H) 6.97 (d, J = 7.3Hz, 1H) 5.36-5.29 (m, 1H) 5.20-5.07 (m, 1H) 4.30 (t, J = 1 0.3Hz, 1H) 4.04-3.72 (m, 2H) 3.00-2.86 (m, 1H) 2.38 (dt, J=14.3, 6.0Hz, 1H) 1.63 (d, J=7.0Hz, 3H) 1.53-1.43 (m, 12H)

[0464] ESI-MS m / z 543, 545 (MH+)

[0465] Example 11(2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-Bromo-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0466] Chloroform (3 mL) was added to the compound of Example 11 (1) (600 mg), and after cooling to 0°C, trifluoroacetic acid (4.44 g) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, acetonitrile (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure again to obtain the amine compound. The obtained compound was used in the next reaction without further purification.

[0467] Acetonitrile (3 mL) was added to the resulting amine, and after cooling to 0°C, acryloyl chloride (99.9 mg) and diisopropylethylamine (713 mg) were added, and stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (ethyl acetate:methanol) to obtain the target product (281 mg).

[0468] 1 HNMR (CDCl3) δ: 8.20 (d, J=7.3Hz, 1H) 7.42-7.36 (m, 4H) 7.32-7.28 (m, 1H) 7.00-6.94 (m, 1H)

[0469] 6.57-6.33 (m, 2H) 5.76-5.66 (m, 1H) 5.36-5.29 (m, 1H) 5.14-5.08 (m, 1H) 4, 71 (t, J = 9.9Hz, 0.7H) 4.42-4.23 (m, 1.6H) 3.83 (t, J=8.6Hz, 0.7H) 3.03-2.92 (m, 1H) 2.60-2.57 (m, 0.3H) 2.44-2.40 (m, 0.7H) 1.64 (d, J= 6.6Hz, 3H) 1.56 (dd, J= 11.7, 6.2Hz, 3H)

[0470] ESI-MS m / z 497, 499 (MH+)

[0471] Example 11(3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-(Cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0472] The compound of Example 11 (2) (65 mg), dichlorobis(triphenylphosphine)palladium (9.2 mg), copper (I) iodide (5.0 mg), cyclopropylacetylene (13.0 mg), triethylamine (39.7 mg), and N,N-dimethylformamide (1.3 mL) were added, and the system was purged with nitrogen, followed by stirring at 70°C for 2.5 hours. Ethyl acetate and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol) to obtain the target compound (50 mg).

[0473] 1 HNMR (CDCl3) δ: 8.22 (d, J = 5.1Hz, 1H) 7.82 (d, J = 7.3Hz, 1H) 7.43-7.35 (m, 4H) 7.30 (t, J = 6 .8Hz, 1H) 6.58-6.34 (m, 2H) 5.77-5.66 (m, 1H) 5.35-5.20 (m, 2H) 4.54 (t, J = 10.1Hz, 0.7H) 4.35-4.25(m, 1.6H)3.88(t, J=8.8Hz, 0.7H)2.90-2.78(m, 1H)2.65-2.56(m, 0.3H)2.49- 2.40 (m, 0.7H) 1.63 (d, J = 7.0Hz, 3H) 1.56-1.45 (m, 4H) 1.03-0.91 (m, 2H) 0.84-0.69 (m, 2H)

[0474] ESI-MS m / z 483 (MH+)

[0475] Example 127 - ((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6- (3,3-Dimethylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine Pyridine-5-carboxamide

[0476] The title compound was obtained in the same manner as in Example 11, except that 3,3-dimethyl-1-butyne was used instead of cyclopropylacetylene in Example 11(3).

[0477] 1HNMR (CDCl3) δ: 8.22 (d, J=5.9Hz, 1H) 7.75 (d, J=7.7Hz, 1H) 7.38 (dt, J=15.5, 7.1Hz, 4H) 7.31 -7.25(m,1H)6.57-6.34(m,2H)5.77-5.65(m,1H)5.44-5.35(m,1H)5.33-5.15(m,1H)4.63(t, J=10.1Hz, 0.7H)4.40-4.20(m, 1.6H)3.89(t, J=8.8Hz, 0.7H)2.90-2.76(m, 1H)2.65-2.55(m, 0.3H) 2.49-2.40 (m, 0.7H) 1.85 (s, 1H) 1.64 (d, J = 7.0Hz, 3H) 1.55 (d, J = 5.9Hz, 3H) 1.26 (s, 9H)

[0478] ESI-MS m / z 499 (MH+)

[0479] Example 13 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-(3-methoxy-3-methylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide

[0480] The title compound was obtained in the same manner as in Example 11, except that cyclopropylacetylene was used instead of 3-methoxy-3-methyl-1-butyne in Example 11(3).

[0481] 1 HNMR (CDCl3) δ: 8.17 (s, 1H) 7.61 (d, J = 7.7Hz, 1H) 7.43-7.35 (m, 4H) 7.30 (d, J = 7.0Hz, 1H) 6. 57-6.33 (m, 2H) 5.81-5.68 (m, 1H) 5.43-5.33 (m, 1H) 5.29-5.12 (m, 1H) 4.59 (t, J = 10.1Hz, 0. 7H)4.38-4.22(m, 1.6H)3.92(t, J=8.6Hz, 0.7H)3.30(s, 3H)2.86-2.72(m, 1H)2.70-2.60(m , 1.3H) 2.52-2.44 (m, 0.7H) 1.64 (d, J = 7.0Hz, 3H) 1.55 (t, J = 5.5Hz, 3H) 1.46 (d, J = 2.2Hz, 6H)

[0482] ESI-MS m / z 515 (MH+)

[0483] Example 14 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- 6-(But-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate amine

[0484] The title compound was obtained in the same manner as in Example 11 (3) except that 1-trimethylsilyl-1-butyne and tetra-n-butylammonium fluoride were used instead of cyclopropylacetylene.

[0485] 1 HNMR (CDCl3) δ: 8.26-8.25 (m, 1H) 7.79 (d, J = 7.3Hz, 1H) 7.42-7.36 (m, 4H) 7.32-7.30 (m, 1H)

[0486] 6.57-6.37 (m, 2H) 5.76-5.66 (m, 1H) 5.33-5.20 (m, 2H) 4.57 (t, J = 10.3Hz, 0.7H) 4.36 - 4.22 (m, 1.6H) 3.88 (t, J = 8.8Hz, 0. 7H) 2.92-2.81 (m, 1H) 2.65-2.57 (m, 0.3H) 2.48-2.38 (m, 2.7H) 1.63 (d, J = 7.0Hz, 3H) 1.54-1.51 (m, 3H) 1.17-1.12 (m, 3H)

[0487] ESI-MS m / z 471 (MH+)

[0488] Example 15 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino- N-(2-(2-fluorophenyl)propan-2-yl)-6-(3-methylbut-1-yn-1-yl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide

[0489] The title compound was obtained by the same procedure as in Example 11, except that 2-(2-fluorophenyl)propane-2-amine was used instead of (R)-(+)-1-phenylethylamine in Example 11(1) and 3-methyl-1-butyne was used instead of cyclopropylacetylene in Example 11(3).

[0490] 1 HNMR (CDCl3) δ: 7.92 (s, 1H) 7.44 (t, J = 7.9Hz, 1H) 7.30-7.23 (m, 1H) 7.14 (t, J = 7.5Hz, 1H) 7.0 2(dd, J=12.6, 8.2Hz, 1H) 6.58-6.35 (m, 2H) 5.80-5.69 (m, 1H) 5.33-5.16 (m, 1H) 4.58 (t, J=9.9 Hz, 0.7H) 4.38-4.23 (m, 1.6H) 3.91 (t, J = 8.4Hz, 0.7H) 3.03-2.93 (m, 1H) 2.89-2.75 (m, 1H) 2. 69-2.60 (m, 0.3H) 2.53-2.43 (m, 0.7H) 1.88 (s, 6H) 1.55 (d, J = 5.1Hz, 3H) 1.36 (d, J = 6.6Hz, 6H)

[0491] ESI-MS m / z 517 (MH+)

[0492] Example 16

[0493] Example 16 (1) (2R, 4S)-4-(benzyloxy)-2-((toluenesulfonyloxy)methyl)pyrrolidine-1-carboxylic acid tert-Butyl acrylate

[0494] Tert-butyl (2R,4S)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g) was dissolved in dichloromethane (20 mL). After cooling to 0°C, 1,4-diazabicyclo[2.2.2]octane (2.2 g) and toluenesulfonyl chloride (1.9 g) were added, and the mixture was warmed to room temperature and stirred for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the desired product (4.32 g).

