Quinazoline compounds for inducing degradation of G12D mutant KRAS protein

Abstract

This invention provides compounds useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer. [Solution] The present inventors investigated compounds useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer and found that quinazoline compounds have an excellent ability to induce the degradation of G12D mutant KRAS protein and possess G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, thus completing the present invention. The quinazoline compound or a salt thereof of the present invention can be used as a therapeutic agent 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 treatment involves 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 is used, but the survival rate is not good. Currently, FOLFRINOX therapy (5-FU, irinotecan and oxyphosphate) is used. A combination therapy of three saliplatin-based chemotherapy agents plus levofolinate is used for pancreatic cancer. Although it is used as standard therapy, it is highly toxic, so patients prescribed it are those with ECOG performance. Patient selection must be done carefully, such as limiting the patient to those with a Status of 1 or less (J. Clin. Oncol., 2018, 36, p.2545-2556). While erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, is approved as a molecularly targeted therapy in combination with gemcitabine, the overall survival extension is only about two weeks compared to gemcitabine alone, and satisfactory therapeutic effects are not achieved. No effective treatments have been found, and there is still a need for highly effective therapies (J. Clin. Oncol., 2007). 25, pp. 1960-1966).

[0003] The RAS protein is a low-molecular-weight guanosine triphosphate (GTP)-binding protein of approximately 21 kDa, consisting of 188-189 amino acids, and is produced from three genes: the KRAS gene, the NRAS gene, and the HRAS gene. There are four main types of RAS proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS). RAS proteins exist in both an active, GTP-bound form and an inactive, GDP-bound form. Proteins are activated by ligand stimulation of cell membrane receptors such as EGFR, which leads to the exchange of guanosine diphosphate (GDP) and GTP. Activated receptor proteins (RAS) bind to up to 20 different effector proteins, including RAF, PI3K, and RALGDS, activating downstream signaling cascades. Conversely, activated RAS becomes inactive through endogenous GTP hydrolysis (GTPase) activity, converting GTP to GDP. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). Therefore, RAS is an important "min" in intracellular signaling pathways such as EGFR. These cells function as "sub-switches" and play a crucial role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, pp.761-774; Nature Rev. Drug Discov., 2014, 13, pp.828-851; Nature Rev. Drug Discov., 2016, 15, pp.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 where it continuously sends signals downstream. This excessive signaling leads to carcinogenesis and accelerated cancer growth. Pancreatic ductal adenocarcinoma is thought to develop in pancreatic intraepithelial neoplasia (PanIN) through a progression from a weak to a strong dysplasia stage, and KRAS gene mutations are already observed in the early stages of PanIN. Subsequently, abnormalities in tumor suppressor genes such as INK4A, p53, and SMAD4 occur, leading to malignancy (Nature Rev. Cancer, 2010, 10, p.683-695). Furthermore, in more than 90% of pancreatic ductal adenocarcinomas, the KRAS gene... Mutations have been observed, with the majority being point mutations at codon 12 located in KRAS exon 2. This is the number (Cancer Cell 2017, 32, p.185-203). From this, it can be concluded that KRAS is involved in the development of pancreatic cancer. It plays an important role in the development process.

[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 disclose KRAS It is described as being useful for cancers with a codon 12 mutation, one of which is the G12D mutation, but its effect on G12D-mutated KRAS cancer is not described. [ka] (A) TIFF2026048973000002.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, technologies such as PROTAC (PROteolysis-Targeting Chimera) and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser) have been developed to induce the degradation of target proteins. Bifunctional compounds, collectively referred to as such, have been discovered and are expected to be one of the novel drug discovery modalities (Drug. Discov. Today Technol., 2019, 31, p15-27). These bifunctional compounds promote the formation of a complex between the target protein and E3 ligase within the cell, and ubiquitin-proteases are involved. The ubiquitin-proteasome system induces the degradation of target proteins. This is one of the intracellular protein degradation mechanisms. A protein called E3 ligase recognizes the protein to be degraded and performs ubiquitination, which then allows degradation by the proteasome to proceed.

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

[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 KRAS proteins have been reported to date (Non-Patent Documents 1, 2, 6, 7, 8, and 12). However, to date, there are 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 project] [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 have diligently investigated compounds useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer, and as a result, have found that a quinazoline compound of formula (I), particularly a substituent at the 8-position of quinazoline and an E3 ligase, is useful. Linking the ligand, or linking the substituent at position 8 of quinazoline with the ligand of the E3 ligase The present invention was completed upon discovering that a bifunctional compound of formula (I), characterized by being linked by a Kerr, has the effect of inducing the degradation of the G12D mutant KRAS protein and possesses G12D mutant KRAS inhibitory activity. 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 refers to naphthyl which may be substituted with OH, or the group consisting of the following formulas (II) and (III). It is a base selected from, [ka] R 1a , R1b is the same as or different from each other, and is H, methyl, F, or Cl, R 1c is F, Cl, methyl or ethyl, R 2 is H, halogen, optionally substituted C 1-3 alkyl, cyclopropyl, or vinyl and R 3 is a saturated or unsaturated 7- to 8-member bridged heterocyclic group containing 1 to 2 nitrogen atoms, R 4 is optionally substituted C 1-6 alkyl, an optionally substituted 4- to 6-member saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, an optionally substituted 5-member heteroaryl containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or an optionally substituted 6-member 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-member saturated heterocyclic group containing 1 heteroatom selected from oxygen, sulfur, and nitrogen, R 6a R 6b is the same as or different from each other, and is H or optionally substituted C 1-6 alkyl or, R 6a R 6b together with the carbon to which they are attached, forms an optionally substituted C 3-6 cycloalkyl, or an optionally substituted 4- to 6-member saturated heterocyclic containing 1 heteroatom selected from oxygen, sulfur, and nitrogen, R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6A 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 contains 1 to 3 phenyl or nitrogen atoms, which may be substituted. It is a good 6-membered heteroaryl, 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 Even if it has been replaced Roridinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C 1-3 Selected from the group consisting of alkylenes and C=O. It is the basis, R L1 H or C 1-3 It is alkyl, Z is a 5-membered heteroatom containing 1 to 4 heteroatoms selected from NH, oxygen, sulfur, and nitrogen. It is Roaranejile. 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 in b) is included in 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 These are selected from the group consisting of H or F, OH and N(CH3)2, which are identical or different from each other. C may be substituted with a group. 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 7is 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 1-3 Alkylene, 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 its salt has the effect of inducing the degradation of the G12D mutant KRAS protein and has G12D mutant KRAS inhibitory activity, and is used as a therapeutic agent for pancreatic cancer, in particular G12D mutant KRAS-positive pancreatic cancer. It can be used. [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 a linear or branched alkyl group with 1 to 12 carbon atoms, for example, me Tyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- These include 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 1-6Alkyl, in some embodiments methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, in some embodiments is methyl, ethyl, n-propyl, isopropyl or sec-butyl, and in some embodiments is methyl, ethyl, isopropyl or tert-butyl, and in some embodiments is methyl, ethyl The components are propyl, n-propyl, isopropyl, and n-butyl, and in one embodiment, 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, these include 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, and diazabicyclo[2.2.1]hepta-5-enyl, and in some embodiments, diazabicyclo[2. 2.2] Octanil, diazabicyclo[3.2.1] Octanil, diazabicyclo[3.1.1] Hep Tanyl or diazabicyclo[2.2.1]heptanyl, and in one embodiment 2,5-diazabi The cyclo[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, and in some embodiments, diazabicyclo[2.2.1]heptanyl, and in other embodiments, 2,5-diazabicyclo[2.2.1]heptanyl. This is clo[2.2.1]heptanyl, and in one embodiment, 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. One embodiment of a "six-membered heteroaryl" is pyridyl. , pyrimidinil, pyrazinil, pyridazinil or triazinil, in some embodiments pyridyl or pyridazinil, in some embodiments pyridyl or pyrimidinil, in some embodiments pyridyl, in some embodiments pyrimidinil.

[0028] "Halogen" means F, Cl, Br, and I. In some cases, it is F, Cl, or Br. In some embodiments, it is F or Cl; in some embodiments, it is F or Br; in some embodiments, it is F; in some embodiments, it is Cl; and in some embodiments, it is Br.

