7h-pyrrolo[2,3-d]pyrimidine-4-amine derivative

Abstract

The present invention provides a novel compound inhibiting EGFR or a salt of the compound. According to one embodiment of the present invention, provided is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

Description

7H-pyrrolo[2,3-d]pyrimidine-4-amine derivative

[0001] The present invention relates to substituted compounds having an inhibitory effect on the epidermal growth factor receptor (EGFR) and pharmaceutical compositions containing these as active ingredients.

[0002] EGFR is a receptor tyrosine kinase that, in normal tissues, binds to its ligand, epidermal growth factor (EGF), and exerts physiological functions, contributing to proliferation and inhibition of apoptosis in epithelial tissue (Non-Patent Literature 1).

[0003] Furthermore, EGFR is also an oncogene, and amplification of the EGFR gene, high expression of the protein, and mutations are known to occur in various types of cancer, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors (Non-Patent Literature 2). In East Asia and Western countries, approximately 90 to 105 people per 100,000 population die from cancer every year, making it one of the leading causes of death (Non-Patent Literature 3). Among these, lung cancer accounts for approximately 1.4 million deaths worldwide annually, and non-small cell lung cancer accounts for more than 80% of lung cancers, so the development of effective treatments is desired (Non-Patent Literature 4).

[0004] In recent years, the causative genes for these cancers have been identified, and mutations in the EGFR gene are one of them, resulting in activated mutant EGFR proteins. Activated mutant EGFR proteins include, for example, those in which a portion of exon 19 (amino acids 746-750, etc.) is deleted (EGFR(Del19)) or those in which amino acid 858 is mutated from leucine to arginine (EGFR(L858R)). In Japan, for example, such mutations have been reported in 20-40% of non-small cell lung cancers, and in Europe and the United States, in 10-15% of non-small cell lung cancers. Non-small cell lung cancers with these mutations are highly sensitive to EGFR kinase inhibitors such as gefitinib (trade name Iressa®) and erlotinib (trade name Tarceva®), and these drugs are used as treatments in Japan, Europe, and the United States. However, after 6-12 months of use, resistance to gefitinib and erlotinib is acquired, weakening the therapeutic effect. This acquired resistance has become a serious problem in the treatment of non-small cell lung cancer with highly sensitive mutant EGFR. It has been found that approximately 50% of this acquired resistance is due to the emergence of resistant mutant EGFR proteins (EGFR(Del19 / T790M) and EGFR(T790M / L858R)) in which a second mutation occurs in the EGFR gene, resulting in a change from threonine to methionine at amino acid 790. Therefore, developing effective therapeutic drugs for non-small cell lung cancer with these drug-resistant mutant EGFRs has become an important challenge (Non-Patent Literature 5).

[0005] Subsequently, EGFR inhibitors effective against resistant mutant EGFR proteins (EGFR(Del19 / T790M) and EGFR(T790M / L858R)) were developed, and osimertinib (trade name Tagrisso®) was approved in Japan, Europe, and the United States. As a result, it came to be used clinically as a second-line treatment prescribed after gefitinib and erlotinib, which are first-line treatments for EGFR-positive lung cancer. However, it was found that the effect weakened again and resistance was acquired after about 10 months of osimertinib use. Genetic analysis revealed that EGFR(Del19 / T790M / C797S) and EGFR(T790M / C797S / L858R) also appeared as osimertinib-resistant mutants, in which the 797th amino acid changed from cysteine ​​to serine. Therefore, there is a need to develop effective treatments for non-small cell lung cancer with EGFR triple mutations, which involve both an activating mutation and two resistance mutations (Non-Patent Literature 6).

[0006] Recently, osimertinib has evolved from being used as a second-line treatment for EGFR-positive non-small cell lung cancer to being used as a first-line treatment in clinical practice. In this case, in addition to the activating mutation, it has been reported that a new resistance mutation occurs, resulting in a double mutant EGFR (Del19 / C797S) or EGFR (L858R / C797S) in which amino acid 797 is mutated to serine. Therefore, in order to be effective against EGFR-positive lung cancer cells that have become drug-resistant or unresponsive to osimertinib, the development of EGFR inhibitors that inhibit this double mutant resistant EGFR protein is necessary (Non-Patent Literature 7).

[0007] International Open Brochure WO2013 / 118817

[0008] Nature Rev. Cancer, vol. 6, pp. 803-811 (2006); Current Opinion in Oncology, vol. 13, pp. 506-513 (2001); International Agency for Research on Cancer, WHO, Cancer Fact Sheets, “All Cancers” (2018) [Retrieved February 13, 2019], Internet<URL: http: / / gco.iarc.fr / today / data / factsheets / cancers / 39-All-cancers-fact-sheet.pdf> Lung Cancer, vol. 69, pp1-12 (2010) Nature Rev. Cancer, vol. 10, pp760-774 (2010) ESMO Open, vol. 1, e000060 (2016) J. Clin. Oncol. , vol. 36, pp841-849 (2018)

[0009] Given the current state of the treatment system, there is a need to develop drugs that are effective in two cases: resistance mutations when osimertinib is used as a second-line treatment and resistance mutations when osimertinib is used as a first-line treatment. Specifically, it is expected that by administering a drug that has weaker inhibitory activity against wild-type EGFR compared to its inhibitory activity against cells expressing erlotinib, gefitinib, or osimertinib drug-resistant mutant EGFR, where in addition to the activating mutation, amino acid 790 is mutated to methionine and amino acid 797 is mutated to serine, or cells expressing osimertinib drug-resistant mutant EGFR where in addition to the activating mutation, amino acid 797 is changed to serine, it will be possible to suppress the proliferation of non-small cell lung cancer cells with drug-resistant mutant EGFR at a dose that does not cause strong side effects in the skin or gastrointestinal tract.

[0010] As mentioned above, EGFR inhibitors are expected to be effective in cancer treatment, but their clinical efficacy is currently insufficient in cancers with activating mutations and osimertinib-resistant mutations.

[0011] In view of the above situation, there is a need for novel compounds or salts thereof that inhibit EGFR. Furthermore, there is also a need for novel compounds or salts thereof that inhibit mutant EGFR, such as EGFR(Del19 / C797S), EGFR(L858R / C797S), EGFR(Del19 / T790M / C797S), and EGFR(L858R / T790M / C797S), but have weak inhibitory activity against wild-type EGFR (WT).

[0012] As a result of intensive investigations, the present inventors have found novel pyrimidine compounds (7H-pyrrolo[2,3-d]pyrimidine-4-amine derivatives) represented by the following formula (I). These compounds are novel compounds characterized by having a pyrrolo[2,3-d]pyrimidine as a basic skeleton, the 5-position of which is substituted with a quinoline ring and the 7-position of which is substituted with a bicyclic ring.

[0013] That is, one embodiment of the present invention provides the following [1] to

[16] . [1] The following general formula (I) [In the formula, R １ is a hydrogen atom or a C1-C3 alkyl group which may have a substituent, X is NR ２ R ３ , OR ４ or a monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent, R ２ is a hydrogen atom or a C1-C6 alkyl group which may have a substituent, R ３ is a hydrogen atom, C(=O)R ５ , C(=S) R ６ , S(=O) ２ R ７ , a C1-C6 alkyl group which may have a substituent, or a C3-C7 cycloalkyl group which may have a substituent, R ４ is a hydrogen atom, a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a carbonylamino group which may have a substituent, R ５R is a optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted amino group, an optionally substituted 4-10 member monocyclic or polycyclic saturated heterocyclic group, an optionally substituted 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or an optionally substituted 6-10 member monocyclic or polycyclic aromatic hydrocarbon group. ６ R is a 4-10 member monocyclic or polycyclic saturated heterocyclic group having 1 to 4 hydrogen atoms, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 mono- or dialkylamino groups, optionally substituted C3-C7 cycloalkyl groups, or optionally substituted heteroatoms selected from nitrogen, oxygen, and sulfur atoms. ７ [2] R １ [1] The compound or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen atom or a C1-C3 alkyl group. [3] X is NR ２ R ３ , OR ４ Alternatively, a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ However, it is a hydrogen atom or a C1-C6 alkyl group, R ３ However, C(=O)R ５ , C(=S)R ６ Or a C1-C6 alkyl group (which may have a 5-7 member monocyclic unsaturated heterocyclic group having 1-3 heteroatoms selected from a cyano group, a halogen atom, or a nitrogen atom, an oxygen atom, and a sulfur atom as substituents), R ４ However, it is a hydrogen atom, R ５However, it may be a substituted C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group, a substituted 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, R ６ The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. １ A compound or a pharmaceutically acceptable salt thereof, wherein X is a hydrogen atom. [6] X is NR ２ R ３ Alternatively, a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ However, it is a hydrogen atom, R ３ However, C(=O)R ５ And R ５ The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein X is a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group, a 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, which may have substituents. [7] X is NR ２ R ３ Alternatively, a 5-7 member monocyclic saturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ However, it is a hydrogen atom, R ３ However, C(=O)R ５ And R ５The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C6 alkyl group which may have a halogen atom, or a 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group which may have a C1-C6 alkyl group and has 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms. [8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein ring A is bicyclo[2.2.1]heptane. [9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein n is 0.

[10] A compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, alkyl groups, haloalkyl groups, cycloalkyl groups, aralkyl groups, alkoxy groups, methylsulfonyl groups, alkoxyalkyl groups, fluoromethoxy groups, mono or dialkylamino groups, carbonylamino groups, oxo groups, carboxyl groups, alkoxycarbonyl groups, saturated or unsaturated heterocyclic groups, and aromatic hydrocarbon groups. [10-1] A compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, alkyl groups, haloalkyl groups, cycloalkyl groups, aralkyl groups, alkoxy groups, methylsulfonyl groups, alkoxyalkyl groups, hydroxyalkyl groups, fluoromethoxy groups, mono or dialkylamino groups, mono or dialkylaminoalkyl groups, carbonylamino groups, oxo groups, oxide groups, carboxyl groups, alkoxycarbonyl groups, phosphine oxide groups, saturated or unsaturated heterocyclic groups, heterocyclic alkyl groups, and aromatic hydrocarbon groups.

[11] The following group of compounds: (1) 6-ethynyl-7-(4-morpholinobicyclo[2.2.1]heptan-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (2) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,(3) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (4) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-2,2-difluoroacetamide (5) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide (5) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (6) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide A compound selected from (7) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide or (8) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-3-carboxamide, or a pharmaceutically acceptable salt thereof. [11-1] The following group of compounds: (1) 6-ethynyl-7-(4-morpholinobicyclo[2.2.1]heptan-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (2) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (3) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-Difluoroacetamide (4) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide (5) N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (6) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide (7) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide (8) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-3-carboxamide (9) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-carboxamide (10) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-carboxamide (11) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,

[12] A compound selected from [3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)isoxazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

[13] An antitumor agent comprising the compound described in any of [1] to [11-1] or a pharmaceutically acceptable salt thereof as an active ingredient.

[14] A pharmaceutical composition comprising the compound described in any of [1] to [11-1] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[15] A method for treating a tumor, characterized by administering the compound described in any of [1] to [11-1] or a pharmaceutically acceptable salt thereof.

[16] A method for treating a tumor, characterized by administering an effective amount of the compound described in any of [1] to [11-1] or a pharmaceutically acceptable salt thereof to a subject requiring it.

[16] A compound described in any of [1] to [11-1] or a pharmaceutically acceptable salt thereof for treating a tumor.

[16] Use of any of the compounds described in [1] to [11-1] or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent.

[0014] According to one aspect of the present invention, a novel compound represented by the general formula (I) or a salt thereof that inhibits EGFR is provided.

[0015] Formula (I) below: [In the formula, R １ is a C1-C3 alkyl group which may have a hydrogen atom or substituents, and X is NR ２ R ３ , OR ４ Alternatively, a monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have substituents, R ２ R is a hydrogen atom or a C1-C6 alkyl group which may have substituents. ３ This is a hydrogen atom, C(=O)R ５ , C(=S) R ６ , S(=O) ２ R ７ R is a C1-C6 alkyl group which may have substituents, or a C3-C7 cycloalkyl group which may have substituents. ４R is a hydrogen atom, a optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, or an optionally substituted carbonylamino group. ５ R is a optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted amino group, an optionally substituted 4-10 member monocyclic or polycyclic saturated heterocyclic group, an optionally substituted 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or an optionally substituted 6-10 member monocyclic or polycyclic aromatic hydrocarbon group. ６ R is a 4-10 member monocyclic or polycyclic saturated heterocyclic group having 1 to 4 hydrogen atoms, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 mono- or dialkylamino groups, optionally substituted C3-C7 cycloalkyl groups, or optionally substituted heteroatoms selected from nitrogen, oxygen, and sulfur atoms. ７ The compound of the present invention, represented by [ ], is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, an optionally substituted 5-10 member saturated or unsaturated heterocyclic group, or an optionally substituted 6-10 member aromatic hydrocarbon group, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, and n is an integer from 0 to 3. The compound of the present invention is a novel compound with pyrrolo[2,3-d]pyrimidine as its basic skeleton.

[0016] [Definition of Substituents] In this specification, unless otherwise explicitly stated, "substituents" include, for example, hydrogen atoms, halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, alkyl groups, haloalkyl groups, cycloalkyl groups, aralkyl groups, alkoxy groups, methylsulfonyl groups, alkoxyalkyl groups, fluoromethoxy groups, mono- or dialkylamino groups, carbonylamino groups, oxo groups, carboxyl groups, alkoxycarbonyl groups, saturated or unsaturated heterocyclic groups, aromatic hydrocarbon groups, etc. If such substituents are present, or unless otherwise explicitly stated, their number is typically one, two, or three, preferably one or two, and most preferably one.

[0017] In one aspect of the present invention, the substituent may be selected from halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, alkyl groups, haloalkyl groups, cycloalkyl groups, aralkyl groups, alkoxy groups, methylsulfonyl groups, alkoxyalkyl groups, hydroxyalkyl groups, fluoromethoxy groups, mono- or dialkylamino groups, mono- or dialkylaminoalkyl groups, carbonylamino groups, oxo groups, oxide groups, carboxyl groups, alkoxycarbonyl groups, phosphine oxide groups, saturated or unsaturated heterocyclic groups, heterocyclic alkyl groups, and aromatic hydrocarbon groups.

[0018] In this specification, "halogen atom" specifically refers to chlorine atom, bromine atom, fluorine atom, and iodine atom, with chlorine atom and fluorine atom being preferred.

[0019] In this specification, "alkyl group" refers to a linear or branched saturated hydrocarbon group, specifically including methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and the like.

[0020] In this specification, "haloalkyl group" refers to a group in which one to all hydrogen atoms of a linear or branched saturated hydrocarbon group are substituted with the aforementioned halogen atoms. Specifically, examples include monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, and the like.

[0021] In this specification, "aralkyl group" refers to a group in which one of the hydrogen atoms of an alkyl group is substituted with an aryl group, and specifically includes the benzyl group (phenylmethyl group), phenethyl group (phenylethyl group), naphthylmethyl group, and naphthylethyl group.

[0022] In this specification, "alkoxy group" refers to an oxy group having the alkyl group, and specifically includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a tert-butoxy group, and the like.

[0023] In this specification, "cycloalkyl group" refers to a monocyclic or polycyclic saturated hydrocarbon group, specifically including cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and the like.