[0495] 1 HNMR (CDCl3) δ: 7.78 (d, J=8.1Hz, 2H), 7.42-7.29 (m, 7H), 4.57-4.41 (m, 2H), 4.39- 3.96(m, 4H), 3.61-3.20(m, 2H), 2.46(s, 3H), 2.27-2.02(m, 2H), 1.48-1.31(m, 9H)

[0496] ESI-MS m / z 462(MH + )

[0497] Example 16(2) (2S,4S)-4-(Benzyloxy)-2-ethylpyrrolidine-1-carboxylic acid tert-butyl ester

[0498] Under a nitrogen atmosphere, copper iodide (2.04 g) was suspended in diethyl ether (12 mL), cooled to 0°C, and a 1.04 M diethyl ether solution of methyl lithium (0.36 mL) was added, followed by stirring at 0°C for 30 minutes. Then, a dichloromethane (4.0 mL) solution of the compound of Example 16 (1) (1.98 g) was added, the mixture was warmed to room temperature, and stirred for 1 hour. After the reaction mixture was cooled to 0°C, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the target product (707 mg).

[0499] 1HNMR (CDCl3) δ: 7.42-7.25 (m, 5H), 4.66-4.40 (m, 2H), 4.17-4.03 (m, 1H), 4.00-3.26 (m, 3H), 2.24-2.09 (m, 1H), 1.96-1.71 (m, 2H), 1.48 (s, 9H), 1.45-1.31 (m, 1H), 0.86 (t, J=7.4Hz, 3H)

[0500] ESI-MS m / z 306(MH + )

[0501] Example 16(3) (2S,4S)-2-ethyl-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0502] The compound of Example 16 (2) (1.06 g) and 10% palladium hydroxide on carbon catalyst (160 mg) were suspended in ethanol (11 mL) and THF (11 mL), replaced with hydrogen, and stirred at room temperature for 20 hours. The reaction mixture was filtered through celite, washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the target product (709 mg).

[0503] 1 HNMR (CDCl3) δ: 4.46-4.36 (m, 1H), 4.02-3.81 (m, 1H), 3.71-3.35 (m, 2H), 2.15-1.9 9(m, 1H), 1.95-1.72(m, 2H), 1.49(s, 9H), 1.46-1.35(m, 1H), 0.86(t, J=7.5Hz, 3H)

[0504] ESI-MS m / z 216(MH + )

[0505] Example 16 (4) (2S, 4R)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine-7- tert-Butyl-2-ethylpyrrolidine-1-carboxylate

[0506] The compound of Example 16 (3) (709 mg) and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.11 g) were dissolved in THF (7.1 mL), cooled to 0°C, and triphenylphosphine (1.3 g) and diisopropyl azodicarboxylate (1.00 mL) were added. The temperature was raised to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the corresponding coupled product. The obtained compound was used in the next reaction without further purification. The obtained coupled product, THF (5.4 mL) and aqueous ammonia (5.4 mL) were added to a pressure tube and stirred at 100°C for 14 hours. The reaction mixture was cooled to room temperature, poured into water (12.8 mL), and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:acetone) to obtain the target product (797 mg).

[0507] 1 HNMR (CDCl3) δ: 8.29 (s, 1H), 7.14 (s, 1H), 5.67 (br s, 2H), 5.32-5.09 (m, 1H), 4.24-4.08 (m, 1H), 3.95-3.79 (m, 1H), 3.46 (dd, J=9.3, 11.0Hz, 1H), 2. 70-2.55 (m, 1H), 2.06-1.95 (m, 1H), 1.59-1.51 (m, 2H), 1.49 (s, 9H), 0.91 (t, J=7.5Hz, 3H) ESI-MS m / z458(MH + )

[0508] Example 16 (5) (2S, 4R)-4-(4-amino-6-bromo-5-(((R)-1-phenylethyl)amino tert-Butyl 7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethylpyrrolidine-1-carboxylate

[0509] The compound of Example 16 (4) (797 mg), dichlorobis(triphenylphosphine)palladium (25 mg), and (R)-(+)-1-phenylethylamine (0.55 mL) were suspended in DMF (8.0 mL), replaced with carbon monoxide, and stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain the corresponding amide. The obtained compound was used in the next reaction without further purification. The obtained amide was dissolved in acetonitrile (8.2 mL), cooled to -10°C, and a solution of N-bromosuccinimide (457 mg) in acetonitrile (8.2 mL) was slowly added dropwise, and the reaction mixture was stirred for 30 minutes. Aqueous sodium sulfite solution and aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:acetone) to obtain the target compound (650 mg).

[0510] 1 HNMR (CDCl3) δ: 8.23 ​​(s, 1H), 7.49-7.29 (m, 5H), 6.98 (d, J=7.4Hz, 1H), 5.41-5.28 (m, 1H), 5.24-5.04 (m, 1H), 4.38-4.22 (m, 1H), 4. 07-3.68 (m, 1H), 3.19-2.83 (m, 1H), 2.43-2.29 (m, 1H), 2.25-1.67 (m, 3H), 1.66 (d, J = 6.9Hz, 3H), 1.51 (s, 9H), 0.98 (t, J = 7.4Hz, 3H)

[0511] ESI-MS m / z 557, 559 (MH + )

[0512] Example 16 (6) 7-((3R,5S)-1-acryloyl-5-ethylpyrrolidin-3-yl)-4-amino- 6-Bromo-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0513] Acetonitrile (9.7 mL) was added to the compound (650 mg) of Example 16 (5), and after cooling to 0°C, sodium iodide (1.05 g) and trimethylsilyl chloride (0.89 mL) were added, and the mixture was stirred at 0°C for 1 hour. Ethanol (9.7 mL), isopropylethylamine (2.0 mL) and acrylic anhydride (0.16 mL) were added to the reaction mixture in sequence, and the mixture was stirred at 0°C for 30 minutes. Aqueous ammonia and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:acetone) to obtain the target product (256 mg).

[0514] 1 HNMR (CDCl3) δ: 8.27-8.16 (m, 1H), 7.47-7.29 (m, 5H), 6.98 (d, J=7.3Hz, 1H), 6.61-6.29 (m, 2H), 5.84-5.63 (m, 1H), 5.43-5.26 (m, 1H), 5 .22-5.01 (m, 1H), 4.80-3.82 (m, 3H), 3.23-2.92 (m, 1H), 2.58-2.30 (m, 1H), 2.22-1.79 (m, 2H), 1.66 (d, J=7.0Hz, 3H), 1.07-0.96 (m, 3H)

[0515] ESI-MS m / z 511, 513 (MH + )

[0516] Example 16 (7) 7-((3R,5S)-1-acryloyl-5-ethylpyrrolidin-3-yl)-4-amino- N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate amine

[0517] A 1.0 M propyne solution in DMF (0.70 mL) was added to the compound of Example 16 (6) (120 mg), acetonitrile (1.2 mL), triethylamine (0.10 mL), PdCl2(PPh3)2 (8.2 mg), and copper (I) iodide (0.4 mg). After nitrogen substitution, the mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous ammonium chloride were added, and then extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol) to obtain the target compound (102 mg).

[0518] 1HNMR (CDCl3) δ: 8.26 (s, 1H), 7.79 (br d, J=7.0Hz, 1H), 7.46-7.30(m, 5H), 6.58-6.31(m, 2H), 5.80-5.65(m, 1H), 5.33-5.15(m, 2H), 4. 59-3.85 (m, 3H), 3.03-2.33 (m, 2H), 2.25-1.70 (m, 5H), 1.65 (d, J=6.8Hz, 6H), 1.09-0.91 (m, 3H)

[0519] ESI-MS m / z 471(MH + )

[0520] Example 17 7-((3R,5S)-1-acryloyl-5-ethylpyrrolidin-3-yl)-4-amino- 6-(Cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0521] The title compound was obtained in the same manner as in Example 16, except that cyclopropylacetylene was used in place of the 1.0 M DMF solution of propyne in Example 16(7).

[0522] 1 HNMR (CDCl3) δ: 8.31-8.16 (m, 1H), 7.84 (d, J=7.4Hz, 1H), 7.46-7.30 (m, 5H), 6.64-6.32 (m, 2H), 5.82-5.67 (m, 1H), 5.39-5.17 (m, 2H), 4 .67-3.81 (m, 3H), 3.02-2.80 (m, 1H), 2.62-1.71 (m, 3H), 1.65 (d, J=6.9Hz, 3H), 1.58-1.47 (m, 1H), 1.06-0.92 (m, 5H), 0.85-0.70 (m, 2H)

[0523] ESI-MS m / z 497(MH + )

[0524] Example 18 7-((3R,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-4- Amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid Amide

[0525] The title compound was obtained by the same procedures as in Example 16, except that (2R,4S)-4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was used in place of the compound in Example 16(3) in Example 16(4), and that cyclopropylacetylene was used in place of a 1.0 M DMF solution of propyne in Example 16(7).

