Quinazoline compounds for inducing degradation of G12D mutant KRAS protein

Abstract

Provided is a compound useful as an active ingredient in a pharmaceutical composition for treating pancreatic cancer. [Solution] The present inventors have investigated compounds useful as active ingredients in pharmaceutical compositions for treating pancreatic cancer and have found that quinazoline compounds have excellent effects of inducing degradation of G12D mutant KRAS protein and inhibiting G12D mutant KRAS, and can be used as therapeutic agents for pancreatic cancer, thereby completing the present invention. The quinazoline compounds of the present invention or salts thereof can be used as therapeutic agents for pancreatic cancer.

Description

[Technical Field]

[0001] The present invention relates to a quinazoline compound that exhibits excellent activity in inducing the degradation of G12D mutant KRAS protein, is useful as a G12D mutant KRAS inhibitor, and is expected to be useful, for example, as an active ingredient in a pharmaceutical composition for the treatment of pancreatic cancer. [Background technology]

[0002] Pancreatic cancer, primarily ductal adenocarcinoma, has a very poor prognosis, with a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, p.7-30), and approximately 460,000 new cases are reported worldwide each year (CA Cancer J. Clin., 2018, 68, p.394-424). The most effective treatment for pancreatic cancer is surgery, but because early detection is difficult, metastasis is common, and surgical treatment is often ineffective. If surgery is not performed, chemotherapy or radiation therapy are used, but the survival rate is not good. Currently, FOLFRINOX therapy (a multi-drug combination therapy consisting of three chemotherapy agents—5-FU, irinotecan, and oxaliplatin—plus levofolinate) is used as the standard treatment for pancreatic cancer. However, due to its high toxicity, patient selection must be careful, with prescriptions limited to patients with an ECOG Performance Status of 1 or less (J. Clin. Oncol., 2018, 36, p.2545-2556). As a molecularly targeted therapy, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved in combination with gemcitabine, but the extension of overall survival is only about two weeks compared to gemcitabine alone, and satisfactory therapeutic effects have not been achieved, so there is still a need for more effective treatments (J. Clin. Oncol., 2007, 25, p.1960-1966).

[0003] RAS proteins are low-molecular-weight guanosine triphosphate (GTP)-binding proteins with a molecular weight of approximately 21 kDa, consisting of 188-189 amino acids. There are four main types of RAS proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) arising from three genes: KRAS, NRAS, and HRAS. RAS proteins exist in both an active GTP-binding form and an inactive GDP-binding form. RAS proteins are activated by ligand stimulation of cell membrane receptors such as EGFR, which leads to the exchange of guanosine diphosphate (GDP) and GTP. Active RAS binds to up to 20 effector proteins, including RAF, PI3K, and RALGDS, activating downstream signaling cascades. On the other hand, active RAS becomes inactive by converting GTP to GDP through endogenous GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). Therefore, RAS plays a crucial role as an important "molecular switch" in intracellular signaling pathways such as EGFR, and is essential in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, p.761-774, Nature Rev. Drug Discov., 2014, 13, p.828-851, Nature Rev. Drug Discov., 2016, 15, p.771-785).

[0004] When amino acid substitutions occur due to mutations in the RAS gene, the function of RAS as a GTPase is impaired and its response to GAP decreases, leading to a constitutively activated state that continuously sends signals downstream. This excessive signaling leads to carcinogenesis and accelerated cancer growth. Pancreatic ductal adenocarcinoma is thought to develop from a weak to a strong stage of atypical lesions in pancreatic intraepithelial neoplasia (PanIN), and KRAS gene mutations are already observed in the early stages of PanIN. Subsequently, abnormalities occur in tumor suppressor genes such as INK4A, p53, and SMAD4, leading to malignancy (Nature Rev. Cancer, 2010, 10, p.683-695). Furthermore, mutations in the KRAS gene are found in more than 90% of pancreatic ductal adenocarcinomas, with the vast majority being point mutations at codon 12 located in KRAS exon 2 (Cancer Cell 2017, 32, p.185-203). This suggests that KRAS plays a crucial role in the carcinogenesis and development of pancreatic cancer.

[0005] KRAS gene mutations include KRAS G12C mutations and KRAS G12D mutations. While G12C mutations in KRAS are frequent in non-small cell lung cancer, they occur in only a few percent of pancreatic cancers (Cancer Cell 2014, 25, p.272-281), highlighting the need for therapeutic agents targeting other KRAS mutations. G12D mutations in KRAS are found in approximately 34% of pancreatic cancers, making them the most common type of KRAS mutation (Nat. Rev. Cancer, 2018, 18, p.767-777).

[0006] Patent documents 1, 2, and 3 disclose RAS inhibitors, and compounds represented by the following formulas (A) and (B) are disclosed in patent documents 2 and 3, respectively. Patent documents 1, 2, and 3 state that these inhibitors are useful for cancers in which a mutation at codon 12 of KRAS is present, and one of these is the G12D mutation, but their effects on G12D mutation KRAS cancer are not described. [ka] (A) TIFF0007851842000002.tif4161(B) (For the meaning of the symbols in the formula, please refer to the relevant publication.)

[0007] Furthermore, KRAS G12D inhibitors are disclosed in Patent Documents 9, 10, and 11.

[0008] In recent years, bifunctional compounds, collectively known as PROTACs (PROteolysis-Targeting Chimeras) and SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers), have been discovered as technologies for inducing the degradation of target proteins, and are expected to be one of the novel drug discovery modalities (Drug. Discov. Today Technol., 2019, 31, p15-27). Bifunctional compounds promote the formation of a complex between the target protein and E3 ligase within the cell, and degradation of the target protein is induced by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms within cells. A protein called E3 ligase recognizes the protein to be degraded and performs ubiquitination, which then leads to degradation by the proteasome.

[0009] There are over 600 types of E3 ligases in the body, which can be broadly classified into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, only a limited number of E3 ligases are used in bifunctional degradation inducers such as PROTAC and SNIPER, with representative examples including Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). In particular, VHL is reported in Patent Document 4, and CRBN is reported in Patent Document 5.

[0010] Bifunctional compounds are compounds in which a ligand for a target protein and a ligand for an E3 ligase are linked by a linker, and bifunctional compounds that degrade the KRAS protein have been reported to date (Non-Patent Documents 1, 2, 6, 7, 8, and 12). However, to date, there have been no reports of bifunctional compounds targeting the G12D mutant KRAS. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] International Publication No. 2016 / 049565 [Patent Document 2] International Publication No. 2016 / 049568 [Patent Document 3] International Publication No. 2017 / 172979 [Patent Document 4] International Publication No. 2013 / 106643 [Patent Document 5] International Publication No. 2015 / 160845 [Patent Document 6] U.S. Patent Application Publication No. 2018 / 0015087 [Patent Document 7] International Publication No. 2019 / 195609 [Patent Document 8] International Publication No. 2020 / 018788 [Patent Document 9] International Publication No. 2021 / 041671 [Patent Document 10] International Publication No. 2021 / 106231 [Patent Document 11] International Publication No. 2021 / 107160 [Patent Document 12] International Publication No. 2021 / 051034 [Non-patent literature]

[0012] [Non-Patent Document 1] Cell. Chem. Biol., 2020, 27, p19-31 [Non-Patent Document 2] ACS Cent. Sci., 2020, 6, p1367-1375 [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] This invention provides a quinazoline compound that is excellent in inducing the degradation of pharmaceutical compositions, such as the G12D mutant KRAS protein, and is useful as a G12D mutant KRAS inhibitor. It is also expected to be useful as an active ingredient in pharmaceutical compositions for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer. [Means for solving the problem]

[0014] The present inventors diligently studied compounds useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer and, as a result, discovered that quinazoline compounds of formula (I), particularly bifunctional compounds of formula (I) characterized by linking a substituent at the 8th position of quinazoline to a ligand of E3 ligase, or linking a substituent at the 8th position of quinazoline to a ligand of E3 ligase with a linker, have excellent activity in inducing the degradation of G12D mutant KRAS protein and inhibiting G12D mutant KRAS, thus completing the present invention. In other words, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients. [ka] (In the formula, R 1 This is a naphthyl group which may be substituted with OH, or a group selected from the group consisting of the following formulas (II) and (III). [ka] R 1a , R 1b These are H, methyl, F, or Cl, which are the same or different from each other. R 1c is F, Cl, methyl or ethyl, R 2 is H, halogen, optionally substituted C 1-3 alkyl, cyclopropyl, or vinyl, R 3 is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms, R 4 is optionally substituted C 1-6 alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms, R 5 is optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 heteroatom selected from oxygen, sulfur and nitrogen, R 6a R 6b are the same or different from each other and are H or optionally substituted C 1-6 alkyl, or R 6a R 6b together with the carbon to which they are attached form an optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4- to 6-membered saturated heterocyclic ring containing 1 heteroatom selected from oxygen, sulfur and nitrogen, R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 6-membered heteroaryl containing 1 to 3 nitrogen atoms, W is an optionally substituted six-membered heteroaryl containing 1 to 3 optionally substituted phenyl or nitrogen atoms. X is a bond, CH2, O, S, or NR 4x And, R 4x is H or C 1-3 It is alkyl, Y is phenylene or pyridinediyl, and the phenylene may be substituted with F. L is -(L 1 -L 2 -L 3 -L 4 )- and, L 1 , L 2 , L 3 , L 4 These are identical or different from each other, combined, O, NR L1 , pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C which may be substituted 1-3 A group selected from the group consisting of alkylenes and C=O, R L1 is H or C 1-3 It is alkyl, Z is a 5-membered heteroarenediyl containing 1 to 4 heteroatoms selected from NH or oxygen, sulfur, and nitrogen. Alternatively, YLZ is given by the following equation (XIII). [ka]

[0015] Furthermore, the present invention relates to a compound of formula (Ib) or a salt thereof, and a pharmaceutical composition containing a compound of formula (Ib) or a salt thereof, and one or more pharmaceutically acceptable excipients. The compound of formula (Ib) is encompassed by the compound of formula (I). [ka] (In the formula, R 1 This is the following equation (IIa) or equation (IIIa): [ka] R 1a , R 1b They are the same or different from each other, and are H or F. R 2 is halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 This is given by the following equation (IV): [ka] R 4 C 1-3 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 It is a cycloalkyl, R 6a , R 6b C may be substituted with the same or different groups selected from the group consisting of H or F, OH and N(CH3)2. 1-3 It is alkyl, or R 6a , R 6b These, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R 7 This is H, a halogen, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), and (IX): [ka] R 7a C may be substituted with H or OH. 1-3 It is alkyl, X is O, Y is phenylene or pyridinediyl. L is bond, C 1-3Alkylene, or C=O, Z is a group selected from NH or the group consisting of the following formulas (X), (XI), and (XII): [ka] Alternatively, YLZ is given by the following equation (XIII). [ka]

[0016] Unless otherwise specified, if a symbol in a chemical formula is used in another chemical formula within this specification, the same symbol shall have the same meaning.

[0017] Furthermore, the present invention relates to a pharmaceutical composition containing a compound of formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients, in particular a pharmaceutical composition for the treatment of pancreatic cancer, in particular a pharmaceutical composition for the treatment of G12D-mutated KRAS-positive pancreatic cancer, in particular a pharmaceutical composition for the treatment of metastatic pancreatic cancer, in particular a pharmaceutical composition for the treatment of locally advanced pancreatic cancer, in particular a pharmaceutical composition for the treatment of recurrent or refractory pancreatic cancer, in particular a pharmaceutical composition for the treatment of pancreatic cancer in patients who have not been treated and / or have been treated, in particular a pharmaceutical composition for the treatment of metastatic G12D-mutated KRAS-positive pancreatic cancer, in particular a pharmaceutical composition for the treatment of locally advanced G12D-mutated KRAS-positive pancreatic cancer, in particular a pharmaceutical composition for the treatment of recurrent or refractory G12D-mutated KRAS-positive pancreatic cancer, and in particular a pharmaceutical composition for the treatment of G12D-mutated KRAS-positive pancreatic cancer in patients who have not been treated and / or have been treated. Furthermore, the pharmaceutical composition includes a therapeutic agent for pancreatic cancer, particularly G12D mutation-positive pancreatic cancer, that contains the compound of formula (I) or a salt thereof. Furthermore, the present invention relates to pancreatic cancer, in particular G12D-mutated KRAS-positive pancreatic cancer, in particular metastatic pancreatic cancer, in particular locally advanced pancreatic cancer, in particular recurrent or refractory pancreatic cancer, in particular pancreatic cancer in untreated and / or previously treated patients, in particular metastatic G12D-mutated KRAS-positive pancreatic cancer, in particular locally advanced G12D-mutated KRAS-positive pancreatic cancer, in particular recurrent or refractory G12D-mutated KRAS-positive pancreatic cancer, in particular G12D-mutated KRAS in untreated and / or previously treated patients The present invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of positive pancreatic cancer, the use of a compound of formula (I) or a salt thereof for the treatment of pancreatic cancer, in particular G12D mutation KRAS-positive pancreatic cancer, a compound of formula (I) or a salt thereof for use in the treatment of pancreatic cancer, in particular G12D mutation KRAS-positive pancreatic cancer, and a method for treating pancreatic cancer, in particular G12D mutation KRAS-positive pancreatic cancer, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a target. The present invention also relates to a compound of formula (I) or a salt thereof that is a G12D mutant KRAS proteolytic agent and / or a G12D mutant KRAS inhibitor, a compound of formula (I) or a salt thereof for use as a G12D mutant KRAS proteolytic agent and / or a G12D mutant KRAS inhibitor, and a G12D mutant KRAS proteolytic agent and / or a G12D mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof. Furthermore, "target" refers to a human or other animal that requires treatment, and in some cases, a human who requires prevention or treatment. [Effects of the Invention]

[0018] The compound of formula (I) or a salt thereof has the effect of inducing the degradation of the G12D mutant KRAS protein and has G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, in particular G12D mutant KRAS-positive pancreatic cancer. [Modes for carrying out the invention]

[0019] The present invention will be described in detail below.

[0020] In this specification, "may be substituted" means unsubstituted or having one to five substituents. In some embodiments, this means unsubstituted or having one to three substituents. If there are multiple substituents, they may be identical or different from one another.

[0021] "C 1-12 "Alkyl" refers to linear or branched alkyl groups with 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (Hereafter, the number of carbon atoms will be expressed similarly). In one embodiment, it is ethyl or dodecyl, and in another embodiment, C 1-6 Alkyl, in some embodiments methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, in some embodiments methyl, ethyl, n-propyl, isopropyl or sec-butyl, in some embodiments methyl, ethyl, isopropyl or tert-butyl, in some embodiments methyl, ethyl, n-propyl, isopropyl, n-butyl, and in some embodiments C 1-3 It is an alkyl group, and in some embodiments it is methyl, ethyl, or isopropyl; in some embodiments it is methyl or ethyl; in some embodiments it is methyl or isopropyl; in some embodiments it is methyl; in some embodiments it is ethyl; and in some embodiments it is isopropyl.

[0022] "C 3-6"Cycloalkyl" refers to cycloalkyl compounds having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, it is cyclobutyl, cyclopentyl, or cyclohexyl; in some embodiments, it is cyclobutyl or cyclopentyl; in some embodiments, it is cyclopentyl or cyclohexyl; in some embodiments, it is cyclopropyl or cyclobutyl; in some embodiments, it is cyclopropyl; in some embodiments, it is cyclobutyl; in some embodiments, it is cyclopentyl; and in some embodiments, it is cyclohexyl.

[0023] "C 1-3 "Alkylene" refers to a linear or branched C molecule. 1-3 Alkylenes include methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In one embodiment, linear or branched C 1-3 It is an alkylene, and in some embodiments it is methylene, ethylene, or trimethylene, in some embodiments it is methylene or ethylene, in some embodiments it is methylene, and in some embodiments it is ethylene.

[0024] A "saturated or unsaturated 7- to 8-membered bridging heterocyclic group" refers to a saturated 7- to 8-membered monocyclic bridging heterocyclic group containing 1 to 2 nitrogen atoms as ring constituent atoms, or a 7- to 8-membered monocyclic bridging heterocyclic group having an unsaturated bond containing 1 to 2 nitrogen atoms. In one embodiment, it is a saturated 7- to 8-membered monocyclic bridging heterocyclic group containing 2 nitrogen atoms, and in another embodiment, it is a saturated 7- to 8-membered monocyclic bridging heterocyclic group containing 2 nitrogen atoms, one of which is bonded to one hydrogen atom. Examples include diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octenyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, and diazabicyclo[2.2.1]heptenyl. In some embodiments, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octa-6-enyl, diazabicyclo[3.2.1]octa-2-enyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]hepta-5-enyl, and in some embodiments, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1]heptanyl or diazabicyclo[2.2.1]heptanyl Zabicyclo[2.2.1]heptanyl, in some embodiments being 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl, in some embodiments being diazabicyclo[2.2.1]heptanyl, in some embodiments being 2,5-diazabicyclo[2.2.1]heptanyl, and in some embodiments being 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0025] A "4- to 6-membered saturated heterocyclic group" is, for example, a 4- to 6-membered saturated heterocyclic group containing one to two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, wherein the sulfur atom contained in the heterocyclic group may be oxidized. One embodiment of a "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocyclic group may be oxidized. In one embodiment, a 5- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocyclic group may be oxidized; in another embodiment, a 5-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocyclic group may be oxidized; in another embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl; in yet another embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , morpholinil, thiomorpholinil, or dioxothiomorpholinil, in some embodiments oxetanil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, piperidinil, or morpholinil, in some embodiments oxetanil, tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, or piperidinil, in some embodiments oxetanil, tetrahydrofuranil, or tetrahydropyranil, in some embodiments pyrrolidinil or piperidinil, in some embodiments oxetanil, in some embodiments tetrahydrofuranil, in some embodiments tetrahydropyranil, in some embodiments pyrrolidinil, in some embodiments piperidinil, in some embodiments morpholinil, and in some embodiments oxazolidinil.