[0029] "C that can be replaced 1-6 "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 3-6 Selected from cycloalkyl, azabicyclo[3.3.0]octanyl, or oxygen, sulfur, and nitrogen. A substituted or otherwise saturated 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms. In some embodiments, this includes 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 compound 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, and in one embodiment, the compound is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxy Methyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranil, tetrahydropyranil, (hydroxymethyl)tetrahydropyranil, (methoxymethyl)tetrahydropyranil, morpholinil, pyrrolidinil, methylpyrrolidinil, piperidinil, or azabicyclo[3.3.0]octanil, which in some embodiments are F,OH,OCH3,N(CH3)2,methyl,cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl (L)cyclopropyl, tetrahydrofuranil, tetrahydropyranil, (hydroxymethyl)tetrahydropyranil, (methoxymethyl)tetrahydropyranil, morpholinil, pyrrolidinil, methylpyrrolidinil, or azabicyclo[3.3.0]octanil, Examples of embodiments include OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, tetrahydro The particles are furanyl, (methoxymethyl)cyclopropyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, or azabicyclo[3.3.0]octanyl, and in some embodiments are F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, tetrahydro The material is dorofuranil, tetrahydropyranil, morpholinil, pyrrolidinil, methylpyrrolidinil, or azabicyclo[3.3.0]octanil, 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 Cycloal It is a kill. 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. 1-3C 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 alkyl, and in one embodiment it is -SO2CH3, F, Cl, OH, methyl, or OCH3. In some embodiments, it is F, Cl, OH, methyl or OCH3; in some embodiments, it is F, OH or OCH3; in some embodiments, it is -SO2CH3, F, Cl or methyl; in some embodiments, it is -SO2CH3 In some embodiments, it is F, Cl or methyl, and in some embodiments, it is methyl, ethyl, It is hydroxymethyl or methoxymethyl, and in some embodiments it is methyl, ethyl or hydroxymethyl, and in some embodiments it is C 1-3 The 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] The permissible substituents in "a substituted 4- to 6-membered saturated heterocyclic group", "a substituted pyrrolidinyl", "a substituted piperidinyl", "a substituted oxetanyl", "a substituted tetrahydrofuranyl", and "a substituted tetrahydropyranyl" are from the group consisting of F, OH, and OCH3. C may be substituted with the selected group. 1-3 Alkyl, F, OH, OCH3, oxo or oxet It is a nyl group. In one embodiment, it is F, OH, or OCH3, and in another embodiment, it may be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 Alkyl, F, oxo or ox It is a cetanyl, and in one embodiment, it is substituted with a group selected from the group consisting of F, OH, and OCH3. It may also be possible C 1-3 It is alkyl or oxo, and in one embodiment consists of F, OH and OCH3. C may be substituted with a group selected from the group. 1-3 It is alkyl, and in one embodiment, F Even if replaced by C 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 uroloethyl or oxetanyl, in some embodiments it is difluoroethyl or oxetanyl, in some embodiments it is methyl, ethyl, hydroxymethyl, methoxymethyl or oxo, in some embodiments it is methyl or oxo, in some embodiments it is hydroxymethyl or methoxymethyl, in some embodiments it is 2,2-difluoroethyl, in some embodiments it is oxetanyl, in some embodiments it is hydroxymethyl, in some embodiments it is methoxymethyl, in some embodiments it is methyl, in some embodiments it is 2-hydroxyethyl, in some embodiments it is 2-methoxyethyl, in some embodiments it is OCH3, and in some embodiments it is oxo. When formula (I) is formula (Ib), the permissible substituents in "optionally substituted pyrrolidinyl" and "optionally substituted piperidinyl" are substituted with F Even if C 1-3 It is alkyl or oxetanyl.

[0032] "Optionally substituted pyrrolidinediyl", "Optionally substituted piperidinediyl", "Optionally substituted piperazinediyl", "Optionally substituted C 1-3 In the alkylene, acceptable substituents include F, OH, OCH3 or substituted Good C 1-3 It is alkyl. In one embodiment, it is F, OH, OCH3, methyl, ethyl, hydroxy It is methyl or methoxymethyl, and in some embodiments it is F, OH, OCH3 or methyl.

[0033] "C that can be distributed even if replaced with F" 1-3 One embodiment of "alkyl" is methyl or ethyl which may be substituted with F. For example, methyl, ethyl, monof These are difluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl. In some embodiments, these are methyl, ethyl, monofluoromethyl, difluoromethyl, or difluoroethyl; in some embodiments, monofluoromethyl or difluoromethyl; in some embodiments, monofluoromethyl or difluoroethyl; in some embodiments, monofluoromethyl; in some embodiments, difluoromethyl; in some embodiments, difluoroethyl; and in some embodiments, 2,2-difluoroethyl.

[0034] "Distributed C substituted with OH" 1-3 One embodiment of "alkyl" is methyl which may be substituted with one OH group or ethyl which may be substituted with one or two OH groups. For example, methyl These are methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1,2-dihydroxyethyl. In some embodiments, it is methyl, ethyl, or hydroxymethyl; in some embodiments, it is methyl or hydroxymethyl; in some embodiments, it is hydroxymethyl or hydroxyethyl; in some embodiments, it is hydroxymethyl; and in some embodiments, it is hydroxyethyl.

[0035] "C may be substituted with OCH3" 1-3 One embodiment of "alkyl" is methyl which may be substituted with one OCH3 or ethyl which may be substituted with one or two OCH3. These are methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 1,2-dimethoxyethyl. In some embodiments, it is methoxymethyl or methoxyethyl, in some embodiments, it is methoxymethyl, and in some embodiments, it 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. In some embodiments, it is methyl, ethyl, dimethylaminomethyl, or dimethylaminoethyl; in some embodiments, it is methyl or dimethylaminomethyl; in some embodiments, it is dimethylaminomethyl; and in some embodiments, it is dimethylaminoethyl.

[0037] One embodiment of "phenylene that may be substituted with F" is phenylene that may be substituted with 1 or 2 F atoms. Another embodiment is phenylene that may be substituted with 1 F atom. It is phenylene, in some embodiments it is phenylene or fluorophenylene, in some embodiments it is phenylene, in some embodiments it is 2-fluoro-1,4-phenylene, and in some embodiments it is Its form 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 aspects, it is pancreatic ductal carcinoma, and in certain aspects, it is pancreatic ductal adenocarcinoma. Further, in certain aspects, it is metastatic pancreatic cancer, in certain aspects, it is locally advanced pancreatic cancer, in certain aspects, it is recurrent or refractory pancreatic cancer, and in certain aspects, it is pancreatic cancer in patients with or without a treatment history.

[0041] "G12D-mutated KRAS-positive pancreatic cancer" refers to pancreatic cancer with a G12D-mutated KRAS. For example, it is pancreatic cancer in which the KRAS G12 D mutation has occurred and is pancreatic cancer with a high positive rate of G12D-mutated KRAS. In certain aspects, it is G12D-mutated KRAS-positive pancreatic ductal carcinoma, and in certain aspects, it is G12D-mutated KRAS-positive pancreatic ductal adenocarcinoma.

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

[0043] Certain aspects 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), and [Chemical formula] R 1a 、R 1b are the same or different from each other and are H, methyl, F, or Cl, R 1c is a compound or a salt thereof, where R is F, Cl, methyl or ethyl. (1-2)R 1 is the following formula (IIa) or formula (IIIa),

Chemical formula

Chemical formula

[0044] R 1 In another aspect, R 1 is formula (II), R 1a is F, and R 1c is methyl, or a salt thereof. In one aspect, R is formula (IIa), R 1 is H or F, or a salt thereof. In one aspect, R 1a is formula (IIa), R 1 is formula (IIa), R 1a is H, or a salt thereof. In one aspect, R 1 is formula (IIIa), R 1a and R 1bA compound or salt thereof which is identical or different from each other, and is H or F. In one embodiment, R 1 Equation (IIIa) is given by R 1a , R 1b However, both are H A compound or a salt thereof. 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 However, both are F A compound or a salt thereof. 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 Alkyl, cyclopropyl, and A compound that is vinyl or a salt thereof. (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 3A 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 3 Compounds 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 A substituted or alternatively substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from alkyl, oxygen, sulfur, and nitrogen, or a substituted or alternatively substituted 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. A compound or salt thereof that is a loaryl, or a substituted six-membered heteroaryl containing one to three 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 OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxy The group consists of methyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. Even if it is replaced, C 1-6Compounds 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 OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxy The group consists of methyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. Even if it is replaced, C 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1-3 A group consisting of pyridyl, F, OH, and OCH3, which may be substituted with alkyl groups. C may be substituted with the selected group. 1-3 Pyrrolidinyl which may be substituted with alkyl, or C which may be substituted with F 1-3 Selected from the group consisting of alkyl and oxetanyl A compound or salt thereof which is piperidinyl that may be substituted with a group. (4-6)R 4 OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxy The group consists of methyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolidinyl, methylpyrrolidinyl, and azabicyclo[3.3.0]octanyl. Even if it is replaced, C 1-6 Alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C 1-3 A 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 is replaced with OCH3 It may also be possible C 1-6 A compound that is alkyl or a salt thereof. In one embodiment, R 4 C 1-3A 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, R 4 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 Alkyl A compound or salt thereof which is piperidinyl which may be substituted with 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 Cycloalkyl A compound or a salt thereof. (5-3)R 5 is ethyl, isopropyl, tert-butyl or C 3-6 Cycloalkyl compounds A substance or its salt. (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 3-6 Cycloalkyl A compound or a salt thereof. In one embodiment, R 5 Compounds in which isopropyl or tert-butyl or its salt. 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 Alki It is R, 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 C1-3 The alkyl may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2, or R 6a , R 6b forms a cyclopropyl together with the carbon to which they are attached, or a salt thereof. (6-4)R 6a is H, and R 6b is optionally substituted with OH, C 1-3 alkyl, or is a salt thereof.