[0024] In this specification, "mono-C1-C6 alkylamino group" refers to an amino group in which one hydrogen atom is replaced by a linear or branched hydrocarbon group having 1 to 6 carbon atoms. Specifically, examples include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, hexylamino group, and the like.

[0025] In this specification, "di-C1-C6 alkylamino group" refers to an amino group in which two hydrogen atoms are replaced by a linear or branched hydrocarbon group having 1 to 6 carbon atoms, specifically including dimethylamino group, diethylamino group, ethylmethylamino group, etc.

[0026] In this specification, "mono or dialkylaminoalkyl group" refers to the alkyl group having at least one mono or dialkylamino group, and examples include mono or di-C1-C6 alkylamino-C1-C6 alkyl groups such as methylaminomethyl group, methylaminoethyl group, ethylaminomethyl group, ethylaminopropyl group, and dimethylaminomethyl.

[0027] In this specification, "alkoxyalkyl group" refers to an alkyl group having at least one alkoxy group, and examples include C1-C6 alkoxy-C1-C6 alkyl groups such as a methoxymethyl group, an ethoxyethyl group, a methoxyethyl group (e.g., a 2-methoxyethyl group), and a methoxypropyl group.

[0028] In this specification, "phosphine oxide group" refers to a phosphonyl group having at least one of the oxide groups (for example, -P(=O)R ２ (where R is represented by a halogen atom, an alkyl group, or an aryl group) Examples include methylphosphine oxide group, dimethylphosphine oxide group, and diphenylphosphine oxide group.

[0029] In this specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic fully saturated heterocyclic group having at least one heteroatom (preferably 1 to 5, more preferably 1 to 3) selected from nitrogen, oxygen, and sulfur atoms. Specifically, examples include azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperazinyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, and 2,6-diazaspiro[3.3]heptane.

[0030] In this specification, "unsaturated heterocyclic group" refers to a monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having at least one heteroatom (preferably 1 to 5, more preferably 1 to 3) selected from nitrogen, oxygen, and sulfur atoms. Specifically, fully unsaturated unsaturated heterocyclic groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl (or isoxazolyl), oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, indolyl, iso Examples of indolyl groups, indazolyl groups, benzimidazolyl groups, benzotriazolyl groups, azaindolyl groups, pyrrolopyridinyl groups, imidazopyridinyl groups, imidazopyradinyl groups, pyrazolopyridinyl groups, triazolopyridinyl groups, pyrrolopyridinyl groups, imidazopyridinyl groups, pyrazolopyridinyl groups, benzofuranyl groups, benzoxazolyl groups, benzothiophenyl groups, benzothiazolyl groups, benzofuranyl groups, quinolyl groups, isoquinolyl groups, quinazolinyl groups, quinoxalyl groups, etc. Examples of partially saturated unsaturated heterocyclic groups include indolinyl groups, methylenedioxyphenyl groups, ethylenedioxyphenyl groups, and dihydrobenzofuranyl groups.

[0031] In this specification, "aromatic hydrocarbon group" refers to a cyclic substituent consisting of carbon and hydrogen having an unsaturated bond, wherein the cyclic π-electron system contains 4e+2 electrons (where e is an integer of 1 or more), and specific examples include the phenyl group, naphthyl group, tetrahydronaphthyl group, etc.

[0032] In this specification, "heterocyclic alkyl group" refers to the alkyl group having a saturated or unsaturated heterocycle, and specifically includes pyridylmethyl group, pyrrolidylmethyl group, morpholinomethyl group, and the like.

[0033] In this specification, "bicyclo ring" refers to a polycyclic (e.g., bicyclic, tricyclic) saturated hydrocarbon in which at least two (e.g., two or three) saturated hydrocarbon rings share at least two carbon atoms with adjacent rings. Specifically, examples include bicyclo[3.2.1]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, etc., with bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane, etc. being preferred.

[0034] In this specification, "spiro ring" refers to a bicyclic organic compound having a ring bonded to only one atom, such as spiro[4.5]decane and 6-oxa-3-azabicyclo[3.2.1]heptane.

[0035] In the compound represented by the general formula (I) of the present invention, R １ This is "a hydrogen atom or a C1-C3 alkyl group".

[0036] R １ The "C1-C3 alkyl group" represented by is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group. １ This is preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

[0037] In the description of groups in this specification, "CA-CB" indicates a group having A to B carbon atoms. For example, "C1-C6 alkyl group" indicates an alkyl group having 1 to 6 carbon atoms, and "C6-C10 aromatic hydrocarbon group" indicates a group to which aromatic hydrocarbon groups having 6 to 10 carbon atoms are bonded. Also, "A to B member" indicates that the number of atoms constituting the ring (number of ring members) is A to B. For example, "4 to 10 member saturated heterocyclic group" means a saturated heterocyclic group with 4 to 10 ring members.

[0038] In the compound represented by the general formula (I) of the present invention, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, preferably bicyclo[2.2.1]heptane.

[0039] In the compound represented by the general formula (I) of the present invention, the bonding configuration of ring A is not limited, and in the case of bicyclo[2.2.1]heptane, for example, it includes the following patterns. Preferably, it is (1). In the case of bicyclo[2.2.2]octane, for example, the following patterns are included. Preferably, (9).

[0040] In the compound represented by the general formula (I) of the present invention, X is NR ２ R ３ , OR ４ Alternatively, it is a monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have substituents.

[0041] In the "monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have substituents" indicated by X, the "monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have substituents" is preferably a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, more preferably a pyridinyl group, pyrimidinyl group, piperazinyl group, piperadyl group, morpholino group, azetidinyl group, pyrrolidinyl group, piperazinyl group, 6-oxa-3-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.2.1]heptane, more preferably a morpholino group, piperazinyl group, and more preferably a morpholino group.

[0042] In the "may have substituents monocyclic or polycyclic saturated or unsaturated heterocyclic group" represented by X, the "substituents" are preferably the substituents described above, more preferably oxo groups or C1-C6 alkyl groups, and more preferably oxo groups or methyl groups.

[0043] The "may have substituents, monocyclic or polycyclic saturated or unsaturated heterocyclic group" represented by X is preferably a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and is a pyridinyl group, pyrimidinyl group, pyrazinyl group, piperazinyl group, 1-methyl-2-oxopiperazinyl group, morpholino group, azetidinyl group, pyrrolidinyl group, piperazinyl group, 6-oxa-3-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.2.1]heptane, or a piperazinyl substituent represented by the following formula. The substituent is preferably a piperazinyl group, a morpholino group, or a piperazinyl-based substituent represented by the above formula, and more preferably a morpholino group.

[0044] X is preferably NR ２ R ３ , OR ４ Alternatively, a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, more preferably NR ２ R ３ , or a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, more preferably NR ２ R ３ , or a 5-7 member monocyclic saturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, more preferably NR ２ R ３ That is the case.

[0045] In the compound represented by the general formula (I) of the present invention, R ２ This is a hydrogen atom or a C1-C6 alkyl group which may have substituents.

[0046] R ２ In the "C1-C6 alkyl group which may have substituents" shown, the "C1-C6 alkyl group" is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group.

[0047] R２ In the "C1-C6 alkyl group which may have substituents" shown, the "substituents" are preferably the substituents mentioned above, and more preferably halogen atoms.

[0048] R ２ The "C1-C6 alkyl group which may have substituents" shown is preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and most preferably a methyl group.

[0049] R ２ Preferably, it is a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom.

[0050] In the compound represented by the general formula (I) of the present invention, R ３ This is a hydrogen atom, C(=O)R ５ , C(=S) R ６ , S(=O) ２ R ７ These are optionally substituted C1-C6 alkyl groups or optionally substituted C3-C7 cycloalkyl groups.

[0051] R ３ In the "C1-C6 alkyl group which may have substituents" shown, the "C1-C6 alkyl group" is preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, and more preferably a methyl group.

[0052] R ３ The "substituents" in the "C1-C6 alkyl group which may have substituents" shown are preferably the substituents described above, more preferably a 5-7 member monocyclic unsaturated heterocyclic group having 1-3 halogen atoms, cyano groups, or heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, more preferably a cyano group or a pyridinyl group.

[0053] R ３The "C1-C6 alkyl group which may have a substituent" represented by is preferably a C1-C6 alkyl group which may have a cyano group or a 5- to 7-membered monocyclic unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a substituent, and more preferably a methyl group, a cyanomethyl group or a pyridinylmethyl group.

[0054] R ３ The "C3-C7 cycloalkyl group which may have a substituent" represented by is preferably a C3-C5 cycloalkyl group, and more preferably a cyclopropyl group or a cyclobutyl group.

[0055] R ３ is preferably C(=O)R ５ , C(=S)R ６ , or a C1-C6 alkyl group which may have a substituent, and more preferably C(=O)R ５ ; C(=S)R ６ ; or a C1-C6 alkyl group which may have a cyano group or a 5- to 7-membered monocyclic unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a substituent, and more preferably C(=O)R ５ , or C(=S)R ６ , and most preferably C(=O)R ５ .

[0056] In the compound represented by the general formula (I) of the present invention, R ４ is a hydrogen atom, a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a carbonylamino group which may have a substituent.

[0057] R ４ The "C1-C6 alkyl group which may have a substituent" represented by is preferably a C1-C6 alkyl group, and more preferably a methyl group.

[0058] R ４ The "C3-C7 cycloalkyl group which may have a substituent" represented by is preferably a C3-C7 cycloalkyl group, and more preferably a cyclopropyl group or a cyclobutyl group.

[0059] R ４ The "carbonylamino group which may have a substituent" represented by ４ is preferably a carbonylamino group which may have a C1-C6 alkyl group, more preferably a methylcarbonylamino group or a dimethylcarbonylamino group.

[0060] R ４ is preferably a hydrogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom.

[0061] In the compound represented by the general formula (I) of the present invention, R ５ is a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, a C1-C6 alkoxy group which may have a substituent, an amino group which may have a substituent, a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group which may have a substituent, a 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group which may have a substituent, or a 6- to 10-membered monocyclic or polycyclic aromatic hydrocarbon group which may have a substituent.

[0062] R ５ The "C1-C6 alkyl group" in the "C1-C6 alkyl group which may have a substituent" represented by ５ is preferably a methyl group.

[0063] R ５ The "substituent" in the "C1-C6 alkyl group which may have a substituent" represented by ５ is preferably the above-mentioned substituent, more preferably a halogen atom, a C1-C6 alkoxy group, a C1-C6 mono- or dialkylamino group, still more preferably a fluorine atom, a methoxy group, an ethoxy group, a monomethylamino group, a dimethylamino group, and most preferably a fluorine atom.

[0064] R ５The "C1-C6 alkyl group which may have substituents" shown is preferably a C1-C6 alkyl group which may have a halogen atom, a C1-C6 alkoxy group, or a C1-C6 mono or dialkylamino group as substituents, more preferably a C1-C6 alkyl group which may have a fluorine atom, a methoxy group, an ethoxy group, a monomethylamino group, or a dimethylamino group as substituents, more preferably a C1-C6 alkyl group which may have a fluorine atom, and most preferably a difluoromethyl group.

[0065] R ５ The "C3-C7 cycloalkyl group which may have substituents" shown is preferably a C3-C5 cycloalkyl group, and more preferably a cyclopropyl group or a cyclobutyl group.

[0066] R ５ The "C1-C6 alkoxy group which may have substituents" shown is preferably a C1-C6 alkoxy group, more preferably a methoxy group, an ethoxy group, or a pyrazine-2-ylmethoxy group, and more preferably an ethoxy group or a pyrazine-2-ylmethoxy group.

[0067] R ５ The "optional amino group having substituents" shown is preferably a C1-C6 mono- or dialkylamino group, more preferably a C1-C6 monoalkylamino group, and more preferably an ethylamino group.

[0068] R ５ The "4-10 member monocyclic or polycyclic saturated heterocyclic group which may have substituents" shown is preferably a 4-10 member monocyclic or polycyclic fully saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and more preferably an azetidinyl group, a pyrrolidinyl group, or a morpholino group.

[0069] R ５The "5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents" shown in the formula is preferably a 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and is preferably a pyridadinyl group, pyrimidinyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, pyridinyl The group is a yl group, imidazolyl group, furanyl group, isoxazolyl group, triazolopyridinyl group, triazolyl group, triazinyl group, thiazolyl group, thiadiazolyl group, imidazopyradinyl group, or pyrazolyl group; more preferably, it is an isoxazolyl group, pyrazolyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, or pyridadinyl group; more preferably, it is a pyrazolyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, or pyridadinyl group.

[0070] In one embodiment of the present invention, R ５ The "5-10 member monocyclic or polycyclic unsaturated heterocyclic group that may have substituents" shown in the formula may be an imidazopyridyl group or an imidazopyradyl group.

[0071] R ５ The "substituents" in the "5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents" shown are preferably the substituents described above, more preferably halogen atoms, cyano groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C1-C6 mono or dialkylamino groups, C1-C6 alkylsulfonyl groups, C3-C7 cycloalkyl groups, or C6-C10 aromatic hydrocarbon groups, more preferably fluorine atoms, chlorine atoms, cyano groups, oxo groups, C1-C6 alkyl groups, monofluoromethyl groups, methoxyethyl groups, methoxy groups, monofluoromethoxy groups, dimethylamino groups, methylsulfonyl groups, cyclopropyl groups, or phenyl groups, more preferably C1-C6 alkyl groups, and most preferably methyl groups.

[0072] In one embodiment of the present invention, R ５ The "substituents" in the "5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents" shown may be hydroxyalkyl groups, mono- or dialkylaminoalkyl groups, phosphine oxide groups, or morpholinomethyl groups, and preferably hydroxymethyl groups, methylaminomethyl groups, dimethylaminomethyl groups, or morpholinomethyl groups.

[0073] R ５The "5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents" shown may have substituents selected from the group consisting of halogen atoms, cyano groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C1-C6 mono or dialkylamino groups, C1-C6 alkylsulfonyl groups, C3-C7 cycloalkyl groups, and C6-C10 aromatic hydrocarbon groups, as well as nitrogen atoms, acids A 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1-4 heteroatoms selected from elementary atoms and sulfur atoms, more preferably a halogen atom, cyano group, oxo group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy-C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 mono or dialkylamino group, C1-C6 alkylsulfonyl group, C3-C7 cycloalkyl group, and C6-C10 aromatic hydrocarbon as substituents. The pyridadinyl group, pyrimidinyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, pyridinyl group, imidazolyl group, furanyl group, isoxazolyl group, triazolopyridinyl group, triazolyl group, triazinyl group, thiazolyl group, thiadiazolyl group, imidazopyradinyl group, or pyrazolyl group may have a group selected from the group consisting of the groups, and more preferably the pyridadinyl group, pyrimidinyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, pyridinyl group, imidazopyradinyl group, imidazopyradinyl group, or pyrazolyl group may have a C1-C6 alkyl group. The group is a dazolyl group, a furanyl group, an isoxazolyl group, a triazolopyridinyl group, a triazolyl group, a triazinyl group, a thiazolyl group, a thiadiazolyl group, an imidazopyradinyl group, or a pyrazolyl group, and more preferably an isoxazolyl group, a pyrazolyl group, an oxazolyl group, an oxazolyl group, an oxadiazolyl group, a pyrazinyl group, or a pyridadinyl group, which may have a C1-C6 alkyl group.