[0026] A "5-membered heteroaryl" is, for example, a 5-membered heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. One aspect of the "5-membered heteroaryl" is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl, oxazolyl, or thiazolyl; another aspect is pyrazolyl, imidazolyl, oxazolyl, or thiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl, or isoxazolyl; another aspect is pyrazolyl, triazolyl, or isoxazolyl; another aspect is pyrazolyl or thiazolyl; another aspect is pyrazolyl or triazolyl; another aspect is pyrazolyl, imidazolyl, another aspect is oxazolyl, another aspect is thiazolyl, and another aspect is triazolyl. Furthermore, a "5-membered heteroarenediyl" is a divalent group obtained by removing one hydrogen atom from a "5-membered heteroaryl" group.

[0027] A "six-membered heteroaryl" is, for example, a six-membered heteroaryl ring containing one to three nitrogen atoms as ring constituent atoms. Certain embodiments of a "six-membered heteroaryl" are pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, or triazinyl, and in some embodiments it is pyridyl or pyridadinyl, in some embodiments it is pyridyl or pyrimidinyl, in some embodiments it is pyridyl, and in some embodiments it is pyrimidinyl.

[0028] "Halogen" refers to F, Cl, Br, and I. In some forms it is F, Cl, or Br; in other forms it is F or Cl; in other forms it is F or Br; in other forms it is F; in other forms it is Cl; and in other forms it is Br.

[0029] "C that can be replaced1-6 "alkyl" and "optionally substituted C" 1-3 Acceptable substituents in "alkyl" include F, OH, OCH3, N(CH3)2, and C 1-3 Alkyl, hydroxymethyl, methoxymethyl, difluoroethyl, or substituted C 3-6The group is a cycloalkyl, azabicyclo[3.3.0]octanyl, or a substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen. In one embodiment, the material is F, OH, OCH3, N(CH3)2, methyl, ethyl, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranil, optionally substituted tetrahydropyranil, morpholinil, optionally substituted pyrrolidinil, optionally substituted piperidinil, or azabicyclo[3.3.0]octanil. In one embodiment, the material is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranil, optionally substituted tetrahydropyranil, morpholinil, optionally substituted pyrrolidinil, piperidinil, or azabicyclo[3.3.0]octanil. In one embodiment, the material is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranil, tetrahydro The octanil is ropyranil, (hydroxymethyl)tetrahydropyranil, (methoxymethyl)tetrahydropyranil, morpholinil, pyrrolidinil, methylpyrrolidinil, piperidinil, or azabicyclo[3.3.0]octanil, and in some embodiments the octanil is F, OH, OCH3, N(CH3)2, methyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranil, tetrahydropyranil, (hydroxymethyl)tetrahydropyranil, (methoxymethyl)tetrahydropyranil, morpholinil, pyrrolidinil, methylpyrrolidinil, or azabicyclo[3.3.0]octanil, and in some embodiments the octanil is OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, tetrahydrofuranil, (methoxymethyl)cyclopropyl[0]octanyl, in some embodiments being F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, or azabicyclo[3.3.0]octanyl, in some embodiments being F, OH or OCH3, in some embodiments being F, OH, OCH3 or N(CH3)2, in some embodiments being F, OH or N(CH3)2, in some embodiments being OH or OCH3, and in some embodiments being OH.

[0030] "Optionally substituted 5-membered heteroaryl," "Optionally substituted 6-membered heteroaryl," "Optionally substituted C 3-6 In the "cycloalkyl," "optionally substituted pyrazolyl," "optionally substituted pyridyl," "optionally substituted pyrimidinyl," "optionally substituted phenyl," and "optionally substituted cyclopropyl" forms, the acceptable substituents include C, which may be substituted with a group selected from the group consisting of OH and OCH3. 1-3 Alkyl, -SO2CH3, halogen, OH, OCH3, or C 3-6 It is a cycloalkyl group. In one embodiment, it may be substituted with a group selected from the group consisting of OH and OCH3. 1-3 C is alkyl, and in some embodiments may be substituted with OH. 1-3 C is alkyl, and in some embodiments may be substituted with OCH3. 1-3 It is alkyl, and in one embodiment, C 1-3 It is an alkyl group, in some embodiments being -SO2CH3, F, Cl, OH, methyl or OCH3, in some embodiments being F, Cl, OH, methyl or OCH3, in some embodiments being F, OH or OCH3, in some embodiments being -SO2CH3, F, Cl or methyl, in some embodiments being -SO2CH3, in some embodiments being F, Cl or methyl, in some embodiments being methyl, ethyl, hydroxymethyl or methoxymethyl, in some embodiments being methyl, ethyl or hydroxymethyl, in some embodiments being C 1-3The alkyl, OCH3, or cyclopropyl, in some embodiments being methyl, ethyl, or cyclopropyl, in some embodiments being methyl or ethyl, in some embodiments being methyl or hydroxymethyl, in some embodiments being ethyl or hydroxymethyl, in some embodiments being hydroxymethyl or methoxymethyl, in some embodiments being methyl, in some embodiments being ethyl, in some embodiments being hydroxymethyl, and in some embodiments being methoxymethyl. When formula (I) is formula (Ib), acceptable substituents in "optionally substituted pyrazolyl", "optionally substituted pyridyl", and "optionally substituted pyrimidinyl" include C 1-3 It is alkyl.

[0031] In the "optionally substituted 4- to 6-membered saturated heterocyclic group", "optionally substituted pyrrolidinyl", "optionally substituted piperidinyl", "optionally substituted oxetanyl", "optionally substituted tetrahydrofuranyl", and "optionally substituted tetrahydropyranyl", the permissible substituents include C, which may be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 The C is alkyl, F, OH, OCH3, oxo, or oxetanyl. In some embodiments, it is F, OH, or OCH3, and in other embodiments, it may be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 C is alkyl, F, oxo, or oxetanyl, and in some embodiments, it may be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 C is alkyl or oxo, and in some embodiments, it may be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 C is alkyl, and in some embodiments may be substituted with F. 1-3 C is alkyl, and in some embodiments may be substituted with OH. 1-3 C is alkyl, and in some embodiments may be substituted with OCH3. 1-3It is an alkyl group, and in some embodiments it is OCH3, methyl, ethyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl or oxetanyl, and in some embodiments it is methyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl or oxetanyl, and in some embodiments it is OCH3, methyl, difluoroethyl, hydroxyethyl, methoxyethyl or oxetanyl, and in some embodiments it is methyl, difluoroethyl, hydroxyethyl, methoxyethyl or oxetanyl, and in some embodiments it is difluoroethyl, hydroxyethyl or methoxyethyl, and in some embodiments it is methyl, ethyl, dif It is uroethyl or oxetanyl, in some embodiments difluoroethyl or oxetanyl, in some embodiments methyl, ethyl, hydroxymethyl, methoxymethyl or oxo, in some embodiments methyl or oxo, in some embodiments hydroxymethyl or methoxymethyl, in some embodiments 2,2-difluoroethyl, in some embodiments oxetanyl, in some embodiments hydroxymethyl, in some embodiments methoxymethyl, in some embodiments methyl, in some embodiments 2-hydroxyethyl, in some embodiments 2-methoxyethyl, in some embodiments OCH3, and in some embodiments oxo. When formula (I) is formula (Ib), some embodiments of the permitted substituents in "optionally substituted pyrrolidinyl" and "optionally substituted piperidinyl" include C which may be substituted with F. 1-3 It is alkyl or oxetanyl.

[0032] "Optionally substituted pyrrolidinediyl", "Optionally substituted piperidinediyl", "Optionally substituted piperazinediyl", "Optionally substituted C 1-3 Allowable substituents in "alkylene" include F, OH, OCH3, or optionally substituted C 1-3It is alkyl. In one embodiment, it is F, OH, OCH3, methyl, ethyl, hydroxymethyl, or methoxymethyl, and in another embodiment, it is F, OH, OCH3, or methyl.

[0033] "C that can be distributed even if replaced with F" 1-3 One embodiment of the alkyl group is methyl which may be substituted with F, or ethyl which may be substituted with F. For example, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl. One embodiment is methyl, ethyl, monofluoromethyl, difluoromethyl, or difluoroethyl; one embodiment is monofluoromethyl or difluoromethyl; one embodiment is monofluoromethyl or difluoroethyl; one embodiment is difluoromethyl or difluoroethyl; one embodiment is monofluoromethyl; one embodiment is difluoromethyl; one embodiment is difluoroethyl; and one embodiment is 2,2-difluoroethyl.

[0034] "Distributed C substituted with OH" 1-3 One embodiment of the alkyl group is methyl which may be substituted with one OH group, or ethyl which may be substituted with one or two OH groups. Examples include methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1,2-dihydroxyethyl. One embodiment is methyl, ethyl, or hydroxymethyl; one embodiment is methyl or hydroxymethyl; one embodiment is hydroxymethyl or hydroxyethyl; one embodiment is hydroxymethyl; and one embodiment is hydroxyethyl.

[0035] "C may be substituted with OCH3" 1-3One embodiment of the alkyl group is methyl which may be substituted with one OCH3 or ethyl which may be substituted with one or two OCH3. Examples include methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 1,2-dimethoxyethyl. One embodiment is methoxymethyl or methoxyethyl, another is methoxymethyl, and yet another is methoxyethyl.

[0036] "C may be substituted with N(CH3)2" 1-3 One embodiment of "alkyl" is methyl which may be substituted with one N(CH3)2 or ethyl which may be substituted with one N(CH3)2. One embodiment is methyl, ethyl, dimethylaminomethyl or dimethylaminoethyl, one embodiment is methyl or dimethylaminomethyl, one embodiment is dimethylaminomethyl, and one embodiment is dimethylaminoethyl.

[0037] One embodiment of "phenylene which may be substituted with F" is phenylene which may be substituted with 1 to 2 F atoms. One embodiment is phenylene which may be substituted with 1 F atom, one embodiment is phenylene or fluorophenylene, one embodiment is phenylene, one embodiment is 2-fluoro-1,4-phenylene, and one embodiment is 3-fluoro-1,4-phenylene.

[0038] The "G12D mutation" refers to a mutation in the wild-type protein in which the amino acid residue corresponding to codon 12 is changed from glycine to aspartic acid.

[0039] "G12D mutation KRAS" refers to KRAS that possesses the "G12D mutation" described above.

[0040] "Pancreatic cancer" refers to a malignant tumor that develops in the pancreas. For example, it includes pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. In certain embodiments, it is pancreatic ductal carcinoma, and in certain embodiments, it is pancreatic ductal adenocarcinoma. Further, in certain embodiments, it is metastatic pancreatic cancer, in certain embodiments, it is locally advanced pancreatic cancer, in certain embodiments, it is recurrent or refractory pancreatic cancer, and in certain embodiments, it is pancreatic cancer in patients with or without a treatment history.

[0041] "G12D-mutated KRAS-positive pancreatic cancer" refers to pancreatic cancer that is G12D-mutated KRAS-positive. For example, it is pancreatic cancer in which the KRAS G12D mutation has occurred and pancreatic cancer with a high positive rate of G12D-mutated KRAS. In certain embodiments, it is G12D-mutated KRAS-positive pancreatic ductal carcinoma, and in certain embodiments, it is G12D-mutated KRAS-positive pancreatic ductal adenocarcinoma.

[0042] Certain embodiments of the compound of formula (I) or its salt in the present invention are shown below. In certain embodiments of the above formula (I), it is a compound defined by the following formula (Ia) or its salt.

Chemical formula

Chemical formula

[0043] Certain embodiments of the compounds of formula (I), formula (Ia), and formula (Ib) of the present invention or their salts are shown below. (1-1)R 1 is naphthyl optionally substituted with OH or a group selected from the group consisting of the following formula (II) and formula (III),

Chemical formula

Chemical formula

Chemical formula

[0044] R 1 In another aspect of R 1 is formula (II), and R 1a is F, and R 1c is methyl, or a salt thereof. In one aspect, R 1 is formula (IIa), and R 1a is H or F, or a salt thereof. In one aspect, R 1 is formula (IIa), and R 1a is H, or a salt thereof. In one aspect, R 1 is formula (IIIa), and R 1a 、R 1b are the same or different from each other, and are a compound that is H or F, or a salt thereof. In one aspect, R 1 is formula (IIIa), and R 1a 、R 1bA compound or salt thereof in which both are H. In one embodiment, R 1 Equation (IIIa) is given by R 1a H is R 1b A compound or salt thereof in which F is present. In one embodiment, R 1 Equation (IIIa) is given by R 1a , R 1b A compound or salt thereof in which both are F. In one embodiment, R 1 Equation (IIIa) is given by R 1a F is R 1b A compound or salt thereof in which H is present. (2-1)R 2 C may be substituted with H, halogen, or 1-3 Compounds or salts thereof that are alkyl, cyclopropyl, or vinyl. (2-2)R 2 is halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, and said C 1-3 The alkyl group may be a compound or salt thereof that is substituted with a group selected from the group consisting of OH and OCH3. (2-3)R 2 is halogen, C 1-3 Compounds or salts thereof that are alkyl, cyclopropyl, or vinyl. (2-4)R 2 A compound or salt thereof in which is cyclopropyl.

[0045] R 2 Another aspect of this is R 2 A compound or salt thereof in which is a halogen. In one embodiment, R 2 C 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 2 A compound or salt thereof in which vinyl is present. (3-1)R 3 A compound or salt thereof in which is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms. (3-2)R 3Compounds or salts thereof in which is 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl. (3-3)R 3 A compound or salt thereof whose formula is (IV) below. [ka] (4-1)R 4 C may be substituted. 1-6 Compounds or salts thereof that are a substituted or possibly substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from alkyl, oxygen, sulfur, and nitrogen, a substituted or possibly substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or a substituted or possibly substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms. (4-2)R 4 C may be substituted. 1-6 Compounds or salts thereof that are alkyl, optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. (4-3)R 4 C may be substituted with a group selected from the group consisting of OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. 1-6 Compounds or salts thereof that are alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. (4-4)R 4 C 1-3 Compounds or salts thereof that are alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. (4-5)R 4 C may be substituted with a group selected from the group consisting of OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1-3 C may be substituted with a group selected from the group consisting of pyridyl, F, OH, and OCH3, which may be alkyl-substituted. 1-3 Pyrrolidinyl which may be substituted with alkyl, or C which may be substituted with F 1-3 A compound or salt thereof that is piperidinyl, which may be substituted with a group selected from the group consisting of alkyl and oxetanyl. (4-6)R 4 C may be substituted with a group selected from the group consisting of OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1-3A compound or salt thereof that is pyrrolidinyl which may be substituted with a group selected from the group consisting of pyridyl, difluoroethyl, hydroxyethyl and methoxyethyl, which may be alkyl-substituted, or piperidinyl which may be substituted with a group selected from the group consisting of difluoroethyl and oxetanyl. (4-7)R 4 C may be substituted with OCH3. 1-6 A compound or salt thereof that is piperidinyl, which may be substituted with alkyl, tetrahydropyranyl, or difluoroethyl.

[0046] R 4 Another aspect of this is R 4 C may be substituted. 1-6 Compounds or salts thereof that are alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. In one embodiment, R 4 A compound or salt thereof in which is tetrahydrofuranil, tetrahydropyranil, optionally substituted pyrrolidinil, or optionally substituted piperidinil. In one embodiment, R 4 A compound or salt thereof in which is tetrahydrofuranil, tetrahydropyranil, or possibly substituted piperidinil. In one embodiment, R 4 A compound or salt thereof in which is tetrahydropyranyl or possibly substituted piperidinyl. In one embodiment, R 4 C may be substituted. 1-6 A compound that is alkyl or a salt thereof. In one embodiment, R 4 C may be substituted with OCH3. 1-6 A compound that is alkyl or a salt thereof. In one embodiment, R 4 C 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 4 A compound or salt thereof in which is oxetanyl. In one embodiment, R 4 A compound or salt thereof in which tetrahydrofuranyl. In one embodiment, R4 A compound or salt thereof in which is tetrahydropyranyl. In one embodiment, R 4 A compound or salt thereof which is a pyrazolyl which may be substituted. In one embodiment, R 4 A compound or salt thereof which is pyridyl which may be substituted. In one embodiment, R 4 A compound or salt thereof which is a pyrimidinyl which may be substituted. In one embodiment, R 4 A compound or salt thereof which is a pyrrolidinyl which may be substituted. In one embodiment, R 4 A compound or salt thereof which is piperidinyl which may be substituted. In one embodiment, R 4 C may be replaced with F. 1-3 A compound or salt thereof which is piperidinyl which may be substituted with alkyl. In one embodiment, R 4 A compound or salt thereof in which piperidinyl may be substituted with difluoroethyl. (5-1)R 5 C may be substituted. 1-6 Alkyl, possibly substituted C 3-6 A compound or salt thereof that is a cycloalkyl or a substituted or substituted 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from oxygen, sulfur, and nitrogen. (5-2)R 5 is methyl, ethyl, isopropyl, tert-butyl, or C 3-6 A cycloalkyl compound or a salt thereof. (5-3)R 5 is ethyl, isopropyl, tert-butyl or C 3-6 A cycloalkyl compound or a salt thereof. (5-4)R 5 isopropyl or C 3-6 A cycloalkyl compound or a salt thereof. (5-5)R 5 A compound or salt thereof in which is isopropyl.