[0048] R 6a , R 6b In another embodiment of R 6a , R 6b are the same or different from each other and are optionally substituted with a group selected from the group consisting of H or F, OH, and N(CH3)2, C 1-3 alkyl, or is a salt thereof. In one embodiment, R 6a ; R 6b are the same or different from each other and are optionally substituted with a group selected from the group consisting of F, OH, and N(CH3)2, C 1-3 alkyl, or a salt thereof. In one embodiment, R 6a , R 6b are both H, or a salt thereof. In one embodiment, R 6a is H and R 6b is optionally substituted with a group selected from the group consisting of F, OH, and N(CH3)2, C 1-3 alkyl, or a salt thereof. In one embodiment, R 6a is H and R 6b is optionally substituted with F, C 1-3 alkyl, or a salt thereof. In one embodiment, R 6a is H and R 6b is optionally substituted with N(CH3)2, C 1-3 alkyl, or a salt thereof. In one embodiment where R 6a , R 6bHowever, 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)R 7 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 Alkyl A compound 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 alkyl compounds A substance or its salt. (7-5)R 7 The group consisting of equations (VI), (VII), (VIII), and (IX) is selected. It is a group, 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 7 A compound or salt thereof in which is a halogen. In one embodiment, R 7 A compound or salt thereof in which is -SO2CH3. In one embodiment, R 7 A compound or salt thereof in which is a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX). In one embodiment, R 7 A compound or salt thereof in which is a group selected from the group consisting of formulas (VI), (VIII), and (IX). In one embodiment, R 7 A compound or salt thereof whose formula is (VI) or (VIII). In one embodiment, R 7 A compound or salt thereof having formula (VI) or (IX). In one embodiment, R 7 A compound or salt thereof whose formula is (VI). In one embodiment, R 7 A compound or salt thereof whose formula is (VII). As for R 7 A compound or salt thereof whose formula is (VIII). In one embodiment, R 7 A compound or salt thereof whose formula is (IX). (7-8)R 7a C may be substituted with H or OH. 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R 7a A compound or salt thereof in which H is present. In one embodiment, R 7a It is replaced by OH Even if C 1-3 A compound that is alkyl or a salt thereof. In one embodiment, R7a C 1-3 Alki A compound or salt thereof that is a compound. (8-1) A substituted compound containing 1 to 3 phenyl or nitrogen atoms, which may have W substituted. A compound of formula (I) or a salt thereof that is a 6-membered heteroaryl compound, which may also be a 6-membered heteroaryl compound. (8-2)W 1 CH is W 2 A compound of formula (Ia) or a salt thereof, wherein the parent compound is C-SO2CH3. (8-3)W 1 , W 2 A compound of formula (Ia) or a salt thereof, which is identical or different from each other, and is CH, CF, CCl, CCH3, or N. (8-4)W 1 , W 2 However, compounds of formula (Ia) that are identical or different from each other, and which are CH, CF, or N That salt. (8-5)W 1 CH is W 2 A compound of formula (Ia) or a salt thereof, wherein CH is present. (9)W 1 , W 2 and R 7 but, i. W 1 CH is W 2 This is C-SO2CH3, and R 7 is H, or, ii. W 1 , W 2 However, they are the same or different from each other, and are CH, CF, CCl, CCH3, or N, and R 7 H, Haro Gen, 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 , R7b However, C may be the same or different, and may be substituted with H or OH. 1-3 Alkyl A compound or salt thereof of formula (Ia). (10-1)X is bonded, CH2, O, S or NR 4x And R 4x is H or C 1-3 A compound that is alkyl or a salt thereof. (10-2) X is O, S, or NR 4x And R 4x is H or C 1-3 Alkyl compounds or their salts . (10-3) A compound or salt thereof in which X is O or NH. (10-4) A compound or salt thereof in which X is O. (11-1) A compound or salt thereof in which Y is phenylene or pyridinediyl, and the phenylene may be substituted with F. (11-2) Compounds or salts thereof in which Y is phenylene or pyridinediyl. (11-3) A compound or salt thereof which is phenylene in which Y may be substituted with F.

[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 in which Y is pyridinediyl A substance or a salt thereof. In one embodiment, a compound or a 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 Pylor may be substituted Lysinediyl, optionally substituted piperidinediyl, optionally substituted piperaz C may be replaced 1-3 A group selected from the group consisting of alkylenes and C=O And, 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 an alkylene, C=O, or a group selected 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 L3 However, 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. 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 Alkylene, C=O, or consisting of the following formulas (XIV) and (XVI) It is a group selected from the group, [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 an alkylene, C=O, or a group selected from 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). Yes, 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 selected from the group consisting of a bond, C=O, or formulas (XIV)-1 and (XVI)-1. It is a base, R L1 C 1-3 It is alkyl, R L2 , R L3 A compound in which is H and n is 1 or salt. (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. 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 1-3 Alkilen A compound or a salt thereof that is C=O. In one embodiment, a compound or a salt thereof in which L is C=O. (13-1) Z contains 1 to 4 heteroatoms selected from NH, oxygen, sulfur, and nitrogen. A compound or salt thereof that is a 5-membered heteroarenediyl. (13-2) A compound or salt thereof in which Z is NH or a group selected from the group consisting of formulas (V), (X), (XI), and (XII) below. [ka] (13-3) A compound or salt thereof in which Z is NH or a group selected from the group consisting of formulas (V)-1, (X)-1, (XI)-1 and (XII)-1. [ka] (L in the formula * (This indicates that it binds with L.) (13-4) Z is selected from NH or from the group consisting of the following formulas (X), (XI), and (XII). The compound that forms the base or a salt thereof. [ka] (13-5) Select Z from the group consisting of NH or the following formulas (X)-1, (XI)-1 and (XII)-1. A compound or salt thereof that is the group being modified. [ka] (L in the formula * (This indicates that it binds with L.) (13-6) A compound or salt thereof in which Z is NH or a group selected from the group consisting of the following formulas (X) and (XI). [ka] (13-7) A compound or salt thereof in which Z is NH or a group selected from the group consisting of formulas (X)-1 and (XI)-1 below. [ka] (L in the formula * (This indicates that it binds with L.) (13-8) A compound or salt thereof in which Z is a group selected from the group consisting of formulas (X) and (XI). (13-9) A compound or salt thereof in which Z is a group selected from the group consisting of formulas (X)-1 and (XI)-1. (13-10) Compounds or salts thereof in which Z is NH. (13-11) A compound or salt thereof where Z is formula (XI). [ka] (13-12) A compound or salt thereof in which Z is formula (XI)-1. [ka] (L in the formula * (This indicates that it binds with L.)

[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, Z is formula (XI)-1 or formula (XII)-1 A compound or a salt thereof that is [formula]. In one embodiment, a compound or a salt thereof where Z is formula (X). In one embodiment, a compound or a salt thereof where Z is formula (X)-1. In one embodiment, a compound or a salt thereof where Z is formula (XII). In one embodiment, a compound or a salt thereof where 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 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 (1-1), (2-1), (3-2), (4-1 A compound of formula (I) or a salt thereof, which is a combination of the embodiments of (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) Equation (I) is Equation (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 (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4) A compound or salt thereof that is a combination of the embodiments of (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 Substituted with alkyl It is a piperidinyl that may be present, R 5 is isopropyl, and R 6a H is R 6b Place in OH Even if it is replaced, C 1-3 It is alkyl, R 7 Equations (VI), (VII), (VIII), and (IX) It is a group selected from the group consisting of R 7a A C is substituted with an OH group. 1-3 Alkyl Ri, W1 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 R 6b A C is substituted with an OH group. 1-3 It is alkyl, R 7is 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 oh Even if C is substituted, it may still be usable. 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 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) (1R)-2-hydroxy-1-[4-(4-methyl-1,3-thia)-1,2,3-(4-methyl-1,3-thia)-1,2,3-(4-methyl-1,3-thia) Azole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-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 [Lu)-1,3-thiazole-5-yl]phenylethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy)(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy)(1R)(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy) Saazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he Butan-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]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (L)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, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (L)oxy)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, (4R)-1-{(2S)-2-[4-(4-{[(6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he Butan-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-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he Butan-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 (1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-methylbutanoyl] Aazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (1R)-2-hydroxy-1-[4-(4-methylbutanoyl)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl Lu-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he Butan-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 [(1R)-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]he Butan-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 (1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-o Xaazole-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]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1- [(1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Thiazol-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- [(1R)-3-methylbutanoyl]-4-hydroxy-N-[(hydroxy)-2-hydroxy-1-{4-[4-(hydroxy) Methyl)-1,3-thiazole-5-yl]phenylethyl]-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- [(1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- Oxazolidined-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- [(1R)-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- [(1R)-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-tri Azole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4- Methyl-1,3-thiazole-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- [(1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Thiazol-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- [(1R)-3-methylbutanoyl]-4-hydroxy-N-[(hydroxy)-2-hydroxy-1-{4-[4-(hydroxy) Methyl)-1,3-thiazole-5-yl]phenylethyl]-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- [(1R)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- Oxazolidined-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- [(1R)-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- [(1R)-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-[(oxane-4 -yl)oxy]quinazoline-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-tri Azole-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4- Methyl-1,3-thiazole-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]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (1R)-2-hydroxy-1-[4-(4-methyl-1,3-thia)-1,2,3-(4-methyl-1,3-thia)-1,2,3-(4-methyl-1,3-thia) Azole-5-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-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 [Lu)-1,3-thiazole-5-yl]phenylethyl]-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy)(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy)(1R)(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxy) Saazolidine-3-yl)phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({6-Cyclopropyl-4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]he Butan-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]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (L)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]he [butan-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(oxan-4-yl) (L)oxy)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, A compound or salt thereof selected from the group consisting of the above.