[0526] 1HNMR(CDCl3)δ: 8.29-8.22(m, 1H), 7.86-7.80(m, 1H), 7.36-7.44(m, 4H), 7.34-7.28(m, 1H) , 6.48-6.37(m, 2H), 5.78-5.69(m, 1H), 5.29-5.15(m, 2H), 4.55-4.30(m, 2H), 3.96-3.65(m, 3H), 3.42 (s, 3H), 3.18-3.06 (m, 0.3H), 2.90-2.80 (m, 0.3H), 2.64-2.58 (m, 0.3H), 2.47-2. 35(m, 0.7H), 1.64(d, 3H, J=6.9Hz), 1.58-1.47(m, 1H), 1.04-0.94(m, 2H), 0.87-0.69(m, 2H)

[0527] ESI-MS m / z 513(MH + )

[0528] Example 197 - ((3R, 5R) -1-acryloyl-5-(ethoxymethyl)pyrrolidin-3-yl) -4- Amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid Amide

[0529] The title compound was obtained by the same procedures as in Example 16, except that tert-butyl (2R,4S)-2-(ethoxymethyl)-4-hydroxypyrrolidine-1-carboxamide was used instead of the compound in Example 16(3) in Example 16(4) and cyclopropylacetylene was used instead of a 1.0 M DMF solution of propyne in Example 16(7).

[0530] 1 HNMR(CDCl3)δ: 8.28-8.18(m, 1H), 7.84(br d, J=7.0Hz, 1H), 7.47-7.29(m, 5H), 6.82-6.35(m, 2H), 5.79-5.68(m, 1H), 5.40-5.14(m, 2H), 4.63-3.53(m, 7H), 3.20-2.79( m, 1H), 2.69-2.40 (m, 1H), 1.67-1.63 (m, 3H), 1.59-1.47 (m, 1H), 1.22 (t, J=7.0Hz, 3H), 1.05-0.92 (m, 2H), 0.87-0.72 (m, 2H)

[0531] ESI-MS m / z 527(MH + )

[0532] Comparative Example 1 4-amino-N-(4-(methoxymethyl)phenyl)-7-(1-methylcyclopropyl)-6- (Propan-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0533] The title compound was obtained by the method described in Example 95 of International Publication No. 2017 / 146116.

[0534] ESI-MS m / z 390 (MH+)

[0535] Comparative Example 2 1-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- (4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine Pyridine-3-carboxamide

[0536] The title compound was obtained by the method described in Example 79 of International Publication No. 2017 / 038838.

[0537] ESI-MS m / z 505 (MH+)

[0538] Comparative Example 3 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- (Cyclohexylmethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0539] The title compound was obtained in the same manner as in Example 1 (5), except that cyclohexylmethanamine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0540] 1 HNMR (DMSO-d6) δ: 8.68-8.31 (m, 1H) 8.20-8.10 (m, 1H) 8.09-7.97 (m, 1H) 7. 59-7.20(m,1H)6.74-6.49(m,1H)6.25-6.09(m,1H)5.78-5.60(m,1H)5.40- 5.20(m,1H)4.44-4.29(m,1H)4.23-3.92(m,2H)3.25-3.12(m,2H)2.76-2. 40(m,2H)2.25(s,3H)1.81-1.45(m,5H)1.43-1.34(m,3H)1.30-0.90(m,6H)

[0541] ESI-MS m / z 449 (MH+)

[0542] Comparative Example 4 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- (2-Methylbenzyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

[0543] The title compound was obtained in the same manner as in Example 1 (5), except that o-tolylmethaneamine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0544] 1HNMR (DMSO-d6) δ: 8.37-8.27 (m, 1H) 8.19-8.09 (m, 1H) 7.39-7.30 (m, 1H) 7.26-7.11 (m, 4H) 6.68-6.48 (m, 1H) 6.24-6.07 (m, 1H) 5.80-5.60 (m , 1H) 5.36-5.17 (m, 1H) 4.52 (d, J = 5.7Hz, 2H) 4.42-4.28 (m, 1H) 4.22-3 .92(m,2H)2.73-2.42(m,2H)2.33(s,3H)2.02(s,3H)1.43-1.32(m,3H)

[0545] ESI-MS m / z 457 (MH+)

[0546] Comparative Example 5 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N- Methyl-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-Formamide

[0547] The title compound was obtained in the same manner as in Example 1 (5), except that (R)-1-(3,5-difluorophenyl)ethane-1-amine was used instead of (R)-1-(3,5-difluorophenyl)ethane-1-amine.

[0548] 1 HNMR (CDCl3) δ: 8.23 ​​(d, J=5.9Hz, 1H) 7.50-7.28 (m, 4H) 7.09-6.88 (m, 1H) 6.57-6.34 (m, 2H)

[0549] 5.79-5.64 (m, 1H) 5.22 (t, J = 9.3Hz, 1H) 4.48 (t, J = 9.7Hz, 0.6H) 4.39 - 4.20 (m, 1.9H) 3.90 (t, J = 8.6Hz, 0.5H) 2.85 (s, 4H) 2.66-2.63 (m, 0.4H) 2.51-2.44 (m, 0.6H) 2.07 (s, 2H) 1.66 (d, J = 4.8Hz, 3H) 1.52 (d, J = 5.9Hz, 3H)

[0550] ESI-MS m / z 471 (MH+)

[0551] Comparative Example 6

[0552] Comparative Example 6 (1) (2S, 4R)-4-(4-amino-5-(((R)-1-phenylethyl)carbamoyl)- 6-(Propan-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpyrrolidine-1-carboxylic acid tert-Butyl ester

[0553] A 1.0 M propyne solution in DMF (2.1 mL) was added to Example 11 (1) (230 mg), acetonitrile (4.6 mL), triethylamine (0.29 mL), PdCl2(PPh3)2 (5.9 mg), and copper (I) iodide (1.6 mg). After nitrogen substitution, the mixture was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added, and then extracted with ethyl acetate. The combined organic layers were washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate) to obtain the target compound (193 mg).

[0554] 1 HNMR (CDCl3) δ: 8.23 ​​(s, 1H) 7.79 (d, J = 6.8Hz, 1H) 7.46-7.27 (m, 5H) 5.40-5.17 (m, 2H) 4.28-3.64 (m, 3H) 2.85-2.68 (m, 1H) 2.46-2.36 (m, 1H)

[0555] 2.15-1.97(m,3H)1.62(d,J=6.8Hz,3H)1.56-1.32(m,12H)

[0556] ESI-MS m / z 503 (MH+)

[0557] Comparative Example 6 (2) 4-amino-7-((3R,5S)-5-methylpyrrolidin-3-yl)-N-((R)-1-phenyl 6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide hydrochloride

[0558] A 4M hydrochloric acid solution in 1,4-dioxane (5 mL) was added to Comparative Example 6 (1) (530 mg) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound (420 mg). ESI-MS m / z 403 (MH+)

[0559] Comparative Example 6 (3) 4-amino-7-((3R,5S)-1-((E)-but-2-enoyl)-5-methylpyrrole alkyl-3-yl)-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d] Pyrimidine-5-carboxamide

[0560] Acetonitrile (0.5 mL) was added to Comparative Example 6 (2) (18 mg), and after cooling to 0°C, acryloyl chloride (0.004 mL) and diisopropylethylamine (0.036 mL) were added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reverse phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the target compound (8.7 mg).

[0561] 1HNMR (CDCl3) δ: 8.31 (s, 1H) 8.14 (d, J = 6.2Hz, 1H) 7.77 (d, J = 7.0Hz, 1H) 7.39-7.36 (m, 4H) 7.33 -7.31 (m, 1H) 7.03 - 6.90 (m, 1H) 6.06 (dd, J = 14.3Hz, 1H) 5.28 - 5.17 (m, 2H) 4.48 (t, J = 10.1Hz, 1H )4.35-4.20(m, 2H)3.88(t, 8.8Hz, 1H)2.84-2.76(m, 1H)2.64-2.40(m, 1H)2.05(d, J=10.6Hz, 3 H) 1.92 (d, J = 6.6Hz, 1H) 1.85 (d, J = 7.0Hz, 2H) 1.62 (d, J = 7.0Hz, 3H) 1.55 (dd, J = 9.0, 5.7Hz, 3H)

[0562] ESI-MS m / z 471 (MH+)

[0563] The compounds synthesized in the above examples and comparative examples are shown below.