[0074] In one embodiment of the present invention, R ５The "5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents" shown include, as substituents, halogen atoms, cyano groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy-C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkoxy groups, C1-C6 mono or dialkylamino groups, C1-C6 alkylsulfonyl groups, C3-C7 cycloalkyl groups, hydroxyalkyl groups, mono or dialkylaminoalkyl groups, phosphine oxide groups, morpholinomethyl groups, and C6-C A 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have a group selected from the group consisting of 10 aromatic hydrocarbon groups, and more preferably a substituent such as a halogen atom, a cyano group, an oxo group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 mono or dialkylamino group, a C1-C6 alkylsulfonyl group, or a C3-C7 hydroxyl group. The pyridadinyl group, pyrimidinyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, pyridinyl group, imidazolyl group, furanyl group, isoxazolyl group, triazolopyridinyl group, triazolyl group, triazinyl group, thiazolyl group, thiadiazolyl group, imidazopyradinyl group, imidazopyridyl group, imidazopyradyl group, or pyrazolyl group may have a group selected from the group consisting of a chloroalkyl group, a hydroxyalkyl group, a mono- or dialkylaminoalkyl group, a phosphine oxide group, a morpholinomethyl group, and a C6-C10 aromatic hydrocarbon group. More preferably, a pyridadinyl group, pyrimidinyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, pyridinyl group, imidazolyl group, furanyl group, isoxazolyl group, triazolopyridinyl group, triazolyl group, triazinyl group, thiazolyl group, thiadiazolyl group, imidazopyradinyl group, imidazopyridyl group, imidazopyradyl group, or pyrazolyl group, which may have a C1-C6 alkyl group, isoxazolyl group, pyrazolyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group,A pyridazinyl group, and more preferably a pyrazolyl group, oxazolyl group, oxadiazolyl group, pyrazinyl group, or pyridazinyl group, which may have a C1-C6 alkyl group.

[0075] In one embodiment of the present invention, R ５ Examples of the "5-10 member monocyclic or polycyclic unsaturated heterocyclic groups that may have substituents" shown include the following structures.

[0076] R ５ The "6-10 member monocyclic or polycyclic aromatic hydrocarbon group which may have substituents" shown is preferably a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, and more preferably a phenyl group.

[0077] R ５Preferably, the substituent is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted amino group, an optionally substituted 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or an optionally substituted 6-10 member monocyclic or polycyclic aromatic hydrocarbon group; more preferably, the substituent is an optionally substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 mono or dialkylamino group, an optionally substituted 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group; more preferably, the substituent may be a halogen atom, a C1-C6 alkoxy group, or a C1-C6 mono or dialkylamino group; C1-C6 alkyl group; C1-C6 alkoxy group; C1-C6 mono or dialkylamino group; the substituent may be a halogen atom A 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have a group selected from the group consisting of a halogen atom, a cyano group, an oxo group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C1-C6 mono or dialkylamino group, a C1-C6 alkylsulfonyl group, a C3-C7 cycloalkyl group, and a C6-C10 aromatic hydrocarbon group; or a 6-10 member aromatic hydrocarbon group, more preferably a C1-C6 alkyl group which may have a halogen atom; or a 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have a C1-C6 alkyl group.

[0078] In one embodiment of the present invention, R ５This is a C1-C6 alkyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, an amino group which may have substituents, a 5-10 member monocyclic or polycyclic unsaturated heterocyclic group which may have substituents, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group which may have substituents; more preferably a C1-C6 alkyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, a C1-C6 mono or dialkylamino group which may have substituents, a C1-C6 alkoxy group which may have substituents, or a C1-C6 mono or dialkylamino group which may have substituents; C1-C6 alkoxy group which may have substituents; C1-C6 mono or dialkylamino group which may have substituents; a halogen atom which may have substituents, a C1-C6 alkoxy group which may have substituents, or a C1-C6 mono or dialkylamino group which may have substituents; , a 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group, heterocyclic alkyl group, or 6-10 member aromatic hydrocarbon group, which may have a group selected from the group consisting of C1-C6 alkoxy-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C1-C6 mono or dialkylamino group, C1-C6 mono or dialkylamino C1-C6 alkyl, C1-C6 alkylsulfonyl group, C3-C7 cycloalkyl, phosphine oxide group and C6-C10 aromatic hydrocarbon group, and which may have a group selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and a C1-C6 alkyl group, and which may have

[0079] In the compound represented by the general formula (I) of the present invention, R ６This is a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 hydrogen atoms, optionally substituted C1-C6 alkyl groups, optionally substituted C1-C6 mono- or dialkylamino groups, optionally substituted C3-C7 cycloalkyl groups, or optionally substituted heteroatoms selected from nitrogen, oxygen, and sulfur atoms.

[0080] R ６ The "C1-C6 alkyl group which may have substituents" shown is preferably a C1-C6 alkyl group, and more preferably an ethyl group.

[0081] R ６ The "C1-C6 mono or dialkylamino group which may have substituents" shown is preferably a C1-C6 mono or dialkylamino group, more preferably a C1-C6 monoalkylamino group, and more preferably an ethylamino group.

[0082] R ６ The "C3-C7 cycloalkyl group which may have substituents" shown is preferably a C3-C7 cycloalkyl group, more preferably a C3-C5 cycloalkyl group, and more preferably a cyclopropyl group or a cyclobutyl group.

[0083] R ６ The "4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" shown in the formula is preferably an azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperazinyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, or 2,6-diazaspiro[3.3]heptane, and more preferably 2,6-diazacyclo[3.3]heptane.

[0084] R ６The "substituents" in the "4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" are preferably the substituents described above, more preferably C1-C6 alkyl groups, and more preferably methyl groups.

[0085] R ６ The "4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" shown is preferably a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have a C1-C6 alkyl group, and more preferably 2-methyl-2,6-diazacyclo[3.3]heptane.

[0086] R ６ Preferably, is a C1-C6 mono- or dialkylamino group which may have substituents, or a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group which may have substituents, and has 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms; more preferably, is a C1-C6 mono- or dialkylamino group which may have substituents, or a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group which may have a C1-C6 alkyl group, and has 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms; more preferably, is an ethylamino group, or 2-methyl-2,6-diazacyclo[3.3]heptane.

[0087] In the compound represented by the general formula (I) of the present invention, R ７ This includes optionally substituted C1-C6 alkyl groups, optionally substituted C3-C7 cycloalkyl groups, optionally substituted 5-10 member monocyclic or polycyclic saturated or unsaturated heterocyclic groups, and optionally substituted 6-10 member monocyclic or polycyclic aromatic hydrocarbon groups.

[0088] R ７ The "C1-C6 alkyl group which may have substituents" shown is preferably a C1-C6 alkyl group, and more preferably a methyl group or an ethyl group.

[0089] R ７ The "C3-C7 cycloalkyl group which may have substituents" shown is preferably a C3-C7 cycloalkyl group, and more preferably a cyclopropyl group or a cyclobutyl group.

[0090] R ７ The "C1-C6 haloalkyl group which may have substituents" shown is preferably a C1-C6 haloalkyl group, and more preferably a trifluoroethyl group.

[0091] R ７ The "5-10 member monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have substituents" shown is preferably a 5-10 member monocyclic or polycyclic saturated or unsaturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, and more preferably a pyridinyl group or pyrimidinyl group.

[0092] R ７ The "6-10 member monocyclic or polycyclic aromatic hydrocarbon group which may have substituents" shown is preferably a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, and more preferably a phenyl group.

[0093] In the compound represented by the general formula (I) of the present invention, n is an integer from 0 to 3, preferably 0 or 1, and more preferably 0.

[0094] In a preferred embodiment of the present invention, in general formula (I), R １ is a hydrogen atom or a C1-C3 alkyl group, and X is NR ２ R ３ , OR ４ Alternatively, a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ R is a hydrogen atom or a C1-C6 alkyl group. ３ This is a hydrogen atom, C(=O)R ５ , C(=S)R ６Alternatively, it may be a C1-C6 alkyl group (which may have a 5-7 member monocyclic unsaturated heterocyclic group having 1-3 cyano groups or heteroatoms selected from nitrogen, oxygen, and sulfur atoms as substituents), R ４ R is a hydrogen atom. ５ R is a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group, a 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, which may have substituents. ６ The compound or a pharmaceutically acceptable salt thereof is a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have a C1-C6 mono or dialkylamino group or a C1-C6 alkyl group, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, and n is 0 or 1.

[0095] More preferably, in the general formula (I) of the present invention, R １ is a hydrogen atom, and X is NR ２ R ３ Alternatively, a 5-7 member monocyclic saturated or unsaturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ R is a hydrogen atom. ３ C(=O)R ５ And R ５ is a C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 mono or dialkylamino group, a 5-10 member monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10 member monocyclic or polycyclic aromatic hydrocarbon group, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, and n is a compound or a pharmaceutically acceptable salt thereof, where n is 0 or 1.

[0096] More preferably, in the general formula (I) of the present invention, R １ is a hydrogen atom, and X is NR ２ R３ Alternatively, a 5-7 member monocyclic saturated heterocyclic group having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, R ２ R is a hydrogen atom. ３ C(=O)R ５ And R ５ The compound or a pharmaceutically acceptable salt thereof is a C1-C6 alkyl group which may have a halogen atom, or a 5-10 member monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group which may have a C1-C6 alkyl group, ring A is bicyclo[2.2.1]heptane, and n is 0.

[0097] Specific examples of the compounds of the present invention include, but are not limited to, the compounds produced in the following examples. One embodiment of the present invention is a compound selected from (1) to (8) below, or a pharmaceutically acceptable salt thereof. These compounds exhibit particularly strong pharmacological activity, sustained high blood concentrations, and good oral absorption. (1) 6-Ethinyl-7-(4-Molfolinobicyclo[2.2.1]heptan-1-yl)-5-(Quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (2) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (3) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide (4) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide (5) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (6) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide (7) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide (8) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-3-carboxamide (9) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,(3-d)pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-carboxamide (10) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-carboxamide (11) N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)isoxazole-5-carboxamide,

[0098] <Method for Producing the Compound Represented by Formula (I)> Next, a method for producing the compound according to the present invention will be described. The compound represented by formula (I) of the present invention can be produced, for example, by the following production method or the method shown in the examples. However, the method for producing the compound represented by formula (I) of the present invention is not limited to these reaction examples. The products obtained in each step can be isolated and purified by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc., or they can be subjected to the next step without isolation and purification. In addition, in the production method below, protecting groups may be introduced or deprotected as needed, regardless of whether they are described or not, and the order of each step may be changed as appropriate. [Production Method 1] [In the formula, Y is NH or O, P １ L is a protecting group for a hydrogen atom or an amino group. １ , L ２ , L ３ and L ４ [where represents a leaving group, and rings A and n have the same meaning as described above.]

[0099] (Step 1) This step is a method for producing a compound represented by general formula (IV) by reacting a compound represented by general formula (II) with a compound represented by general formula (III) in the presence of a base. In general formula (II), L １ The leaving group represented by is either a fluorine atom or a chlorine atom. Also, L ２The leaving group represented by is an iodine atom or a bromine atom. Compounds represented by general formulas (II) and (III) can be commercially available or produced according to known methods. One to ten moles of the compound represented by general formula (III) can be used per mole of the compound represented by general formula (II), preferably one to three moles. The base used in this step can be an organic base such as triethylamine, diisopropylethylamine, or pyridine, or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, or potassium-tert-butyrate. The amount of the base used is usually one mole to an excess mole, preferably one to three moles, per mole of the compound represented by general formula (II). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include, for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, or a mixture thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 50°C to 120°C. The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

[0100] (Step 2) This step is a process for producing the compound represented by formula (VI) by a Sonogashira reaction between the compound represented by formula (IV) and the compound represented by formula (V). The Sonogashira reaction can be carried out by a commonly known method (for example, the method described in Chemical Reviews, Vol. 1 07, p. 874 (2007)) or a similar method, and can be carried out, for example, in the presence of a transition metal catalyst and a base, in a solvent that does not adversely affect the reaction. As the transition metal catalyst, for example, palladium catalysts (e.g., palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, tris(dibenzylideneacetone)dipalladium(O), etc.) and copper catalysts (e.g., copper bromide, copper iodide, etc.) can be used alone or in combination. The appropriate amount of transition metal catalyst that can be used is in the range of 0.001 to 1 mole per mole of the compound represented by formula (IV). If necessary, triphenylphosphine, tri(2-furyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri-i-propylbiphenyl, etc. can be used as palladium ligands. The reaction solvents that can be used are not particularly limited as long as they do not participate in the reaction, but examples include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethyl sulfoxide, water, or mixtures thereof.In this process, organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, and potassium tert-butyrate can be used as the base. The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours. The reaction temperature is usually from 25°C to 200°C, preferably from 30°C to 100°C.

[0101] (Step 3) This step is a method for producing a compound represented by general formula (VII) by reacting a compound represented by general formula (VII) in the presence of a base. In this step, an organic base such as diisopropylethylamine, pyridine, or tetrabutylammonium fluoride, or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, or potassium-tert-butyrate can be used as the base. Examples of reaction solvents that can be used include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethyl sulfoxide, water, or a mixture thereof. The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours. The reaction temperature is usually from 25°C to 200°C, preferably from 50°C to 100°C.

[0102] (Step 4) This step involves halogenating the compound represented by formula (VII) in the presence or absence of a base to produce the compound represented by formula (VIII). In general formula (VIII), L ３The leaving group represented by is a chlorine atom, a bromine atom, or an iodine atom. This step can be carried out using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, and iodine. The solvent is not particularly limited as long as it does not hinder the reaction, but for example, it can be carried out in a suitable solvent that does not hinder the reaction, such as acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone. Examples of bases that can be used are organic bases such as diisopropylethylamine, pyridine, and tetrabutylammonium fluoride, or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, and potassium-tert-butyrate. The reaction temperature is usually 0°C to 100°C, preferably room temperature or reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

[0103] (Step 5) This step is a method for producing a compound represented by general formula (IX) by reacting a compound represented by general formula (VIII) with ammonia or a salt thereof. The amount of ammonia or a salt thereof used in this step is usually equimolar to excess moles per mole of the compound represented by general formula (VIII). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or a mixture thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 70°C to 120°C. The reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.

[0104] (Step 6) This step is a method for producing a compound represented by structural formula (X) from a compound represented by structural formula (IX) under acidic conditions. Examples of acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, tosylic acid, etc. The amount of acid used is 1 mole to an excess amount, preferably 1 mole to 100 moles, per mole of the compound represented by structural formula (IX). The solvent used in the reaction can be any solvent that does not adversely affect the reaction, such as water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc., or mixtures thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 25°C to 80°C. The reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.