[0058] Compounds of formula (I) may have tautomers and geometric isomers depending on the type of substituent. In this specification, the compound of formula (I) may be described in only one form of its isomer, but the present invention also includes other isomers, as well as isomers separated therefrom 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, are examples. Specifically, hydrochloric acid, hydrobromic acid, iodide Examples include acid addition salts with inorganic acids such as hydrogen acids, 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 labels one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. This includes all compounds of formula (I) or salts thereof. 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 ( 35 The 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 are Due to the ease of use and detection of the bell, it can be used for this purpose. Substitution with heavier isotopes, for example, hydrogen to deuterium ( 2 Substitution with H) offers therapeutic advantages due to improved metabolic stability (e.g., increased half-life in vivo, reduced required dose, drug (There may be cases where the interaction decreases.) 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 substituents. In this case, depending on the type of functional group... In some cases, it is technically effective in manufacturing to replace the functional group in question with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups are described in "Greene's Protective Groups" by PGM Wuts and TW Greene. Examples of protecting groups can be found in "in Organic Synthesis," 5th edition, 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(diphenylphosphin)ferrocene]palladium(II) dichloromethyl phosphate Lido-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 and the triphe. Nylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethyl group Examples include diyl groups and tert-butylsulfinyl groups. 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 particularly limited, but include 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 particularly limited. Examples of acids that can be used include 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. It is also possible to do so. Examples of protecting groups include the tert-butyl(dimethyl)silyl group and the (trimethylsilyl) group. Examples include the lyl(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 Therefore, a protecting group that can be deprotected under different deprotection conditions is selected, and the deprotection is carried out in stages. They can also provide protection. 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) was subjected to ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The solution is purified, the fraction containing the target substance is collected, the solution is made basic with saturated sodium bicarbonate aqueous solution, and then extracted with CHCl3 / MeOH(5 / 1). The combined organic layer is dried over anhydrous sodium sulfate. The solution is concentrated under reduced pressure, and 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 these A mixture of these can be used. Examples of copper salts include CuI, CuSO4, CuOTf, etc. As a reducing agent Examples include sodium ascorbate. Carrying 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) may be advantageous for smooth reaction. [Literature] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599. Note that the PG of compound (2) 2 The compound obtained by first subjecting it to a deprotection reaction is used in this reaction You may respond.

[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 under reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not 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 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 the mixture is heated in a reaction-inert solvent in the presence of a condensing agent, from cooling to heating, preferably at -20°C. The mixture is stirred at a temperature of 0°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 condensing agents include hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium (PyBOP), O-(7-aza). Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate Salt (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) Examples include diphenyl phosphate azide (DPPA). The use of additives (e.g., 1-hydroxybenzotriazole) may be preferable in the reaction. Examples include TEA, DIPEA, or NMM. In some cases, carrying out the reaction in the presence of an organic base, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, can be advantageous in ensuring the reaction proceeds smoothly. 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 is a leaving group, BLG is a boronic acid group, boronic acid pinacol ester This indicates a boronic acid group protected by a boronic acid protecting group such as a boric acid 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 the mixture is carried out in a solvent inert to the reaction, or without a solvent, under cooling to heating under reflux, preferably 0 The mixture is stirred at a temperature of 0°C to 80°C for typically 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, and ethyl acetate. Examples include 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 - Suzuki-Miyaura Ka This is a method for producing compound (14) by a plucking reaction. Examples of boronic acid groups used here are not limited to boronic acid groups, 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 heated in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature under reflux, preferably from 20°C to 140°C, for typically 0.1 hours to 5 days. Stir. 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 these. Examples of mixtures include: 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, and [1,1'-bis(diphenylphosphine)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, palladium acetate Examples include um(II), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphate. Fin, dicyclohexyl (2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl) phosphate The reaction is carried out in the presence of ligands such as 1,1'-bis(diphenylphosphin)ferrocene. In some cases, heating the mixture by microwave irradiation can be advantageous in order to facilitate the 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 R2 If the atom is a hydrogen atom, compound (14) can be produced by the catalytic hydrogenation reaction of compound (13).

[0083] (Fifth step) This step involves the Suzuki-Miyaura coupling reaction between compound (14) and compound (15). This is a method for manufacturing an object (16). The reaction conditions are the same as those for the fourth step of raw material synthesis 3. If compound (16) has axial chirality, it is obtained as a mixture of diastereomers, but it can be removed using normal reconciliation operations, such as ODS column chromatography or silica gel column chromatography. Each diastereomer can be isolated by performing a splitting using tography.

[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 typically 0.1 hours to 5 days. The solvents used are 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 limited to, but include, for example, organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, tBuOK, sodium hydroxide, Examples of inorganic bases include sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The reaction can be carried out in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride. There are times when it is advantageous. 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 compound (2) in which the protecting group is subjected to a deprotection reaction. The resulting compounds can then be separated using conventional methods such as ODS column chromatography or silica chromatography. Each diastereomer can be isolated by performing separation using 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 Compounds in which the corresponding part is a hydroxyl group are halogenated By converting to LG 1 Compounds in which halogens are used can be produced. Examples of halogenating agents include, but are not limited to, thionyl chloride, phosphorus oxychloride, hydrobromic acid, and phosphorus tribromide. 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 Compounds in which the corresponding part is a hydroxyl group are found in the presence of a base. Furthermore, by sulfonylation, LG 1 It is possible to produce compounds in which the group is a sulfonyl group. The sulfonylation reagents used here are not particularly limited, but include, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. The bases are not particularly limited, but include, for example, TEA, DIPEA, pyridine, and tetramethylethylenediamine. 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 Alkylthiols, for example, Examples include tanthiol 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.3 This 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 - Suzuki-Miyaura Ka This is a method for producing compound (21) by the Plapping reaction. 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 step involves a Suzuki-Miyaura coupling reaction between compound (21) and compound (15). This is a method for manufacturing an object (22). 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 with an equal or excess amount of oxidizing agent, under cooling to heating, preferably from -20°C to 80°C, for typically 0.1 hours to 3 days. In the reaction, m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, Alternatively, oxidation using 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. Examples include sid, 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) has axial chirality, it is obtained as a mixture of diastereomers, but it can be removed using normal reconciliation operations, such as ODS column chromatography or silica gel column chromatography. Each diastereomer can be isolated by performing a splitting using tography.

[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 2 The compound (2) in which the protecting group is subjected to a deprotection reaction. The resulting compounds can then be separated using conventional methods such as ODS column chromatography or silica chromatography. Each diastereomer can be isolated by performing separation using 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 with an equal or excess amount of diazo transfer reagent, preferably at 0°C to 50°C, from cooling to heating, for typically 0.1 hours to 3 days. Examples of diazo transfer reagents are not particularly limited, but include trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or its salts, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), etc., 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. It can be advantageous to carry out the reaction in a solvent. Examples of solvents include THF, dichloromethane, etc. Examples include rogenic hydrocarbons, 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 L2 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, A2 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., A 1 boronic acid groups etc. When 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) In this step, if Z is NH, the ipso reaction or batch reaction between compound (36) and compound (37) is performed. This is a method for producing compound (38) by the Quad-Hartwig amination reaction. 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, this process involves Z containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. In the case of a 5-membered heteroaryl compound, the Suzuki-Miyaura coupling of compound (36) and compound (37) This is a method for producing compound (38) by a reaction. 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 an amidation reaction between 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 is hydrogen Atom, carboxyl group or boronic acid group, etc. 4 Is it a hydrogen atom, or a group consisting of Cl, Br, and I? The base selected from BLG 1 (This indicates a boronic acid group, etc.)