[0047] R 5 Another aspect of this is R 5 isopropyl, tert-butyl or C 3-6A compound that is cycloalkyl or a salt thereof. In one embodiment, R 5 A compound or salt thereof in which is isopropyl or tert-butyl. In one embodiment, R 5 A compound or salt thereof in which is isopropyl or cyclopropyl. In one embodiment, R 5 A compound or salt thereof in which is tert-butyl. In one embodiment, R 5 C 3-6 A cycloalkyl compound or a salt thereof. (6-1)R 6a , R 6b H or C may be the same or different from each other and may be substituted. 1-6 It is alkyl, or R 6a , R 6b These may be substituted together with the carbon atoms to which they are bonded. 3-6 Compounds or salts thereof that form a substituted 4- to 6-membered saturated heterocycle containing a cycloalkyl or one heteroatom selected from oxygen, sulfur, and nitrogen. (6-2) R 6a , R 6b If they are the same or different from each other, H or C 1-3 Alkyl, and the C 1-3 The alkyl group may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, or R 6a , R 6b They become C together with the carbon they are bonded to. 3-6 A compound or salt thereof that forms a cycloalkyl group. (6-3)R 6a , R 6b If they are the same or different from each other, H or C 1-3 Alkyl, and the C 1-3 The alkyl group may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2, or R 6a , R 6b However, compounds or salts thereof that, together with the carbon atoms to which they are bonded, form cyclopropyl compounds. (6-4)R 6a H is R 6b A C is substituted with an OH group.1-3 A compound that is alkyl or a salt thereof.

[0048] R 6a , R 6b Another aspect of this is R 6a , R 6b C may be the same or different from each other and may be substituted with a group selected from the group consisting of H or F, OH and N(CH3)2. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 6a , R 6b C may be the same or different from each other and may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 6a , R 6b A compound or salt thereof in which both are H. In one embodiment, R 6a H is R 6b C may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 6a H is R 6b C may be replaced with F. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 6a H is R 6b C may be substituted with N(CH3)2. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 6a , R 6b However, compounds or salts thereof that, together with the carbon atoms to which they are bonded, form cyclopropyl compounds. (7-1)R 7 H, halogen, C 1-3 Alkyl, -SO2CH3, C 3-6 Compounds or salts thereof that are a substituted or possibly substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from cycloalkyl, oxygen, sulfur, and nitrogen, a substituted or possibly substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms. (7-2)R7 H, halogen, C 1-3 Alkyl, -SO2CH3, C 3-6 A cycloalkyl group, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV): [ka] R 7a , R 7b However, C may be the same or different, and may be substituted with H or OH. 1-3 A compound that is alkyl or a salt thereof. (7-3)R 7 is H, a halogen, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), and (IX), [ka] R 7a C may be substituted with H or OH. 1-3 A compound that is alkyl or a salt thereof. (7-4)R 7 is H, a halogen, or a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX), R 7a A C is substituted with an OH group. 1-3 A compound that is alkyl or a salt thereof. (7-5)R 7 is a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX), R 7a A C is substituted with an OH group. 1-3 A compound that is alkyl or a salt thereof. (7-6)R 7 A compound or salt thereof in which H is present.

[0049] R 7 Another aspect of this is R 7 H, halogen, C 1-3 A compound or salt thereof that is alkyl or -SO2CH3. In one embodiment, R 7A compound in which R is halogen or a salt thereof. In one embodiment, R 7 is a compound in which R is -SO2CH3 or a salt thereof. In one embodiment, R 7 is a compound in which R is a group selected from the group consisting of formula (VI), formula (VII), formula (VIII) and formula (IX) or a salt thereof. In one embodiment, R 7 is a compound in which R is a group selected from the group consisting of formula (VI), (VIII) and (IX) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (VI) or (VIII) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (VI) or (IX) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (VI) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (VII) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (VIII) or a salt thereof. In one embodiment, R 7 is a compound in which R is formula (IX) or a salt thereof. (7-8)R 7a is optionally substituted with H or OH C 1-3 alkyl or a salt thereof. In one embodiment, R 7a is a compound in which R is H or a salt thereof. In one embodiment, R 7a is optionally substituted with OH C 1-3 alkyl or a salt thereof. In one embodiment, R 7a is C 1-3 alkyl or a salt thereof. (8-1) A compound of formula (I) or a salt thereof in which W is optionally substituted phenyl or optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms. (8-2)W 1 is CH, and W 2 is C-SO2CH3, a compound of formula (Ia) or a salt thereof. (8-3)W 1 and W 2 are the same or different from each other and are CH, CF, CCl, CCH3 or N, a compound of formula (Ia) or a salt thereof. (8-4)W 1 and W 2A compound of formula (Ia) or a salt thereof, wherein the groups are the same or different and are CH, CF, or N. (8-5)W 1 where W is CH 2 A compound of formula (Ia) or a salt thereof, wherein W is CH. (9)W 1 W 2 and R 7 are such that i. W is CH, W is C-SO2CH3, R is H, or 1 W is CH, 2 W is C-SO2CH3, R is H, or 7 ii. W and W are the same or different and are CH, CF, CCl, CCH3 or N, and R is H, halogen, C alkyl, -SO2CH3, C 1 cycloalkyl, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII) and (XXIV), 2 where R and R are the same or different and are H or optionally substituted C 7 alkyl. 1-3 A compound of formula (Ia) or a salt thereof, 3-6 where R and R are the same or different and are H or optionally substituted C

Chemical formula

[0050] Another embodiment of Y is a compound or salt thereof in which Y is 1,4-phenylene or 2,5-pyridinediyl. In one embodiment, a compound or salt thereof in which Y is phenylene. In one embodiment, a compound or salt thereof in which Y is 1,4-phenylene. In one embodiment, a compound or salt thereof in which Y is pyridinediyl. In one embodiment, a compound or salt thereof in which Y is 2,5-pyridinediyl. (12-1)L is -(L 1 -L 2 -L 3 -L 4 )- and, L 1 , L 2 , L 3 , L 4 They are the same or different from each other, combined, O, NR L1 , pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C which may be substituted 1-3 A group selected from the group consisting of alkylenes and C=O, R L1 is H or C 1-3 A compound that is alkyl or a salt thereof. (12-2)L is bonded, C 1-3 The group is selected from alkylene, C=O, or from the group consisting of the following formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX): [ka] R L1 is H or C 1-3 It is alkyl, R L2 , R L3However, the same or different C may be H, F, OH, OCH3, or substituted. 1-3 It is alkyl, R L is CH or N, A compound or salt thereof in which n is an integer between 1 and 2. (12-3)L is bonded, C 1-3 Alkylene, C=O, or a group selected from the group consisting of the following formulas (XIV)-1, (XV)-1, (XVI)-1, (XVII)-1, (XVIII)-1 and (XIX)-1, [ka] (Y in the formula * This indicates that it will combine with Y. R L1 is H or C 1-3 It is alkyl, R L2 , R L3 However, the same or different C may be H, F, OH, OCH3, or substituted C. 1-3 It is alkyl, R L is CH or N, A compound or salt thereof in which n is an integer between 1 and 2. (12-4) L is bonded, C 1-3 The group is selected from alkylene, C=O, or the group consisting of the following formulas (XIV) and (XVI). [ka] R L1 C 1-3 It is alkyl, R L2 , R L3 H is, A compound or salt thereof in which n is 1. (12-5)L is bonded, C 1-3 The group is selected from alkylene, C=O, or the group consisting of the following formulas (XIV)-1 and (XVI)-1, [ka] (Y in the formula* This indicates that it will combine with Y. R L1 C 1-3 It is alkyl, R L2 , R L3 H is, A compound or salt thereof in which n is 1. (12-6) L is a bond, C=O, or a group selected from the group consisting of formulas (XIV) and (XVI), R L1 C 1-3 It is alkyl, R L2 , R L3 A compound or salt thereof in which H is and n is 1. (12-7) L is a bond, C=O, or a group selected from the group consisting of formulas (XIV)-1 and (XVI)-1, and R L1 C 1-3 It is alkyl, R L2 , R L3 A compound or salt thereof in which H is and n is 1. (12-8) L is a group selected from C=O or the group consisting of formulas (XIV) and (XVI), and R L1 C 1-3 It is alkyl, R L2 , R L3 A compound or salt thereof in which H is and n is 1. (12-9) L is a group selected from the group consisting of C=O or formulas (XIV)-1 and (XVI)-1, and R L1 C 1-3 It is alkyl, R L2 , R L3 A compound or salt thereof in which H is and n is 1. (12-10)L bonded, C 1-3 Alkylenes, or compounds with a C=O structure, or salts thereof. (12-11) A compound or salt thereof in which L is a bond.

[0051] Another aspect of L is that L is combined with C 1-3 A compound or salt thereof that is alkylene. In one embodiment, a compound or salt thereof in which L is bonded or C=O. In one embodiment, L is C 1-3A compound that is an alkylene or a salt thereof. In one embodiment, a compound in which L is C=O or a salt thereof. (13-1) A compound or a salt thereof in which Z is NH or a 5-membered heteroarylene diyl containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. (13-2) A compound or a salt thereof in which Z is NH or a group selected from the group consisting of the following formula (V), formula (X), formula (XI), and formula (XII).

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0052] Another embodiment of Z is a compound or salt thereof in which Z is a group selected from the group consisting of formulas (X), (XI), and (XII). In one embodiment, a compound or salt thereof in which Z is a group selected from the group consisting of formulas (X)-1, (XI)-1, and (XII)-1. In one embodiment, a compound or salt thereof in which Z is formula (XI) or formula (XII). In one embodiment, a compound or salt thereof in which Z is formula (XI)-1 or formula (XII)-1. In one embodiment, a compound or salt thereof in which Z is formula (X). In one embodiment, a compound or salt thereof in which Z is formula (X)-1. In one embodiment, a compound or salt thereof in which Z is formula (XII). In one embodiment, a compound or salt thereof in which Z is formula (XII)-1. (14-1) A compound or salt thereof in which YLZ is of the following formula (XIII). [ka] (14-2) A compound or salt thereof in which YLZ is the following formula (XIII)-1. [ka] (In the formula O-CH2 * This indicates bonding with the carbon atom of O-CH2. (15) A compound or salt thereof that is any two or more non-contradictory combinations of the embodiments described in (1-1) to (14-2) above.

[0053] Specifically, the following embodiments are examples of the combinations described in (15) above. (16-1) A compound of formula (I) or a salt thereof that is a combination of the embodiments of (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), (11-1), (12-1), and (13-1), or a combination of the embodiments of (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), and (14-1). (16-2) A compound of formula (I) or a salt thereof that is a combination of the embodiments of (1-1), (2-1), (3-2), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), (11-1), (12-2), and (13-2), or a combination of the embodiments of (1-1), (2-1), (3-2), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), and (14-1). (16-3) A compound or salt thereof in which formula (I) is formula (Ia), and is a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2), (11-1), (12-2), and (13-2), or a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2), and (14-1). (16-3-i) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-5), (8-2), (10-2), (11-1), (12-2), and (13-2), or a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-5), (8-2), (10-2), and (14-1). (16-3-ii) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-2), (8-3), (10-2), (11-1), (12-2), and (13-2), or a combination of the embodiments of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-2), (8-3), (10-2), and (14-1). (16-4) A compound or salt thereof in which formula (I) is formula (Ia), and is a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (9), (10-3), (11-1), (12-4), and (13-2), or a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (9), (10-3), and (14-1). (16-4-i) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-5), (8-2), (10-3), (11-1), (12-4) and (13-2), or a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-5), (8-2), (10-3) and (14-1). (16-4-ii) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-2), (8-3), (10-3), (11-1), (12-4), and (13-2), or a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-2), (8-3), (10-3), and (14-1). (16-5) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-2), (8-3), (10-3), (11-1), (12-4), and (13-2). (16-6) A compound or salt thereof in which formula (I) is formula (Ib), and is a combination of the embodiments of (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4), (11-2), (12-10), and (13-4), or a combination of the embodiments of (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4), and (14-1). (16-7) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-6), and (13-6). (16-8) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-7), and (13-7). (16-9) A compound or salt thereof in which formula (I) is formula (Ia) and is a combination of the embodiments of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-8) and (13-10), or a combination of the embodiments of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-11) and (13-8). (16-10) Equation (I) is equation (Ia), R 1 Equation (IIa) is given by R 1a F is R 2 It is cyclopropyl, and R 3 Equation (IV) is given by R 4 C may be substituted with OCH3. 1-6 C may be substituted with alkyl, tetrahydropyranyl, or F. 1-3 A piperidinyl which may be substituted with an alkyl group, R 5 is isopropyl, and R 6a H is R 6b A C is substituted with an OH group. 1-3It is alkyl, R 7 is a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX), and R 7a A C is substituted with an OH group. 1-3 It is alkyl, W 1 CH is W 2 A compound or salt thereof in which is CH, X is O, Y is phenylene which may be substituted with F, L is a bond, and Z is formula (XI). (16-11) Equation (I) is equation (Ia), R 1 Equation (IIa) is given by R 1a F is R 2 It is cyclopropyl, and R 3 Equation (IV) is given by R 4 C may be substituted with OCH3. 1-6 piperidinyl which may be substituted with alkyl, tetrahydropyranyl or difluoroethyl, 5 is isopropyl, and R 6a H is R 6b A C is substituted with an OH group. 1-3 It is alkyl, R 7 is a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX), and R 7a A C is substituted with an OH group. 1-3 It is alkyl, W 1 CH is W 2 A compound or salt thereof in which is CH, X is O, Y is phenylene which may be substituted with F, L is a bond, and Z is formula (XI). (16-12) Equation (I) is equation (Ia), R 1 Equation (IIa) is given by R 1a F is R 2 It is cyclopropyl, and R 3 Equation (IV) is given by R 4 C may be substituted with OCH3. 1-6 piperidinyl which may be substituted with alkyl, tetrahydropyranyl or difluoroethyl, 5 is isopropyl, and R 6a H is R6b A C is substituted with an OH group. 1-3 It is alkyl, R 7 is a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX), and R 7a A C is substituted with an OH group. 1-3 It is alkyl, W 1 CH is W 2 A compound or salt thereof in which is CH, X is O, Y is phenylene which may be substituted with F, L is a bond, and Z is formula (XI)-1. (16-13) Equation (I) is equation (Ib), R 1 Equation (IIa) is given by R 1a F is R 2 It is cyclopropyl, and R 3 Equation (IV) is given by R 4 is tetrahydropyranyl or optionally substituted piperidinyl, and R 5 is isopropyl, and R 6a H is R 6b A C is substituted with an OH group. 1-3 It is alkyl, R 7 is equation (VI), (VIII), or (IX), and R 7a A C is substituted with an OH group. 1-3 A compound or salt thereof that is alkyl, where X is O, Y is phenylene, L is a bond, and Z is formula (XI). (16-14) Equation (I) is equation (Ib), R 1 Equation (IIa) is given by R 1a F is R 2 It is cyclopropyl, and R 3 Equation (IV) is given by R 4 is tetrahydropyranyl, and R 5 is isopropyl, and R 6a H is R 6b A C is substituted with an OH group. 1-3 It is alkyl, R 7 If equation (VI) or (VIII), then R 7a C 1-3A compound or salt thereof that is alkyl, where X is O, Y is 1,4-phenylene, L is a bond, and Z is formula (XI)-1.

[0054] Examples of specific compounds included in the present invention include, in one embodiment, the following compounds. (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl)oxy]methyl}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A compound or salt thereof selected from the group consisting of the above.

[0055] Examples of specific compounds included in the present invention include, in one embodiment, the following compounds. (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A compound or salt thereof selected from the group consisting of the above.

[0056] Examples of specific compounds included in the present invention include, in one embodiment, the following compounds. (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A compound or salt thereof selected from the group consisting of the above.

[0057] Examples of specific compounds included in the present invention include, in one embodiment, the following compounds. (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, A compound or salt thereof selected from the group consisting of the above.

[0058] Compounds of formula (I) may have tautomers or geometric isomers depending on the type of substituent. In this specification, compounds of formula (I) may be described in only one form of isomer, but the present invention also includes other isomers, as well as separated isomers or mixtures thereof. Furthermore, compounds of formula (I) may have chiral carbon atoms or axial chirality, and diastereomers based on these may exist. The present invention also includes isolated diastereomers of compounds of formula (I), or mixtures thereof.

[0059] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, etc., by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 1985, 5, pp. 2157-2161 and "Pharmaceutical Development", Vol. 7 Molecular Design, Hirokawa Shoten, 1990, pp. 163-198.

[0060] Furthermore, a salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the type of substituent, it may form an acid addition salt or a salt with a base. For example, salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specifically, examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; and salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine, as well as ammonium salts.

[0061] Furthermore, the present invention also encompasses various hydrates and solvates of the compound of formula (I) and its salts, as well as materials with crystalline polymorphisms.

[0062] Furthermore, the present invention encompasses all compounds of formula (I) or salts thereof that are pharmaceutically acceptable and labeled with one or more radioactive or non-radioactive isotopes. Examples of suitable isotopes used for isotope labeling of the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C, 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N etc.), oxygen ( 15 O, 17 O and 18 O etc.), fluorine ( 18 F etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), sulfur ( 35The isotopes (such as S) are enclosed within the structure. It can be used in research such as tissue distribution studies of compounds, drugs, and / or substrates of the present invention that are labeled with isotopes. For example, tritium ( 3 H), carbon-14 ( 14 Radioactive isotopes such as C) can be used for this purpose due to their ease of labeling and simple detection. Substitution with heavier isotopes, for example, hydrogen to deuterium ( 2 Substitution with H) may offer therapeutic advantages due to improved metabolic stability (e.g., increased half-life in vivo, reduced required dose, and reduced drug interactions). Positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 Substitution with N, etc., can be used in positron emission tomography (PET) studies to test substrate receptor occupancy. The isotope-labeled compounds of the present invention can generally be produced by conventional methods known to those skilled in the art, or by using appropriate isotope-labeled reagents instead of unlabeled reagents, using the same methods as in the examples or production examples.