[0105] (Step 7) This step is a method for producing a compound represented by structural formula (XII) by coupling a compound represented by general formula (X) with 3-quinoline boronic acid. This step can be carried out in accordance with commonly known methods (for example, Chemical Reviews, Vol. 95, p2457, 1995), and can be carried out, for example, in the presence of a transition metal catalyst and a base, in a solvent that does not adversely affect the reaction. The amount of 3-quinoline boronic acid used can be 1 to 10 moles per mole of the compound represented by general formula (X), preferably 1 to 3 moles. As transition metal catalysts, for example, palladium catalysts (e.g., palladium acetate, palladium chloride, terakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride, etc.) and nickel catalysts (e.g., nickel chloride, etc.) can be used. If necessary, ligands (e.g., triphenylphosphine, tri-tert-butylphosphine, etc.) may be added, and metal oxides (e.g., copper oxide, silver oxide, etc.) may be used as co-catalysts. The amount of transition metal catalyst used varies depending on the type of catalyst, but is typically 0.0001 to 1 mole, preferably 0.01 to 0.5 moles, per mole of compound represented by general formula (X). The amount of ligand used is typically 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of compound represented by general formula (X). The amount of co-catalyst used is typically 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of compound represented by general formula (X). Examples of bases include organic amine compounds (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal salts (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), alkali metal alkoxides (e.g., sodium methyloxide, sodium ethyloxide, potassium tert-propyloxide, etc.). The amount of base used is usually 0.1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by general formula (X).Any solvent that does not adversely affect the reaction is acceptable, and examples include hydrocarbon solvents (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (e.g., chloroform, 1,2-dichloroethane, etc.), nitryl solvents (e.g., acetnitryl, etc.), ether solvents (e.g., 1,2-dimethylethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., dimethylformamide, dimethyl sulfoxide, etc.), water, or mixtures thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 60°C to 120°C. The reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.

[0106] (Step 8) This step involves reacting a compound represented by formula (XII) with a compound represented by formula (XIII) to produce a compound represented by formula (XIV). In general formula (XIII), L ４The leaving group represented by is a hydrogen atom or an acetyl group. This step can be carried out in accordance with commonly known methods (e.g., Synthetic Communications, Vol. 19, p561, 19895), and can be carried out, for example, in the presence of a base and in a solvent that does not adversely affect the reaction. Examples of bases include alkali metal salts (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), alkali metal alkoxides (e.g., sodium methyloxide, sodium ethyloxide, potassium-tert-butoxide, etc.). Any solvent that does not adversely affect the reaction can be used, such as hydrocarbon solvents (e.g., benzene, toluene, xylene, etc.), nitryl solvents (e.g., acetnitryl, etc.), ether solvents (e.g., 1,2-dimethylethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., dimethylformamide, dimethyl sulfoxide, etc.), water, or mixtures thereof. The reaction temperature is usually -100°C to 100°C, preferably -78°C to 50°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

[0107] [Manufacturing method 2] [In the formula, Y is NH or O, P １ L is a protecting group for a hydrogen atom or an amino group. ５ , L ６ and L ７ R indicates a leaving group, １ Rings A and n are defined as above.

[0108] (Step 9) This step is a method for producing a compound represented by general formula (XVII) by reacting a compound represented by general formula (XV) with a compound represented by general formula (XVI) in the presence of a base. ５The leaving group represented by is a fluorine atom or a chlorine atom. Compounds represented by general formulas (XV) and (XVI) can be commercially available or manufactured according to known methods. One to ten moles of the compound represented by general formula (XVI) can be used per mole of the compound represented by general formula (XV), preferably one to three moles. The base used in this step can be an organic base such as triethylamine, diisopropylethylamine, or pyridine, or an inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium phosphate, or potassium tert-butyrate. The amount of the base used is usually one mole to an excess mole, preferably one to three moles, per mole of the compound represented by general formula (XV). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include, for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, or a mixture thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 50°C to 120°C. The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours.

[0109] (Step 10) This step involves halogenating a compound represented by formula (XVII) in the presence or absence of a base to produce a compound represented by formula (XVIII). In general formula (XVIII), L ６The leaving group represented by is a chlorine atom, a bromine atom, or an iodine atom. This step can be carried out using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, and iodine. The solvent is not particularly limited as long as it does not hinder the reaction, but for example, it can be carried out in a suitable solvent that does not hinder the reaction, such as acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc. Examples of bases that can be used are organic bases such as diisopropylethylamine, pyridine, tetrabutylammonium fluoride, or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, potassium-tert-butyrate, etc. The reaction temperature is usually 0°C to 100°C, preferably room temperature or reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

[0110] (Step 11) This step is a method for producing a compound represented by general formula (XIX) by reacting a compound represented by general formula (XVIII) with ammonia or a salt thereof. The amount of ammonia or a salt thereof used in this step is usually equimolar to excess moles per mole of the compound represented by general formula (XVIII). The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or a mixture thereof. The reaction temperature is usually from 0°C to 200°C, preferably from 70°C to 120°C. The reaction time is usually from 5 minutes to 7 days, preferably from 1 hour to 24 hours.

[0111] (Step 12) This step is a method for producing a compound represented by structural formula (XXI) by coupling a compound represented by general formula (XIX) with 3-quinoline boronic acid (general formula (XX)). This step can be carried out in accordance with commonly known methods (for example, Chemical Reviews, Vol. 95, p2457, 1995), and can be carried out, for example, in the presence of a transition metal catalyst and a base, in a solvent that does not adversely affect the reaction. The amount of 3-quinoline boronic acid used can be 1 to 10 moles, preferably 1 to 3 moles, per mole of the compound represented by general formula (XIX). As transition metal catalysts, for example, palladium catalysts (e.g., palladium acetate, palladium chloride, terakis(triphenylphosphine)palladium, 1,1'-bis(diphenylphosphine)ferrocene-palladium(II) dichloride, chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), etc.), nickel catalysts (e.g., nickel chloride, etc.) can be used, and if necessary, ligands (e.g., triphenylphosphine, tri-tert-butylphosphine, etc.) may be added, and metal oxides (e.g., copper oxide, silver oxide, etc.) may be used as co-catalysts. The amount of transition metal catalyst used varies depending on the type of catalyst, but is usually 0.0001 to 1 mole, preferably 0.01 to 0.5 moles, per mole of compound represented by general formula (XIX). The amount of ligand used is usually 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of compound represented by general formula (XIX). The amount of co-catalyst used is usually 0.0001 to 4 moles, preferably 0.01 to 2 moles, per mole of compound represented by general formula (XIX). Examples of bases include organic amine compounds (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal salts (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, etc.), metal hydrides (e.g., potassium hydride, sodium hydride, etc.), alkali metal alkoxides (e.g., sodium methyloxide, sodium ethyloxide, potassium tert-butoxide, etc.).The amount of base used is usually 0.1 to 10 moles, preferably 1 to 5 moles, per mole of the compound represented by general formula (XIX). The solvent can be any solvent that does not adversely affect the reaction, and examples include hydrocarbon solvents (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbon solvents (e.g., chloroform, 1,2-dichloroethane, etc.), nitryl solvents (e.g., acetonitol, etc.), ether solvents (e.g., 1,2-dimethylethane, tetrahydrofuran, 1,4-dioxane, etc.), alcohol solvents (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., dimethylformamide, dimethyl sulfoxide, etc.), water, or mixtures thereof. The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C. The reaction time is usually 5 minutes to 7 days, preferably 1 hour to 24 hours.

[0112] (Step 13) This step involves halogenating the compound represented by formula (XXI) in the presence or absence of a base to produce the compound represented by formula (XXII). In general formula (XXII), L ７ The leaving group represented by is a chlorine atom, a bromine atom, or an iodine atom. This step can be carried out using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, and iodine. The solvent is not particularly limited as long as it does not hinder the reaction, but for example, it can be carried out in a suitable solvent that does not hinder the reaction, such as acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc. Examples of bases that can be used are organic bases such as diisopropylethylamine, pyridine, tetrabutylammonium fluoride, or sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, potassium-tert-butyrate, etc. The reaction temperature is usually 0°C to 100°C, preferably room temperature or reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.

[0113] (Step 14) This step is a step to produce a compound represented by formula (XXIV) by a Sonogashira reaction between a compound represented by formula (XXII) and a compound represented by formula (XXIII). The Sonogashira reaction can be carried out by a commonly known method (for example, the method described in Chemical Reviews, Vol. 107, p. 874 (2007)) or a similar method, and can be carried out, for example, in the presence of a transition metal catalyst and a base, in a solvent that does not adversely affect the reaction. As the transition metal catalyst, for example, palladium catalysts (e.g., palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, tris(dibenzylideneacetone)dipalladium(O), etc.) and copper catalysts (e.g., copper bromide, copper iodide, etc.) can be used alone or in combination. The appropriate amount of transition metal catalyst that can be used is in the range of 0.001 to 1 mole per mole of the compound represented by formula (XXII). If necessary, triphenylphosphine, tri(2-furyl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-tri-i-propylbiphenyl, etc. can be used as palladium ligands. The reaction solvents that can be used are not particularly limited as long as they do not participate in the reaction, but examples include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, benzene, toluene, acetonitrile, dimethyl sulfoxide, water, or mixtures thereof.In this process, organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium phosphate, sodium phosphate, and potassium tert-butyrate can be used as the base. The reaction time is usually from 5 minutes to 7 days, preferably from 30 minutes to 24 hours. The reaction temperature is usually from 25°C to 200°C, preferably from 30°C to 100°C.

[0114] [Manufacturing method 3] [In the formula, Y is NH, P １ The symbol indicates a protecting group for the amino group, and rings A and R １ And n are the same as above.

[0115] (Step 15) This step is to deprotect the amino group of the compound represented by formula (XXIV) to produce the compound represented by formula (XXV). Deprotection can be carried out by commonly known methods, such as the method described in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons (1981), or a similar method. When a tert-butoxycarbonyl group is used as the protecting group, examples of deprotection reagents include hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid. The amount of reagent used is preferably 1 to 100 moles per mole of compound (XXIV). The solvent used in the reaction can be any solvent that does not adversely affect the reaction, such as water, methanol, ethanol, methylene chloride, chloroform, or a mixture thereof. The reaction temperature is typically 0°C to 200°C, preferably 0°C to 80°C. The reaction time is typically 5 minutes to 7 days, preferably 1 hour to 48 hours.

[0116] [Manufacturing method 4] [In the formula, ring A, R １ , R ２ , R ３ And n are the same as above.

[0117] (Step 16) This step is a method for producing the compound of the present invention represented by general formula (XXVI) by an acylation reaction between the compound represented by general formula (XXV) and a carboxylic acid or acid halide, or acid anhydride, or isocyanate, or isothiocyanate, or amine. The acylation reagent is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compound represented by general formula (XXV). The acylation reagent can be a commercially available product or produced according to known methods. The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include, for example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidine-2-one, dimethyl sulfoxide, or a mixture thereof. The reaction temperature is usually -78 to 200°C, preferably 0 to 70°C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours. The reaction can use a coupling agent as needed, and examples of coupling agents include diphenyl phosphate azide, N,N'-dicyclohexylcarbodiimide, benzotriazole-1-yloxy-trisdimethylaminophosphonium salt, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole, 2-chloro-1,3-dimethylimidazolinium chloride, O-(7-azabenzotriazolinium-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate, carbonyldiimidazole, and the like.

[0118] Furthermore, the above reaction may be modified by adding a base as needed. Examples of bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, colidine, 4-(N,N-dimethylamino)pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount added is 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by general formula (XXV). This step can also be used to produce the compound represented by general formula (XXVI) by reacting the compound represented by general formula (XXV) with an alkyl halide in the presence of a base. The alkyl halide is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compound represented by the general formula (XXV). The alkyl halide can be a commercially available product or produced according to known methods. The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable solvents include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidine-2-one, dimethyl sulfoxide, or a mixture thereof. Examples of bases include organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, colidine, 4-(N,N-dimethylamino)pyridine, potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyllithium, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and sodium hydride. The amount added is 1 to 100 moles, preferably 1 to 10 moles, per mole of the compound represented by the general formula (XXV).The reaction temperature is typically -78 to 200°C, preferably 50 to 100°C. The reaction time is typically 5 minutes to 3 days, preferably 5 minutes to 10 hours. This process can also produce the compound represented by general formula (XXVI) by subjecting the compound represented by general formula (XXV) and an aldehyde reagent to a reductive amination reaction in the presence of a reducing agent.

[0119] The aldehyde reagent is used in an amount of 0.5 to 10 moles, preferably 1 to 3 moles, per mole of the compound represented by general formula (XXV). The aldehyde reagent can be a commercially available product or manufactured according to known methods. The reducing agent is not particularly limited, but examples include metal hydride complexes, such as 0.1 mole to a large excess of sodium borohydride, sodium cyanoborohydride, or triacetoxyborohydride. Additives may be added to the reaction as needed, such as acids, bases, inorganic salts, or organic salts, such as 0.01 mole to a large excess of trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, potassium carbonate, sodium hydroxide, lithium hydroxide, sodium sulfate, magnesium sulfate, tetraisopropyl orthotitanate, or zinc chloride. The reaction solvent is not particularly limited as long as it does not hinder the reaction, but suitable examples include toluene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidine-2-one, dimethyl sulfoxide, methanol, ethanol, 2-propanol, tert-butyl alcohol, or a mixture thereof. The reaction temperature is usually -78 to 200°C, preferably 0 to 60°C. The reaction time is usually 5 minutes to 3 days, preferably 5 minutes to 10 hours.

[0120] If the compound of the present invention has isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, then, unless otherwise specified, any isomer or mixture thereof is included in the compound of the present invention. For example, if the compound of the present invention has optical isomers, then, unless otherwise specified, the racemate and the optical isomers separated from the racemate are also included in the compound of the present invention. A salt of the compound of the present invention means a pharmaceutically acceptable salt, and may include a base addition salt or an acid addition salt.

[0121] The compounds or salts thereof of the present invention may be amorphous or crystalline, and the crystalline form may be single or a polymorphic mixture, both of which are included in the compounds or salts thereof of the present invention. Crystals can be produced by crystallization using known crystallization methods. The compounds or salts thereof of the present invention may be solvates (e.g., hydrates, etc.) or solvates, both of which are included in the compounds or salts thereof of the present invention. Isotopes (e.g., ３ H, １４ C, ３５ S, １２５ Compounds labeled with I, etc., are also included in the compounds or salts thereof of the present invention.

[0122] When the compound of the present invention or a salt thereof is used as a pharmaceutical, a pharmaceutically acceptable carrier may be added as needed, and various dosage forms may be adopted depending on the purpose of prevention or treatment. These forms may be, for example, oral preparations, injections, suppositories, ointments, patches, etc., and oral preparations are preferably used. Each of these dosage forms can be manufactured by pharmaceutical methods known and commonly used by those skilled in the art. One embodiment of the present invention provides an antitumor agent containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment of the present invention, the antitumor agent is an antitumor agent for oral administration. Another embodiment of the present invention provides a method for the prevention and / or treatment of a tumor, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need. Another embodiment of the present invention provides a method for the prevention and / or treatment of a tumor, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof orally to a subject in need. Another embodiment of the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for manufacturing an antitumor agent. Furthermore, one embodiment of the present invention provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for producing an antitumor agent for oral administration. Furthermore, one embodiment of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of tumors. Furthermore, one embodiment of the present invention provides the compound of the present invention or a pharmaceutically acceptable salt thereof for oral administration for use in the prevention and / or treatment of tumors.

[0123] In this specification, the term “effective amount” of the compound of the present invention refers to the amount (therapeutic effective amount) of the compound that causes a biological or medical response in a subject, such as a decrease or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of a condition, slowing or delaying the progression of a disease, or preventing a disease. In this specification, the term “subject” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles, wild boars, bears, tigers, and lions. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In one embodiment, the subject may be a human being diagnosed with a condition or disease as disclosed herein that requires treatment.