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

[0121] (first step) This process is A 3 If R is a hydrogen atom, for example, 7 This 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 the mixture is stirred in a reaction-inert solvent, in the presence of a base and a palladium catalyst, from room temperature to reflux, preferably from 20°C to 140°C, for typically 0.1 hours to 5 days. Examples of solvents, though not particularly limited, include ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidin-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, and [1,1'-bis(diphenylphosphine)ferrocene]palladium Radium(II) dichloride dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4- Dien-3-one / palladium (3:2), (2-dicyclohexylphosphin-2',6'-diisopropyl Ropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanes Examples include ruhonates and palladium(II) acetate. Furthermore, heating the mixture by microwave irradiation may be advantageous in facilitating 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, for example, consisting of formulas (IX), (XX), (XXI), (XXII), and (XXIV). This method involves producing compound (45) by an Ullmann reaction between compound (42), which is a group selected from the group, 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 Compound (42) whose formula is (VII) This is a method for producing compound (45) by a decarboxylation coupling reaction between (41) and compound (45). 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 If is a group selected from the group consisting of Cl, Br and I, then compound (44) and A method for producing compound (45) by a Suzuki-Miyaura coupling reaction with compound (43). be. The reaction conditions are the same as those for the fourth step of raw material synthesis 3. Furthermore, this process is A 4 If is a hydrogen atom, for example, equation (IX), equation (XX), equation (XXI), equation Compound (45) is produced by a Chan-Lam-Evans coupling reaction between compound (44), which is a group selected from the group consisting of (XXII) and formula (XXIV), and compound (43). This is the method. 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, but can be separated using normal methods, such as octadecylsilyl (ODS) Each diastereomer can be isolated by performing separation using 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. By measuring KRAS G12D expression levels using the sandwich ELISA method, the KRAS expression levels of the test compound can be determined. The resolution process was evaluated. 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 (10 samples ranging from 10 μM to 0.3 nM final concentrations) were diluted 100-fold in fresh 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 used in MaxiSorp 384-well plates. 20 μL was added to each well of a thermos plate (Thermo Scientific), sealed, and 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. KRAS detection was performed using capture antibody from the previous day. The MaxiSorp 384-well plates that had been processed 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. After processing, 20 μL of cell lysate sample was added to each well. β-actin detection was performed as follows: Place 20 μL of the cell lysate sample directly into each well of a MaxiSorp 384-well plate. After adding the substance and applying a seal, the sample was left to stand overnight at 4°C. The following day, the KRAS detection plate was washed with PBS containing 0.05% Tween-20, and then the detection antibody was used as a block. 20 μL of anti-Ras (G12D Mutant Specific) antibody (Cell Signaling Technology), diluted 1,000-fold with King's solution, was added to each well and allowed to stand at room temperature for 5 hours. The supernatant was then removed by centrifugation (using a centrifugal dehydrator; the same method was used for subsequent supernatant removals), washed with PBS containing 0.05% Tween-20, and then diluted 1,000-fold with blocking solution as a secondary antibody. Each of the following samples was taken: 20 μL each of the extracted anti-rabbit IgG HRP-linked antibody (Cell Signaling Technology). The solution was added to a cell and allowed to stand at room temperature for 1 hour. The supernatant was removed by centrifugation of the plate, yielding a 0.05% solution. After washing with PBS containing Tween-20, 20 μL of BM chemiluminescent ELISA substrate (Merck) was added to each well. In addition, the luminescence was measured using 2103 EnVision (PerkinElmer). Furthermore, the β-actin detection plate was washed with PBS containing 0.05% Tween-20 and treated with blocking solution for 60 minutes, and then the detection antibody Each of the following was 20 μL each of anti-β-actin antibody (Abcam) diluted 1,000 times with blocking solution. The solution was added to the wells and allowed to stand at room temperature for 5 hours. The supernatant was then collected by centrifugation of the plate. After removing the residue and washing with PBS containing 0.05% Tween-20, the secondary antibody was diluted 1,000-fold with blocking solution. 20 μL of anti-Mouse IgG HRP-linked antibody (Cell Signaling Technology) was added to each well and allowed to stand at room temperature for 1 hour. The supernatant was then removed by centrifugation, and the plate was washed with PBS containing 0.05% Tween-20. BM chemiluminescent ELISA substrate was then added to each well, and the luminescence was measured using EnVision. The signal value upon addition of DMSO, corrected for the amount of β-actin, was 100%, and the compound of Example No. 7 was 10 μM. The signal value at the time of addition is set to 0%, and the 50% decomposition value of the KRAS amount (DC) 50 ) Sigmoid-Emax model nonlinear The molecular weights were calculated using regression analysis. The molecular weights of the test compounds were 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: 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). The cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum. The procedure was carried out at 37°C in the presence of 5% CO2. The following day, the test compound (10 samples ranging from final concentrations of 10 μM to 0.3 nM) was used as a positive control at a final concentration of 10 The μM compound of Example No. 26 (Example No. 8 for Examples No. 74 and 75), and As a negative control, DMSO, the solvent for the test compound, was diluted 500-fold with fresh medium, and 20 μL was added to each well, after which the mixture was 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 then fixed by standing at room temperature for 30 minutes. After removing the supernatant, add 20 μL each of PBS containing 0.1% Triton X-100 (Amersham Biosciences) to each wafer. The solution was added to the 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. This 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 supernatant was removed in the same manner hereafter), and each well was washed by adding 25 μL of PBS to each well and removing the supernatant. Washing was performed a total of two times. The supernatant was removed by centrifugation, and 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well. After standing at room temperature for 30 minutes, centrifugation was performed. Remove the supernatant by heart, and add 20 μL each of a 1,000-fold diluted solution of anti-Ras (G12D Mutant Specific) antibody and anti-β-Actin antibody in blocking solution to each well as the primary antibody, and leave overnight at 4°C. It was left to stand. 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) in blocking solution was added to each well as secondary antibodies. 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, leave the plate at room temperature for 2 hours. The samples were air-dried, 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 β-actin signal value, was set to 100%, and the example number was set to 10 μM. The signal value when 26 compounds are added is set to 0%, and the 50% decomposition value of KRAS (DC) 50 ) Sigmoid-Emax The molecular weights were calculated using model nonlinear regression analysis. The molecular weights of the test compounds were calculated as follows: Example No. 30: trihydrochloride, Example No. 46: tetrahydrochloride, and other Example Nos.: the molecular weight of the free form (not forming 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. Downstream of the KRAS signaling pathway are threonine 202 (Thr202) and threonine 204 of ERK. By measuring the phosphorylation of syn (Tyr204) using Cell ELISA, we can determine the ERK reaction of the test compound. The antioxidant effect was evaluated. 2.0 x 10⁶ AsPC-1 cells per well 4 To form cells, 36 μL / well, 384 wells The cells were seeded on a Greiner bio-one medium. Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum, under 5% CO2 conditions at 37°C. The following day, the test compound (six samples ranging from a final concentration of 10 μM to 3.0 nM), trametinib (a MEK inhibitor) at a final concentration of 1 μM as a positive control, and DMSO, the solvent for the test compound, as a negative control, were prepared fresh. The solution was diluted 100-fold with a culture medium, 4 μL was added to each well, and then incubated for 24 hours. Immediately after incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque] diluted with PBS) was added to each well, and the cells were fixed by standing at room temperature for 90 minutes. The plate was then centrifuged. The supernatant was removed by (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, centrifugation was performed. The supernatant was removed, and the same procedure was repeated. Next, 20 μL of 0.5% SDS-containing PBS 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 it was left to stand 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. Furthermore, it 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 to each well and removing the supernatant by centrifugation. A total of three washes were performed. After purification, 15 μL of Goat anti-Rabbit IgG H&L (IRDye 800CW), diluted 1,000-fold with blocking solution, was added to each well as a secondary antibody and allowed to stand at room temperature for 1 hour. The plate was then centrifuged. After removing the supernatant, 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 of the plate, the plate was left as is. The samples were air-dried at room temperature for more than 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 molecular weight of the test compound was calculated using a sigmoid-emax model nonlinear regression analysis. The amounts were calculated as follows: Example No. 22: dihydrochloride, Examples No. 2-7, 9-12, 14-18, and 30: trihydrochloride, Examples No. 19 and 46: 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 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. Spheroid 3D culture revealed the anchorage-independent cell proliferation inhibitory effect of the test compound. I evaluated it. 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. 50 The following was calculated using a sigmoid-Emax model nonlinear regression analysis of the test compound. The molecular weight 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: 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 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 cells / mL for 4-6 weeks Male nude mice of a certain age (CAnN.Cg-Foxn1) nu / CrlCrlj (nu / nu), Charles River Co., Ltd. Japan The tumor was implanted subcutaneously in a volume of 100 μL. Approximately two weeks after implantation, tumor volume and body weight were measured for each group. The animals were divided into groups to be nearly equivalent, 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. Compounds of Examples 8, 48 and 70 The ingredients are ethanol (Fujifilm Wako Pure Chemical Industries), 5% glucose solution (Otsuka Pharmaceutical), and 1M hydrochloric acid (Kanto Chemical Industries). The compounds of Example 22 and Example 26 were dissolved in a solvent in a liquid-volume ratio of 4:84.4:1.1:1:9:0.5 using propylene glycol (Fujifilm Wako Pure Chemical Industries), Tween 80 (Nacalai Tesque), and Otsuka Saline Injection (Otsuka The pharmaceutical compound was dissolved in a solvent in a liquid-to-liquid ratio of 6.7:3.3:90. The compound of 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 drug was administered twice, once a week apart. Tumor size 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 is equal to the tumor volume of the group administered the test compound on the day before administration. The tumor regression rate (%) of the test compound was calculated by defining 100% inhibition as the tumor volume of the solvent group two weeks after the first administration as 0% inhibition. Furthermore, if the tumor volume of the group administered with the test compound fell below the tumor volume on the day before administration, the tumor volume on the day before administration was defined as 0% regression, and a tumor volume of 0 was defined as 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. Using human recombinant KRAS G12D, SOS, and c-Raf proteins, these proteins The inhibitory effect of the test compound on complex formation was investigated using time-resolved fluorescence-fluorescence resonance energy transition (TR-FRET) spectroscopy. 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 of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (PerkinElmer; 100 ng / mL) (10 Add (μL) and use EnVision 2104 (PerkinElmer) at an excitation wavelength of 337 nm, then at 620 nm. The fluorescence intensity at 665 nm was also measured. After standardizing the values ​​using the fluorescence intensity at a 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. The 50% inhibition concentration (IC) was then 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) exhibited G12D mutant KRAS degradation activity (Test Examples 1-1 and 1-2). Furthermore, G12D mutant KRAS inhibitory activity was confirmed (Test Example 5). Additionally, several compounds of formula (I) exhibited ERK, which is downstream of the KRAS signaling pathway. The phosphorylation inhibitory effect was confirmed (Test Example 2). In addition, several compounds of formula (I) showed inhibitory effects on cell proliferation against human G12D mutant KRAS-positive pancreatic cancer lines (Test Example 3), and antitumor effects were 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 combined with at least one inert excipient. It is mixed with the agent. The composition may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. The tablets or pills may be coated with a sugar coating 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 2 to 4 doses. For intravenous administration, the appropriate daily dose is approximately 0.0001 to 10 mg / kg per body weight, administered in one to multiple doses per day. For transmucosal administration, per body weight... Approximately 0.001 to 100 mg / kg is administered once or multiple times a day. The dosage is determined on an individual basis, taking into account symptoms, age, sex, etc.