[0564] [Table 1]

[0565]

[0566]

[0567]

[0568] [Table 2]

[0569]

[0570] Experimental Example 1 Inhibitory effect on phosphorylation activity of wild-type and mutant EGFR (in in vitro) assay

[0571] The in vitro inhibitory activity measurement of the compounds against wild-type and mutant EGFR was commissioned to CarnaBiosciences Co., Ltd. (Kinase Profiling Book, https: / / www.carnabio.com / japanese / produc / search.cgi?mode=profiling).

[0572] Specifically, first, the compound of the present invention is serially diluted with dimethyl sulfoxide (DMSO). Then, EGFR protein, substrate peptide (Srctide, final concentration is 1 μM), magnesium chloride (final concentration is 5 mM), manganese chloride (final concentration is 1 mM), ATP (final concentration is near the Km of each EGFR), and a DMSO solution of the compound of the present invention (final concentration of DMSO is 1%) are added to a kinase reaction buffer (20 mM HEPES (pH 7.5), 1 mM dithiothreitol, 0.01% Triton X-100), and incubated at room temperature for 1 hour to perform a kinase reaction. Termination buffer is added thereto to stop the kinase reaction. Finally, LabChip TM Using an EZ Reader II (Parkin Elmer), unphosphorylated substrate peptides (S) and phosphorylated peptides (P) were separated and detected by microfluidic capillary electrophoresis. The phosphorylation level was determined from the peak heights of the S and P peaks. The IC50 value (nM) was defined as the compound concentration that inhibited the phosphorylation reaction by 50%, and is shown in the table below.

[0573] [Table 3]

[0574]

[0575] From the above results, it can be seen that the compounds of the present invention have excellent inhibitory activity against wild-type and mutant EGFR.

[0576] Experimental Example 2: Proliferation inhibition of EGFR overexpressing cell lines and exon 20 insertion mutant EGFR expressing cell lines Determination of inhibitory activity

[0577] The proliferation inhibitory activity against EGFR-overexpressing cell lines and exon 20 insertion mutant EGFR-expressing cell lines was evaluated using the following cells: MDA-MB-468 cells (ATCC), an EGFR-overexpressing human breast cancer cell line; NCI-H1975 cells (ATCC), L858R and T790M mutant EGFR-positive human lung cancer cells; and MCF10A cells, a human normal breast cell line into which the EGFR gene (WT, D769_N7 The cells expressing the 70insASV mutant, D770_N771insSVD mutant, and H773_V774insNPH mutant were MCF10A_EGFR cells, MCF10A_EGFR / V769_D770insASV cells, MCF10A_EGFR / D770_N771insSVD cells, and MCF10A_EGFR / H773_V774insNPH cells (Fukushima Medical University, a public university corporation).

[0578] MDA-MB-468 cells were suspended in Leibovitz's L-15 medium containing 10% inactivated fetal bovine serum. NCI-H1975 cells were suspended in RPMI-1640 medium containing 10% inactivated fetal bovine serum. MCF10A_EGFR cells, MCF10A_EGFR / V769_D770insASV cells, MCF10A_EGFR / D770_N771insSVD cells, and MCF10A_EGFR / H773_V774insNPH cells were suspended in DMEM / Ham's F-12 medium (containing L-glutamine, phenol red, HEPES, and sodium pyruvate) containing a final concentration of 10 μg / mL insulin, 500 ng / mL hydrocortisone, and 5 μmol / L forskolin, and containing 5% inactivated horse serum. The cell suspension was inoculated into each well of a 96-well flat-bottom plate in a manner such that the number of cells per well was 500. MDA-MB-468 cells were cultured in a culture vessel without carbon dioxide at 37°C for 1 day, and other cells were cultured in a culture vessel containing 5% carbon dioxide at 37°C for 1 day. Regarding the compound of the present invention, after being prepared to 1 mM using DMSO, it was diluted to 1 / 200 using culture medium to prepare a 5 μM solution. Then, the DMSO solution of the compound of the present invention was diluted with the culture medium used for cell suspension and added in a manner such that the final concentration of the test compound became 1000 nM. MDA-MB-468 cells were cultured in a culture vessel without carbon dioxide, and other cells were cultured in a culture vessel containing 5% carbon dioxide at 37°C for further 3 days.

[0579] Cell counts at the start of culture (day 0) and after culture (day 3) were measured using CellTiter-Glo (registered trademark) 2.0 Reagent (Promega) according to the manufacturer's instructions. The proliferation inhibition rate was calculated using the following formula, and the concentration of the test compound that inhibited 50% (GI50 (nM)) was determined. The results are shown in Table 4.

[0580] 1)T day3 ≥C day0 Situation

[0581] Growth rate (%) = (T day3 -C day0 ) / (C day3 -C day0 )×100

[0582] T: Luminescence intensity of the wells to which the test compound was added

[0583] C: Luminescence intensity of the wells without addition of the test compound

[0584] day0: day when the test compound is added

[0585] Day 3: Evaluation day

[0586] 2)T day3 <C day0 Situation

[0587] Growth rate (%) = (T day3 -C day0 ) / (C day0 )×100

[0588] T: Luminescence intensity of the wells to which the test compound was added

[0589] C: Luminescence intensity of the wells without addition of the test compound

[0590] day0: day when the test compound is added

[0591] Day 3: Evaluation day

[0592] [Table 4]

[0593]

[0594] From the above results, it can be seen that the compound group of the present invention has excellent cell proliferation inhibitory activity against MDA-MB-468 cells, which are wild-type EGFR overexpression strains, MCF10A_EGFR cells into which wild-type EGFR is gene-introduced and expressed, NCI-H1975 cells, which are L858R and T790M mutant EGFR-positive cells, and exon 20 insertion mutant EGFR-expressing cell lines (MCF10A_EGFR / V769_D770insASV cells, MCF10A_EGFR / D770_N771insSVD cells, and MCF10A_EGFR / H773_V774insNPH cells).

[0595] Experimental Example 3: Determination of the proliferation inhibitory activity of exon 20 insertion mutant EGFR expressing cell lines

[0596] The proliferation inhibitory activity of the exon 20 insertion mutant EGFR was evaluated using the following cells: NCI-H1975 cells, H1975-EGFRinsSVD cells in which the intrinsic EGFR (T790M / L858R) was knocked out by genetic modification to express the D770_N771insSVD mutant EGFR, and LXF 2478 cells (Charles River), a tumor from a human lung cancer patient positive for the V769_D770insASV mutant EGFR.

[0597] H1975-EGFRinsSVD cells were selected by sequencing. The PB-CMV-MCS-EF1-RFP+Puro vector encoding D770_N771insSVD (insSVD) was introduced into NCI-H1975 cells along with the SuperPiggyBac Transposase expression vector by electroporation using the Amaxa(registered trademark) Cell Line Nucleofector(registered trademark) Kit R. After selection with puromycin (SIGMA), XTN(registered trademark) TALENs Site-Specific Nucleases (Transposagen) were introduced by electroporation using the Amaxa(registered trademark) Cell Line Nucleofector(registered trademark) Kit R, thereby knocking out the endogenous EGFR (T790M / L858R).

[0598] When evaluating the cell proliferation inhibitory effect, each cell was suspended in RPMI-1640 culture medium. The cell suspension was inoculated in each well of a 96-well flat-bottom plate in a manner such that the number of cells per well became 3,000, and cultured at 37°C in an incubator containing 5% carbon dioxide for 1 day. Regarding the compound of the present invention and the comparative example compound, after being dissolved in DMSO to 1 mM, the final concentration of the highest concentration of the test compound was 1000 nM and the ratio was 3 using a Tecan D300e digital dispenser (Tecan), and cultured at 37°C in an incubator containing 5% carbon dioxide for 3 days. The measurement of the number of cells at the beginning of culture (day 0) and after culture (day 3) was performed using CellTiter-Glo (registered trademark) 2.0 Reagent (Promega) according to the manufacturer's recommended operating instructions. The proliferation inhibition rate was calculated by the following formula to determine the concentration of the test compound that inhibited 50% (GI50 (nM)). The results are shown in Table 5.

[0599] 1)T day3 ≥C day0 Situation

[0600] Growth rate (%) = (T day3 -C day0 ) / (C day3 -C day0 )×100

[0601] T: Luminescence intensity of the wells to which the test compound was added

[0602] C: Luminescence intensity of the wells without addition of the test compound

[0603] day0: day when the test compound is added

[0604] Day 3: Evaluation day

[0605] 2)T day3 <C day0 Situation

[0606] Growth rate (%) = (T day3 -C day0 ) / (C day0 )×100

[0607] T: Luminescence intensity of the wells to which the test compound was added

[0608] C: Luminescence intensity of the wells without addition of the test compound

[0609] day0: day when the test compound is added

[0610] day3: evaluation day.

[0611] [Table 5]

[0612]

[0613] From the above results, it was found that the compound group of the present invention also has excellent cell proliferation inhibitory activity in exon 20 insertion mutant EGFR-expressing cell lines (H1975-EGFRinsSVD and LXF 2478).

[0614] Test Example 4 Evaluation of oral absorbability

[0615] The compound of the present invention was suspended or dissolved in a 0.5% HPMC aqueous solution and 0.1N hydrochloric acid and orally administered to BALB / cA mice (Japan Clea Co., Ltd.) at a dose of 50 mg / kg / day. Blood was collected from the facial vein at 0.5, 1, 2, 4, and 6 hours after oral administration to obtain plasma. The compound concentration in the obtained plasma was measured by LC-MS / MS to evaluate oral absorption. The results are shown in Table 6 below.

[0616] [Table 6]

[0617] Example No. AUC0-6hr (μM·hr) Example No. AUC0-6hr (μM·hr) 1 50 2 15 3 24 4 12 5 20 6 17 7 15 8 15 9 51 10 50 11 31 12 36 13 18 14 27 15 34 16 15 17 21 18 15 19 6.1 Comparative Example 2 1.5

[0618] The above results show that the compound of the present invention has sufficient plasma concentrations and exhibits good oral absorption. In contrast, the oral absorption of Comparative Example 2 is more than 4 times weaker than that of the compound of the present invention.

[0619] Test Example 5 Evaluation of brain migration

[0620] The compound of the present invention was suspended or dissolved in a 0.5% HPMC aqueous solution and 0.1N hydrochloric acid and orally administered to BALB / cA mice (Clea Co., Ltd., Japan) at a dose of 50 mg / kg / day. After oral administration, blood was collected from the facial vein 0.5 hours later, the whole brain was removed to obtain plasma and brain samples. Three times the amount of water was added to the obtained brain sample, and the sample was homogenized using an ultrasonic homogenizer to obtain a brain homogenate. The compound concentrations in the obtained plasma and brain homogenate were measured using LC-MS / MS, and brain migration was evaluated based on the compound concentrations in the brain and plasma. The results are shown in Table 7 below.

[0621] [Table 7]

[0622]

[0623] The above results indicate that the compound of the present invention exhibits higher brain / plasma concentrations (Kp values) than Comparative Example 2, demonstrating good brain migration. Furthermore, the brain concentration of the compound in Comparative Example 2 was attenuated by more than 80 times compared to the compound of the present invention.

[0624] Test Example 6: Anti-tumor effect confirmation test on subcutaneous transplantation model of H1975-EGFRinsSVD cell line (invivo)

[0625] The H1975-EGFRinsSVD cell line was cultured in RPMI-1640 (containing 4.5 g / L glucose, 10 mM HEPES, and 1 mM sodium pyruvate) (Fujifilm Wako Pure Chemical Industries, Ltd.) medium containing inactivated 10% fetal bovine serum (FBS) in a 5% CO2 incubator at 37°C.

[0626] H1975-EGFRinsSVD cells were cultured at 8×10 7 The cells were resuspended in PBS at a concentration of 10 cells / mL. 8 × 10 cells / mL were injected subcutaneously into the right chest of 6-week-old nude mice (BALB / cAJcl-nu / nu, Japan Clea Co., Ltd.) using a 1 mL tuberculin syringe and a 25G needle. 6 cells / 0.1mL as the unit for transplanting cell suspension.

[0627] The tumor volume in nude mice reached 100-200 mm 3 At around 1:00 p.m., the mice were randomly assigned by stratification so that the tumor volume of each group was uniform, with 6 mice assigned to each group.

[0628] Examples 2, 11, and 12 were used as test compounds, and a 0.5% HPMC aqueous solution was used as a control. Examples 2, 11, and 12 were orally administered at doses of 25 mg / kg / day, 25 mg / kg / day, and 50 mg / kg / day, respectively.

[0629] The test compound or control was orally administered once a day for 14 consecutive days (Day 1-14) starting from the second day of grouping.

[0630] In order to compare the changes in tumor proliferation over time when each test compound is administered, the tumor volume (hereinafter referred to as "TV") is measured at a frequency of twice a week. In addition, an electronic balance for animals is used for the determination of body weight. The body weight change rate (BWC) is also referred to as "BWC" below. The body weight change rate (BWCn) on the nth day is calculated by the following formula based on the body weight (BWn) on the nth day. The changes in the average values ​​of TV and BWC of each individual over time are shown in Figure 1 and Figure 2 .

[0631] BWCn (%) = [(body weight on day n) - (body weight on the day of grouping)] / (body weight on the day of grouping) × 100

[0632] If the average TV value of the compound-administered group on the final evaluation day (Day 15) is lower than that of the control group and shows a statistically significant difference (Dunnett's multiple comparison test), the compound is considered effective (P < 0.001), which is indicated by * in the figure. Figure 1 .

[0633] The results analyzed using a Dunnett's multiple comparison test showed that the compounds of the invention were statistically significantly lower (P < 0.001) than the control group. These experimental results demonstrate that the compounds of Examples 2, 11, and 12 exhibit excellent antitumor effects against the exon 20 insertion mutant EGFR cell line (H1975-EGFRinsSVD) subcutaneously on the right thorax of nude mice. Furthermore, none of the mice administered with any of the compounds experienced weight loss exceeding 20%.

[0634] Test Example 7: Luciferase gene introduced into exon 20 insertion mutant EGFR expressing cell line (H1975- In vivo anti-tumor effect confirmation test in a brain transplantation model of EGFRinsSVD-Luc

[0635] The antitumor and life-extending effects of the inventive compounds in a brain direct transplantation model were evaluated using the H1975-EGFRinsSVD-Luc cell line, which is a human mutant EGFR-introduced cell line and into which luciferase was introduced.

[0636] H1975-EGFRinsSVD-Luc cells were prepared by introducing the luciferase-encoding pJTI (registered trademark) FAST DEST vector and the pJTI (registered trademark) PhiC31 Integrase expression vector into NCI-H1975-EGFRins SVD cells by electroporation using the Amaxa (registered trademark) Cell Line Nucleofector (registered trademark) Kit R, and then selecting the cells with hygromycin B (Nacalai Tesque Co., Ltd.).

[0637] The H1975-EGFRinsSVD-Luc strain was cultured in RPMI-1640 (containing 4.5 g / L glucose, 10 mM HEPES, and 1 mM sodium pyruvate) (Fujifilm Wako Pure Chemical Industries, Ltd.) medium containing inactivated 10% fetal bovine serum (FBS) in a 5% CO2 incubator at 37°C.

[0638] H1975-EGFRinsSVD-Luc cells were cultured at 12.5×10 7 cells / mL in PBS.

[0639] Nude mice (BALB / cAJcl-nu / nu, Japan Clea Co., Ltd.) aged approximately 6 to 7 weeks were fixed in a brain positioning device using mouse ear bars. The skin on the top of the head was disinfected by applying a disinfectant containing Isodine (polyvinylpyrrolidone iodine) using a sterile cotton swab and then incised with a scalpel.

[0640] A hole was made in the skull using a micro drill, and 2 μL of the cell suspension was transplanted into the brain at a flow rate of 0.8 μL / min using a needle, a manipulator, and a syringe pump.

[0641] As a rough guide to brain tumor size, total flux (photons / second) was measured in all surviving cases 26 days after transplantation using an IVIS (PerkinElmer, Inc., model: Lumina II). Based on the results, 10 animals were randomly assigned to each group in a stratified manner so that the average total flux across groups was uniform.

[0642] The compound of Example 11 was used as a test compound, and a 0.5% HPMC aqueous solution was used as a control. Example 11 was administered at a dose of 12.5 mg / kg / day or 25 mg / kg / day.

[0643] The compound of the present invention or the control was orally administered once a day starting from the second day of grouping for 38 consecutive days (Day 27-64).