[0063] (Manufacturing method) Compounds of formula (I) and their salts can be produced by applying various known synthetic methods, taking advantage of their characteristics based on their basic structure or the type of substituent. In such cases, depending on the type of functional group, it may be technically effective in the manufacturing process to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at a stage from the starting material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 5th edition, by PGM Wuts and TW Greene, John Wiley & Sons Inc., 2014, and these can be appropriately selected and used depending on the reaction conditions. In this method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as needed. Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at a stage from the starting material to the intermediate, similar to the protecting group described above, or by carrying out further reactions using the obtained compound of formula (I). The reactions can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, and dehydration. The following describes typical methods for producing the compound of formula (I). Each method can also be carried out by referring to the references provided in the description. Note that the production methods of the present invention are not limited to the examples shown below.

[0064] In this specification, the following abbreviations may be used. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct, Pd / C: palladium carbon.

[0065] (Manufacturing method 1) [ka] (PG in the formula 1 is R 3 Protecting groups of NH contained in PG 2 is R 1 This indicates the protecting group (NH or OH) or hydrogen atom contained within. (The same applies hereafter.)

[0066] The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction. Examples of protecting groups that can be deprotected under acidic conditions include the tert-butoxycarbonyl group, triphenylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethanediyl group, and tert-butylsulfinyl group. This reaction is carried out by stirring under cooling and then under reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not limited to alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN or water, and mixtures thereof. Examples of deprotection reagents are not limited to acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, and methanesulfonic acid. Deprotection can also be performed by catalytic hydrogenation by selecting a protecting group. Examples of protecting groups include the benzyl group, p-methoxybenzyl group, and benzyloxycarbonyl group. Deprotection can also be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include the tert-butyl(dimethyl)silyl group and (trimethylsilyl)ethoxymethyl group. Furthermore, examples of protecting groups that can be deprotected under basic conditions include the acetyl group, trifluoroacetyl group, and benzoyl group. Also, PG 1 PG 2 Alternatively, one can select different protecting groups that can be deprotected under different deprotection conditions and perform deprotection in a stepwise manner. For references regarding this reaction, see, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014. If the starting compound (1) has axial chirality, this reaction may be carried out using the stereoisomer obtained by separating compound (1).

[0067] The hydrochloride salt of the compound of formula (I) can be obtained by subjecting the compound of formula (I) to the following procedure as a salt-forming reaction. The compound of formula (I), which is thought to form a salt with hydrochloric acid based on its chemical structure, is dissolved in CH2Cl2 and MeOH. Hydrogen chloride (4M DOX solution, 10 equivalents) is added under ice cooling, and the mixture is stirred for 30 minutes under ice cooling. The reaction mixture is concentrated under reduced pressure, and diethyl ether is added to the resulting residue. The resulting solid is filtered and dried under reduced pressure to obtain the hydrochloride salt of the compound of formula (I).

[0068] The hydrochloride salt of the compound of formula (I) can be obtained by performing the following desalting procedure. The hydrochloride salt of the compound of formula (I) is purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), the fraction containing the target product is collected, basicized with saturated sodium bicarbonate aqueous solution, and then extracted with CHCl3 / MeOH(5 / 1). The combined organic layers are dried over anhydrous sodium sulfate, the solution is concentrated under reduced pressure, the resulting solid is washed with diethyl ether, and dried under reduced pressure to obtain the compound of formula (I).

[0069] (Raw material synthesis 1) [ka] (Y in the formula 1 (This indicates CH, CF, or N. The same applies below.)

[0070] This method is the first method for producing compound (1)-1 contained in raw material compound (1).

[0071] (first step) This process is a method for producing compound (1)-1 by a cycloaddition reaction between compound (2) and compound (3). This reaction uses equal amounts of compound (2) and compound (3), or an excess amount of one, and stirs the mixture of these compounds for 0.1 hours to 5 days, preferably in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a solvent that is inert to the reaction, or without a solvent, under cooling to heating under reflux, preferably at 0°C to 100°C. Examples of solvents used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and mixtures thereof. Examples of copper salts include CuI, CuSO4, and CuOTf. Examples of reducing agents include sodium ascorbate. Carrying out the reaction in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, tris[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]amine (TBTA), etc., may be advantageous in ensuring the reaction proceeds smoothly. [Literature] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599. Note that the PG of compound (2) 2 This reaction may also be carried out using a compound obtained by first subjecting the compound to a deprotection reaction.

[0072] (Raw material synthesis 2) [ka] (where R is C) 1-3 This indicates an alkyl group. (The same applies below.)

[0073] This method is a second method for producing compound (1)-1 contained in raw material compound (1).

[0074] (first step) This process is a method for producing compound (5) by a cycloaddition reaction between compound (2) and compound (4). The reaction conditions are the same as those for the first step of raw material synthesis 1.

[0075] (Second process) This process is a method for producing compound (6) by hydrolyzing compound (5). This reaction is carried out by stirring compound (5) under cooling and then under heating and reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include alcohols, acetone, N,N-dimethylformamide, and tetrahydrofuran. In some cases, a mixed solvent of the above solvents with water may be preferable for the reaction. Examples of hydrolysis reagents are not particularly limited, but include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and trimethyltin hydroxide. For references regarding this reaction, see, for example, the following: "Experimental Chemistry Course (5th Edition)," Vol. 16 (2005), edited by The Chemical Society of Japan (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0076] (Third step) This process is a method for producing compound (1)-1 by the amidation reaction of compound (6) and compound (7). This reaction uses equal amounts of compound (6) and compound (7), or an excess amount of one, and stirs the mixture in a reaction-inert solvent in the presence of a condensing agent, under cooling to heating, preferably at -20°C to 60°C, for typically 0.1 hours to 5 days. Examples of solvents are not particularly limited, but include aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, N,N-dimethylformamide, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of coupling agents include hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium (PyBOP), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), and diphenyl phosphate azide (DPPA). The use of additives (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. Carrying the reaction in the presence of organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as potassium carbonate, sodium carbonate, or potassium hydroxide, may be advantageous for smooth reaction. Alternatively, a method can be used in which compound (6) is converted to a reactive derivative before undergoing an acylation reaction. Examples of reactive carboxylic acid derivatives include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, and active esters obtained by condensation with 1-hydroxybenzotriazole. The reaction between these reactive derivatives and compound (7) can be carried out in a solvent that is inert to reactions, such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, under cooling to heating, preferably at -20°C to 120°C. [Literature] S.R. Sandler and W. Karo, "Organic Functional Group Preparations," 2nd edition, Vol. 1, Academic Press Inc., 1991. "Experimental Chemistry Course (5th Edition)," Vol. 16 (2005), edited by The Chemical Society of Japan (Maruzen)

[0077] (Raw material synthesis 3) [ka] (PG in the formula 3 OH is a protecting group, LG 1 represents a leaving group, BLG represents a boronic acid group, a boronic acid group protected by a boronic acid protecting group such as a boronic acid pinacol ester group, or a trifluoroborate base (hereinafter sometimes referred to as boronic acid group, etc.). Examples of leaving groups shown here include Cl, Br, methanesulfonyl group, and p-toluenesulfonyl group.

[0078] This method is the first method for producing raw material compound (2).

[0079] (first step) This process is a method for producing compound (10) by an ipso substitution reaction between compound (8) and compound (9). This reaction uses equal amounts of compound (8) and compound (9), or an excess amount of one, and stirs the mixture in a solvent inert to the reaction, or without a solvent, under cooling to heating under reflux, preferably at 0°C to 80°C, for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN, and mixtures thereof. Carrying the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), and tBuOK, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate may be advantageous for the reaction to proceed smoothly. Furthermore, compound (10) can be produced by catalytic hydrogenation of the compound obtained by the Mizoroki-Heck reaction between compound (8) and compound (9).

[0080] (Second process) This process is a method for producing compound (12) by an ipso substitution reaction between compound (10) and compound (11). The reaction conditions are the same as those for the first step of raw material synthesis 3. Furthermore, compound (12) can be produced by Negishi coupling of compound (10) with a compound obtained by converting the hydrogen atoms of compound (11) to halogens.

[0081] (Third step) This process involves compound (12) and PG. 3 This is a method for producing compound (13) by an ipso substitution reaction with -OH. The PG used here 3 Examples of -OH groups include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions are the same as those for the first step of raw material synthesis 3.

[0082] (Fourth step) This process involves compound (13) and R 2 -A method for producing compound (14) by a Suzuki-Miyaura coupling reaction with a boronic acid derivative consisting of a boronic acid group, etc. Examples of boronic acid groups, etc. used here are not particularly limited, but include boronic acid groups, boronic acid ester groups, boronic acid pinacol ester groups, triol borate bases, and trifluoroborate bases. This reaction involves compound (13) and R 2- An equal or excess amount of a boronic acid derivative consisting of a boronic acid group, etc., is used, and the mixture is stirred in a reaction-inert solvent in the presence of a base and a palladium catalyst from room temperature under reflux, preferably from 20°C to 140°C, for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidined-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium(3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, and palladium(II) acetate. The presence of ligands such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, and 1,1'-bis(diphenylphosphin)ferrocene may be advantageous for smoother reaction. Furthermore, heating the mixture by microwave irradiation may also be advantageous for smoother reaction. [Literature] J. Am. Chem. Soc., 2005, 127, p.4685-4696 Org. Lett. 2011, 13, p.3948-3951 Org. Lett. 2012, 14, p.1278-1281 R 2 If the atom is a hydrogen atom, compound (14) can be produced by the catalytic hydrogenation reaction of compound (13).

[0083] (Fifth step) This process is a method for producing compound (16) by a Suzuki-Miyaura coupling reaction between compound (14) and compound (15). The reaction conditions are the same as those for the fourth step of raw material synthesis 3. If compound (16) exhibits axial chirality, it may be obtained as a mixture of diastereomers, but each diastereomer can be isolated by a standard resolution procedure, such as ODS column chromatography or silica gel column chromatography.

[0084] (Sixth step) This process is a method for producing compound (17) by deprotecting compound (16) through a catalytic hydrogenation reaction. This reaction can be carried out by stirring compound (16) under a hydrogen atmosphere, at atmospheric pressure to pressurized pressure, in a reaction-inert solvent such as MeOH, EtOH, or ethyl acetate, in the presence of a metal catalyst, under cooling to heating, preferably at room temperature, for 1 hour to 5 days. As the metal catalyst, palladium catalysts such as Pd / C or palladium black, platinum catalysts such as platinum plates or platinum oxide, and nickel catalysts such as reduced nickel or Raney nickel can be used.

[0085] (Seventh step) This process is a method for producing compound (2) by the reaction of compound (17) and compound (18). This reaction is carried out by using equal amounts or an excess amount of compound (17) and compound (18), and reacting the mixture in the presence of a base, in a solvent inert to the reaction, under cooling to heating under reflux, preferably at 0°C to 80°C, for usually 0.1 hours to 5 days. The solvent used here is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases are not particularly limited, but examples include organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. In some cases, it may be advantageous to carry out the reaction in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride. For references regarding this reaction, see, for example, the following: The Chemical Society of Japan (ed.), "Experimental Chemistry Course," 5th edition, Vol. 14, Maruzen, 2005. Note that compound (2) may have axial chirality and is obtained as a mixture of diastereomers, but PG 2 The diastereomers of compound (2), in which the protecting group is , or the compound obtained by subjecting compound (2) to a deprotection reaction, can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. The reaction conditions for the deprotection reaction used here are the same as those described in Manufacturing Method 1. Furthermore, compound (18) is LG 1 By halogenating a compound in which the corresponding part is a hydroxyl group, LG 1 Compounds in which the halogenating agent is a halogen can be produced. Examples of halogenating agents used here are not limited to thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, etc. For references regarding this reaction, see, for example, the following: The Chemical Society of Japan (ed.), "Experimental Chemistry Course," 5th edition, Vol. 13, Maruzen, 2004. Furthermore, compound (18) is LG 1 By sulfonyling a compound in which the corresponding part is a hydroxyl group in the presence of a base, LG 1 Compounds in which the base is a sulfonyl group can be produced. Examples of sulfonylation reagents used here are not limited to methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, etc. Examples of bases are not limited to TEA, DIPEA, pyridine, tetramethylethylenediamine, etc. For references regarding this reaction, see, for example, the following: Synthesis 1999, 9, p.1633-1636

[0086] (Raw material synthesis 4) [ka] (R in the formula LG is C 1-12 (Alkyl alkyl group, n represents 1 or 2.)

[0087] This method is a second method for producing the raw material compound (16).

[0088] (first step) This process involves compound (10) and R LG This is a method for producing compound (19) by an ipso substitution reaction with -SH. The R used here LG - An example of SH is C 1-12 Examples of alkylthiols include ethanethiol and dodecanethiol. The reaction conditions are the same as those for the first step of raw material synthesis 3.

[0089] (Second process) This process involves compound (19) and PG. 3This is a method for producing compound (20) by an ipso substitution reaction with -OH. The PG used here 3 Examples of -OH groups include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions are the same as those for the first step of raw material synthesis 3.

[0090] (Third step) This process involves compound (20) and R 2 -This is a method for producing compound (21) by a Suzuki-Miyaura coupling reaction with a boronic acid derivative consisting of a boronic acid group, etc. The reaction conditions are the same as those for the fourth step of raw material synthesis 3. R 2 If the atom is a hydrogen atom, compound (21) can be produced by a catalytic hydrogenation reaction of compound (20).

[0091] (Fourth step) This process is a method for producing compound (22) by a Suzuki-Miyaura coupling reaction between compound (21) and compound (15). The reaction conditions are the same as those for the fourth step of raw material synthesis 3.

[0092] (Fifth step) This process is a method for producing compound (23) by the oxidation reaction of compound (22). This reaction involves treating compound (22) in a reaction-inert solvent under cooling to heating, preferably from -20°C to 80°C, with an equal or excess amount of oxidizing agent for typically 0.1 hours to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used. Examples of solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, oxone, activated manganese dioxide, chromic acid, potassium permanganate, and sodium periodate. [Literature] The Chemical Society of Japan (ed.), "Experimental Chemistry Course," 5th edition, Vol. 17, Maruzen, 2004.

[0093] (Sixth step) This process is a method for producing compound (16) by an ipso substitution reaction between compound (23) and compound (24). The reaction conditions are the same as those for the first step of raw material synthesis 3. If compound (16) exhibits axial chirality, it may be obtained as a mixture of diastereomers, but each diastereomer can be isolated by a standard resolution procedure, such as ODS column chromatography or silica gel column chromatography.

[0094] (Raw material synthesis 5) [ka]

[0095] This method is a second method for producing the raw material compound (2).

[0096] (first step) This process is a method for producing compound (25) by deprotecting compound (23) through a catalytic hydrogenation reaction. The reaction conditions are the same as those for the sixth step of raw material synthesis 3.

[0097] (Second process) This process is a method for producing compound (26) by the reaction of compound (25) and compound (18). The reaction conditions are the same as those for the seventh step of raw material synthesis 3.

[0098] (Third step) This process is a method for producing compound (2) by an ipso substitution reaction between compound (26) and compound (24). The reaction conditions are the same as those for the first step of raw material synthesis 3. Note that compound (2) may have axial chirality and is obtained as a mixture of diastereomers, but PG 2The diastereomers of compound (2), in which the protecting group is , or the compound obtained by subjecting compound (2) to a deprotection reaction, can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. The reaction conditions for the deprotection reaction used here are the same as those described in Manufacturing Method 1.

[0099] (Raw material synthesis 6) [ka] (PG in the formula 4 PG 5 (This indicates a protecting group.)

[0100] This method is a method for producing raw material compound (3).

[0101] (first step) This process is a method for producing compound (28) by an amidation reaction between compound (7) and compound (27). The reaction conditions are the same as those for the third step of raw material synthesis 2.

[0102] (Second process) This process is a method for producing compound (29) by subjecting compound (28) to a deprotection reaction. The reaction conditions are the same as those described in Manufacturing Method 1.

[0103] (Third step) This process is a method for producing compound (31) by an amidation reaction between compound (29) and compound (30). The reaction conditions are the same as those for the third step of raw material synthesis 2.

[0104] (Fourth step) This process is a method for producing compound (32) by subjecting compound (31) to a deprotection reaction. The reaction conditions are the same as those described in Manufacturing Method 1.

[0105] (Fifth step) This process is a method for producing compound (3) by the reaction of compound (32) with a diazo transfer reagent. This reaction involves treating compound (32) in a reaction-inert solvent under cooling to heating, preferably from 0°C to 50°C, with an equal or excess amount of a diazotransfer reagent for typically 0.1 hours to 3 days. Examples of diazotransfer reagents are not particularly limited, but include trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or its salts, and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP). It may be advantageous to carry out the reaction in the presence of organic bases such as TEA, 4-dimethylaminopyridine (DMAP), 2,6-lutidine, and a catalytic amount of copper salts such as CuSO4. Examples of solvents include halogenated hydrocarbons such as THF and dichloromethane, MeCN, alcohols, water, and mixtures thereof. [Literature] J. Org. Chem. 2012, 77, p.1760-1764 Nature 2019, 574, pp. 86-89 Org. Biomol. Chem. 2014, 12, p.4397-4406

[0106] (Raw material synthesis 7) [ka] (LG in the formula 2 is a leaving group, PG 6 (This indicates a protecting group for NH.)

[0107] This manufacturing method is a method for producing raw material compound (1)-2 or raw material compound (1)-3 contained in raw material compound (1). Here, raw material compound (1)-3 is L 2 NR L1 The method for producing pyrrolidinediyl, piperidinediyl, or piperazinediyl is shown.

[0108] (first step) This process is a method for producing compound (2)-1 by the reaction of compound (17) and compound (33). The reaction conditions are the same as those for the seventh step of raw material synthesis 3.

[0109] (Second process) This process is a method for producing compound (2)-2 by hydrolyzing compound (2)-1. The reaction conditions are the same as those for the second step of raw material synthesis 2.

[0110] (Third step) This process is a method for producing compound (1)-2 by the amidation reaction of compound (32) and compound (2)-2. The reaction conditions are the same as those for the third step of raw material synthesis 2.