[0144] Although it varies 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 of one or more active ingredients, and in some embodiments, 0.01 to 50% by weight of one or more active ingredients. It contains the compound of formula (I) or a salt thereof.

[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. Also, 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 be produced by combining these production methods. It can also be manufactured by combination 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 mixture and extracted with ethyl acetate. The organic layer was washed with an 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 it was heated to room temperature. The mixture was stirred. 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-diaza To a mixture of tert-butyl bicyclo[2.2.1]heptane-2-carboxylate (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL), and DABCO (1.15 g), cesium carbonate (50.3 g) was added 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 while washing with water, and dried overnight under reduced pressure to obtain (1S,4S)-5-{7-bromo-8-fluoro-6-iodine}. Do-2-[(oxan-4-yl)oxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (32.8 g) was obtained as a solid.

[0152] Manufacturing Example 5 Under an argon stream, (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-carboxylic acid tert-buty To a mixture of 11.9 g of tBuOK, 2.37 g of benzyl alcohol, and 40 mL of THF, 2.54 g of tBuOK was added under ice cooling and stirred at the same temperature for 1.5 hours. Ice water and saturated aqueous ammonium chloride 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 alcohol A mixture of uric acid (1.27 g), tripotassium phosphate (5.67 g), and PdCl2(dppf)·CH2Cl2 (600 mg). The mixture was stirred at 100°C for 3 hours. After the reaction mixture cooled 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 anhydrous. The solution was dried over magnesium sulfate and 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) oxyquinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- Tyl (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- A mixture of (0.12 g) ylphosphine, (2-dicyclohexylphosphin-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) is degassed and argon-dioxide After substitution, the mixture was 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 it was 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 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 and (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) was obtained 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 also obtained. It was used in the following reaction.

[0155] Manufacturing Example 14 The low-polarity diastereomer mixture obtained in Production Example 11 is (1S,4S)-5-{8-(benzyme). (Luoxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-ind To a solution of tert-butyl zole-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (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 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). (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]quinazoline-4-yl}-2,5-diazabic 8.11 g of tert-butyl chloro[2.2.1]heptane-2-carboxylate was obtained as a foamy solid.

[0156] Manufacturing Example 22 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-yl [Dazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (7.48 g), DMF (70 mL) To a mixture of 1.9 g of 1-(chloromethyl)-4-ethynylbenzene, 6.2 g of cesium carbonate was added 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 off, and (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) was foamed It was obtained as a solid.

[0157] Manufacturing example 32 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylsulfanyl)-7-[6- To a solution of 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) in CH2Cl2 (13 mL), 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. Mixed. The reaction mixture was then treated with a 10% sodium thiosulfate aqueous solution and saturated sodium bicarbonate under ice cooling. An aqueous solution was added. The aqueous layer and the organic layer were separated, and the obtained aqueous layer was extracted with ethyl acetate. The obtained organic layer was mixed and dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and (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) was added to the oily substance. It was obtained as such.

[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]quinazoline-4-yl A mixture of tert-butyl diazabicyclo[2.2.1]heptane-2-carboxylate (1.32 g), DMAc (15 mL), and 4-ethyl-3-hydroxypyridine (525 mg) was 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-f Luoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (10 g) and CH2Cl2 (150 mL) To the mixture of ), m-chloroperbenzoic acid (approximately 30% hydrated, 3.3 g) was added under ice cooling, and the mixture was incubated at the same temperature for 3 hours. The mixture was stirred. 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 obtained foamy solid was dissolved in THF (100 mL), and under an argon atmosphere and cooled in an ice / MeOH bath, 4-hydroxypipette Lysine-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. The aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated sodium chloride aqueous solution, and dried with 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 and (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] Nazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl(3.77 g) was obtained as an oily substance. In addition, fractions containing a highly polar diastereomer mixture (peaks 3, 4, same axial 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-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (1.75 g) as a solid. The low-polarity diastereomer mixture was obtained. The 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 heated in an ice / MeOH bath. tBuOK (269 mg) was added under cooling conditions, and the mixture was stirred at room temperature for 3 hours. Under ice cooling conditions, saturated ammonium chloride aqueous solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were then mixed with water and saturated sodium chloride. The samples were washed with aqueous solution and dried over anhydrous magnesium sulfate. The drying agent 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 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 (peaks 1, 2, 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-{[(3S)-oxolan-3-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (346 mg) as a solid. In addition, fractions containing a high-polarity 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-in Dazole-4-yl]-2-{[(3S)-oxolan-3-yl]oxyquinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (329 mg) was obtained as a solid. Low electrode A mixture of diastereomers of the sex 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]heptane-2-carboxylate tert-butyl(4.24 g), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy A mixture of C-1-[4-(4-methyl-1,3-thiazole-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) was mixed with anhydrous copper(II) sulfate (389 mg) at room temperature and stirred at room temperature for 2.5 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was separated into ethyl acetate. The organic layers were extracted, washed with saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was then chromatographed using silica gel column chromatography. Purified with (CHCl3 / MeOH), (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl Ru-1-(oxan-2-yl)-1H-indazole-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-Hydazole-4-yl] Roxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl] [Tyl]carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl]-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazoline-4-yl] tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (5.62 g) is used as a solid. I obtained it by doing so.

[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} [(Iyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidine-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (1.1 g), THF (22 mL), tetra-n-butylammonium fluoride (1M THF) To the mixture of solution (2.57 mL), acetic acid (90 μL) was added at room temperature and the mixture was stirred at 60°C for 15 hours. After cooling to room temperature, ethyl acetate and saturated ammonium chloride aqueous solution were added and the mixture was separated. The aqueous layer was extracted with ethyl acetate / methanol (10 / 1), and the combined organic layer was then mixed with saturated sodium chloride aqueous solution. Washed and dried with anhydrous sodium sulfate. Insoluble matter was filtered off and 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-inda Zol-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]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1] 951 mg of tert-butyl butan-2-carboxylate 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- [Iyl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(piperidine-4-yl)oxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1] A mixture of heptane-2-carboxylate tert-butyl (250 mg), oxetane-3-one (43 mg), and CH2Cl2 (3 mL) was mixed with sodium triacetoxyborohydride (122 mg) at room temperature and stirred for 16 hours at room temperature. A saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes at room temperature. Extraction was performed with CHCl3 / MeOH (5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. The soluble material was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (CHCl3). Purified with (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}carbamyl [1-(oxetane-3-yl)piperidine-4-yl]oxyquinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (220 mg) was obtained as a solid.