[0124] One embodiment of the present invention provides a pharmaceutical composition comprising the compound of the present invention or a salt thereof. A pharmaceutical composition of one embodiment of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides the use of the compound of the present invention or a salt thereof for producing a pharmaceutical composition. Another embodiment of the present invention provides the compound of the present invention or a salt thereof for use as a pharmaceutical.

[0125] When the compound or salt thereof of the present invention is used as a pharmaceutical, it may be combined with a pharmaceutically acceptable carrier as needed, and various dosage forms may be adopted depending on the purpose of prevention or treatment. These forms may include, for example, oral preparations, injections, suppositories, ointments, patches, etc., with oral preparations being preferred. Each of these dosage forms can be manufactured by pharmaceutical methods known and commonly used by those skilled in the art.

[0126] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, which are incorporated as excipients, binders, disintegrants, lubricants, coatings, and colorants in solid formulations, and as solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, sweeteners, and stabilizers may be used as needed.

[0127] When preparing oral solid dosage forms, tablets, coated tablets, granules, powders, capsules, etc., can be manufactured by conventional methods after adding excipients, and optionally binders, disintegrants, lubricants, colorants, flavorings, and odor-masking agents, etc., to the compound of the present invention. When preparing injectable preparations, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc., can be added to the compound of the present invention, and subcutaneous, intramuscular, and intravenous injectable preparations can be manufactured by conventional methods.

[0128] The amount of the compound of the present invention to be incorporated into each of the above-mentioned dosage units is not fixed and depends on the symptoms of the target patient, the dosage form, etc. However, it is generally preferable that the amount per dosage unit be 0.05 to 1000 mg for oral preparations, 0.01 to 500 mg for injectable preparations, and 1 to 1000 mg for suppositories. Furthermore, the daily dose of the drug having the above-mentioned dosage forms varies depending on the symptoms of the target patient, weight, age, sex, etc., and cannot be determined in general terms, but it is generally preferable that the amount of the compound of the present invention be 0.05 to 5000 mg per day for an adult (weight 50 kg), preferably 0.1 to 1000 mg.

[0129] The tumors covered by the present invention are not particularly limited, but examples include head and neck cancer, digestive tract cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, scavenging mesothelioma, etc.)), breast cancer, reproductive tract cancer (ovarian cancer, vulvar cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.)), urinary tract cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, urothelial carcinoma, renal pelvis cancer, urethral cancer, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, brain tumors, malignant schwannomas, neuroendocrine tumors, thyroid cancer, etc.). Preferably, the target tumors are head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors, with lung cancer being particularly preferred. Here, cancer includes not only the primary tumor but also cancers that have metastasized to other organs (such as the liver). Furthermore, the compounds of the present invention or their salts have excellent inhibitory activity against mutant EGFRs. Examples of such mutant EGFRs include drug-resistant mutant EGFRs and highly sensitive mutant EGFRs. Therefore, the compounds of the present invention or their salts are also useful as antitumor agents against the aforementioned malignant tumors that have mutant EGFRs.

[0130] A compound or salt thereof according to one aspect of the present invention has excellent EGFR inhibitory activity. In particular, it exhibits excellent inhibitory activity against EGFR(Del19 / C797S), EGFR(L858R / C797S), EGFR(Del19 / T790M / C797S), and EGFR(L858R / T790M / C797S), making it useful as an antitumor agent. Furthermore, it has excellent selectivity for mutant EGFR, and has the advantage of fewer side effects caused by wild-type EGFR and other kinases.

[0131] In this specification, “wild-type EGFR” refers to, for example, the amino acid sequence of GenBank accession number: NP_005219.2. In this specification, “exon 19” refers to the region 729–823 in the amino acid sequence of wild-type EGFR (for example, GenBank accession number: NP_005219.2).

[0132] In this specification, "Del19" refers to a mutation in which one or more amino acids are deleted in the exon 19 region of the wild-type EGFR. This also includes mutations in which one or more arbitrary amino acids are inserted in addition to the deletion of the said region. Exon 19 deletion mutations include mutations in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), mutations in which seven amino acids from leucine at position 747 to proline at position 753 in the exon 19 region are deleted followed by the insertion of serine (Del 747-P753insS), mutations in which five amino acids from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and mutations in which four amino acids from leucine at position 747 to alanine at position 750 in the exon 19 region are deleted followed by the insertion of proline (Del 747-A750insP). Preferably, a mutation is observed in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750).

[0133] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to these examples. Unless otherwise specified, commercially available reagents were used in the examples. Prepacked columns from Teruko Scientific or Biotage were used for silica gel column chromatography and basic silica gel column chromatography. Reverse-phase preparative HPLC column chromatography was performed under the following conditions. The injection volume and gradient were set as appropriate. Column: OSAKA SODA CAPCELL PAK C18 MGIII, 30 x 50 mm, 5 μm UV detection: 254 nm Column flow rate: 40 mL / min Mobile phase: Water / acetonitrile (0.1% formic acid) Injection volume: 0.1–1.0 mL Gradient: Water / acetonitrile 10% → 90% (7 min) NMR spectra were obtained using AL400 (400 MHz; JEOL), Mercury400 (400 MHz; Agilent Technologies), AVANCE NEO (400 MHz; Bruker), and AVANCE III. Using an HD (500 MHz; Bruker) spectrometer, measurements were performed using tetramethylsilane as the internal reference when the deuterated solvent contained tetramethylsilane, and using the NMR solvent as the internal reference otherwise. The total δ values ​​are expressed in ppm. LCMS spectra were also measured using a Waters SQD under the following two conditions, and the [M+H]+ values ​​are shown. MS detection: ESI positive UV detection: 254 and 210 nm Column flow rate: 0.5 mL / min Mobile phase: Water / acetonitrile (0.1% formic acid) Injection volume: 1 μL Column: Acquity BEH, 2.1 x 50 mm, 1.7 μm Gradient: Time (min) Water / acetonitrile (0.1% formic acid) 0 95 5 0.1 95 5 2.1 5 95 3.0 STOP The meaning of the abbreviations is shown below.s: singlet d: doublet t: triplet q: quartet dd: double doublet m: multiplet br: broad brs: broad singlet DMSO-d6: deuterated dimethyl sulfoxide CDCl3: deuterated chloroform THF: tetrahydrofuran DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide DME: 1,2-dimethoxyethane DMSO: dimethyl sulfoxide HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate. DIPEA: Diisopropylethylamine TBAF: Tetrabutylammonium fluoride NMP: N-Methylpyrrolidine-2-one DMPU: N,N-Dimethylpropylene urea WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBT: 1-Hydroxybenzotriazole NBS: N-Bromosuccinimide.

[0134] [Production Example 1] Preparation of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (Step 1) A mixture of 4,6-dichloro-5-iodopyrimidine (0.38 g), tert-butyl(4-aminobicyclo[2.2.1]heptan-1-yl)carbamate (0.30 g), DIPEA (0.69 ml), and THF (3 ml) was stirred overnight at 70°C. After the reaction mixture was cooled to room temperature, it was concentrated. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl(4-((6-chloro-5-iodopyrimidine-4-yl)amino)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-1)).

[0135] (Step 2) A mixture of the compound from Production Example (1-1) (390 mg), tri(2-furyl)phosphine (39 mg), tris(dibenzylideneacetone)dipalladium (0) (38 mg), copper(I) iodide (32 mg), propargylaldehyde diethyl acetal (0.24 ml), DIPEA (0.22 ml), and DMF (5.9 ml) was stirred at 70°C for 3 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl(4-((6-chloro-5-(3,3-diethoxypropyne-1-yl)pyrimidine-4-yl)amino)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-2)).

[0136] (Step 3) A mixture of the compound from Production Example (1-2) (325 mg), TBAF (THF solution, 1 M, 0.7 ml), and THF (3.5 ml) was stirred at 70°C for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain (4-(4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-3)).

[0137] (Step 4) To a mixture of the compound from Production Example (1-3) (329 mg) and DMF (3.3 ml), NBS (72 mg) was added at room temperature and stirred for 1 hour. Saturated sodium sulfite aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl(4-(5-bromo-4-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-4)).

[0138] (Step 5) A mixture of the compound from Production Example (1-4) (358 mg), DME (2 ml), and aqueous ammonia (2 ml) was placed in a pressure-resistant reaction vessel and stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate, and then the organic layer was concentrated. THF (1.8 ml), acetic acid (1.8 ml), and water (0.4 ml) were added to the resulting residue and stirred at 45°C for 16 hours. After concentrating the reaction mixture, it was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl(4-(4-amino-5-bromo-6-formyl-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-5)).

[0139] (Step 6) A mixture of the compound from Production Example (1-5) (4.1 g), 3-quinoline boronic acid (1.8 g), tetrakis(triphenylphosphine)palladium (0) (460 mg), sodium carbonate (2.1 g), DME (4 ml), and water (21 ml) was heated under a nitrogen atmosphere and refluxed for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl(4-(4-amino-6-formyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-6)).

[0140] (Step 7) A mixture of the compound from Production Example (1-6) (3.9 g), dimethyl (1-diazo-2-oxopropyl)phosphonate (4.8 ml), potassium carbonate (3.3 g), and methanol (60 ml) was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (1-7)).

[0141] (Step 8) To a 40 ml solution of the compounds of Production Examples (1-7) in dichloromethane, 40 ml of trifluoroacetic acid was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water, neutralized with an aqueous sodium hydroxide solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound (7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine).

[0142] [Production Example 2] Production of 7-(4-aminobicyclo[2.2.2]octan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine The title compound (7-(4-aminobicyclo[2.2.2]octan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine) was obtained by following the same method as in Production Example 1 (steps 1-8), except that tert-butyl(4-aminobicyclo[2.2.1]heptan-1-yl)carbamate was used instead of tert-butyl(4-aminobicyclo[2.2.2]octan-1-yl)carbamate used in step 1 of Production Example 1.

[0143] [Production Example 3] Preparation of tert-butyl(4-(4-amino-6-bromo-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Step 1) A mixture of 2-(4,6-dichloropyrimidine-5-yl)acetaldehyde (4.6 g), tert-butyl(4-aminobicyclo[2.2.1]heptan-1-yl)carbamate (5.0 g), DIPEA (7.7 ml), and acetonitrile (50 ml) was stirred at 100°C for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated. After dilution with ethyl acetate (50 ml) and water (10 ml), the insoluble matter was filtered off. The organic layer was washed with saturated brine, then with an aqueous solution of ammonium chloride, followed by saturated brine, then dried over anhydrous magnesium sulfate and concentrated to obtain crude tert-butyl(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Preparation Example (3-1)).

[0144] (Step 2) To a 50 ml solution of the compound of Production Example (3-1) in NMP, 4.3 g of NBS was added at 0°C and the mixture was stirred at room temperature for 30 minutes. 5 ml of saturated sodium sulfite aqueous solution and 100 ml of water were gradually added to the reaction mixture and the mixture was stirred for 10 minutes. The resulting solid was filtered and washed with water to obtain tert-butyl(4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (3-2)).

[0145] (Step 3) A mixture of the compound from Production Example (3-2) (11.1 g), DME (110 ml), and aqueous ammonia (55 ml) was placed in a pressure-resistant reaction vessel and stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, water (150 ml) was added, and the mixture was stirred for 30 minutes. The resulting solid was filtered and washed with water to obtain tert-butyl(4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (Production Example (3-3)).

[0146] (Step 4) A mixture of the compound from production example (3-3) (4.3 g), 3-quinoline boronic acid (2.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (240 mg), sodium carbonate (2.2 g), THF (44 ml), and water (22 ml) was heated under a nitrogen atmosphere and refluxed for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate (44 ml) and saturated sodium bicarbonate aqueous solution (10 ml) were added, and the mixture was stirred overnight. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in acetonitrile (25 ml), heated under reflux for 5 hours, and cooled to 0°C. The solid was filtered and washed with acetonitrile to obtain tert-butyl(4-(4-amino-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (production example (3-4)).

[0147] (Step 5) To a solution of compound (60 mg) of the compound from production example (3-4) in THF (2 ml), NBS (25 mg) was added at 0°C and stirred for 15 minutes. A 5% aqueous sodium sulfite solution and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl(4-(4-amino-6-bromo-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (production example (3-5)).

[0148] [Example 1] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)benzamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg) obtained in Preparation Example 1 was added to a solution of THF (1 ml) with DIPEA (0.013 ml) and benzoyl chloride (0.006 ml). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0149] [Example 2] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (7 mg) obtained in Preparation Example 1 in THF (1 ml), DIPEA (0.013 ml), pyrimidine-5-carboxylic acid (24 mg) were added, and HATU (10 mg) was added. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained residue was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0150] [Example 3] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-4-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (7 mg) obtained in Preparation Example 1 in THF (1 ml), DIPEA (0.013 ml), pyridazine-4-carboxylic acid (24 mg) were added, and HATU (10 mg) was added. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography to obtain the title compound.

[0151] [Example 4] 2-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)amino)acetonitrile A mixed solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg) obtained in Production Example 1, THF (1 ml), and acetonitrile (1 ml) was mixed with DIPEA (0.013 ml) and bromoacetonitrile (0.003 ml). The mixture was stirred at room temperature for 1 hour and overnight at 50°C, and the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0152] [Example 5] 4-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methylpiperazine-2-one (Step 1) To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (20 mg) obtained in Production Example 1 in dichloromethane (0.5 ml), triethylamine (0.011 ml) and methyl bromoacetate (0.005 ml) were added, and after stirring overnight at room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain methyl (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)glycinate. (Step 2) To a methanol (0.2 ml) solution of the methyl (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)glycinate obtained in Step 1 above, tert-butylmethyl (2-oxoethyl)carbamate (0.01 ml) was added, and under stirring, a 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution (0.3 ml) was added, and the mixture was stirred overnight at 60°C. 0.3 ml of 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution was added again to the reaction mixture, and the mixture was stirred for a further day. After cooling to room temperature, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred for three days. The reaction mixture was concentrated, neutralized with saturated sodium bicarbonate aqueous solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound.

[0153] [Example 6] N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.2]octan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide The title compound was obtained by following the same method as in Example 1, except that 7-(1-amino-4-bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine and 1-methyl-1H-pyrazole-5-carbonyl chloride were used instead of 7-(1-amino-4-bicyclo[2.2.2]octanyl)-6-ethynyl-5-(quinoline-3-yl)pyrrolo[2,3-d]pyrimidine-4-amine and 1-methyl-1H-pyrazole-5-carbonyl chloride, respectively, as used in Example 1.

[0154] [Example 7] 4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.2]octan-1-ol The title compound was obtained by following the same method as in Production Example 1 (Step 1-7), except that 4-aminobicyclo[2.2.2]octan-1-ol was used instead of tert-butyl(4-aminobicyclo[2.2.1]heptan-1-yl)carbamate used in Production Example 1 (Step 1).

[0155] [Example 8] 6-Ethynyl-7-(4-((pyridine-3-ylmethyl)amino)bicyclo[2.2.2]octan-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine To a solution of 7-(4-aminobicyclo[2.2.2]octan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg) obtained in Preparation Example 2, potassium carbonate (17 mg), DIPEA (0.02 ml), and 3-(chloromethyl)pyridine hydrochloride (20 mg) were added. The reaction mixture was stirred at 80°C for 2 days. After cooling to room temperature, the mixture was purified by basic silica gel column chromatography to obtain the title compound.