[0111] (Fourth step) This process is a method for producing compound (35) by an amidation reaction between compound (32) and compound (34). The reaction conditions are the same as those for the third step of raw material synthesis 2.

[0112] (5th process, 6th process) This process involves a deprotection reaction of compound (35) to produce compound (1)-3 by an amidation reaction between the compound obtained and compound (2)-2. The reaction conditions for the deprotection reaction are the same as those described in Manufacturing Method 1. The reaction conditions for the amidation reaction are the same as those for the third step of raw material synthesis 2.

[0113] (Raw material synthesis 8) [ka] (If Z is NH in the formula, A 1 A is a hydrogen atom, A 2 In the case of a 5-membered heteroarene diyl in which is a halogen and Z contains 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, A 1 When is a group selected from the group consisting of Cl, Br, and I, A 2 This indicates a boronic acid group, etc., A1 When is a boronic acid group, A 2 (This indicates a group selected from the group consisting of Cl, Br, and I.)

[0114] This method is for producing raw material compound (1)-4.

[0115] (first step) This process, when Z is NH, is a method for producing compound (38) by an ipso reaction or Buchwald-Hartwig amination reaction between compound (36) and compound (37). The reaction conditions for the Ipso reaction are the same as those for the first step of raw material synthesis 3. For references on the Buchwald-Hartwig amination reaction, see, for example, the following: J. Am. Chem. Soc., 2020, 142, p.15027-15037 Furthermore, in the case where Z is a five-membered heteroaryl compound containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, this process is a method for producing compound (38) by a Suzuki-Miyaura coupling reaction between compound (36) and compound (37). The reaction conditions are the same as those for the fourth step of raw material synthesis 3. For references regarding the reaction when Z is given by equation (V), you can refer to the following, for example. J. Org. Chem., 2000, 65, p.1516-1524 Chemical Communications 2014, 50, p.1867-1870 Bioorg. Med. Chem. Lett., 2001, 11, p.2061-2065

[0116] (Second process) This process is a method for producing compound (39) by the reaction of compound (38) and compound (17). The reaction conditions are the same as those for the seventh step of raw material synthesis 3. Furthermore, this process can also produce compound (39) by the Mitsunobu reaction between compound (38) and compound (17). For references on the Mitsunobu reaction, you can refer to the following, for example. Chem. Asian J. 2007, 2, p.1340 - 1355

[0117] (Third step) This process is a method for producing compound (40) by hydrolyzing compound (39). The reaction conditions are the same as those for the second step of raw material synthesis 2.

[0118] (Fourth step) This process is a method for producing compound (1)-4 by the amidation reaction of compound (40) and compound (29). The reaction conditions are the same as those for the third step of raw material synthesis 2.

[0119] (Raw material synthesis 9) [ka] (PG in the formula 7 PG is a protecting group. 8 PG 9 PG 10 The hydrogen atom or protecting group is the same or different, A 3 A is a hydrogen atom, carboxyl group or boronic acid group, etc. 4 This is a hydrogen atom, or a group selected from the group consisting of Cl, Br, and I, BLG 1 (This indicates a boronic acid group, etc.)

[0120] This manufacturing method is R 7 This is a method for producing a starting compound (7) in which is a group selected from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV).

[0121] (first step) This process is A 3 If R is a hydrogen atom, for example, 7This is a method for producing compound (45) by a Mizoroki-Heck reaction between compound (42), whose formula is (VI), and compound (41). This reaction uses equal amounts of compound (42) and compound (41), or an excess amount of one, and stirs the mixture in a reaction-inert solvent in the presence of a base and a palladium catalyst from room temperature under reflux, preferably from 20°C to 140°C, for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, but include ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidinion-2-one, ethyl acetate, water, and mixtures thereof. Examples of bases include tripotassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium(3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, and palladium(II) acetate. Furthermore, heating the mixture by microwave irradiation may be advantageous in order to facilitate the reaction. For references regarding the reaction, you can refer to the following, for example. Synthesis 2020, 52, p.2521-2527 PNAS 2016, 113, pp. 7124-7129 Alternatively, compound (45) may be produced by an Ullmann reaction between compound (42), which is a group selected from the group consisting of formulas (IX), (XX), (XXI), (XXII), and (XXIV), and compound (41). For references regarding the reaction, you can refer to the following, for example. Angew. Chem. Int. Ed., 2003, 42, p.5400-5449 Furthermore, this process is A 3 If it is a carboxyl group, for example R 7 This is a method for producing compound (45) by a decarboxylation coupling reaction between compound (42), whose formula is (VII), and compound (41). For references regarding the reaction, you can refer to the following, for example. Science, 2006, 313, pp. 662-664 Furthermore, this process is A 3 If it is a boronic acid group, for example, R 7 This method involves producing compound (45) by a Suzuki-Miyaura coupling reaction between compound (42), whose group is selected from the group consisting of formulas (VI), (VIII), and (XXIII), and compound (41). The reaction conditions are the same as those for the fourth step of raw material synthesis 3.

[0122] (Second process) This process is a method for producing compound (43) by a reaction in which the bromo group of compound (41) is replaced with a boronic acid group or the like. For references regarding the reaction, you can refer to the following, for example. Eur. J. Med. Chem., 2019, 162, p.407-422 J. Org. Chem. 2020, 85, 16, p.10966-10972 J. Am. Chem. Soc., 2010, 132, p.17701-17703

[0123] (Third step) This process is A 4 This method involves producing compound (45) by a Suzuki-Miyaura coupling reaction between compound (44) and compound (43), where is a group selected from the group consisting of Cl, Br, and I. The reaction conditions are the same as those for the fourth step of raw material synthesis 3. Furthermore, this process is A 4This method involves producing compound (45) by a Chan-Lam-Evans coupling reaction between compound (44), which is a group selected from the group consisting of formulas (IX), (XX), (XXI), (XXII), and (XXIV), for example, when is a hydrogen atom, and compound (43). For references regarding the reaction, you can refer to the following, for example. Adv. Synth. Catal. 2020, 362, p.3311-3331.

[0124] (Fourth step) This process is a method for producing compound (7) by subjecting compound (45) to a deprotection reaction. The reaction conditions are the same as those described in Manufacturing Method 1.

[0125] The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate, or crystalline polymorph, or as an amorphous solid. Salts of the compound of formula (I) can also be produced by conventional salt-making reactions. Isolation and purification are carried out using standard chemical procedures such as extraction, fractional crystallization, and various fractional chromatography techniques. Various isomers can be produced by selecting appropriate starting compounds, or separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods for racemates (e.g., fractional crystallization leading to diastereomer salts with optically active bases or acids, or chromatography using chiral columns, etc.), or they can be produced from appropriate optically active starting compounds. Furthermore, the compound of formula (I) or its intermediate may have axial chirality and may be obtained as a mixture of diastereomers. However, each diastereomer can be isolated by conventional resolution operations, such as resolution using octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

[0126] The pharmacological activity of the compound of formula (I) was confirmed by the following tests.

[0127] Test Example 1-1: Evaluation of KRAS degradation activity against the human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1. The KRAS degradation activity of the test compound was evaluated by measuring KRAS G12D expression levels using the sandwich ELISA method. AsPC-1 cells (ATCC, CRL-1682) were placed in 1.8 x 10⁶ wells. 4 To develop into cells, 90 μL of each seed was seeded into 96-well plates (IWAKI). Cell culture conditions were 37°C in the presence of 5% CO2 using RPMI1640 medium (Merck) containing 10% fetal bovine serum (Cytiva). The following day, 10 test compounds (ranging from 10 μM to 0.3 nM final concentrations) were diluted 100-fold in fresh culture medium and added to each well in 10 μL. The same procedure was performed for 4 wells. In addition, for sandwich ELISA plate preparation, capture antibody (anti-KRAS antibody, LS Bio), mixed with Phosphate Buffered Saline [PBS; Fujifilm Wako Pure Chemical Industries] at a 1,000-fold dilution, was added to each well of a MaxiSorp 384-well plate (Thermo Scientific) in 20 μL. After sealing, the plates were left to stand overnight at 4°C. 24 hours after treatment with the test compound, the culture supernatant was discarded, and 50 μL of cell lysate (prepared by adding 1 / 100 and 1 / 500 volumes of Halt Protease Phosphatese Inhibitor Cocktail [Thermo Scientific] and Benzonase Nuclease [Merck] to RIPA buffer [Thermo Scientific]) was immediately added to each well to lyse the cells. Then, the four wells treated in the same way were combined into one to prepare a total of 200 μL of cell lysate sample. For KRAS detection, MaxiSorp 384-well plates, which had been treated with capture antibody the previous day, were washed with PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 diluted 20-fold with deionized water) (25 μL twice) and then treated with blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) for 60 minutes before adding 20 μL of cell lysate sample to each well. For β-actin detection, cell lysate sample was added directly to each well of a MaxiSorp 384-well plate in 20 μL portions, sealed, and left to stand overnight at 4°C. The following day, the KRAS detection plate was washed with PBS containing 0.05% Tween-20. Then, 20 μL of anti-Ras (G12D Mutant Specific) antibody (Cell Signaling Technology), diluted 1,000-fold with blocking solution, was added to each well as the detection antibody, and the plate was left to stand at room temperature for 5 hours. After that, the supernatant was removed by centrifugation (using a centrifugal dehydrator; the supernatant was removed in the same manner hereafter), washed with PBS containing 0.05% Tween-20, and then 20 μL of anti-Rabbit IgG HRP-linked antibody (Cell Signaling Technology), diluted 1,000-fold with blocking solution, was added to each well as the secondary antibody, and the plate was left to stand at room temperature for 1 hour. The supernatant was removed by centrifugation of the plates, and after washing with PBS containing 0.05% Tween-20, 20 μL of BM chemiluminescent ELISA substrate (Merck) was added to each well, and the luminescence was measured using a 2103 EnVision (PerkinElmer). For β-actin detection, the plates were washed with PBS containing 0.05% Tween-20 and treated with blocking solution for 60 minutes. Then, 20 μL of anti-β-actin antibody (Abcam), diluted 1,000-fold with blocking solution, was added to each well as the detection antibody, and the plates were left to stand at room temperature for 5 hours. After that, the supernatant was removed by centrifugation of the plates, and after washing with PBS containing 0.05% Tween-20, 20 μL of anti-Mouse IgG HRP-linked antibody (Cell Signaling Technology), diluted 1,000-fold with blocking solution, was added to each well as the secondary antibody, and the plates were left to stand at room temperature for 1 hour. The supernatant was then removed by centrifugation of the plate, and after washing with PBS containing 0.05% Tween-20, 20 μL of BM chemiluminescent ELISA substrate was added to each well, and the luminescence was measured using EnVision. The signal value when DMSO was added, corrected for the amount of β-actin, was set to 100%, and the signal value when the compound of Example No. 7 (10 μM) was added was set to 0%, and the 50% decomposition value of the amount of KRAS (DC) was set to 50%. 50The molecular weight was calculated using a sigmoid-Emax model nonlinear regression analysis. The molecular weight of the test compounds was calculated as follows: Example No. 22: dihydrochloride, Examples Nos. 2-7, 9-12, and 14-18: trihydrochloride, Example No. 19: tetrahydrochloride, Example No. 21: pentahydrochloride, and for all other Example Nos. 21: the molecular weight of the free form that does not form a salt. The results for several test compounds of formula (I) are shown in Table 1.

[0128] [Table 1]

[0129] Test Example 1-2: Evaluation of KRAS degradation activity against the human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1. The KRAS degradation activity of the test compound was evaluated by measuring KRAS G12D expression levels using Cell ELISA. 2.0 x 10⁶ AsPC-1 cells per well 4 To develop into cells, 20 μL of each seed was seeded into a 384-well plate (Greiner bio-one). Cell culture conditions were 37°C in the presence of 5% CO2 using RPMI1640 medium containing 10% fetal bovine serum. The following day, 20 μL each of the test compounds (10 samples ranging from a final concentration of 10 μM to 0.3 nM), compound No. 26 (for examples No. 74 and 75, compound No. 8) at a final concentration of 10 μM as a positive control, and DMSO, the solvent of the test compounds, diluted 500-fold in fresh medium as a negative control, were added to each well and incubated overnight. The following day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (Fujifilm Wako Pure Chemical Industries) was added to each well. The cells were fixed by standing at room temperature for 30 minutes. After that, the supernatant was removed, and 20 μL of PBS containing 0.1% Triton X-100 (Amersham Biosciences) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed, and each well was washed by adding 25 μL of PBS and removing the supernatant. Washing was performed a total of two times. Next, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator; the same method was used for subsequent supernatant removals), and each well was washed by adding 25 μL of PBS and removing the supernatant. Washing was performed a total of two times. The supernatant was removed by centrifugation, and 20 μL of Intercept Blocking Buffer was added to each well. After standing at room temperature for 30 minutes, the supernatant was removed by centrifugation, and 20 μL each of a 1,000-fold diluted solution of anti-Ras (G12D Mutant Specific) antibody and anti-β-Actin antibody, prepared using the blocking buffer, was added to each well as the primary antibody, and the mixture was left to stand overnight at 4°C. The following day, the plate was centrifuged to remove the supernatant, and each well was washed by adding 25 μL of PBS and removing the supernatant. This washing was performed a total of two times. After removing the supernatant by centrifugation, 20 μL each of a 1,000-fold diluted solution of Donkey anti-Mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) and Goat anti-Rabbit IgG H&L (IRDye 800CW) (Li-COR Biosciences) was added to each well as secondary antibodies using blocking solution. After standing at room temperature for 1 hour, the supernatant was removed, and each well was washed by adding 25 μL of PBS and removing the supernatant. This washing was performed a total of two times. After removing the supernatant by centrifugation of the plate, the plate was air-dried at room temperature for at least 2 hours, and the fluorescence signals at 700 nm and 800 nm were measured using Aerius (LI-COR Biosciences). The signal value when DMSO was added, corrected for the signal value of β-actin, was set to 100%, and the signal value when the compound of Example No. 26 (10 μM) was added was set to 0%, and the 50% decomposition value of the KRAS amount (DC) was set to 50%. 50 The formula (I) was calculated using a sigmoid-Emax model nonlinear regression analysis. The molecular weight of the test compounds was calculated as follows: Example No. 30: trihydrochloride, Example No. 46: tetrahydrochloride, and other Example Nos. 46: molecular weight of the free form that does not form a salt. The results for several test compounds of formula (I) are shown in Table 2.

[0130] [Table 2]

[0131] Test Example 2: Evaluation of ERK phosphorylation inhibitory effect on the human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1. The inhibitory effect of the test compound on ERK phosphorylation was evaluated by measuring the phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is downstream of the KRAS signaling pathway, using Cell ELISA. 2.0 x 10⁶ AsPC-1 cells per well 4 To develop into cells, 36 μL / well was seeded into a 384-well plate (Greiner bio-one). Cell culture conditions were 37°C in the presence of 5% CO2 using RPMI1640 medium containing 10% fetal bovine serum. The following day, 4 μL each of the test compound (six concentrations ranging from 10 μM to 3.0 nM), 1 μM trametinib (a MEK inhibitor) as a positive control, and DMSO (the solvent for the test compound) as a negative control were diluted 100-fold in fresh medium and added to each well, followed by 24 hours of incubation. Immediately after incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque] diluted in PBS) was added to each well, and the cells were fixed by standing at room temperature for 90 minutes. Subsequently, the supernatant was removed by centrifugation (using a centrifugal dehydrator; the supernatant was removed in the same manner hereafter), and 20 μL of PBS containing 0.1% Triton X-100 was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation, and the same procedure was repeated. Next, 20 μL of PBS containing 0.5% SDS was added to each well, and after standing at room temperature for 30 minutes, the supernatant was removed by centrifugation. Subsequently, 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well and stood at room temperature for 1 hour. The supernatant was removed by centrifugation, and 10 or 15 μL of phosphorylated ERK (Thr202 / Tyr204) antibody (Phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204)(D13.14.4E) XP Rabbit mAb; Cell Signaling Technology), diluted 2,500 times with blocking solution, was added to each well as the primary antibody, and the mixture was left to stand overnight at 4°C. The following day, the plate was centrifuged to remove the supernatant, and each well was washed by adding 50 μL of PBS containing 0.05% Tween-20 and removing the supernatant by centrifugation. A total of three washes were performed. After washing, 15 μL of Goat anti-Rabbit IgG H&L (IRDye 800CW), diluted 1,000-fold with blocking solution, was added to each well as the secondary antibody and allowed to stand at room temperature for 1 hour. The supernatant was removed by centrifugation, and each well was washed three times with PBS containing 0.05% Tween-20 in the same manner as after the primary antibody reaction. After removing the supernatant by centrifugation, the plate was air-dried at room temperature for at least 3 hours, and the fluorescence signal at 800 nm was measured using Aerius. The signal value when DMSO is added is set to 100%, and the signal value when 1 μM trametinib is added is set to 0%, and the 50% inhibition value (IC) is defined. 50 The formula (I) was calculated using a sigmoid-Emax model nonlinear regression analysis. The molecular weight of the test compounds was calculated as follows: Example No. 22: dihydrochloride, Examples Nos. 2-7, 9-12, 14-18, and 30: trihydrochloride, Examples Nos. 19 and 46: tetrahydrochloride, Example No. 21: pentahydrochloride, and for all other Example Nos. 21: molecular weight of the free form that does not form a salt. The results for several test compounds of formula (I) are shown in Table 3.