[0164] Manufacturing example 53 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-yl [Ndazol-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]methyl Toxy}-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-di Add DIPEA (99 μL) to a mixture of fluoroethyl (124 mg) and MeCN (3 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (1S,4S)-5-(6-cyclopropyl-2-{[1-(2,2-difluoroethyl)piperidine-4-yl]oxy}-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-inda Zol-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 [L]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}quinazoline-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 the resulting residue was mixed with DMF (7 mL) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole-4-yl]-8-hydroxy-2-[(oxan-2-yl] under ice cooling. Add tert-butyl (450 mg) and cesium carbonate (260 mg) to the mixture and tert-butyl (4-yl) quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, and tert-butyl (450 mg) to the mixture and tert-butyl (260 mg) to the mixture, The mixture was stirred overnight. 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 (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}meth Xy)-2-[(oxan-4-yl)oxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]he 670 mg of tert-butyl butan-2-carboxylate was obtained 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. After drying the combined organic layers with anhydrous sodium sulfate The 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). Purified with silica gel (CHCl3 / MeOH), (2S)-2-{5-[({4-[(1S,4S)-5-(tert-butoxycal Bonyl)-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]-1-oxo-1,3-dihydro-2H-isoindole-2-yl}-3-methylbutanoic acid (372 mg) was obtained 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) [enyl]methoxy}-2-[(oxan-4-yl)oxy]quinazoline-4-yl}-2,5-diazabitic [2.2.1]Heptane-2-carboxylate tert-butyl (3.97 g) 1,2-dichloroethane (60 mL) To the solution, 3.35 g of trimethyltin(IV) hydroxide was added at room temperature and the mixture was stirred at 80°C for 18 hours. After cooling to room temperature, hydrochloric acid (1 M, 60 mL) was added and the mixture was extracted with CHCl3 / MeOH(9 / 1). The organic layer was washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble matter was filtered off and the mixture was removed under reduced pressure. The mixture was concentrated. 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-diazabici Chlo[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} A mixture of 150 mg HATU (70 mg) was added under ice cooling, and the mixture was stirred under ice cooling for 1 hour. Water, saturated sodium chloride 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 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 (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl) oxyquinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- Chil (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) The mixture of palladium acetate (0.23 g) was degassed and replaced with argon gas at 115°C. The mixture was stirred overnight. 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) and (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[(oxyloxy) San-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) was obtained 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)quinazoline-4-yl]-2,5-dia Zabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.52 g), (3-bromo-5-fluorinated (4-methylphenoxy)(tert-butyl)di(methyl)silane (0.84 g), tripotassium phosphate (1.85 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl) Sphin (0.15 g), (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-bi Phenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.27 g), DOX (20 mL), and water (4 mL) were added sequentially, and degassing / argon gas replacement was performed while stirring at room temperature. Then, the mixture was stirred at 90°C for 5 hours under an argon atmosphere. Further stirring was performed at 100°C for 7 hours. The mixture was stirred. The reaction solution 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 and obtained (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicycline [2.2.1]Heptane-2-carboxylate tert-butyl (580 mg) was obtained as a foamy solid. Collect fractions containing the highly polar diastereomer (peak-2), (1S,4S)-5-{8-(be (360 mg) tert-butyl ((xan-4-yl)oxy)-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 was obtained as a foamy solid. A low-polarity diastereomer was then obtained. It was used in the reaction.

[0171] Manufacturing example 68 Under a nitrogen atmosphere, (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5- Hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazoline-4-yl}-2,5- To a solution of tert-butyl diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg) in DMF (5 mL), cesium carbonate (180 mg) and chloro(methoxy)methane (35 μL) were added 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 then mixed with water and saturated sodium chloride aqueous solution. The solution was added and washed. The organic layer was dried over anhydrous magnesium sulfate, then 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 {(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carb In a solution of tert-butyl methyl phosphate (3.34 g) in CH2Cl2 (25 mL) and MeOH (25 mL), -20 to -10 Hydrogen chloride (4M DOX solution, 25.6 mL) was added under cooling to °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 (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 To a mixture of g) and DMF (40 mL), DIPEA (7.8 mL) was added under ice cooling, followed by HATU (4.5 g) being added gradually 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 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). (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxy Ethyl carbamoyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl (5.01 g) It was obtained 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) are mixed, then DIPEA (6.2 mL) is added, and the mixture is cooled on ice. HATU (3.61 g) was added gradually, and the mixture was stirred under ice for 1 hour and then at room temperature for 1 hour. Under ice, water, saturated sodium chloride aqueous solution, and ethyl acetate were added, and the aqueous layer was separated. After extracting the aqueous layer with ethyl acetate, it was extracted 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 analyzed by silica gel column chromatography (CHCl3 / MeOH). Purified using ) and N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-H Droxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide A solid (4.43 g) was obtained.

[0177] Manufacturing example 83 To a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}-L-prolineamide (4.43 g) 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, and L-valyl was added. Lu-(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) was obtained as a solid.

[0178] Manufacturing example 88 L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazo To a mixture of 1.71 g of 2-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride, 3.2 mL of TEA, 20 mL of THF, and 20 mL of MeCN, a solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (1.06 g) in MeCN (5 mL) was added dropwise over 10 minutes or more 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. 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) and (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydro Xy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiaazole-5-yl)phenyl]ethyl}-L-prolineamide (1.07 g) was obtained 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, (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindole-2- Methyl(Iyl)-3-methylbutanoate (600 mg), (2-trimethylsilyl)-ethoxymethyltri A mixture of potassium fluoroborate (876 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (151 mg), sodium carbonate (390 mg), DOX (9 mL), and water (1.8 mL) is mixed with palladium acetate (41 mg) at room temperature and heated at 130°C for 4 hours under microwave irradiation. The mixture was stirred. After cooling to room temperature, ethyl acetate was added, followed by filtration with Celite and washing with ethyl acetate. Water was added to the obtained 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 resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain the coupling reaction product (600 mg). To a solution of the obtained coupling reaction product in CH2Cl2 (4.2 mL), trifluoroacetic acid (2.1 mL) was added under ice cooling and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. Purified with (basic silica gel, hexane / ethyl acetate), (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindole-2-yl]-3-methylbutanoate methyl (190 mg) ) was obtained 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 then mixed with n-butyllithium (1.57 M hexane). Add 15.2 mL of the liquid dropwise and stir under ice cooling for 1 hour. Reaction mixture: dry ice-MeOH refrigerant Under cooling conditions, 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) was added to the reaction mixture. Add (mL) dropwise and stir at the same temperature for 1 hour. Add saturated ammonium chloride aqueous solution to the reaction mixture and stir while raising the temperature to room temperature. Extract the reaction mixture with ethyl acetate, wash the organic layer with saturated sodium chloride aqueous solution, and dry with anhydrous sodium sulfate. Filter off insoluble matter and concentrate the filtrate under reduced pressure. The obtained residue was subjected to silica gel column chromatography (H The substance was purified with xane / 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 N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (500 mg), N-methyl-2-nitrobenzenesulfonamide (376 mg), tri-n-butylphosphine To a mixture of (0.51 mL) and THF (7 mL), 1,1'-azobis(N,N-dimethylformamide) (353 mg) was added gradually under ice cooling, and the mixture was stirred at room temperature for 8 hours. Diluted with ethyl acetate, saturated carbonate The mixture was washed with aqueous sodium hydrogen solution, water, and saturated aqueous sodium chloride 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 tert-butyl {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate (667 mg) as a solid.

[0184] Manufacturing example 98 Under an argon atmosphere, {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate tert-butyl (665 mg), 4-methyl-1,3-thiazo A mixture of 235 μL of iodine, 253 mg of potassium acetate, and 13 mL of DMAc was mixed with 29 mg of palladium acetate 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, 4-tert-butylbenzene was added to a mixture of {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate tert-butyl (130 mg), potassium carbonate (84 mg), and DMF (1.3 mL) at room temperature. Add 82 μL of thiol and stir at room temperature for 3 hours. Add ethyl acetate and water and remove the aqueous layer. Separation was performed. 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 with 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 {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiazole-5-yl)phenyl]ethyl}carbamate tert-butyl (60 mg) 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) is treated with formaldehyde under ice cooling. Add 26 μL of 37% aqueous solution and stir for 10 minutes under the same conditions. Then add triacetoxyhydrate. Sodium borohydride (67 mg) was added and the mixture was stirred at room temperature for 1 hour. CHCl3 was added to dilute the mixture. Next, saturated sodium bicarbonate 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 with anhydrous sodium sulfate. Insoluble matter The mixture was filtered off and 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 oily substance.

[0187] Manufacturing Example 102 N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.05 g), A mixture of 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, cooled to room temperature, was 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, {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxymethyl-1,3,2-dioxymethyl-1,4,5,5-tetra Saborolan-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 Add palladium acetate (200 mg) to a mixture of (mL) and water (6 mL) at room temperature and heat at 100°C for 3 The mixture was stirred for several hours. After cooling to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The mixture was then 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, 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyeth methyl phenyl-1,3-thiaazole-4-carboxylate (1.01 g) in CH2Cl2 (20 mL) solution Then, add diisobutylaluminum hydride (1M toluene solution, 11 mL) dropwise under ice cooling, and ice The mixture was stirred for 1 hour under cold conditions. MeOH was added under ice conditions to stop the reaction, and 10% sodium tartrate was added. A 60 mL aqueous solution of lium and CHCl3 were added and stirred overnight. The solution was separated, and the aqueous layer was extracted with CHCl3. 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 MeOH (10 mL), and sodium borohydride (350 mg) was added under ice cooling. Stirred for 1 hour below. Water was added and extracted with CHCl3, and the organic layer was dried with anhydrous sodium sulfate. The mixture was filtered to remove insoluble matter and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) and [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thia Obtain 588 mg of tert-butyl azole-5-yl]phenylethyl]carbamate as a solid. Ta.

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

[0191] Manufacturing Example 107 (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 a DOX (1.69 mL) solution, Copper(I) iodide (32 mg), racemic-(1R,2R)-cyclohexane-1,2-diamine (20 mg) (μL) potassium carbonate (290 mg) was added. 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 filtration. 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 acetate. Lu-4-[4-(2-oxo-1,3-oxazolidined-3-yl)phenyl]-1,3-oxazolidined-3- Tert-butyl carboxylate (120 mg) was obtained as a solid.

[0192] Manufacturing example 109 1-(4-bromophenyl)-2-fluoroethanone (2.7 g), (S)-2-methylpropane-2-sulfur To a solution of finamide (3.03 g) in THF (27 mL), tetraisopropyl orthotitanate (11.1 g) was added and stirred at 40°C for 12 hours. The BH3·THF complex (1 M THF solution) was cooled on ice (0-5°C). Add 18.4 mL of solution and stir for 2 hours. After stopping the reaction by adding water, filter the mixture using Celite and extract the filtrate with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the insoluble material 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 oily substance.