[0156] [Example 9] 6-Ethynyl-7-(4-Molfolinobicyclo[2.2.1]heptan-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine A mixture of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (40 mg), DIPEA (0.11 ml), 1-bromo-2-(2-bromoethoxy)ethane (0.26 ml), and DMF (5 ml) was stirred overnight at 80°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography and concentrated. The residue was washed with ethyl acetate to obtain the title compound.

[0157] [Example 10] (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methanol The title compound was obtained by following the same method as in Production Example 1 (Steps 1-7), except that (4-aminobicyclo[2.2.1]heptan-1-yl)methanol was used instead of tert-butyl(4-aminobicyclo[2.2.1]heptan-1-yl)carbamate used in Production Example 1 (Step 1).

[0158] [Example 11] 7-(4-(dimethylamino)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine A 37% aqueous formaldehyde solution (0.01 ml) was added to a mixed solution of methanol (0.5 ml) and THF (0.5 ml) of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg) obtained in Preparation Example 1. The mixture was then mixed with methanol (0.5 ml) and THF (0.5 ml), and a separately prepared 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution (0.1 ml) was added. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0159] [Example 12] Ethyl (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate The title compound was obtained by the same method as in Example 1, except that ethyl chloroformate was used instead of the benzoyl chloride used in Example 1.

[0160] [Example 13] N-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide (Step 1) To a mixed solution of (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methanol (200 mg) obtained in Example 10 with dichloromethane (4.9 ml) and THF (4.9 ml), methanesulfonyl chloride (0.076 ml) and triethylamine (0.272 ml) were added under an ice bath. The mixture was stirred at room temperature for 1.5 hours, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography and concentrated. The residue was washed with ethyl acetate to obtain (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methylmethanesulfonate. (Step 2) A mixture of (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methylmethanesulfonate (139 mg), sodium azide (55 mg), and DMSO (5.7 ml) was stirred at 80°C for 24 hours, and then stirred overnight at 60°C. The reaction mixture was diluted with water, filtered, and the residue was washed with water. Triphenylphosphine (0.089 mg) was added to a THF solution (5.6 ml) of the obtained residue, and the mixture was stirred overnight at 40°C. Water (0.10 ml) was added to the reaction mixture, and the mixture was stirred at 40°C for 6 hours to concentrate the reaction mixture. The obtained residue was purified by basic silica gel column chromatography to obtain 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine.(Step 3) 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg), 1-methyl-1H-pyrazole-5-carboxylic acid (1.7 mg), and HATU (6.9 mg) were dissolved in DMSO (0.5 ml), to which DIPEA (0.0064 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase HPLC to obtain the title compound.

[0161] [Example 14] N-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methyl)-5-methylpyrazine-2-carboxamide The title compound was obtained by the same method as in Example 13 (Step 3), except that 5-methylpyrazine-2-carboxylic acid was used instead of 1-methyl-1H-pyrazole-5-carboxylic acid used in Example 13 (Step 3).

[0162] [Example 15] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-chloropyrazine-2-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Preparation Example 1 in DMF (1 ml), DIPEA (0.004 ml), 5-chloropyrazine-2-carboxylic acid (5 mg) were added, and WSC (4 mg) and HOBT (3 mg) were added. After stirring at 50°C for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0163] [Example 16] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (4 mg) obtained in Preparation Example 1 in THF (1 ml), DMF (0.05 ml), DIPEA (0.006 ml), [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid (1.7 mg) were added, and HATU (6 mg) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0164] [Example 17] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-(2-methoxyethyl)-1H-pyrazole-5-carboxamide The title compound was obtained by following the same method as in Example 2, except that DMSO was used instead of THF as in Example 2, and 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid was used instead of pyrimidine-5-carboxylic acid.

[0165] [Example 18] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1,2,3-thiadiazole-5-carboxamide The title compound was obtained by the same method as in Example 17, except that 1,2,3-thiadiazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0166] [Example 19] N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1,2,4-triazine-3-carboxamide The title compound was obtained by following the same method as in Example 13 (Step 3), except that 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was used instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine used in Example 13 (Step 3), and sodium 1,2,4-triazine-3-carboxylate was used instead of 5-methylpyrazine-2-carboxylic acid.

[0167] [Example 20] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-carboxamide The title compound was obtained by the same method as in Example 17, except that 1-cyclopropyl-1H-pyrazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0168] [Example 21] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1H-pyrazole-1-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (9.5 mg) obtained in Preparation Example 1 in DMF (0.4 ml), carbonyldiimidazole (8 mg) was added and stirred at room temperature for 1 hour. Pyrazole (5 mg) was added and stirred overnight at room temperature, then water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0169] [Example 22] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-1,2,3-triazole-5-carboxamide The title compound was obtained by the same method as in Example 17, except that 1-methyl-1H-1,2,3-triazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0170] [Example 23] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-imidazole-2-carboxamide The title compound was obtained by the same method as in Example 17, except that 1-methyl-1H-imidazole-2-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0171] [Example 24] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide The title compound was obtained by the same method as in Example 1, except that 1-methyl-1H-pyrazole-5-carbonyl chloride was used instead of the benzoyl chloride used in Example 1.

[0172] [Example 25] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide The title compound was obtained by the same method as in Example 17, except that 1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0173] [Example 26] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-phenyl-1H-pyrazole-5-carboxamide The title compound was obtained by the same method as in Example 17, except that 1-phenyl-1H-pyrazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0174] [Example 27] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide 2 ml of a dichloromethane solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25 mg) was mixed with a dichloromethane solution of 2,2-difluoroacetic anhydride (0.0079 ml) (0.5 ml) under an ice bath and stirred under an ice bath for 1 hour. The reaction mixture was purified by silica gel column chromatography to obtain the title compound.

[0175] [Example 28] N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-2-methoxyacetamide The title compound was obtained by following the same method as in Example 13 (Step 3), except that 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was used instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine used in Example 13 (Step 3), and 2-methoxyacetic acid was used instead of 5-methylpyrazine-2-carboxylic acid.

[0176] [Example 29] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-3-(fluoromethyl)-1-methyl-1H-pyrazole-5-carboxamide (Step 1) A suspension of potassium tert-butoxide (6.1 g) in THF (50 ml) was added to a mixed solution of 2-acetylfuran (3.0 g) and diethyl oxalate (8.0 g) in 1,2-dimethoxyethane (50 ml). After stirring at room temperature for 2 hours, the solvent was removed by reduced pressure and 1 M hydrochloric acid (20 ml) was added. After extraction with ethyl acetate, the organic layer was washed with water and concentrated to obtain ethyl 4-(furan-2-yl)-2,4-dioxobutanoate. (Step 2) To a solution of ethyl 4-(furan-2-yl)-2,4-dioxobutanoate (2.4 g) obtained in Step 1 in 1,1,1,3,3,3-hexafluoroisopropanol (25 ml), methylhydrazine (1.1 ml) was added and the mixture was stirred at room temperature. After the reaction was complete, the mixture was concentrated and the resulting residue was purified by silica gel column chromatography to obtain ethyl 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxylate. (Step 3) To a suspension of lithium aluminum hydride (0.5 g) in THF (10 ml), ethyl 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-carboxylate (1.5 g) was added under ice bath. The reaction mixture was stirred at 60°C, and after the reaction was complete, it was cooled to room temperature and saturated aqueous sodium sulfate (5 ml) was added. The residue was filtered, the solution was concentrated, and then purified by silica gel column chromatography to obtain (5-(furan-2-yl)-1-methyl-1H-pyrazole-3-yl)methanol. (Step 4) To a solution of 5-(furan-2-yl)-1-methyl-1H-pyrazole-3-yl)methanol (0.16 g) in dichloromethane (2 ml), bis(2-methoxyethyl)aminosulfate fluoride (0.34 ml) was added under ice bath. After stirring at room temperature for 1 hour, saturated aqueous solution of sodium bicarbonate (1 ml) was added, and after extraction with ethyl acetate, the organic layer was washed with water. After concentrating the organic layer, the obtained residue was purified by silica gel column chromatography to obtain 3-(fluoromethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole.(Step 5) 3-(fluoromethyl)-5-(furan-2-yl)-1-methyl-1H-pyrazole (62 mg) was mixed with acetonitrile (2 ml), carbon tetrachloride (2 ml), and water (3 ml). Sodium periodate (0.73 g) and ruthenium(III) chloride hydrate (5 mg) were added and the mixture was stirred at room temperature. After the reaction was complete, the residue was filtered and the filtrate was concentrated to obtain 5-(fluoromethyl)-2-methyl-pyrazole-3-carboxylic acid. (Step 6) To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Production Example 1 in THF (2 ml), DMF (0.02 ml), DIPEA (0.007 ml), and 5-(fluoromethyl)-2-methylpyrazole-3-carboxylic acid (2.0 mg) were added, and HATU (7 mg) was added. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound.

[0177] [Example 30] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-4-(methylsulfonyl)picolinamide (Step 1) A mixture of methyl 4-chloropicolinic acid (343 mg), sodium methanesulfinate (204 mg), copper(I) chloride (19.8 mg), quinoline (26 mg), and NMP (3 ml) was stirred at 140°C for 5.5 hours under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate, insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain methyl 4-(methylsulfonyl)picolinic acid. (Step 2) To a THF solution (1.3 ml) of methyl 4-(methylsulfonyl)picolinate (113 mg), 2.6 ml of 0.2 N sodium hydroxide aqueous solution was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain sodium 4-(methylsulfonyl)picolinate. (Step 3) The title compound was obtained by the same method as in Example 13 (Step 3), except that 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was used instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine used in Example 13 (Step 3), and sodium 4-(methylsulfonyl)picolinate was used instead of 5-methylpyrazine-2-carboxylic acid.

[0178] [Example 31] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-4-methoxynicotinamide The title compound was obtained by the same method as in Example 29 (step 6), except that 4-methoxynicotinic acid was used instead of 5-(fluoromethyl)-2-methylpyrazole-3-carboxylic acid used in Example 29.

[0179] [Example 32] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethylamino)pyrazine-2-carboxamide The title compound was obtained by the same method as in Example 17, except that 5-(dimethylamino)pyrazine-2-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0180] [Example 33] N-(4-(4-amino-6-(propin-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (Step 1) To a DMSO (2 ml) solution of tert-butyl(4-(4-amino-6-bromo-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (40 mg) obtained in Production Example 3, bis(triphenylphosphine)palladium(II) dichloride (10 mg), copper(I) iodide (6 mg), DIPEA (0.02 ml), and propyne DMF solution (1 M, 0.15 ml) were added, and the mixture was stirred overnight at 80°C under a nitrogen atmosphere. The reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain tert-butyl(4-(4-amino-6-(propyne-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate. (Step 2) Instead of the tert-butyl(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate used in Production Example 1 (Step 8), the tert-butyl(4-(4-amino-6-(propyne-1-yl)-5-(quinoline-3-yl) By following the same method as in Production Example 1 (Step 8), except that the -7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate, we obtained 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-(propyne-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine.(Step 3) The title compound was obtained by the same method as in Example 15, except that 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine and 1-methyl-1H-pyrazole-5-carboxylic acid obtained in Step 2 above were used instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-(propyne-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine and 1-methyl-1H-pyrazole-5-carboxylic acid obtained in Step 2 above, instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-(propyne-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine and 1-methyl-1H-pyrazole-5-carboxylic acid obtained in Step 2 above.

[0181] [Example 34] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-cyanonicotinamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Preparation Example 1 in DMF (1 ml), DIPEA (0.004 ml) and 5-cyanopyridine-3-carboxylic acid (5 mg) were added, and WSC (4 mg) and HOBT (3 mg) were added. After stirring at 50°C for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0182] [Example 35] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-fluoronicotinamide To a DMSO (1 ml) solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Preparation Example 1, DIPEA (0.004 ml) and 5-fluoropyridine-3-carboxylic acid (5 mg) were added, and WSC (4 mg) and HOBT (3 mg) were added. After stirring at 50°C for 1 hour, the reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0183] [Example 36] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide The title compound was obtained by the same method as in Example 17, except that lithium 5-methyl-1,2,4-oxadiazole-3-carboxylate was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0184] [Example 37] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide The title compound was obtained by following the same method as in Example 29 (step 6), except that 5-methylpyrazine-2-carboxylic acid was used instead of 5-(fluoromethyl)-2-methylpyrazole-3-carboxylic acid used in Example 29.

[0185] [Example 38] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-6-(fluoromethoxy)pyrazine-2-carboxamide (Step 1) A mixture of 6-bromopyrazine-2-ol (221 mg), fluoromethyl 4-methylbenzenesulfonic acid (200 mg), cesium carbonate (383 mg), and DMPU (1.6 ml) was stirred at 70°C for 4 hours. After the reaction mixture was cooled to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-bromo-6-(fluoromethoxy)pyrazine. (Step 2) A mixed solution of 2-bromo-6-(fluoromethoxy)pyrazine (179 mg) in DMA (1.5 ml) and methanol (3 ml) was placed in a pressure tube, sodium acetate (124 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (28 mg) were added, and the mixture was stirred at 50°C for 18 hours under a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with water and ethyl acetate, insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain methyl 6-(fluoromethoxy)pyrazine-2-carboxylate. (Step 3) Sodium 6-(fluoromethoxy)pyrazine-2-carboxylate was obtained by the same method as in Example 30 (Step 2), except that methyl 6-(fluoromethoxy)pyrazine-2-carboxylate was used instead of methyl 4-(methylsulfonyl)picolinate used in Example 30 (Step 2).(Step 4) The title compound was obtained by the same method as in Example 13 (Step 3), except that 7-(4-(aminomethyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine was used instead of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine used in Example 13 (Step 3), and sodium 6-(fluoromethoxy)pyrazine-2-carboxylate was used instead of 5-methylpyrazine-2-carboxylic acid.

[0186] [Example 39] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)acetamide The title compound was obtained by the same method as in Example 1, except that acetic anhydride was used instead of benzoyl chloride used in Example 1.

[0187] [Example 40] 7-(4-((dimethylamino)methyl)bicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (Step 1) A mixture of (4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)methanol (30 mg), des-martin periodinane (47 mg), and dichloromethane (2.9 ml) obtained in Example 10 was stirred at room temperature for 10 minutes. The reaction mixture was diluted with an aqueous sodium thiosulfate solution and saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saline solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-carbaldehyde. (Step 2) 0.5 ml of methanol solution of 4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-carbaldehyde (5 mg) was added to 0.012 ml of 2 M dimethylamine THF solution. The reaction mixture was stirred at room temperature for 30 minutes, and then 0.07 ml of 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution was added. The reaction mixture was stirred at 40°C for 30 minutes, then purified and concentrated by basic silica gel column chromatography. The resulting residue was purified by reverse-phase HPLC to obtain the title compound.

[0188] [Example 41] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)furan-2-carboxamide The title compound was obtained by the same method as in Example 1, except that 2-furan carbonyl chloride was used instead of the benzoyl chloride used in Example 1.