[0132] [Table 3]

[0133] Test Example 3: Evaluation of anchorage-independent cell proliferation inhibitory effect on the human G12D mutant KRAS-positive pancreatic cancer cell line AsPC-1. The anchorage-independent inhibitory effect of the test compound on cell proliferation was evaluated using spheroid 3D culture. AsPC-1 cells 5 x 10⁶ per well 2 To ensure cell development, 36 μL / well of cells were seeded into a 384-well plate with a low cell-adsorption U-bottom (PrimeSurface: Sumitomo Bakelite Co., Ltd.). Cell culture was performed under the same conditions as in Experimental Example 2. The following day, the test compound (six concentrations ranging from 10 μM to 3.0 nM) and DMSO, the solvent for the test compound, were diluted 100-fold in fresh medium and added to each well in 4 μL increments as a negative control. After incubation for 6 days at 37°C in the presence of 5% CO2, 20 μL of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring at room temperature for 1 hour using a plate mixer (FINEPCR), the luminescence signal was measured using an ARVO X3 (PerkinElmer). The signal value in DMSO treatment is set to 100%, and the signal value in cell-free medium only is set to 0%, with the 50% inhibition value (IC) being defined. 50The formula (I) was calculated using a sigmoid-Emax model nonlinear regression analysis. The molecular weight of the test compounds was calculated as follows: Example No. 22: dihydrochloride, Examples Nos. 2-7, 9-12, 14-18, and 30: trihydrochloride, Examples Nos. 19 and 46: tetrahydrochloride, Example No. 21: pentahydrochloride, and for all other Example Nos. 21: molecular weight of the free form that does not form a salt. The results for several test compounds of formula (I) are shown in Table 4.

[0134] [Table 4]

[0135] Test Example 4: Evaluation of antitumor activity in human G12D mutant KRAS-positive pancreatic cancer strain PK-59-bearing mice. PK-59 cells (RIKEN BRC, RCB1901) were cultured at 37°C in RPMI1640 medium containing 10% fetal bovine serum in the presence of 5% CO2. The PK-59 cells were harvested, suspended in PBS, and an equal volume of Matrigel (Becton Dickinson) was added to form a 1.0 x 10⁶ cell culture. 7 ~2.0x10 7 Cell suspension prepared at 1 / mL was used to feed 4-6 week old male nude mice (CAnN.Cg-Foxn1). nuThe test compound was implanted subcutaneously in a volume of 100 μL. Approximately two weeks after implantation, the animals were divided into groups so that the tumor volume and body weight were approximately the same for each group, and administration of the test compound was started the following day. The experiment was conducted with 5 animals each in the solvent group and the test compound administration group. The compounds for Examples 8, 48, and 70 were dissolved in ethanol (Fujifilm Wako Pure Chemical Industries), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Chemical), 50% (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) aqueous solution (ROQUETTE), HCO-40 (Nikko Chemicals), and 1M sodium hydroxide aqueous solution (Kanto Chemical) in a liquid-to-volume ratio of 4:8, 4.4:1, 1:1, 9, and 0.5. The compounds in Examples 22 and 26 were dissolved in propylene glycol (Fujifilm Wako Pure Chemical Industries), Tween 80 (Nacalai Tesque), and Otsuka saline solution (Otsuka Pharmaceutical) in a liquid-to-liquid ratio of 6.7:3.3:90. The compound in Example 39 was dissolved in propylene glycol, ethanol, 50% HP-βCD aqueous solution, HCO-40, and 5% glucose solution in a liquid-to-liquid ratio of 10:8:10:10:62. The test compound or solvent dissolved in each solvent was administered intravenously. The administration was performed twice, once a week apart. Tumor diameter and body weight were measured twice a week. The following formula was used to calculate the tumor volume. [tumor volume (mm²] 3 )] = [Longest diameter of tumor (mm)] x [Shortest diameter of tumor (mm)] 2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated by setting the tumor volume of the test compound administration group on the day before administration to 100% inhibition and the tumor volume of the solvent group two weeks after the first administration to 0% inhibition. In addition, if the tumor volume of the test compound administration group was lower than the tumor volume on the day before administration, the tumor regression rate (%) of the test compound was calculated by setting the tumor volume on the day before administration to 0% regression and a tumor volume of 0 to 100% regression. The molecular weight of the test compound was calculated as follows: Example No. 22: dihydrochloride salt, Example No. 22: molecular weight of the free form that does not form a salt. The results for several test compounds of formula (I) are shown in Table 5.

[0136] [Table 5]

[0137] Test Example 5: Evaluation of KRAS G12D / SOS / c-Raf complex formation inhibitory effect The inhibitory effect of the test compound on the complex formation of human recombinant KRAS G12D, SOS, and c-Raf proteins was investigated using time-resolved fluorescence-fluorescence resonance energy transfer (TR-FRET). Biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 μL; 400 nM) dissolved in assay buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, pH 7.0) and the test compound were added in 2.5 μL volumes from 40,000 nM to 40 nM. To this, c-Raf (amino acid region 51-131) GST (2.5 μL; 130 nM) containing Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μL; 1.3 μM) and GTP (Sigma-Aldrich; 2 μM) was added and the mixture was allowed to stand at room temperature for 1 hour. Subsequently, a mixture (10 μL) of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (PerkinElmer; 100 ng / mL) was added, and the fluorescence intensity at 620 nm and 665 nm was measured using EnVision 2104 (PerkinElmer) under excitation wavelength conditions of 337 nm. After standardizing the values ​​using the fluorescence intensity at the reference wavelength of 620 nm, the signal value under solvent treatment was defined as 0% inhibition, and the signal value without GTP addition was defined as 100% inhibition, and the 50% inhibition concentration (IC) was defined. 50 The result was calculated using a sigmoid-emax model nonlinear regression analysis.

[0138] The results of the above tests confirmed that several compounds of formula (I) degrade G12D mutant KRAS (Test Examples 1-1 and 1-2). Furthermore, G12D mutant KRAS inhibitory activity was confirmed (Test Example 5). In addition, several compounds of formula (I) inhibited the phosphorylation of ERK, which is downstream of the KRAS signaling pathway (Test Example 2). Moreover, several compounds of formula (I) inhibited cell proliferation against human G12D mutant KRAS-positive pancreatic cancer lines (Test Example 3), and antitumor activity was confirmed in mice carrying human G12D mutant KRAS-positive pancreatic cancer lines (Test Example 4). Therefore, compounds of formula (I) can be used for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.

[0139] A pharmaceutical composition containing one or more compounds of formula (I) or salts thereof as an active ingredient can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers. Administration may be by oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or by parenteral administration in the form of injections such as intra-articular, intravenous, or intramuscular injections, transmucosal preparations, or inhalations.

[0140] For oral administration, solid compositions such as tablets, powders, and granules are used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a gastric-soluble or enteric-soluble film as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, or elixirs, and generally include inert diluents such as purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary agents such as solubilizers, wetting agents, and suspensions, as well as sweeteners, flavoring agents, fragrances, and preservatives.

[0141] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as ethyl alcohol (EtOH). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These are sterilized, for example, by filtration through a bacterial retention filter, formulation with a bactericide, or irradiation. Alternatively, sterile solid compositions may be prepared and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0142] Inhalants and nasal preparations, and other transmucosal preparations, are used in solid, liquid, or semi-solid form and can be manufactured according to conventionally known methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, and thickeners, may be added as appropriate. Administration can be carried out using a suitable inhalation or blowing device. For example, known devices such as metered-dose inhalation devices or sprayers can be used to administer the compound alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers may be for single or multiple doses, and can utilize dry powder or powder-containing capsules. Alternatively, they may be in the form of a pressurized aerosol spray using a suitable excipient, such as a suitable gas like chlorofluoroalkane or carbon dioxide.

[0143] For oral administration, the appropriate daily dose is approximately 0.001 to 100 mg / kg per body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered in one dose or divided into two to four doses. For intravenous administration, the appropriate daily dose is approximately 0.0001 to 10 mg / kg per body weight, administered in one to several doses per day. For transmucosal administration, approximately 0.001 to 100 mg / kg per body weight is administered in one to several doses per day. The dosage should be determined appropriately on an individual basis, taking into account symptoms, age, sex, etc.

[0144] Depending on the route of administration, dosage form, site of administration, and type of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in some embodiments, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof that are active ingredients.

[0145] The compound of formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases in which the aforementioned compound of formula (I) is considered effective. This combination may be administered simultaneously, separately and consecutively, or at desired time intervals. The simultaneously administered formulation may be a combination formulation or formulated separately. [Examples]

[0146] The method for producing the compound of formula (I) will be described in more detail below based on the examples. However, the present invention is not limited to the compounds described in the following examples. Furthermore, the methods for producing the raw materials are shown in the production examples. Moreover, the method for producing the compound of formula (I) is not limited to the production methods of the specific examples shown below; the compound of formula (I) can also be produced by a combination of these production methods or by methods obvious to those skilled in the art.

[0147] In this specification, compound naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for naming compounds.

[0148] Furthermore, for convenience, concentration is expressed as M in mol / L. For example, a 1M sodium hydroxide solution means a 1 mol / L sodium hydroxide solution.

[0149] As used herein, "amorphous solid form" includes both forms that do not show peaks in powder X-ray diffraction (XRD) patterns and forms with low crystallinity. XRD was performed using an Empyrean tube with the following conditions: tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step size: 0.013°, wavelength: 1.5418 Å, and measurement diffraction angle range (2θ): 2.5~40°.

[0150] Manufacturing Example 1 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was cooled on ice. Then, DIPEA (240 mL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (48 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total volume of the solution was approximately 400 mL. A mixed solvent (hexane / ethyl acetate = 1 / 4, 1000 mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered to obtain (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (123 g) as a solid.

[0151] Manufacturing Example 2 (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL), and DABCO (1.15 g) were mixed with cesium carbonate (50.3 g) while stirring at room temperature, and the mixture was stirred overnight at room temperature under an argon atmosphere. Approximately 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was filtered off while being washed with water, and dried overnight under reduced pressure to obtain (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (32.8 g) as a solid.

[0152] Manufacturing Example 5 Under an argon stream, a mixture of (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (11.9 g), benzyl alcohol (2.37 g), and THF (40 mL) was mixed with tBuOK (2.54 g) under ice cooling and stirred at the same temperature for 1.5 hours. Ice water and saturated ammonium chloride aqueous solution were added to the reaction mixture, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixed solvent of hexane / ethyl acetate (6 / 1) was added to the resulting residue and stirred for a while. The precipitated solid was filtered and dried to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (11.8 g) as a solid.

[0153] Manufacturing Example 8 Under an argon atmosphere, (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropyl Boronic acidA mixture of (1.27 g), tripotassium phosphate (5.67 g), and PdCl2(dppf)·CH2Cl2 (600 mg) was stirred at 100°C for 3 hours. After allowing the reaction mixture to cool to room temperature, the solution was concentrated under reduced pressure. Saturated sodium chloride aqueous solution was added to the resulting residue and extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (3.8 g) as a foamy solid.

[0154] Manufacturing Example 11 (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (3.15 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.92 g), tripotassium phosphate (4.1 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.12 g) A mixture of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.2 g), DOX (40 mL), and water (8 mL) was degassed and purged with argon while stirring at room temperature, and then stirred at 100°C for 2.5 hours under an argon atmosphere. Water (approximately 150 mL) was added to the reaction mixture cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain fractions containing (1) a low-polarity diastereomer mixture (peaks 1 and 2; peaks 1 and 2 were homoaxially chiral) and (2) a high-polarity diastereomer mixture (peaks 3 and 4; peaks 3 and 4 were homoaxially chiral). Of these, fractions containing a low-polarity diastereomer mixture (peak-1,2, same-axis chiral) were collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.42 g) as a foamy solid.Furthermore, fractions containing a highly polar diastereomer mixture (peaks 3, 4, same-axis chirality) were collected to obtain (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.37 g) as a foamy solid. A low-polarity diastereomer mixture was used in the following reaction.

[0155] Manufacturing Example 14 To a solution of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (10 g) in MeOH (200 mL), 10% Pd / C (50% hydrated, 2 g) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (8.11 g) as a foamy solid.

[0156] Manufacturing Example 22 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (7.48 g), DMF (70 mL), and 1-(chloromethyl)-4-ethynylbenzene (1.9 g) were mixed with cesium carbonate (6.2 g) while stirring at room temperature, and the mixture was stirred at 60°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to cool to room temperature, ice water and saturated ammonium chloride aqueous solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and the resulting solid was filtered to obtain (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (8.12 g) as a foamy solid.

[0157] Manufacturing example 32 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.3 g) was added to a CH2Cl2 (13 mL) solution, and m-chloroperbenzoic acid (approximately 30% hydrated, 358 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Under ice cooling, a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The aqueous layer and organic layer were separated, and the obtained aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.32 g) as an oily substance.

[0158] Manufacturing example 34 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.32 g), DMAc (15 mL), and 4-ethyl-3-hydroxypyridine (525 mg) were mixed with cesium carbonate (1.9 g) and DABCO (160 mg) at room temperature and stirred under a nitrogen atmosphere at 80°C for 2 hours and then at 100°C for 2 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-[(4-ethylpyridine-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (774 mg) as an oily substance.

[0159] Manufacturing example 36 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (10 g) and CH2Cl2 (150 mL) were mixed and m-chloroperbenzoic acid (approximately 30% hydrated, 3.3 g) was added under ice cooling and stirred at the same temperature for 3 hours. Saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution were added to the reaction mixture under ice cooling and stirred for a while. The aqueous layer and organic layer were separated, and the obtained aqueous layer was extracted with CH2Cl2. The obtained organic layers were mixed and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the resulting solution was concentrated under reduced pressure to obtain the oxidized product as a foamy solid. The resulting foamy solid was dissolved in THF (100 mL), and under an argon atmosphere, while cooling in an ice / MeOH bath, 4-hydroxypiperidine-1-carboxylic acid 2-(trimethylsilyl)ethyl (4.17 g) and tBuOK (2.2 g) were added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, saturated ammonium chloride aqueous solution, water, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain fractions containing (1) a low-polarity diastereomer mixture (peaks 1 and 2; peaks 1 and 2 are homoaxially chiral) and (2) a high-polarity diastereomer mixture (peaks 3 and 4; peaks 3 and 4 are homoaxially chiral). Of these, fractions containing a low-polarity diastereomer mixture (peak-1,2, same-axis chiral) were collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (3.77 g) as an oily substance.Furthermore, fractions containing a highly polar diastereomer mixture (peaks 3, 4, monoaxially chiral) were collected to obtain (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.75 g) as a solid. A low-polarity diastereomer mixture was used in the following reaction.

[0160] Manufacturing example 37 Under an argon atmosphere, a mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethanesulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (935 mg), (3S)-oxolan-3-ol (163 μL), and THF (10 mL) was mixed with tBuOK (269 mg) under cooling in an ice / MeOH bath, and stirred at room temperature for 3 hours. Under ice cooling, saturated ammonium chloride aqueous solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain fractions containing (1) a low-polarity diastereomer mixture (peaks 1 and 2; peaks 1 and 2 are monoaxially chiral) and (2) a high-polarity diastereomer mixture (peaks 3 and 4; peaks 3 and 4 are monoaxially chiral). Of these, the fraction containing the low-polarity diastereomer mixture (peaks 1 and 2, monoaxially chiral) was collected to obtain (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-{[(3S)-oxolan-3-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (346 mg) as a solid. Furthermore, fractions containing a highly polar diastereomer mixture (peaks 3, 4, same-axis chirality) were collected to obtain (1S, 4S)-5-[8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-{[(3S)-oxolan-3-yl]oxy}quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (329 mg) as a solid. A low-polarity diastereomer mixture was used in the following reaction.

[0161] Manufacturing example 40 (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (4.24 g), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (2.30 g), sodium ascorbate (1.45 g), tert-butyl alcohol (35 mL), THF (35 mL), and water (35 mL) To a mixture of (mL), anhydrous copper(II) sulfate (389 mg) was added at room temperature and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl(5.62 g) was obtained as a solid.

[0162] Manufacturing example 51 Under an argon atmosphere, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamate} A mixture of tert-butyl (1.1 g) of tert-butyl (1.1 g) of THF (22 mL) and tetra-n-butylammonium fluoride (2.57 mL, 1 M THF solution) was mixed with acetic acid (90 μL) at room temperature and stirred at 60°C for 15 hours. After cooling to room temperature, ethyl acetate and saturated ammonium chloride aqueous solution were added and liquid-liquid separated. The aqueous layer was extracted with ethyl acetate / methanol (10 / 1), the combined organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl(951) (mg) was obtained as a solid.

[0163] Manufacturing example 52 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (250 mg), oxetane-3-one (43 A mixture of (1S,4S)-5-(6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazo)]-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazo)]-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazo)] 220 mg of tert-butyl diazepam (1-(oxetan-3-yl)piperidine-4-yl)oxyquinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate was obtained as a solid.

[0164] Manufacturing example 53 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (250 mg), trifluoromethanesulfonic acid 2,2-difluoroethyl (124 mg) A mixture of (1S,4S)-5-(6-cyclopropyl-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy C-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (196 mg) was obtained as a solid.

[0165] Manufacturing example 54 To a solution of (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-3-methylbutanoate (190 mg) in CH2Cl2 (12 mL), thionyl chloride (500 μL) was added under an argon atmosphere and ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the resulting residue, DMF (7 mL), (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (450 mg), and cesium carbonate (260 mg) were added under ice cooling, and the mixture was stirred overnight at 60°C under an argon atmosphere. The reaction mixture was filtered through Celite, and the residue on the Celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-({2-[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (670 mg) as a foamy solid.

[0166] Manufacturing example 56 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-({2-[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]-1-oxo-2,3-dihydro-1H-isoindole-5-yl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (670 mg) was added to a 7 mL solution of MeOH, to which a 1 M sodium hydroxide aqueous solution (2.5 mL) was added under ice cooling and stirred at room temperature for 3 days. After neutralization with the addition of 1 M hydrochloric acid (2.5 mL) under ice cooling, CHCl3 and water were added and the solution was separated, and the aqueous layer was extracted with CHCl3. The combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH), and then again by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain (2S)-2-{5-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-3-methylbutanoic acid (372 mg) as a foamy solid.