[0193] Manufacturing example 156 To a solution of (4-ethynyl-3-fluorophenyl)methanol (110 mg) in CH2Cl2 (2 mL) under a nitrogen atmosphere and ice cooling, DIPEA (200 μL) was added, followed by the addition of 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 then mixed with water. The sample was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the sample was concentrated under reduced pressure to obtain 4-(chloromethyl)-1-ethynyl-2-fluorobenzene (122 mg) as an oily substance.

[0194] Manufacturing example 189 (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5- A mixture of 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) is prepared at room temperature, to which (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) was added and the mixture was stirred at 50°C for 3 hours. Ice, 2% ethylenediaminetetraacetate disodium aqueous solution, and saturated sodium chloride aqueous solution were poured into the reaction vessel and extracted three times with CH2Cl2. The combined organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off. The residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH), and (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl Ru-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 mixed with 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). In addition, the mixture was stirred at 170°C for 30 minutes under microwave irradiation. After cooling to room temperature, it was diluted with ethyl acetate. The mixture was saturated, 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-oxazolidine-3-carboxylate tert-butyl (215 mg) as a solid.

[0196] Manufacturing example 239 (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidined-3-carboxylic acid 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 saturated with sodium chloride. After washing with an aqueous solution, the material 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 (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, dried under reduced pressure, and 4-bromo-6-fluoro Ro-2-(triphenylmethyl)-2H-indazole (508.98 g) was obtained as a solid.

[0198] Manufacturing example 246 4-Bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) 2-methyl A mixture of tetrahydrofuran (1000 mL) is subjected to lithium diisopropyl alcohol under a nitrogen atmosphere at -78°C. Add ropyramide (2 M THF solution, 214.28 mL) and stir the mixture at -78°C for 2.5 hours. Add methyl iodide (26.68 mL) at -78°C and stir at 25°C for 2.5 hours. Add water (2000 mL) to stop the reaction and extract twice with ethyl acetate (800 mL). After drying the combined organic layers over anhydrous sodium sulfate, insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 mL) / petroleum ether (50 mL) was added to the resulting residue to powderize it, then filtered and dried under reduced pressure. 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) It 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 then treated with anhydrous sodium sulfate. After drying, insoluble matter was filtered off. Activated carbon (50 g) was added to the resulting solution and incubated at 20°C for 1 hour. The mixture was stirred and filtered while washing three times with ethyl acetate (50 ml). The filtrate was concentrated, and methanol (200 mL) was added to the resulting residue to make a powder. This powder was then 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 Chil-2H-indazole (110 g) was obtained as a solid.

[0200] Manufacturing example 248 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-flu Oro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (350 mg), 2-aminoethanol N-methyl-2-pyrrolidone (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. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain a residue which 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-(triphenyl [(2-hydroxyethyl)amino]quinazoline-4-yl]-2-[(2-hydroxyethyl)amino]quinazoline-4-yl] tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (198 mg) is a solid. I obtained it by doing so.

[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-hydroxybuta To tert-butyl hydroxyquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (75 mg), add dehydrated THF (2 mL), and under an argon gas atmosphere, add sodium hydride (55% mineral oil dispersion, 20 mg) while cooling and stirring in an ice-methanol bath, then 1 The mixture was stirred at room temperature for several hours. The reaction vessel was then immersed again in an ice-methanol bath and cooled while stirring. After adding methyl methyl (20 μL), the mixture was sealed in an argon-filled balloon and stirred overnight at room temperature. The reaction vessel was filled with ice and saturated ammonium chloride solution, and extracted twice with ethyl acetate. The 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) and (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]hept 74 mg of tert-butyl tan-2-carboxylate was obtained 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]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl Add MeOH (3 mL) to (211 mg) and stir at room temperature to 4-methylbenzene-1-sulfonic acid After adding monohydrate (48 mg), the mixture was 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 resulting 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 (87 mg) tert-butyl 1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate is used as a solid. (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl) Methoxy]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypro [poxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- Chill (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) is mixed with DMF (25 mL) and triethylamine (3 mL). In addition, 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 under an argon atmosphere, and then stirred for 2 hours under cooling at the same temperature under an argon atmosphere. The reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were extracted with 1 M hydrochloric acid / ice water (1 / 1), water, and saturation. The samples were sequentially washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain (3R)-3-hydroxy Pyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl (3.6 g) was obtained as an oily substance.

[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- [Iyl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazole-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]he A mixture of tert-butyl butan-2-carboxylate (5.61 g) and CH2Cl2 (60 mL) is mixed with trifluorocarbon Acetic acid (27 mL) 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, saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted three times with CHCl3 / MeOH(5 / 1). The combined organic layer was then dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solution under reduced pressure was subjected to ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The product was separated and purified using a solution. Saturated sodium bicarbonate aqueous solution was added to the fraction containing the target product, and it was extracted 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 after stirring at a bath temperature of 80°C for 10 minutes, it was stirred overnight at room temperature. Hexane (70 mL) was added. After stirring at room temperature for 1 hour, filter the resulting solid and add isopropyl acetate / hexane (1 / 1). After washing, it was 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]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 (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- [(Iyl)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-methyl Aazole-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. The mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the resulting residue. 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]quinazolin-8-yl}oxy) [methyl]phenyl}-1H-1,2,3-triazol-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) was obtained as a solid.

[0207] Example 20 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-yl [Ndazol-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 mL) Hydrogen chloride (4M DOX solution, 0.988 mL) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. After concentrating under reduced pressure, add CHCl3 and saturated sodium bicarbonate aqueous solution and stir for a while. The aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH(5 / 1), and the combined organic layer was extracted with anhydrous sodium sulfate. The solution was dried with um. After filtering off the insoluble matter, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH), and then by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target substance was collected, made basic with saturated sodium bicarbonate aqueous solution, and then extracted twice with CHCl3 / MeOH (5 / 1). The organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble material, 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 mL) DIPEA (50 μL) and HATU (35 mg) were sequentially added to the mixture 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]hept 59 mg of tert-butyl tan-2-carboxylate was obtained. Subsequently, the obtained compound was converted to CH2Cl2(0.5 Dissolve in (0.5 mL) MeOH, and add hydrogen chloride (4M DOX solution, 0.5 mL) under ice cooling. The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was filtered off. After washing with diethyl ether, it was 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)ox [C]quinazoline-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazole-1-yl)-3-methyl [Tylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazole-5-yl]phenyl}ethyl]-L-prolineamide n hydrochloride (43 mg) as a solid I obtained it by doing so.

[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)fer [Nyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1 To a solution of tert-butyl diazepam (158 mg) of tert-butyl diazepam (2 mL) of diazepam (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]heptane-2-carboxylate, methanesulfonic acid (100 μL) was added at room temperature. The mixture was stirred at 50°C for 16 hours and then concentrated under reduced pressure. The residue was analyzed by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Separation and purification were performed. A 5% sodium bicarbonate aqueous solution was added to the fraction containing the target substance, and CHCl3 was added. The mixture was extracted twice with MeOH(9 / 1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was reduced. The solution was concentrated under pressure. EtOH was added to the residue to dissolve it, and the concentration was repeated twice under reduced pressure. Diethyl ether was added, the resulting solid was filtered off, washed with diethyl ether, and dried under reduced pressure. (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-[(oxa [-4-yl]oxyquinazoline-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) was obtained 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: Manufacturing example number, Ex: Example number, PSyn: Manufacturing example number manufactured using a similar method, Syn: Example number manufactured using a similar method (for example, Syn: 8 means that it was manufactured using a similar method to Example 8) Syn: 18# indicates that the hydrochloride salt obtained by the same method as in Example 18 was subjected to the desalting reaction described in Production Method 1. Str: Chemical structural formula (chemical structural formula with an asterisk "*" is used) The compound indicates that the axial or central chirality of the compound is singular. n HCl:n hydrochloric acid Salt (Compounds with manufacturing example numbers are monohydrochloride to trihydrochloride salts, and compounds with example numbers are monohydrochloride to pentahydrochloride salts.), DAT: Physicochemical data, ESI+: m / z values ​​in mass spectrometry (ionization method ESI, unless otherwise specified [M+H]) + ), 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 H-NMR (500 MHz) The delta value (ppm) of the peak, s: single line (spectrum), d: double line (spectrum), dd: double line Double line (spectrum), t: triple line (spectrum), q: quadruple line (spectrum), m: multiple lines (spectrum), br: broad line (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] TIFF2026048973000177.tif77155TIFF2026048973000178.tif39153TIFF2026048973000179.tif39151TIFF2026048973000180.tif37153 TIFF2026048973000181.tif37151TIFF2026048973000182.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, and is 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. Compound of formula (I) or salt thereof 【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】 (That is the case.)

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 compound or salt thereof 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 The following equation (IV) is given, 【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 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 is 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. 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 compound or salt thereof 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 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 compound or salt thereof 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 compound or salt thereof 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 compound or salt thereof according to claim 1.

7. A pharmaceutical composition comprising the compound or salt thereof described in claim 1, and one or more pharmaceutically acceptable excipients.

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