[0644] The presence or absence of antitumor effects was determined using logarithmic conversion (Log10) of the total flux on the day of antitumor effect assessment (Day 47) 3 weeks after drug administration from the second day of grouping (Day 27).

[0645] A graph was created with the vertical axis representing the average total flux value of each group and the horizontal axis representing the number of days after transplantation, and the temporal changes in the total flux during the drug administration period were observed.

[0646] To determine the presence of a lifespan-extending effect, the number of survival days from cell transplantation to the final evaluation day (Day 0-65) of the lifespan-extending effect in the test compound group was analyzed using a Log-Rank test compared with the control group.

[0647] The results are shown in the following Figure 3 and Figure 4 Dunnett's multiple comparison test analyzed the logarithmic transformation (Log10) of the total flux on Day 47 for each group. The results showed that the test compound group had a statistically significant (5% on both sides) lower flux than the control group (P < 0.001). These test results indicate that the compounds of the present invention have an antitumor effect against the exon 20 insertion mutant EGFR-expressing cell line (H1975-EGFRinsSVD-Luc) transplanted into the brains of nude mice.

[0648] Furthermore, the Log-Rank test was used to analyze the survival days from cell transplantation to the final evaluation day (Day 0-65) of the lifespan extension effect in the test compound group compared with the control group. Statistically significant lifespan extension effects were confirmed compared with the control group (P < 0.05).