[0167] Manufacturing example 61 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (3.97 g) was added to 1,2-dichloroethane (60 mL) and trimethyltin(IV) hydroxide (3.35 g) at room temperature, and the mixture was stirred at 80°C for 18 hours. After cooling to room temperature, hydrochloric acid (1M, 60 mL) was added, and the mixture was extracted with CHCl3 / MeOH(9 / 1). The organic layer was washed with 1M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (3.26 g) as a solid.

[0168] Manufacturing example 63 (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (150 mg), 3-{4-[(1R)-1-amino-2-hydroxyethyl]phenyl}-1,3-oxazolidine-2-one n hydrochloride (60 mg), DIPEA (70 μL), DMF (3 To a mixture of (mL), HATU (70 mg) was added under ice cooling and stirred for 1 hour under ice cooling. Water, saturated sodium chloride aqueous solution, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl(173) (mg) was obtained as a solid.

[0169] Manufacturing example 66 A mixture of (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (6.5 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (7.6 g), triphenylphosphine (0.53 g), potassium acetate (4.9 g), DOX (120 mL), and palladium acetate (0.23 g) was degassed, replaced with argon gas, and stirred overnight at 115°C. The reaction solution, cooled to room temperature, was filtered by Celite while washing with a small amount of dioxane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[(oxan-4-yl)oxy]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (5.47 g) as a foamy solid.

[0170] Manufacturing example 67 (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[(oxan-4-yl)oxy]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.52 g), (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (0.84 g), tripotassium phosphate (1.85 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.15 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.27 g), DOX (20 mL), and water (4 mL) were added sequentially. Degassing / argon gas substitution was performed while stirring at room temperature, and the mixture was stirred at 90°C for 5 hours under an argon atmosphere. It was then stirred at 100°C for 7 hours. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain fractions containing (1) a low-polarity diastereomer (peak-1) and (2) a high-polarity diastereomer (peak-2). Of these, the fraction containing the low-polarity diastereomer (peak-1) was collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (580 mg) as a foamy solid.Furthermore, fractions containing the highly polar diastereomer (peak-2) were collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (360 mg) as a foamy solid. The low-polarity diastereomer was used in the following reaction.

[0171] Manufacturing example 68 Under a nitrogen atmosphere, a solution of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (250 mg) in DMF (5 mL) was mixed with cesium carbonate (180 mg) and chloro(methoxy)methane (35 μL) under ice cooling, and stirred at room temperature for 15 hours. Under ice cooling, cesium carbonate (260 mg) and chloro(methoxy)methane (50 μL) were added, and the mixture was stirred at room temperature for a further 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[3-fluoro-5-(methoxymethoxy)-2-methylphenyl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (186 mg) as an oily substance.

[0172] Manufacturing example 69 Under an argon atmosphere, a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (4.43 g), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.67 g), potassium carbonate (3.87 g), DOX (80 mL), and water (8 mL) was mixed with PdCl2(dppf)·CH2Cl2 (1.14 g) and stirred at 100°C for 16 hours. After cooling to room temperature, ethyl acetate was added, filtered by Celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain {(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carbamate tert-butyl (3.74 g) as a solid.

[0173] Manufacturing example 71 To a solution of {(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carbamate tert-butyl (3.34 g) in CH2Cl2 (25 mL) and MeOH (25 mL), hydrogen chloride (4M DOX solution, 25.6 mL) was added under cooling to -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]ethane-1-ol n-hydrochloride (3.06 g) as a solid.

[0174] Manufacturing example 73 A mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]ethane-1-ol n-hydrochloride (3.43 g), (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.81 g), and DMF (40 mL) was mixed with DIPEA (7.8 mL) under ice cooling, then HATU (4.5 g) was gradually added under ice cooling, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 1 hour. Under ice cooling, water, saturated sodium chloride aqueous solution, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, then extracted with ethyl acetate / isopropyl alcohol (9 / 1), the organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl (5.01 g) as an oily substance.

[0175] Manufacturing example 76 (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl (5.01 g) was dissolved in CH2Cl2 (35 mL) and MeOH (30 mL), to which hydrogen chloride (4M DOX solution, 28 mL) was added under cooling to -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide n hydrochloride (4.71 g) as a solid.

[0176] Manufacturing example 79 (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (3.81 g), N-(tert-butoxycarbonyl)-L-valine (2.16 g), and DMF (45 mL) were mixed with DIPEA (6.2 mL), and then HATU (3.61 g) was gradually added under ice cooling. The mixture was stirred under ice cooling for 1 hour and then at room temperature for 1 hour. Under ice cooling, water, saturated sodium chloride aqueous solution, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, then with ethyl acetate / isopropyl alcohol (9 / 1), and the combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (4.43 g) as a solid.

[0177] Manufacturing example 83 N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}L-prolineamide (4.43 g) was dissolved in CH2Cl2 (35 mL) and MeOH (35 mL). Hydrogen chloride (4M DOX solution, 20 mL) was added under cooling to -20 to -15°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}L-prolineamide n hydrochloride (4.21 g) as a solid.

[0178] Manufacturing example 88 A mixture of L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), and MeCN (20 mL) was gradually added dropwise over 10 minutes or more to a MeCN (5 mL) solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (1.06 g) under ice cooling, and the mixture was stirred under ice cooling for 5 hours. Water, saturated sodium chloride aqueous solution, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (1.07 g) as a solid.

[0179] Manufacturing example 93 A mixture of L-valine methyl hydrochloride (1.96 g), MeCN (45 mL), and DIPEA (5 mL) was mixed with 3.00 g of 4-bromo-2-(bromomethyl)benzoate under water cooling. The mixture was slowly heated to 80°C and stirred for 2 days. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / ethyl acetate) to obtain (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-3-methylbutanoate methyl (2.86 g) as a solid.

[0180] Manufacturing example 94 Under an argon atmosphere, a mixture of (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-3-methylbutanoate (600 mg), (2-trimethylsilyl)-ethoxymethyltrifluoroborate potassium (876 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (151 mg), sodium carbonate (390 mg), DOX (9 mL), and water (1.8 mL) was mixed with palladium acetate (41 mg) at room temperature and stirred at 130°C for 4 hours under microwave irradiation. After cooling to room temperature, ethyl acetate was added, followed by filtration with Celite and washing with ethyl acetate. Water was added to the resulting filtrate and liquid-liquid was separated, and the organic layer was washed with saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain the coupling reaction product (600 mg). Trifluoroacetic acid (2.1 mL) was added to a CH2Cl2 (4.2 mL) solution of the obtained coupling reaction product under ice cooling and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-3-methylbutanoate methyl (190 mg) as a solid.

[0181] Manufacturing example 95 Under an argon atmosphere, a mixture of ethyl 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl]butanoate (190 mg), 4-bromobenzyl alcohol (100 mg), PdCl2(dppf)·CH2Cl2 (45 mg), and tripotassium phosphate (227 mg) was mixed with DOX (2 mL) and water (0.4 mL), and stirred at 100°C for 12 hours. After the reaction mixture cooled to room temperature, it was filtered through Celite and the Celite was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain ethyl 2-{4-[4-(hydroxymethyl)phenyl]-1H-pyrazole-1-yl}-3-methylbutanoate (157 mg) as an oily substance.

[0182] Manufacturing example 96 Under an argon atmosphere, a solution of 2,2,6,6-tetramethylpiperidine (4.4 mL) in THF (80 mL) was cooled with dry ice-MeOH refrigerant (-78°C), and n-butyllithium (1.57 M hexane solution, 15.2 mL) was added dropwise, and the mixture was stirred under ice cooling for 1 hour. The reaction mixture was cooled with dry ice-MeOH refrigerant, and a solution of (3-bromo-5-fluorophenoxy)(tert-butyl)di(methyl)silane (5.21 g) in THF (20 mL) was added, and the mixture was stirred at the same temperature for 1 hour. Methyl iodide (2.2 mL) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was stirred while raising the temperature to room temperature. Ethyl acetate was added to the reaction mixture for extraction, and the organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (5.13 g) as an oily substance.

[0183] Manufacturing example 97 To a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (500 mg), N-methyl-2-nitrobenzenesulfonamide (376 mg), tri-n-butylphosphine (0.51 mL), and THF (7 mL), 1,1'-azobis(N,N-dimethylformamide) (353 mg) was gradually added under ice cooling, and the mixture was stirred at room temperature for 8 hours. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, water, and saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate tert-butyl (667 mg) as a solid.

[0184] Manufacturing example 98 Under an argon atmosphere, a mixture of {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate tert-butyl (665 mg), 4-methyl-1,3-thiaazole (235 μL), potassium acetate (253 mg), and DMAc (13 mL) was mixed with palladium acetate (29 mg) and stirred at 100°C for 16 hours. After cooling to room temperature, ethyl acetate and water were added, and the insoluble matter was filtered off using Celite. The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate (268 mg) as a solid.

[0185] Manufacturing example 99 Under an argon atmosphere, 130 mg of tert-butyl {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamate, 84 mg of potassium carbonate, and 1.3 mL of DMF were mixed with 82 μL of 4-tert-butylbenzenethiol at room temperature and stirred for 3 hours at room temperature. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain 60 mg of tert-butyl {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamate as an oily substance.

[0186] Manufacturing example 100 A mixture of {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate tert-butyl (55 mg) and THF (1 mL) was mixed with formaldehyde (37% aqueous solution, 26 μL) under ice cooling and stirred for 10 minutes under the same conditions. Sodium triacetoxyborohydride (67 mg) was then added and stirred at room temperature for 1 hour. After dilution with CHCl3, saturated sodium bicarbonate aqueous solution was added and stirred for a while, and the aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH(5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to obtain {(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate tert-butyl (75 mg) as an oil.

[0187] Manufacturing Example 102 A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL), and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred overnight at 100°C under an argon atmosphere. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and filtered by Celite. The filtrate was washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate tert-butyl (3.21 g) as an oily substance.

[0188] Manufacturing Example 103 Under an argon atmosphere, a mixture of {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate tert-butyl (3.21 g), 5-bromo-1,3-thiaazole-4-carboxylate methyl ester (2.6 g), tripotassium phosphate (3.8 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (730 mg), DOX (30 mL), and water (6 mL) was mixed with palladium acetate (200 mg) at room temperature and stirred at 100°C for 3 hours. After cooling to room temperature, ethyl acetate was added and the mixture was washed with water and saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and insoluble matter was filtered off and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate methyl (1.48 g) as a solid.

[0189] Manufacturing Example 104 Under a nitrogen atmosphere, 11 mL of diisobutylaluminum hydride (1 M toluene solution) was added dropwise to a 20 mL solution of methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiaazole-4-carboxylate in CH2Cl2 under ice cooling, and the mixture was stirred for 1 hour under ice cooling. MeOH was added under ice cooling to stop the reaction, and 60 mL of 10% aqueous potassium sodium tartrate solution and CHCl3 were added and the mixture was stirred overnight. The mixture was separated, the aqueous layer was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was dissolved in 10 mL of MeOH, and sodium borohydride (350 mg) was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Water was added, and the mixture was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain tert-butyl [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazole-5-yl]phenyl}ethyl]carbamate (588 mg) as a solid.

[0190] Manufacturing Example 106 To a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (1 g), 2,2-dimethoxypropane (3.3 mL), and acetone (15 mL), boron trifluoride diethyl ether complex (26 μL) was added and the mixture was stirred at room temperature for 1 hour. TEA (66 μL) was added and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate tert-butyl (1.09 g) as a solid.

[0191] Manufacturing Example 107 To a solution of (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate tert-butyl (300 mg) and 1,3-oxazolidine-2-one (183 mg) in DOX (1.69 mL), copper(I) iodide (32 mg), racemic-(1R,2R)-cyclohexane-1,2-diamine (20 μL), and potassium carbonate (290 mg) were added at room temperature. The mixture was stirred under microwave irradiation at 140°C for 2 hours and then at 150°C for 1 hour. Ethyl acetate and water were added, and the mixture was filtered by Celite. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3-oxazolidined-3-yl)phenyl]-1,3-oxazolidined-3-carboxylate tert-butyl (120 mg) as a solid.

[0192] Manufacturing example 109 To a solution of 1-(4-bromophenyl)-2-fluoroethanone (2.7 g) and (S)-2-methylpropane-2-sulfinamide (3.03 g) in THF (27 mL), tetraisopropyl orthotitanate (11.1 g) was added and the mixture was stirred at 40°C for 12 hours. Under ice cooling (0-5°C), BH3·THF complex (1 M THF solution, 18.4 mL) was added and the mixture was stirred for 2 hours. After stopping the reaction by adding water, the mixture was filtered with Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and insoluble matter was filtered off. The solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain (S)-N-[(1R)-1-(4-bromophenyl)-2-fluoroethyl]-2-methylpropane-2-sulfinamide (3.2 g) as an oil.

[0193] Manufacturing example 156 Under a nitrogen atmosphere and ice-cooled conditions, a solution of (4-ethynyl-3-fluorophenyl)methanol (110 mg) in CH2Cl2 (2 mL) was mixed with DIPEA (200 μL), followed by methanesulfonyl chloride (80 μL). The reaction mixture was stirred overnight at room temperature, then water was added and the mixture was extracted with CHCl3. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to obtain 4-(chloromethyl)-1-ethynyl-2-fluorobenzene (122 mg) as an oil.

[0194] Manufacturing example 189 (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2-hydroxyethyl)amino]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (49 mg), tBuOH (0.5 mL), THF (0.5 mL), and water (0.5 mL) are mixed at room temperature with (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}L-prolineamide (33 mg), copper(I) iodide (7 mg), and sodium ascorbate (21 mg) Add mg of the solution and stir at 50°C for 3 hours. Pour ice, a 2% aqueous solution of disodium ethylenediaminetetraacetate, and a saturated aqueous solution of sodium chloride into the reaction vessel and extract three times with CH2Cl2. The combined organic layer was dried over anhydrous magnesium sulfate. After filtering off insoluble matter and concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH). (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2-hydroxyethyl)amino]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl(62 (mg) was obtained as a solid.

[0195] Manufacturing example 238 Under an argon atmosphere, bis(tri-tert-butylphosphine)palladium (0) (18 mg) was added to a mixture of 4-methyl-1,3-oxaazole-5-carboxylic acid (178 mg), tetra-n-butylammonium chloride (195 mg), (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidined-3-carboxylic acid tert-butyl (250 mg), cesium carbonate (344 mg), and DMF (2.5 mL). The mixture was stirred at 170°C for 30 minutes under microwave irradiation. After cooling to room temperature, the mixture was diluted with ethyl acetate, insoluble matter was removed by Celite filtration, the filtrate was washed with water and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazolidone-5-yl)phenyl]-1,3-oxazolidined-3-carboxylate tert-butyl (215 mg) as a solid.

[0196] Manufacturing example 239 (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidined-3-carboxylate tert-butyl (858 mg), 2-methyl-1H-imidazole (500 mg), copper(I) iodide (95 mg), quinoline-8-ol (138 mg), and potassium carbonate (670 mg) were suspended in DMSO (10 mL) and reacted at 150°C for 3 hours under microwave irradiation in an argon atmosphere. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(2-methyl-1H-imidazole-1-yl)phenyl]-1,3-oxazolidined-3-carboxylate tert-butyl (500 mg) as an oily substance.

[0197] Manufacturing example 245 A mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL), and CH2Cl2 (1880 mL) was mixed with 1,1',1''-(chloromethanetriyl)tribenzene (335 g) at room temperature and stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1.5 L) to separate the organic and aqueous layers, and the aqueous layer was extracted three times with CH2Cl2 (400 mL). The combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue and powdered (0°C, 2 hours), then filtered and dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

[0198] Manufacturing example 246 To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL), lithium diisopropylamide (2 M THF solution, 214.28 mL) was added at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 hours. Methyl iodide (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to stop the reaction, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was mixed with ethyl acetate (50 mL) / petroleum ether (50 mL) and powdered. After filtration and drying under reduced pressure, 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) was obtained as a solid.

[0199] Manufacturing example 247 A mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL) was mixed with palladium acetate (4.52 g) at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and filled with nitrogen gas three times each, and then stirred at 100°C under a nitrogen atmosphere for 12 hours. After cooling, water (1500 mL) was added, and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layers were dried over anhydrous sodium sulfate, and insoluble matter was filtered off. Activated carbon (50 g) was added to the obtained solution and stirred at 20°C for 1 hour, then filtered while washing three times with ethyl acetate (50 ml). The filtrate was concentrated, methanol (200 mL) was added to the resulting residue to powderize it, and the powder was filtered and dried under reduced pressure to obtain 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0200] Manufacturing example 248 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (350 mg), 2-aminoethanol (1 mL), and N-methyl-2-pyrrolidone (2 mL) were mixed and reacted at 130°C for 30 minutes under microwave irradiation. The reaction solution was diluted with ice water and saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]-2-[(2-hydroxyethyl)amino]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (198 mg) as a solid.

[0201] Manufacturing example 249 (1S,4S)-5-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-{[(2R,3R)-3-hydroxybutan-2-yl]oxy}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (75 mg) was mixed with anhydrous THF (2 mL), and under an argon gas atmosphere, sodium hydride (55% mineral oil dispersion, 20 mg) was added while cooling and stirring in an ice-methanol bath, followed by stirring at room temperature for 1 hour. The reaction vessel was again immersed in an ice-methanol bath and methyl iodide (20 μL) was added while cooling and stirring, followed by stirring overnight at room temperature under a sealed balloon filled with argon gas. Ice and saturated ammonium chloride aqueous solution were poured into the reaction vessel, and it was extracted twice with ethyl acetate. The collected organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (74 mg) as a foamy solid.