[0189] [Example 42] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)imidazo[1,2-a]pyrazine-8-carboxamide The title compound was obtained by the same method as in Example 17, except that imidazo[1,2-a]pyrazine-8-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0190] [Example 43] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)isonicotinamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (9 mg) obtained in Production Example 1 in THF (0.5 ml), DIPEA (0.008 ml) and isonicotinic acid (42 mg) were added, and HATU (13 mg) was added. After stirring at room temperature for 30 minutes, dichloromethane (0.5 ml) was added, and after stirring overnight, the reaction mixture was concentrated. The obtained residue was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0191] [Example 44] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)isoxazole-5-carboxamide The title compound was obtained by the same method as in Example 1, except that isoxazole-5-carbonyl chloride was used instead of the benzoyl chloride used in Example 1.

[0192] [Example 45] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)nicotinamide The title compound was obtained by the same method as in Example 43, except that nicotinic acid was used instead of isonicotinic acid used in Example 43.

[0193] [Example 46] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide The title compound was obtained by the same method as in Example 17, except that oxazole-2-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0194] [Example 47] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-5-carboxamide The title compound was obtained by the same method as in Example 17, except that oxazole-5-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0195] [Example 48] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide The title compound was obtained by the same method as in Example 2, except that 2-pyrazinecarboxylic acid was used instead of pyrimidine-5-carboxylic acid used in Example 2.

[0196] [Example 49] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-3-carboxamide The title compound was obtained by the same method as in Example 17, except that pyridazine-3-carboxylic acid was used instead of 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylic acid used in Example 17.

[0197] [Example 50] 1-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-3-ethylurea The title compound was obtained by the same method as in Example 1, except that ethyl isocyanate was used instead of the benzoyl chloride used in Example 1.

[0198] [Example 51] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-2-carboxamide A mixed solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg), pyrimidine-2-carboxylic acid (2.5 mg), HATU (14.5 mg), and DIPEA (0.013 ml) in THF (1 ml) and DMF (0.01 ml) was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography to obtain the title compound.

[0199] [Example 52] 1-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-3-ethylthiourea The title compound was obtained by the same method as in Example 1, except that ethyl isothiocyanate was used instead of benzoyl chloride used in Example 1.

[0200] [Example 53] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)thiazole-2-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Preparation Example 1 in DMF (1 ml), DIPEA (0.004 ml) and thiazole-2-carboxylic acid (5 mg) were added, and WSC (4 mg) and HOBT (3 mg) were added. After stirring at 50°C for 1 hour, the reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0201] [Example 54] 6-Ethinyl-7-(4-(((2-fluoroethyl)amino)methyl)bicyclo[2.2.1]heptan-1-yl)-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine A mixed solution of 4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-carbaldehyde (7.7 mg), 2-fluoroethylamine hydrochloride (3.8 mg), and DIPEA (0.0066 ml) in methanol (0.5 ml) and THF (0.5 ml) obtained in Example 40 (Step 1) was stirred at room temperature for 30 minutes. 0.1 ml of a 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes, and then purified and concentrated by basic silica gel column chromatography. The resulting residue was purified by reverse-phase HPLC to obtain the title compound.

[0202] [Example 55] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.2]octan-1-yl)-2-(dimethylamino)acetamide To a solution of 7-(4-aminobicyclo[2.2.2]octan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (5 mg) obtained in Production Example 2 in DMF (1 ml), DIPEA (0.004 ml) and N,N-dimethylglycine (0.003 ml) were added, and WSC (4 mg) and HOBT (3 mg) were added. After stirring at 60°C for 2 hours, the reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0203] [Example 56] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.2]octan-1-yl)-6-methyl-2,6-diazaspiro[3.3]heptan-2-carbothioamide To a solution of 7-(4-aminobicyclo[2.2.2]octan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (10 mg) obtained in Production Example 2 in DMF (1 ml), DIPEA (0.013 ml) and 1,1'-thiocarbonyldiimidazole (9 mg) were added and stirred at room temperature for 30 minutes. Furthermore, 9 mg of 2-methyl-2,6-diazaspiro[3.3]heptane dihydrochloride was added, and the mixture was stirred at 60°C for 4 hours. The reaction mixture was purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0204] [Example 57] N-[4-(4-amino-6-ethynyl-5-quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)-1-bicyclo[2.2.1]heptan-1-yl]-N,5-dimethylpyrazine-2-carboxamide (Step 1) A mixture of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (100 mg) obtained in Example 37 and N,N-dimethylformamide dimethylacetal (1 ml) was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, diisopropyl ether (1 ml) was added, and the mixture was stirred at room temperature for 1 hour. The obtained solid was filtered and washed with diisopropyl ether to obtain crude (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide. (Step 2) A mixture of crude (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (10 mg) and THF (1 ml) obtained in Step 1 was mixed with iodomethane (0.02 ml) and an excess amount of sodium hydride, and stirred at room temperature for 15 minutes. DMF (0.2 ml) was added to the reaction mixture and stirred for a further 30 minutes. The reaction mixture was concentrated and purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0205] [Example 58] N-[4-(4-amino-6-ethynyl-5-quinoline-3-ylpyrrolo[2,3-d]pyrimidine-7-yl)-1-bicyclo[2.2.1]heptan-1-yl]-N-methyloxazole-2-carboxamide (Step 1) Instead of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide used in Example 57, N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide obtained in Example 46 Crude (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide was obtained by following the same method as in Example 57 (Step 1), except that chloro[2.2.1]heptan-1-yl)oxazole-2-carboxamide was used. (Step 2) To the mixture of crude (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide (7 mg) and THF (2 ml) obtained in Step 1, iodomethane (0.02 ml) and an excess amount of sodium hydride were added, and the mixture was stirred at room temperature for 15 minutes, then stirred at 50°C for 20 minutes. The reaction mixture was diluted with water and ethyl acetate, the organic layer was washed with water and saturated brine, and then dried and filtered over anhydrous sodium sulfate to concentrate the mixture. The obtained residue was purified by silica gel column chromatography to obtain (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-N-methyloxazole-2-carboxamide.(Step 3) A mixture of (E)-N-(4-(4-(((dimethylamino)methylene)amino)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-N-methyloxazole-2-carboxamide (7 mg) obtained in Step 2 above and 7 M ammonia methanol solution (1 ml) was stirred overnight at room temperature, and then stirred at 60°C for 4 hours. The reaction mixture was concentrated and purified by reverse-phase preparative HPLC (water:acetonitrile (0.1% formic acid)) to obtain the title compound.

[0206] [Example 59] Pyrazine-2-ylmethyl(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate 1,1'-carbonyldiimidazole (147 mg) was added to a solution of pyrazine-2-ylmethanol (100 mg) in THF (1 ml) and stirred at room temperature for 2 hours. 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (15 mg) obtained in Production Example 1 was added to the reaction mixture and stirred at 40°C for 12 hours. The reaction mixture was concentrated, and the resulting residue was purified by reverse-phase HPLC to obtain the title compound.

[0207] [Example 60] 2-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamoyl)pyridine-1-oxide To a DMSO (1 ml) solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (20 mg) obtained in Preparation Example 1, DIPEA (0.013 ml) and picolinic acid-N-oxide (7 mg) were added, and WSC (15 mg) and HOBT (12 mg) were added. After stirring at room temperature for 22 hours, the reaction mixture was purified by reverse-phase preparative HPLC to obtain the title compound.

[0208] [Example 61] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)morpholine-4-carboxamide To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (7.5 mg) obtained in Preparation Example 1 in THF (1 ml), DIPEA (0.03 ml) and tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (4.7 mg) were added and stirred at room temperature for 10 minutes. After concentrating the reaction mixture, it was purified by reverse-phase preparative HPLC to obtain the title compound.

[0209] [Example 62] (S)-N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)morpholine-2-carboxamide (Step 1) To a DMSO (2 ml) solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (60 mg) obtained in Production Example 1, DIPEA (0.04 ml), (S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (33 mg), and HATU (69 mg) were added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl(S)-2-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamoyl)morpholine-4-carboxylate. (Step 2) To the tert-butyl (S)-2-((4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamoyl)morpholine-4-carboxylate (87 mg) obtained in Step 1, chloroform (1 ml) and trifluoroacetic acid (0.5 ml) were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by basic silica gel column chromatography to obtain the title compound.

[0210] [Example 63] (S)-N-(4-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-4-methylmorpholine-2-carboxamide To a mixture of (S)-N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-4-methylmorpholine-2-carboxamide (72 mg), THF (2 ml), and 37% formaldehyde aqueous solution (0.05 ml) obtained in Example 63, 0.5 M sodium borohydride-0.25 M zinc chloride methanol solution (0.5 ml) was added and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by basic silica gel column chromatography to obtain the title compound.

[0211] [Example 64] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)imidazo[1,2-a]pyridine-3-carboxamide The title compound was obtained by the same method as in Example 16, except that imidazo[1,2-a]pyridine-3-carboxylic acid was used instead of [1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid used in Example 16.

[0212] [Example 65] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)imidazo[1,2-a]pyrazine-3-carboxamide The title compound was obtained by following the same method as in Example 13 (Step 3), except that imidazo[1,2-a]pyrazine-3-carboxylic acid was used instead of 1-methyl-1H-pyrazole-5-carboxylic acid used in Example 13 (Step 3).

[0213] [Example 66] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(hydroxymethyl)pyrazine-2-carboxamide (Step 1) Molecular sieve 3A (0.1 g), methyl orthoformate (0.26 ml), and p-toluenesulfonic acid monohydrate (0.23 g) were added to a methanol (1.0 ml) solution of methyl 5-formylpyrazinecarboxylate and stirred overnight at 70°C. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to obtain methyl 5-(dimethoxymethyl)pyrazinecarboxylate. (Step 2) To a mixed solvent of methyl 5-(dimethoxymethyl)pyrazinecarboxylate (0.26 g) obtained in Step 1 above, 2.4 ml of 0.5 M aqueous sodium hydroxide solution was added at 0°C and stirred for 1 hour. Sodium 5-(dimethoxymethyl)pyrazinecarboxylate was obtained by concentrating the reaction mixture. (Step 3) To a solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (200 mg) obtained in Production Example 1 in DMSO (5.1 ml), 0.26 ml of DIPEA, sodium 5-(dimethoxymethyl)pyrazinecarboxylate (0.11 g) obtained in Step 2 above, and 0.29 g of HATU were added and stirred at room temperature for 1 hour. Water (10 ml) was added to the reaction mixture and stirred at room temperature for 1 hour, after which the solid was filtered off. The obtained solid was suspended in a mixed solvent of ethyl acetate (4 ml) and methanol (4 ml) and stirred at room temperature for 1 hour. The solid was filtered off and washed with methanol to obtain N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethoxymethyl)pyrazine-2-carboxamide.(Step 4) To a solution of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethoxymethyl)pyrazine-2-carboxamide (0.33 g) obtained in Step 3 above, trifluoroacetic acid (3.3 ml) and water (1.6 ml) were added, and the mixture was stirred overnight at 60°C. The reaction mixture was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate-THF (1:1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to obtain crude N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-formylpyrazine-2-carboxamide. (Step 5) To a mixed solution of crude N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-formylpyrazine-2-carboxamide (10 mg) obtained in Step 4 above, with THF (1 ml) and methanol (1 ml), sodium borohydride (1.4 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by reverse-phase preparative HPLC to obtain the title compound.

[0214] [Example 67] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-((methylamino)methyl)pyrazine-2-carboxamide Crude N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-formylpyrazine-2-carboxamide (10 mg) obtained in Example 66 (Step 4) was mixed with THF (0.5 ml) and methanol (0.5 ml) to which 2 M methylamine methanol solution (0.03 ml) was added and stirred at room temperature for 30 minutes. 0.1 ml of 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution was added to the reaction mixture and the mixture was stirred at room temperature for 1.5 hours. 0.03 ml of 2 M methylamine methanol solution was then added to the reaction mixture, and after 30 minutes, 0.1 ml of 0.5 M sodium cyanoborohydride-0.25 M zinc chloride methanol solution was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by reverse-phase preparative HPLC to obtain the title compound.

[0215] [Example 68] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-((dimethylamino)methyl)pyrazine-2-carboxamide The title compound was obtained by following the same method as in Example 67, except that dimethylamine hydrochloride was used instead of the 2M methylamine methanol solution used in Example 67, and DIPEA (0.06 ml) was added.

[0216] [Example 69] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(morpholinomethyl)pyrazine-2-carboxamide The title compound was obtained by the same method as in Example 67, except that morpholine was used instead of the 2M methylamine methanol solution used in Example 67.

[0217] [Example 70] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-(dimethylphosphoryl)picolinamide (Step 1) To a solution of methyl 6-bromonicotinate (0.05 g) in 1,4-dioxane (1 ml), tripotassium phosphate (0.15 g), dimethylphosphine oxide (0.036 ml), and nickel(II) 1,3-bis(diphenylphosphino)propane chloride (0.013 g) were added and stirred at 120°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography to obtain methyl 5-(dimethylphosphoryl)picolinate. (Step 2) To a solution of methyl 5-(dimethylphosphoryl)picolinate (0.019 g) obtained in Step 1 above in THF (0.5 ml) and methanol (0.5 ml), 1N sodium hydroxide aqueous solution (0.5 ml) was added and stirred at room temperature for 2 hours. 1N hydrochloric acid (0.5 ml) was added to the reaction mixture and concentrated to obtain crude 5-(dimethylphosphoryl)picolinic acid. (Step 3) The title compound was obtained by following the same method as in Example 13 (Step 3), except that crude 5-(dimethylphosphoryl)picolinic acid obtained in Step 2 above was used instead of 1-methyl-1H-pyrazole-5-carboxylic acid used in Example 13 (Step 3).

[0218] The chemical structural formulas and physical properties of the compounds in Examples 1 to 70 are shown in Table 1 below.

[0219] Comparative Example A (R)-1-(3-(4-amino-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)pyrroridine-1-yl)propa-2-en-1-one

[0220] Comparative Example B (R)-1-(3-(4-amino-6-ethinyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)pyrrolidine-1-yl)propa-2-en-1-one The image was synthesized in accordance with the method described in the international publication WO2013 / 118817.

[0221] Test Examples The compounds of the above examples and comparative examples were evaluated using the following test methods. Test Example 1 Various EGFR kinase activity inhibitory activity tests (in vitro) 1) Measurement of EGFR (d746-750 / T790M / C797S) kinase inhibitory activity The inhibitory activity of the compounds of the above examples and comparative examples against EGFR (d746-750 / T790M / C797S) kinase activity was measured. Of the materials used for this inhibitory activity measurement, the kinase protein used was obtained by expressing the cytoplasmic domain of human EGFR (d746-750 / T790M / C797S) with a glutathione-S-transferase (GST) tag fused to the amino terminus in insect cells Sf9 using a baculovirus expression system, and purifying it using a glutathione Sepharose column (SEQ ID NO: 1). As a substrate peptide, we synthesized a peptide with biotinylated N-terminants (biotin-EEPLYWSFPAKKK) based on PerkinElmer's LabChip® series reagent FL-Peptide 22.