[0649] In summary, the compound of the present invention or a salt thereof has EGFR inhibitory activity and brain migration, and can be used as an EGFR inhibitor or a therapeutic agent for EGFR-positive tumors. Sequence Listing <110> Taiho Pharmaceutical Co., Ltd. <120> EGFR inhibitors <130> G2643 <150> JP 2020-121525 <151> 2020-07-15 <160> 6 <170> PatentIn version 3.5 <210> 1 <211> 3633 <212> DNA <213> <400> 1 atgcgaccct ccgggacggc cggggcagcg ctcctggcgc tgctggctgc gctctgcccg 60 gcgagtcggg ctctggagga aaagaaagtt tgccaaggca cgagtaacaa gctcacgcag 120 ttgggcactt ttgaagatca ttttctcagc ctccagagga tgttcaataa ctgtgaggtg 180 gtccttggga atttggaaat tacctatgtg cagaggaatt atgatctttc cttcttaaag 240 accatccagg aggtggctgg tttgtcctc attgccctca acacagtgga gcgaattcct 300 ttggaaaacc tgcagatcat cagaggaaat atgtactacg aaaattccta tgccttagca 360 gtcttatcta actatgatgc aaataaaacc ggactgaagg agctgcccat gagaaattta 420 caggaaatcc tgcatggcgc cgtgcggttc agcaacaacc ctgccctgtg caacgtggag 480 agcatccagt ggcgggacat agtcagcagt gactttctca gcaacatgtc gatggacttc 540 cagaaccacc tgggcagctg ccaaaagtgt gatccaagct gtcccaatgg gagctgctgg ggtgcaggag aggagaactg ccagaaactg accaaaatca tctgtgccca gcagtgctcc gggcgctgcc gtggcaagtc ccccagtgac tgctgccaca accagtgtgc tgcaggctgc 720 acaggcccc gggagagcga ctgcctggtc tgccgcaaat tccgagacga agccacgtgc 780 aaggacacct gccccccact catgctctac aaccccacca cgtaccagat ggatgtgaac cccgagggca fathercagctt tggtgccacc tgcgtgaaga agtgtccccg fathertgtg gtgacagatc acggctcgtg cgtccgagcc tgtggggccg acagctatga gatggagga gacggcgtcc gcaagtgtaa gaagtgcgaa gggccttgcc gcaaagtgtg taacggaata ggtattggtg father ctcactctcc father cgate acacttcaaa aactgcacct ccatcagtgg cgatctccac atcctgccgg tggcatttag gggtgactcc ttcacacata ctcctcctct ggatccacag gaactggata ttctgaaaac cgtaagga atcacagggt ttttgctgat tcaggcttgg cctgaaaaca ggacggacct ccatgccttt gagaacctag aaatcatacg cggcaggacc aagcaacatg gtcagttttc tcttgcagtc gtcagcctga acataacatc cttgggatta cgctccctca aggagataag tgatggagat gtgataattt cage aaatttgtgc tatgcaata caataactg gaaaaaactg tttgggacct ccggtcagaa aaccaaaatt ataagcaaca gaggtgaaaa cagctgcaag gccacaggcc aggtctgcca tgccttgtgc tccccgagg gctgctgggg cccggagccc 1560 agggactgcg tctcttgccg gaatgtcagc cgaggcaggg aatgcgtgga caagtgcaac cttctggagg gtgagccaag ggagtttgtg gagaactctg agtgcataca gtgccaccca gagtgcctgc ctcaggccat gaacatcacc tgcacaggac ggggaccaga caactgtatc cagtgtgccc actacattga cggcccccac tgcgtcaaga cctgcccggc aggagtcatg ggagaaaca acaccctggt ctggaagtac gcagacgccg gccatgtgtg ccacctgtgc catccaaact gcacctacgg atgcactggg ccaggtcttg aaggctgtcc aacgaatggg cctaagatcc cgtccatcgc cactggggatg gtggggggcc tcctcttgct gctggtggtg gccctgggga tcggctctt catgcgaagg cgccacatcg ttcggaagcg cacgctgcgg 2040 aggctgctgc aggaggga gcttgtggag cctcttacac ccagtggaga agctcccac 2100 caagctctct tgaggatctt gaaggaact gattcaaa agatcaagt gctgggctcc 2160 ggtgcgttcg gcacggtgta taagggactc tggatcccag aaggtgagaa agttaaaatt 2220 cccgtcgcta tcaggaatt agagaagca acatctccga aagccaaca ggaatccctc 2280 gatgaagcct acgtgatggc cagcgtggac aacccccacg tgtgccgcct gctggggcatc 2340 tgcctcacct cccaccgtgca gctcatcacg cagctcatgc ccttcggctg cctcctggac 2400 tatgtccggg aacacaaaga caatattggc tcccagtacc tgctcaactg gtgtgtgcag 2460 atcgcaaagg gcatgaacta cttgaggac cgtcgcttgg tgcaccgcga cctggcagcc 2520 aggaacgtac tggtgaaaac accgcagcat gtcagatca cagattttgg gctggccaaa 2580 ctgctgggtg cggagagaa agaataccat gcagaaggag gcaagtgcc tatcaagtgg 2640 atggcattgg aatcaattt acacagaatc tatacccacc agagtgatgt ctggagctac 2700 ggggtgactg tttgggagtt gatgaccttt ggatccaagc catatgacgg aatccctgcc 2760 agcgagatct cctccatcct ggagaaagga gaacgcctcc ctcagccacc catatgtacc 2820 atcgatgtct acatgatcat ggtcaagtgc tggatgatag acgcagatag tcgcccaaag 2880 ttccgtgagt tgatcatcga attctccaaa atggcccgag acccccagcg ctaccttgtc 2940 attcaggggg atgaaagaat gcatttgcca agtcctacag actccaactt ctaccgtgcc 3000 ctgatggatg aagaagacat ggacgacgtg gtggatgccg acgagtacct catcccacag 3060 cagggcttct tcagcagccc ctccacgtca cggactcccc tcctgagctc tctgagtgca 3120 accagcaaca attccaccgt ggcttgcatt gatagaaatg ggctgcaaag ctgtcccatc 3180 aaggaagaca gcttcttgca gcgatacagc tcagacccca caggcgcctt gactgaggac 3240 agcatagacg acaccttcct cccagtgcct gaatacataa accagtccgt tcccaaaagg 3300 cccgctggct ctgtgcagaa tcctgctat cacaatcagc ctctgaaccc cgcgcccagc 3360 agagacccac actaccagga cccccacagc actgcagtgg gcaaccccga gtatctcaac 3420 actgtccagc ccacctgtgt caacagcaca ttcgacagcc ctgcccactg ggcccagaaa 3480 ggcagccacc aaattagcct ggacaccct gactaccaccc aggactctt tcccagga 3540 gccaagccaa atggcatctt taagggctcc acagctgaa atgcagaata cctaagggtc 3600 gcgccacaaa gcagtgaatt tattggagca tga 3633 <210> 2 <211> 1210 <212> PRT <213> <400> 2 Met Arg Pro Ser Gly Thr Ala Gly Ala Leu Leu Ala Leu Leu Ala Ala 1 5 10 15 Wing Leu Cys Pro Wing Ser Arg Wing Leu Glu Glu Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Glue With Thr Tyr Val Gln Arg Asn Tyr Asp With Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Leu Ala Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210 <210> 3 <211> 3276 <212> DNA <213> <400> 3 atgcgaccct ccgggacggc cggggcagcg ctcctggcgc tgctggctgc gctctgcccg 60 gcgagtcggg ctctggagga aaagaaagtt tgccaaggca cgagtaacaa gctcacgcag 120 ttgggcactt ttgaagatca ttttctcagc ctccagagga tgttcaataa ctgtgaggtg 180 gtccttggga atttggaaat tacctatgtg cagaggaatt atgatctttc cttcttaaag 240 accatccagg aggtggctgg tttgtcctc attgccctca acacagtgga gcgaattcct 300 ttggaaaacc tgcagatcat cagaggaaat atgtactacg aaaattccta tgccttagca 360 gtcttatcta actatgatgc aaataaaacc ggactgaagg agctgcccat gagaaattta 420 cagggccaaa agtgtgatcc aagctgtccc aatgggagct gctggggtgc aggagaggag 480 aactgccaga aactgaccaa aatcatctgt gcccagcagt gctccgggcg ctgccgtggc 540 aagtccccca gtgactgctg ccacaaccag tgtgctgcag gctgcacagg cccccgggag 600 agcgactgcc tggtctgccg caaattccga gacgaagcca cgtgcaagga cacctgcccc 660 ccactcatgc tctacaaccc caccacgtac cagatggatg tgaaccccga gggcaaatac 720 agctttggtg ccacctgcgt gaagaagtgt ccccgtaatt atgtggtgac agatcacggc 780 tcgtgcgtcc gagcctgtgg ggccgacagc tatgagatgg aggaagacgg cgtccgcaag 840 tgtaagaagt gcgaagggcc ttgccgcaaa gtgtgtaacg gaataggtat tggtgaattt 900 aaagactcac tctccataaa tgctacgaat attaaacact tcaaaaactg cacctccatc 960 agtggcgatc tccacatcct gccggtggca tttaggggtg actctcttcac acatactcct 1020 cctctggatc caaggaact ggatattctg aaaaccgtaa aggaaatcac agggtttttg 1080 ctgattcagg cttggcctga aaacggacg gacctccatg cctttgagaa cctagaaatc 1140 atacgcggca ggaccaagca acatggtcag ttttctcttg cagtcgtcag cctgaacata 1200 acatccttgg gattacgctc cctcaaggag ataagtgatg gagatgtgat aatttcagga 1260 aacaaaaatt tgtgctatgc aaatacaata aactggaaaa aactgtttgg gacctccggt 1320 cagaaaacca aaattataag caacagaggt gaaaacagct gcaaggccac aggccaggtc 1380 tgccatgcct tgtgctcccc cgagggctgc tggggcccgg agcccaggga ctgcgtctct 1440 tgccggaatg tcagccgagg cagggaatgc gtggacaagt gcaaccttct ggagggtgag 1500 ccaagggagt ttgtggagaa ctctgagtgc atacagtgcc acccagagtg cctgcctcag 1560 gccatgaaca tcacctgcac aggacgggga ccagacaact gtatccagtg tgcccactac 1620 attgacggcc cccactgcgt caagacctgc ccggcaggag tcatgggaga aaacaacacc 1680 ctggtctgga agtacgcaga cgccggccat gtgtgccacc tgtgccatcc aaactgcacc 1740 tacggatgca ctgggccagg tcttgaaggc tgtccaacga atgggcctaa gatcccgtcc 1800 atcgccactg ggatggtggg ggccctcctc ttgctgctgg tggtggccct ggggatcggc 1860 ctcttcatgc gaaggcgcca catcgttcgg aagcgcacgc tgcggaggct gctgcaggag 1920 agggagcttg tggagcctct tacacccagt ggagaagctc ccaaccaagc tctcttgagg 1980 atcttgaagg aaactgaatt caaaaagatc aaagtgctgg gctccggtgc gttcggcacg 2040 gtgtataagg gactctggat cccagaaggt gagaaagtta aaattcccgt cgctatcaag 2100 gaattaagag aagcaacatc tccgaaagcc aacaaggaaa tcctcgatga agcctacgtg 2160 atggccagcg tggacaaccc ccacgtgtgc cgcctgctgg gcatctgcct cacctccacc 2220 gtgcagctca tcacgcagct catgcccttc ggctgcctcc tggactatgt ccgggaacac 2280 aaagacaata ttggctccca gtacctgctc aactggtgtg tgcagatcgc aaagggcatg 2340 aactacttgg aggaccgtcg cttggtgcac cgcgacctgg cagccaggaa cgtactggtg 2400 aaaacaccgc agcatgtcaa gatcacagat tttgggctgg ccaaactgct gggtgcggaa 2460 gagaaagaat accatgcaga aggaggcaaa gtgcctatca agtggatggc attggaatca 2520 attttacaca gaatctatac ccaccagagt gatgtctgga gctacggggt gactgtttgg 2580 gagttgatga cctttggatc caagccatat gacggaatcc ctgccagcga gatctcctcc 2640 atcctggaga aaggaacg cctccctcag ccacccatat gtaccatcga tgtctacatg 2700 atcatggtca agtgctggat gatagacgca gatagtcgcc caaagttccg tgagttgatc 2760 atcgaattct ccaaaatggc ccgagacccc cagcgctacc ttgtcattca gggggaatgaa 2820 agaatgcatt tgccaagtcc tacagactcc aacttctacc gtgccctgat ggatgaagaa 2880 gacatggacg acgtggtgga tgccgacgag tacctcatcc cacagcaggg cttcttcagc 2940 agcccctcca cgtcacggac tcccctcctg agctctctga gtgcaaccag caacaattcc 3000 accgtggctt gcattgatag aaatgggctc caaagctgtc ccatcaagga agacagcttc 3060 3120 ttcctcccag tgcctggtga gtggcttgtc tggaaacagt cctgctcctc aacctctcg 3180 acccactcag cagcagccag tctccagtgt ccaagccagg tgctccctcc agcatctcca 3240 gagggggaa cagtggcaga tttgcagaca cagtga 3276 <210> 4 <211> 1091 <212> PRT <213> <400> 4 Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Gly Gln Lys 130 135 140 Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu 145 150 155 160 Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly 165 170 175 Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala 180 185 190 Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys 195 200 205 Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu 210 215 220 Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr 225 230 235 240 Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val 245 250 255 Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu 260 265 270 Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys 275 280 285 Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu 290 295 300 Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile 305 310 315 320 Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe 325 330 335 Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr 340 345 350 Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn 355 360 365 Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg 370 375 380 Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile 385 390 395 400 Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val 405 410 415 Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp 420 425 430 Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn 435 440 445 Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu 450 455 460 Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser 465 470 475 480 Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu 485 490 495 Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln 500 505 510 Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly 515 520 525 Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro 530 535 540 His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr 545 550 555 560 Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His 565 570 575 Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro 580 585 590 Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala 595 600 605 Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg 610 615 620 Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu 625 630 635 640 Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln 645 650 655 Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val 660 665 670 Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro 675 680 685 Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu 690 695 700 Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val 705 710 715 720 Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys 725 730 735 Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys 740 745 750 Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr 755 760 765 Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu 770 775 780 Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val 785 790 795 800 Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu 805 810 815 Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro 820 825 830 Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His 835 840 845 Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr 850 855 860 Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser 865 870 875 880 Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile 885 890 895 Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser 900 905 910 Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg 915 920 925 Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu 930 935 940 Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu 945 950 955 960 Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln 965 970 975 Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser 980 985 990 Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 995 1000 1005 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1010 1015 1020 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1025 1030 1035 Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln 1040 1045 1050 Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu 1055 1060 1065 Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu 1070 1075 1080 Thr Val Ala Asp Leu Gln Thr Gln 1085 1090 <210> 5 <211> 2832 <212> DNA <213> <400> 5 atgcgaccct ccgggacggc cggggcagcg ctcctggcgc tgctggctgc gctctgcccg 60 gcgagtcggg ctctggagga aaagaaaggt aattatgtgg tgacagatca cggctcgtgc 120 gtccgagcct gtggggccga cagctatgag atggaggaag acggcgtccg caagtgtaag 180 aagtgcgaag ggccttgccg caaagtgtgt aacggaatag gtattggtga atttaaagac 240 tcactctcca taaatgctac gaatattaaa cacttcaaaa actgcacctc catcagtggc 300 gatctccaca tcctgccggt ggcatttagg ggtgactcct tcacacatac tcctcctctg 360 gatccacagg aactggatat tctgaaaacc gtaaaggaaa tcacagggtt tttgctgatt 420 caggcttggc ctgaaaacag gacggacctc catgcctttg agaacctaga aatcatacgc 480 ggcaggacca agcaacatgg tcagttttct cttgcagtcg tcagcctgaa cataacatcc 540 ttgggattac gctccctcaa ggataagt gatggagatg tgataatttc aggaaacaaa 600 aatttgtgct atgcaaatac aataaactgg aaaaaactgt ttgggacctc cggtcagaaa 660 accaaaatta taagcaacag aggtgaaaac agctgcaagg ccacaggcca ggtctgccat 720 gccttgtgct cccccgaggg ctgctggggc ccggagccca gggactgcgt ctcttgccgg 780 aatgtcagcc gaggcaggga atgcgtggac aagtgcaacc ttctggaggg tgagccaagg 840 gagtttgtgg agaactctga gtgcatacag tgccaccag agtgcctgcc tcaggccatg 900 aacatcacct gcacaggacg gggaccagac aactgtatcc agtgtgccca ctacattgac 960 ggccccact gcgtcaagac ctgcccggca ggagtcatgg gagaaaaaa caccctggtc 1020 tggaagtcg cagacgccgg ccatgtgtgc cacctgtgcc atccaaactg cacctacgga 1080 tgcactgggc caggtcttga aggctgtcca acgaatgggc ctaagatccc gtccatcgcc 1140 actgggatgg tggggccct cctcttgctg ctggtggtgg ccctggggat cggcctcttc 1200 atgcgaaggc gccacatcgt tcggaagcgc acgctgcgga ggctgctgca ggagagggag 1260 cttgtggagc ctcttacacc cagtggagagaa gctcccaacc aagctctctt gaggatcttg 1320 aaggaactg aattcaaaaa gatcaaagtg ctgggctccg gtgcgttcgg cacggtgtat 1380 aagggactct ggatcccaga aggtgagaaa gttaaaattc ccgtcgctat caaggaatta 1440 agagaagcaa catctccgaa agccaacaag gaaatcctcg atgaagccta cgtgatggcc 1500 agcgtggaca acccccacgt gtgccgcctg ctgggcatct gcctcacctc caccgtgcag 1560 ctcatcacgc agctcatgcc cttcggctgc ctcctggact atgtccggga acaaagac 1620 aatattggct cccagtacct gctcaactgg tgtgtgcaga tcgcaaaggg catgaactac 1680 ttggaggacc gtcgcttggt gcaccgcgac ctggcagcca ggaacgtact ggtgaaaaca 1740 ccgcagcatg tcaagatcac agattttggg ctggccaaac tgctgggtgc ggaagaaa 1800 1860 cacagaatct atacccacca gagtgatgtc tggagctacg gggtgactgt ttgggagttg 1920 atgacctttg gatccaagcc atatgacgga atccctgcca gcgagatctc ctccatcctg 1980 gagaaggag aacgcctccc tcagccaccc atatgtacca tcgatgtcta catgatcatg 2040 gtcaagtgct ggatgataga cgcagatagt cgcccaaagt tccgtgagtt gatcatcgaa 2100 ttctccaaaa tggcccgaga cccccagcgc taccttgtca ttcaggggga tgaaagaatg 2160 catttgccaa gtcctacaga ctccaacttc taccgtgccc tgatggatga agaagacatg 2220 gacgacgtgg tggatgccga cgagtacctc atcccacagc agggcttctt cagcagcccc 2280 tccacgtcac ggactcccct cctgagctct ctgagtgcaa ccagcaacaa ttccaccgtg 2340 gcttgcattg atagaaatgg gctgcaaagc tgtcccatca aggaagacag cttcttgcag 2400 cgatacagct cagaccccac aggcgccttg actgaggaca catagacga caccttcctc 2460 ccagtgcctg aatacataaa ccagtccgtt cccaaaaggc ccgctggctc tgtgcagaat 2520 cctgtctatc acaatcagcc tctgaacccc gcgcccagca gagacccaca ctaccaggac 2580 ccccacagca ctgcagtggg caacccccgag tatctcaaca ctgtccagcc cacctgtgtc 2640 aacagcacat tcgacagccc tgcccactgg gcccagaaag ccagccacca aattagcctg 2700 gacaaccctg actaccagca ggacttcttt cccaaggaag ccaagccaaa tggcatcttt 2760 aagggctcca cagctgaaaa tgcagaatac ctaagggtcg cgccacaaag cagtgaattt 2820 attggagcat ga 2832 <210> 6 <211> 943 <212> PRT <213> <400> 6 Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Gly Asn Tyr 20 25 30 Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser 35 40 45 Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly 50 55 60 Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp 65 70 75 80 Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr 85 90 95 Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp 100 105 110 Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu 115 120 125 Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro 130 135 140 Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg 145 150 155 160 Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu 165 170 175 Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly 180 185 190 Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile 195 200 205 Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile 210 215 220 Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His 225 230 235 240 Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys 245 250 255 Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys 260 265 270 Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys 275 280 285 Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys 290 295 300 Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp 305 310 315 320 Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn 325 330 335 Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu 340 345 350 Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly 355 360 365 Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val 370 375 380 Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe 385 390 395 400 Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu 405 410 415 Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro 420 425 430 Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile 435 440 445 Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp 450 455 460 Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu 465 470 475 480 Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala 485 490 495 Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly 500 505 510 Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe 515 520 525 Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser 530 535 540 Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr 545 550 555 560 Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val 565 570 575 Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala 580 585 590 Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys 595 600 605 Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr 610 615 620 Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu 625 630 635 640 Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile 645 650 655 Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys 660 665 670 Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala 675 680 685 Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met 690 695 700 Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met 705 710 715 720 His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp 725 730 735 Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro 740 745 750 Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu 755 760 765 Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp 770 775 780 Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln 785 790 795 800 Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 805 810 815 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys 820 825 830 Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu 835 840 845 Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr 850 855 860 Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val 865 870 875 880 Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His 885 890 895 Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys 900 905 910 Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala 915 920 925 Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala 930 935 940

Claims

1. Use of a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for EGFR-positive tumors, Where, R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent; R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents; R3 represents a hydrogen atom, or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents; R4 represents a hydrogen atom or a C1-C4 alkyl group; R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms.

2. The use according to claim 1, characterized in that: The pyrimidine compound is a compound represented by the following general formula (II): Where, R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent; R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents; R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents; R4 represents a hydrogen atom or a C1-C4 alkyl group; R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms.

3. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R2 in the general formula (I) or the general formula (II) is a C1-C6 alkyl group which may have 1 to 5 C1-C4 alkoxy groups as substituents.

4. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R3 in the general formula (I) or the general formula (II) is a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents.

5. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R5 in the general formula (I) or (II) is a phenyl group which may have 1 or 2 substituents selected from fluorine atoms and chlorine atoms.

6. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R1 in the general formula (I) or the general formula (II) is a methyl group, a tert-butyl group or a cyclopropyl group.

7. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R2 in the general formula (I) or (II) is methyl, ethyl, methoxymethyl or ethoxymethyl.

8. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R3 in the general formula (I) or (II) is a methyl group.

9. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound in which R4 in the general formula (I) or (II) is a hydrogen atom.

10. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound wherein R5 in the general formula (I) or (II) is a phenyl group.

11. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is a compound selected from the following (1) to (3), (1) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-N-((R)-1-phenylethyl)-6-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3) 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(3,3-dimethylbut-1-yn-1-yl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

12. The use according to claim 1 or 2, characterized in that: The pyrimidine compound is 7-((3R,5S)-1-acryloyl-5-methylpyrrolidin-3-yl)-4-amino-6-(cyclopropylethynyl)-N-((R)-1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

13. The use according to claim 1 or 2, characterized in that: EGFR-positive tumors are malignant tumors with EGFR overexpression, EGFR gene amplification, or EGFR mutation.

14. Use of a pyrimidine compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating EGFR-positive tumors, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier. Where, R1 represents a C1-C4 alkyl group or a C3-C4 cycloalkyl group which may have a C1-C4 alkoxy group as a substituent; R2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group which may have 1 to 5 C1-C4 alkoxy groups or fluorine atoms as substituents; R3 represents a hydrogen atom or a C1-C4 alkyl group which may have 1 to 5 fluorine atoms as substituents; R4 represents a hydrogen atom or a C1-C4 alkyl group; R5 represents a phenyl group which may have 1 to 3 substituents selected from fluorine atoms and chlorine atoms.

15. The use according to claim 14, characterized in that: EGFR-positive tumors are malignant tumors with EGFR overexpression, EGFR gene amplification, or EGFR mutation.

Images