[0202] Manufacturing example 252 (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (211 mg) was mixed with MeOH (3 mL), and 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added while stirring at room temperature. The mixture was then stirred at room temperature under an argon atmosphere for 1 hour. Ice and saturated sodium bicarbonate aqueous solution were added to the reaction vessel, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain the low-polarity diastereomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl(87) Using (mg) as a solid, the highly polar diastereomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (59 mg) was obtained as a solid. The low-polarity diastereomer was used in the following reaction.

[0203] Manufacturing example 281 (3R)-pyrrolidine-3-ol (1.7 g) was mixed with DMF (25 mL) and triethylamine (3 mL). Under an argon atmosphere, 1-({[2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (4.5 g) was gradually added while cooling and stirring in an ice / methanol bath. The mixture was then stirred for 2 hours under the same temperature and argon atmosphere. The reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were sequentially washed with 1 M hydrochloric acid / ice water (1 / 1), water, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain (3R)-3-hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl (3.6 g) as an oil.

[0204] The compounds shown in Tables 6 to 101 below were prepared using the same manufacturing method as described in the above-mentioned manufacturing example. The manufacturing method, structure, and physicochemical data for each compound are also shown in Tables 6 to 101.

[0205] Example 8 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (5.61 g), CH2Cl2 (60 mL), and trifluoroacetic acid (27 70 mL of saturated sodium bicarbonate solution was added under cooling (internal temperature: below -5°C), and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution was added to the residue. After extraction three times with CHCl3 / MeOH(5 / 1), the combined organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solution under reduced pressure was separated and purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Saturated sodium bicarbonate aqueous solution was added to the fraction containing the target product, and extraction three times with CHCl3 / MeOH(5 / 1). The combined organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain the product. Isopropyl acetate (70 mL) was added to the obtained product, and the mixture was stirred at a bath temperature of 80°C for 10 minutes, followed by stirring overnight at room temperature.Adding hexane (70 mL) and stirring at room temperature for 1 hour, the resulting solid was filtered, washed with isopropyl acetate / hexane (1 / 1), and dried overnight under reduced pressure at 40°C to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (3.01 g) as a solid.

[0206] Example 7 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (1.04 g) was dissolved in CH2Cl2 (9 mL) and MeOH (9 mL), and then hydrogen chloride (4M DOX solution, 3 mL) was added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was filtered off and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (1.04 g) as a solid.

[0207] Example 20 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (170 mg), CH2Cl2 (2 mL), and MeOH (2 To a mixture of (mL), hydrogen chloride (4M DOX solution, 0.988 mL) was added under ice cooling and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and after adding CHCl3 and saturated sodium bicarbonate aqueous solution and stirring for a while, the aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH(5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH), followed by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target product was collected, made basic with saturated sodium bicarbonate aqueous solution, and extracted twice with CHCl3 / MeOH(5 / 1). The combined organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble matter, the solid obtained by concentrating under reduced pressure was washed with diethyl ether and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide (74 mg) as a solid.

[0208] Example 18 Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (65 mg), (2R)-2-amino-2-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethane-1-ol n hydrochloride (25 mg), DMF (1 To a mixture of (mL), DIPEA (50 μL) and HATU (35 mg) were sequentially added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3 / MeOH) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl(59 A certain amount (mg) was obtained. Subsequently, the obtained compound was dissolved in CH2Cl2 (0.5 mL) and MeOH (0.5 mL), and hydrogen chloride (4M DOX solution, 0.5 mL) was added under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure.Diethyl ether was added to the resulting residue, and the precipitated solid was filtered off, washed with diethyl ether, and then dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide n hydrochloride (43 mg) as a solid.

[0209] Example 49 Under a nitrogen atmosphere, (1S,4S)-5-(6-cyclopropyl-8-{[3-fluoro-4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (158 mg) of EtOH(2 100 μL of methanesulfonic acid was added to a mL solution at room temperature. The mixture was stirred at 50°C for 16 hours and then concentrated under reduced pressure. The residue was separated and purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). 5% sodium bicarbonate aqueous solution was added to the fraction containing the target product, and it was extracted twice with CHCl3 / MeOH(9 / 1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was dissolved with EtOH, and the concentration under reduced pressure was repeated twice. Diethyl ether was added, the resulting solid was filtered off, washed with diethyl ether, and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (50 mg) as a solid.

[0210] The example compounds shown in Tables 102 to 126 below were prepared in the same manner as the manufacturing methods described in the examples above. The manufacturing methods and physicochemical data for each example compound are shown in Tables 127 to 131 below.

[0211] Furthermore, the following abbreviations may be used in the tables below. PEx: Production example number, Ex: Example number, PSyn: Production example number produced by the same method, Syn: Example number produced by the same method (for example, Syn: 8 indicates that it was produced by the same method as Example 8, and Syn: 18# indicates that the hydrochloride salt obtained by the same method as Example 1 was subjected to the desalting reaction described in Production Method 1), Str: Chemical structural formula (compounds with an asterisk "*" in the chemical structural formula indicate that the axial or central chirality of the compound is singular). n HCl: n hydrochloride salt (compounds with a production example number are monohydrochloride to trihydrochloride salts, and compounds with an example number are monohydrochloride to pentahydrochloride salts), DAT: Physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [MH]) - ), NMR: in DMSO-d6 1 δ value (ppm) of the peak in H-NMR (500 MHz), NMR (100°C): in DMSO-d6 at 100°C 1 The delta value (ppm) of the peak in 1H-NMR (500 MHz), where s: singleline (spectrum), d: doubleline (spectrum), dd: double doubleline (spectrum), t: tripleline (spectrum), q: quadrupleline (spectrum), m: multiline (spectrum), br: broadline (spectrum) (e.g., br s).

[0212] [Table 6]

[0213] [Table 7]

[0214] Table 8

[0215] Table 9

[0216] Table 10

[0217] Table 11

[0218] Table 12

[0219] Table 13

[0220] Table 14

[0221] Table 15

[0222] Table 16

[0223] Table 17

[0224] Table 18

[0225] Table 19

[0226] Table 20

[0227] Table 21

[0228] Table 22

[0229] Table 23

[0230] Table 24

[0231] Table 25

[0232] Table 26

[0233] Table 27

[0234] Table 28

[0235] Table 29

[0236] Table 30

[0237] Table 31

[0238] Table 32

[0239] Table 33

[0240] Table 34

[0241] Table 35

[0242] Table 36

[0243] Table 37

[0244] Table 38

[0245] Table 39

[0246] Table 40

[0247] Table 41

[0248] Table 42

[0249] Table 43

[0250] Table 44

[0251] Table 45

[0252] Table 46

[0253] Table 47

[0254] Table 48

[0255] Table 49

[0256] Table 50

[0257] Table 51

[0258] Table 52

[0259] Table 53

[0260] Table 54

[0261] Table 55

[0262] Table 56

[0263] Table 57

[0264] Table 58

[0265] Table 59

[0266] Table 60

[0267] Table 61

[0268] Table 62

[0269] Table 63

[0270] Table 64

[0271] Table 65

[0272] Table 66

[0273] Table 67

[0274] Table 68

[0275] Table 69

[0276] Table 70

[0277] Table 71

[0278] Table 72

[0279] Table 73

[0280] Table 74

[0281] Table 75

[0282] Table 76

[0283] Table 77

[0284] Table 78

[0285] Table 79

[0286] Table 80

[0287] Table 81

[0288] Table 82

[0289] Table 83

[0290] Table 84

[0291] Table 85

[0292] Table 86

[0293] Table 87

[0294] Table 88

[0295] Table 89

[0296] Table 90

[0297] Table 91

[0298] Table 92

[0299] Table 93

[0300] Table 94

[0301] Table 95

[0302] Table 96

[0303] Table 97

[0304] Table 98

[0305] Table 99

[0306] Table 100

[0307] Table 101

[0308] Table 102

[0309] Table 103

[0310] Table 104

[0311] Table 105

[0312] Table 106

[0313] Table 107

[0314] Table 108

[0315] Table 109

[0316] Table 110

[0317] Table 111

[0318] Table 112

[0319] Table 113

[0320] Table 114

[0321] Table 115

[0322] Table 116

[0323] Table 117

[0324] Table 118

[0325] Table 119

[0326] Table 120

[0327] Table 121

[0328] Table 122

[0329] Table 123

[0330] Table 124

[0331] Table 125

[0332] Table 126

[0333] Table 127

[0334] Table 128

[0335] Table 129

[0336] Table 130

[0337] Table 131

[0338] Furthermore, as examples of specific compounds of formula (I) encompassed by the present invention, compounds having any of the following structures are shown. These compounds can also be produced by the representative production methods, production examples and examples shown above, or combinations thereof, or by methods obvious to those skilled in the art. Furthermore, these compounds exhibit excellent activity in inducing the degradation of G12D mutant KRAS protein and are expected to be useful as G12D mutant KRAS inhibitors, and can be used as active ingredients in pharmaceutical compositions, such as pharmaceutical compositions for the treatment of pancreatic cancer. [ka] TIFF0007851842000177.tif77155TIFF0007851842000178.tif39153TIFF0007851842000179.tif39151TIFF0007851842000180.tif37153 TIFF0007851842000181.tif37151TIFF0007851842000182.tif37153 [Industrial applicability]

[0339] The compound of the present invention or a salt thereof exhibits excellent activity in inducing the degradation of the G12D mutant KRAS protein, making it useful as a G12D mutant KRAS inhibitor. It can be used as an active ingredient in pharmaceutical compositions, such as pharmaceutical compositions for the treatment of pancreatic cancer.

Claims

1. (a) Formula (I): 【Chemistry 1】 (In the formula, R 1 This is a naphthyl group which may be substituted with OH, or a group selected from the group consisting of the following formulas (II) and (III): 【Chemistry 2】 R 1a , R 1b These are H, methyl, F, or Cl, which are the same or different from each other. R 1c is F, Cl, methyl, or ethyl, R 2 This is H, halogen, and C which may be substituted. 1-3 Alkyl, cyclopropyl, or vinyl, R 3 This is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms. R 4 is an optionally substituted C 1-6 alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms, R 5 C may be substituted 1-6 Alkyl, possibly substituted C 3-6 A cyclic or substituted 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from oxygen, sulfur, and nitrogen, R 6a , R 6b These are H or C, which may be identical or different from each other and may be substituted. 1-6 It is alkyl, or R 6a , R 6b These may be substituted together with the carbon atoms to which they are bonded. 3-6 It forms a cycloalkyl or a substituted 4- to 6-membered saturated heterocycle containing one heteroatom selected from oxygen, sulfur, and nitrogen, R 7 H, halogen, C 1-3 Alkyl, -SO 2 CH 3 , C 3-6 A substituted or otherwise saturated 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from cycloalkyl, oxygen, sulfur, and nitrogen; a substituted or otherwise 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms. W is an optionally substituted six-membered heteroaryl compound containing one to three optionally substituted phenyl or nitrogen atoms. X is a bond, CH2, O, S, or NR 4x And, R 4x H or C 1-3 It is alkyl, Y is phenylene or pyridinediyl, and the phenylene may be substituted with F. L is -(L 1 -L 2 -L 3 -L 4 )- and, L 1 , L 2 , L 3 , L 4 These are identical or different from each other, combined, O, NR L1 , pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C which may be substituted 1-3 A group selected from the group consisting of alkylenes and C=O, R L1 H or C 1-3 It is alkyl, Z is a five-membered heteroarenediyl containing 1 to 4 heteroatoms selected from NH or oxygen, sulfur, and nitrogen. Alternatively, YLZ is given by the following formula (XIII): 【Transformation 3】 (is) A compound or salt thereof, (b) One or more pharmaceutically acceptable excipients, A pharmaceutical composition for the treatment of pancreatic cancer, containing [the specified ingredient].

2. R 3 is 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, or 2,5-diazabicyclo[2.2.1]heptanyl, L is bonded, C 1-3 The group is an alkylene, C=O, or a group selected from the group consisting of the following formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX): 【Chemistry 4】 R L1 However, H or C 1-3 It is alkyl, R L2 , R L3 However, they are the same or different from each other: H, F, OH, OCH 3 Or C may be substituted. 1-3 It is alkyl, R L However, it is CH or N, n is an integer between 1 and 2. Z is NH or the following equations (V), (X), (XI), and (XII): 【Transformation 5】 The pharmaceutical composition according to claim 1, wherein the group is selected from the group consisting of the following.

3. Equation (I) is the following equation (Ia), 【Transformation 6】 R 1 However, the following equation (IIa) or equation (IIIa) is obtained: 【Transformation 7】 R 1a , R 1b However, they are the same or different from each other, and are H, methyl, F, or Cl. R 2 C may be substituted with H, halogen, or 1-3 Alkyl, cyclopropyl, or vinyl, R 3 This is given by the following equation (IV): 【Transformation 8】 R 4 However, C may be substituted. 1-6 Alkyl, optionally substituted oxetanyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, R 5 However, methyl, ethyl, isopropyl, tert-butyl, or C 3-6 It is a cycloalkyl, R 6a , R 6b However, they are the same or different from each other, H or C 1-3 Alkyl, and the C 1-3 Alkyl groups are F, OH, OCH 3 and N(CH 3 ) 2 It may be substituted with a group selected from the group consisting of R 6a , R 6b They become C together with the carbon they are bonded to. 3-6 Forming a cycloalkyl group, W 1 , W 2 and R 7 but, i. W 1 CH is W 2 C-SO 2 CH 3 And R 7 is H, or, ii. W 1 , W 2 However, they are the same or different from each other: CH, CF, CCl, CCH 3 or N, R 7 H, halogen, C 1-3 Alkyl, -SO 2 CH 3 , C 3-6 A cycloalkyl group, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV): 【Chemistry 9】 R 7a , R 7b However, C may be the same or different, and may be substituted with H or OH. 1-3 It is alkyl, X is O, S, or NR 4x And, R 4x However, H or C 1-3 It is alkyl, Y is phenylene or pyridinediyl, and the phenylene may be substituted with F. L is a bond, C 1-3 an alkylene, C=O or a group selected from the group consisting of the following formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII) and formula (XIX), 【Chemistry 10】 R L1 is H or C 1-3 It is alkyl, R L2 , R L3 However, the same or different C may be H, F, OH, OCH3, or substituted C. 1-3 It is alkyl, R L is CH or N, n is an integer between 1 and 2, Z is a group selected from NH or the group consisting of the following formulas (V), (X), (XI), and (XII). 【Chemistry 11】 Alternatively, YLZ is given by the following formula (XIII): 【Chemistry 12】 The pharmaceutical composition according to claim 2.

4. R 2 is halogen, C 1-3 alkyl, cyclopropyl, or vinyl, provided that the C 1-3 alkyl may be substituted with a group selected from the group consisting of OH and OCH 3 and may be optionally substituted with a group selected from the group consisting of OH and OCH R 4 But, OH, OCH 3 , N(CH 3 ) 2 C may be substituted with a group selected from the group consisting of (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, X is either O or NH, L is bonded, C 1-3 The group is selected from alkylene, C=O, or the group consisting of the following formulas (XIV) and (XVI), 【Chemistry 13】 R L1 However, C 1-3 It is alkyl, R L2 , R L3 However, H is, The pharmaceutical composition according to claim 3, wherein n is 1.

5. R 1 The following equation (IIa) is given, 【Chemistry 14】 R 1a F is, R 2 It is cyclopropyl, R 4 OCH 3 Even if replaced by C 1-6 piperidinyl which may be substituted with alkyl, tetrahydropyranyl or difluoroethyl, R 5 It is isopropyl, R 6a H is, R 6b A C is substituted with an OH group. 1-3 It is alkyl, R 7 is a group selected from the group consisting of the following formulas (VI), (VII), (VIII) and formula (IX), 【Chemistry 15】 R 7a A C is substituted with an OH group. 1-3 It is alkyl, W 1 CH is W 2 CH is, X is O, It is a phenylene in which Y may be substituted with F. L is a bond, Z is given by the following equation (XI): 【Chemistry 16】 The pharmaceutical composition according to claim 4.

6. Equation (I) is given by the following equation (Ib): 【Chemistry 17】 R 1 However, the following equation (IIa) or equation (IIIa) is obtained: [Chemistry 18] R 1a , R 1b However, they are the same or different from each other, and are H or F. R 2 However, halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 However, the following equation (IV) is given, 【Chemistry 19】 R 4 However, C 1-3 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, R 5 However, ethyl, isopropyl, tert-butyl, or C 3-6 It is a cycloalkyl, R 6a , R 6b However, if they are the same or different from each other, H or F, OH and N(CH) 3 ) 2 C may be substituted with a group selected from the group consisting of the above. 1-3 It is alkyl, or R 6a , R 6b These, together with the carbon atoms to which they are bonded, form a cyclopropyl group. R 7 However, the group is selected from H, halogens, or the group consisting of the following formulas (VI), (VII), (VIII), and (IX). 【Chemistry 20】 R 7a However, C may be substituted with H or OH. 1-3 It is alkyl, X is O, Y is phenylene or pyridinediyl, L is bonded, C 1-3 Alkylene, or C=O, Z is a group selected from NH or the group consisting of the following formulas (X), (XI), and (XII): 【Chemistry 21】 Alternatively, YLZ is given by the following formula (XIII): 【Chemistry 22】 The pharmaceutical composition according to claim 1.

7. the below described: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl)oxy]methyl}phenyl)-1H-1,2,3-triazole-1-yl]-3-methylbutanoyl}-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A pharmaceutical composition for the treatment of pancreatic cancer comprising a compound selected from the group consisting of the following.

8. the below described: (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A pharmaceutical composition for the treatment of pancreatic cancer comprising a compound selected from the group consisting of the following.

9. the below described: (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiaazole-5-yl]phenyl}ethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-yl]oxy}quinazoline-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazole-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, and, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxaazole-5-yl)phenyl]ethyl}-L-prolineamide, A pharmaceutical composition for the treatment of pancreatic cancer comprising a compound selected from the group consisting of the following.

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