[0222] The method for measuring inhibitory activity is as follows. First, each compound of the present invention was dissolved in dimethyl sulfoxide (DMSO), and then serial dilutions were prepared with DMSO. Next, the serial dilution solution of the compound (final concentration of DMSO at the time of the kinase reaction was 2.5%) or DMSO (final concentration was 2.5%) was mixed with a solution containing substrate peptide (final concentration 250 nM), magnesium chloride (final concentration 10 mM), manganese chloride (final concentration 10 mM), and ATP (final concentration 6 μM) in a kinase reaction buffer (Karna BioScience Co., Ltd.). Then, the EGFR (d746-750 / T790M / C797S) protein was added, and the mixture was incubated at 25°C for 120 minutes to carry out the kinase reaction. Next, EDTA was added to stop the reaction to a final concentration of 24 mM. A phosphorylated tyrosine detection solution containing europium-labeled antiphosphorylated tyrosine antibody PT66 (Perkin-Elmer) and SureLight APC-SA (Perkin-Elmer) was added, and the mixture was allowed to stand at room temperature for at least 2 hours. As background, DMSO was used instead of the compound's DMSO solution, and EDTA was added before the addition of EGFR (d746-750 / T790M / C797S) protein, followed by incubation at 25°C for 120 minutes. The detection solution was also added to this mixture and allowed to stand for at least 2 hours. Finally, for all the test samples, the fluorescence intensity upon excitation with 337 nm was measured at two wavelengths, 620 nm and 665 nm, using a PHERAstar FS (BMG LABTECH), and the ratio of the fluorescence intensity at the two wavelengths was obtained as data.

[0223] In the analysis of the measurement data, the fluorescence intensity ratio data for samples in which a kinase reaction was performed by adding DMSO at a final concentration of 2.5% was defined as a phosphorylation inhibition rate of 0%, and the fluorescence intensity ratio data in the background was defined as a phosphorylation inhibition rate of 100%. The compound concentration that inhibits the phosphorylation reaction by EGFR (d746-750 / T790M / C797S) by 50% was defined as the IC50 value (nM).

[0224] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0225] The measurement data is shown in Table 2.

[0226] 2) Measurement of EGFR (L858R / T790M / C797S) kinase inhibitory activity The inhibitory activity of the compound of the present invention against EGFR (L858R / T790M / C797S) kinase activity was measured.

[0227] The materials used, measurement methods, and data analysis methods are almost the same as those described in the section on the measurement of EGFR (d746-750 / T790M / C797S) kinase inhibitory activity. However, among the materials, the kinase protein used was obtained by expressing the cytoplasmic domain of human EGFR (L858R / T790M / C797S) with a GST tag fused to the amino terminus in insect cells Sf9 using a baculovirus expression system, and purifying it using a glutathione Sepharose column (SEQ ID NO: 2). In the measurement method, the final concentration of ATP was set to 0.5 μM. Finally, the IC50 value (nM) of each compound against EGFR (L858R / T790M / C797S) was determined by data analysis.

[0228] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0229] The measurement data is shown in Table 3.

[0230] 3) Measurement of EGFR (d746-750 / C797S) kinase inhibitory activity The inhibitory activity of the compounds of the present invention against EGFR (d746-750 / C797S) kinase activity was measured.

[0231] The materials used, measurement methods, and data analysis methods were almost the same as those described in the section on the measurement of EGFR (d746-750 / T790M / C797S) kinase inhibitory activity. However, among the materials, the kinase protein used was purified recombinant human EGFR (d746-750 / C797S) protein purchased from SignalChem, and the kinase reaction buffer used was 13.5 mM Tris (pH 7.5), 2 mM dithiothreitol, and 0.009% Tween-20. In the measurement method, the final concentration of ATP was 14 μM, the final concentration of magnesium chloride was 20 mM, the final concentration of manganese chloride was 12.5 mM, the kinase reaction incubation was 60 minutes, and the final concentration of EDTA used to stop the kinase reaction was 40 mM. Finally, the IC50 value (nM) for each compound's EGFR (d746-750 / C797S) was determined through data analysis.

[0232] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0233] The measurement data is shown in Table 4.

[0234] 4) Measurement of EGFR (L858R / C797S) kinase inhibitory activity The inhibitory activity of the compound of the present invention against EGFR (L858R / C797S) kinase activity was measured.

[0235] The materials used, measurement methods, and data analysis methods were almost the same as those described in the section on EGFR (d746-750 / C797S) kinase inhibitory activity measurement. However, among the materials, purified recombinant human EGFR (C797S / L858R) protein purchased from SignalChem was used as the kinase protein, and the final ATP concentration in the measurement method was 4 μM, with a kinase reaction incubation period of 90 minutes. Finally, the IC50 value (nM) for each compound against EGFR (L858R / C797S) was determined by data analysis.

[0236] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0237] The measurement data is shown in Table 5.

[0238] 5) EGFR(WT) The inhibitory activity of the compounds of the present invention against EGFR(WT) kinase activity was measured.

[0239] The materials used, measurement methods, and data analysis methods were almost the same as those described in the section on EGFR (d746-750 / T790M / C797S) kinase inhibitory activity measurement. However, among the materials, purified recombinant human EGFR (WT) purchased from Carnabioscience was used as the kinase protein, and the final concentration of ATP in the measurement method was set to 1.5 μM. Finally, the IC50 value (nM) for each compound against EGFR (WT) was determined by data analysis.

[0240] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0241] The measurement data is shown in Table 6.

[0242] From the results of Test Example 1, 1) to 5), it was confirmed that the compound of the present invention exhibits potent inhibitory activity against not only EGFR (d746-750 / C797S) and EGFR (L858R / C797S), but also EGFR (d746-750 / T790M / C797S) and EGFR (L858R / T790M / C797S) compared to known compounds. Furthermore, comparison with Comparative Examples A and B revealed that the presence of an alkyne at position 6 and a bicyclocyclic ring structure at position 7 significantly affects the inhibitory activity. Such differences in activity due to substituents have never been clarified before, making this a surprising finding.

[0243] Test Example 2 Growth inhibitory activity test (in vitro) against wild-type and mutant EGFR-expressing cell lines (1) Mouse cell lines Ba / F3-EGFR(d746-750 / T790M / C797S) that have been transfected with EGFR(d746-750 / T790M / C797S) and stably expressing EGFR(L858R / T790M / C797S) and mouse cell lines Ba / F3-EGFR(L858R / T790M / C797S) that have been transfected with EGFR(L858R / T790M / C797S) and mouse cell line Ba / F3-EGFR(WT) that have been transfected with wild-type EGFR and stably expressing it were each suspended in RPMI-1640 cell culture medium (RPMI-1640, 10% FBS, penicillin 100 units / ml, streptomycin 0.1 mg / ml). The mouse cell line Ba / F3-EGFR(WT) was suspended in RPMI-1640 cell medium containing a final EGF concentration of 50 ng / ml. The mouse cell lines Ba / F3-EGFR(d746-750 / T790M / C797S), Ba / F3-EGFR(L858R / T790M / C797S), and Ba / F3-EGFR(WT), which stably expresses EGFR (d746-750 / T790M / C797S), were prepared using the nucleotide sequences encoding the proteins of SEQ ID NO: 1 and SEQ ID NO: 2, in accordance with Test Example 1 in WO2018 / 079310. Cell suspensions were seeded into each well of a 96-well flat-bottom plate. The compound of the present invention was dissolved in DMSO, and serial dilutions of the test compound were prepared using DMSO (1000 times the final concentration). The DMSO solution of the test compound or DMSO was diluted with RPMI-1640 cell culture medium for each cell, and this was added to each well of the cell culture plate to a final DMSO concentration of 0.1%, and the cells were cultured in a 5% carbon dioxide incubator at 37°C for 3 days. The number of cells before and after the addition of the DMSO solution of the test compound was measured using CellTiter-Glo® (Promega Corporation) according to the protocol recommended by Promega Corporation.

[0244] For each cell, the cell proliferation inhibition rate in wells to which the test compound was added at various concentrations was calculated using the following formula. Then, the inhibition rate at each concentration for each test compound was plotted, and the IC50 (nM) concentration of the test compound at which cell viability reached 50% was determined using curve fitting software XLfit (IDBS). Cell viability (%) = T / C x 100 T: Luminescence intensity of wells cultured for 3 days with test compound solution C: Luminescence intensity of wells cultured for 3 days with DMSO

[0245] In addition, Comparative Examples A (Example 3 in WO2013 / 118817) and B (Example 35 in WO2013 / 118817), which have the following known EGFR inhibitory activity, were used as control compounds.

[0246] These results are shown in Table 7.

[0247] The compounds of the present invention showed a weak growth inhibitory effect on wild-type EGFR-expressing cell lines. In contrast, they were shown to have a strong growth inhibitory effect on EGFR (d746-750 / T790M / C797S)-expressing cell lines and EGFR (L858R / T790M / C797S)-expressing cell lines. From these results, it became clear that the compounds of the present invention selectively exhibit growth inhibitory activity against mutant EGFR-expressing cell lines.

[0248] Test Example 3: Inhibitory Effect Tests of Various EGFR Kinases (in vitro) 1) Measurement of EGFR (d746-750 / T790M / C797S) Kinase Inhibitory Activity The inhibitory activity of the compounds in the above examples against EGFR (d746-750 / T790M / C797S) kinase activity was measured using the same procedure as in 1) of Test Example 1. The measurement data is shown in Table 8.

[0249] 2) Measurement of EGFR (L858R / T790M / C797S) kinase inhibitory activity The inhibitory activity of the compound of the present invention against EGFR (L858R / T790M / C797S) kinase activity was measured using the same procedure as in 2) of Test Example 1. The measurement data is shown in Table 9.

[0250] 3) Measurement of EGFR(d746-750 / C797S) kinase inhibitory activity The inhibitory activity of the compound of the present invention against EGFR(d746-750 / C797S) kinase activity was measured using the same procedure as in 3) of Test Example 1. The measurement data is shown in Table 10.

[0251] 4) Measurement of EGFR(L858R / C797S) kinase inhibitory activity The inhibitory activity of the compound of the present invention against EGFR(L858R / C797S) kinase activity was measured using the same procedure as in 4) of Test Example 1. The measurement data is shown in Table 11.

[0252] 5) EGFR(WT) The inhibitory activity of the compound of the present invention against EGFR(WT) kinase activity was measured using the same procedure as in 5) of Test Example 1. The measurement data is shown in Table 12.

[0253] From the results of Test Example 2, 1) to 5), it was confirmed that the compound of the present invention has potent inhibitory activity not only against EGFR (d746-750 / C797S) and EGFR (L858R / C797S), but also against EGFR (d746-750 / T790M / C797S) and EGFR (L858R / T790M / C797S).

[0254] Test Example 4: Growth Inhibitory Activity Test against Wild-Type and Mutant EGFR-Expressing Cell Lines (in vitro) The growth inhibitory activity of the compound of the present invention against wild-type and mutant EGFR-expressing cell lines was tested using the same procedure as in Test Example 2. The measurement data is shown in Table 13.

[0255] The compounds of the present invention showed a weak growth inhibitory effect on wild-type EGFR-expressing cell lines. In contrast, they were shown to have a strong growth inhibitory effect on EGFR (d746-750 / T790M / C797S)-expressing cell lines and EGFR (L858R / T790M / C797S)-expressing cell lines. From these results, it became clear that the compounds of the present invention selectively exhibit growth inhibitory activity against mutant EGFR-expressing cell lines.

[0256] Sequence: EGFR d746-750 / TT790M / C797S (Sequence Number 1) EGFR L858R / TN98M / CN97S(Sequence No. 2)

[0257] SEQ ID NOs: 1 and 2: Synthetic Proteins

Claims

1. A compound represented by the following general formula (I): [In the formula, R １ is a hydrogen atom or an optionally substituted C1-C3 alkyl group, and X is NR ２ R ３ , OR ４ or a monocyclic or polycyclic saturated or unsaturated heterocyclic group which may have a substituent, R ２ is a hydrogen atom or an optionally substituted C1-C6 alkyl group, R ３ is a hydrogen atom, C(=O)R ５ , C(=S) R ６ , S(=O) ２ R ７ , an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C7 cycloalkyl group, R ４ is a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, or an optionally substituted carbonylamino group, and R ５ is an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 cycloalkyl group, an optionally substituted C1-C6 alkoxy group, an optionally substituted amino group, an optionally substituted 4-10-membered monocyclic or polycyclic saturated heterocyclic group, an optionally substituted 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group, or an optionally substituted 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group, and R ６ is a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 mono- or di-alkylamino group, an optionally substituted C3-C7 cycloalkyl group, or an optionally substituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, ７ is a C1-C6 alkyl group which may have substituents, a C3-C7 cycloalkyl group which may have substituents, a 5-10 membered saturated or unsaturated heterocyclic group which may have substituents, or a 6-10 membered aromatic hydrocarbon group which may have substituents, ring A is bicyclo[2.2.1]heptane or bicyclo[2.2.2]octane, and n is an integer of 0 to 3, or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom or a C1-C3 alkyl group.

3. X is NR ２ R ３ , OR ４ or a 5- to 7-membered monocyclic saturated or unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, ２ is a hydrogen atom or a C1-C6 alkyl group, and R ３ But C(=O)R ５ , C(=S)R ６ or a C1-C6 alkyl group (which may have, as a substituent, a cyano group, a halogen atom, or a 5- to 7-membered monocyclic unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom), ４ is a hydrogen atom, and R ５ is an optionally substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 mono- or di-alkylamino group, an optionally substituted 5-10-membered monocyclic or polycyclic unsaturated heterocyclic group, or a 6-10-membered monocyclic or polycyclic aromatic hydrocarbon group, and R ６ is a 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, which optionally has a C1-C6 mono- or dialkylamino group, or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

5. R １ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

6. X is NR ２ R ３ or a 5- to 7-membered monocyclic saturated or unsaturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, ２ is a hydrogen atom, and R ３ But C(=O)R ５ and R ５ is an optionally substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 mono- or di-alkylamino group, an optionally substituted 5- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group, or a 6- to 10-membered monocyclic or polycyclic aromatic hydrocarbon group, or a pharmaceutically acceptable salt thereof.

7. X is NR ２ R ３ or a 5- to 7-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, ２ is a hydrogen atom, and R ３ But C(=O)R ５ and R ５ is a C1-C6 alkyl group optionally having a halogen atom, or a 5-10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and optionally having a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring A is bicyclo[2.2.1]heptane.

9. The compound according to any one of claims 1 to 8, wherein n is 0, or a pharmaceutically acceptable salt thereof.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the substituent is selected from a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, an alkyl group, a haloalkyl group, a cycloalkyl group, an aralkyl group, an alkoxy group, a methylsulfonyl group, an alkoxyalkyl group, a hydroxyalkyl group, a fluoromethoxy group, a mono- or dialkylamino group, a mono- or dialkylaminoalkyl group, a carbonylamino group, an oxo group, an oxide group, a carboxyl group, an alkoxycarbonyl group, a phosphine oxide group, a saturated or unsaturated heterocyclic group, a heterocyclic alkyl group, and an aromatic hydrocarbon group.

11. The following compounds: (1) 6-ethynyl-7-(4-morpholinobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (3) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-2,2-difluoroacetamide (4) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methyl-1,2,4-oxadiazole-3-carboxamide (5) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (6) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)oxazole-2-carboxamide (7) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide (8) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)pyridazine-3-carboxamide (9) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)pyrimidine-5-carboxamide (10) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,(11) N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-1-cyclopropyl-1H-pyrazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

12. An antitumor agent comprising, as an active ingredient, the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. A method for treating a tumor, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

15. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for treating tumors.

16. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent.