Quinazoline compounds for inducing degradation of g12d mutant kras proteins

Abstract

The present application provides a compound useful as an effective ingredient of a pharmaceutical composition for treating pancreatic cancer. The present inventors have researched a compound useful as an effective ingredient of a pharmaceutical composition for treating pancreatic cancer, and found that a quinazoline compound has excellent G12D mutant KRAS protein decomposition-inducing action and G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, thereby completing the present application. The quinazoline compound or salt thereof of the present application can be used as a therapeutic agent for pancreatic cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition, an action excellent in inducing decomposition of a G12D mutant KRAS protein, useful as a G12D mutant KRAS inhibitor, useful as an effective ingredient of a pharmaceutical composition for treatment of pancreatic cancer, for example. BACKGROUND

[0002] Pancreatic cancer, which is mainly pancreatic ductal adenocarcinoma, is a cancer with a 5-year survival rate of 10% or less (CA Cancer J. Clin., 2016, 66, p. 7-30), and the prognosis is very poor. About 460,000 new cases are reported worldwide every year (CA Cancer J. Clin., 2018, 68, p. 394-424). The most effective therapy for pancreatic cancer is surgery, but since it is difficult to detect early, most have already metastasized, and a treatment effect based on surgery cannot be expected in many cases. When surgery is not performed, chemotherapy and radiation therapy are used, but the survival rate is not optimistic. Currently, FOLFRINOX therapy (a multi-agent combination therapy in which leucovorin is added to 5-FU, irinotecan, and oxaliplatin, which are three chemotherapy agents) has been used as a standard therapy for pancreatic cancer, but since the toxicity is strong, patients who receive the treatment are limited to those with ECOG Performance Status of 1 or less, and the selection of patients needs to be carefully performed (J. Clin. Oncol., 2018, 36, p. 2545-2556). As a molecular targeted therapeutic drug, erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, has been approved for use in combination therapy with gemcitabine, but the overall survival period is about 2 weeks longer than when gemcitabine is used alone, and a satisfactory therapeutic effect has not been obtained, and a highly effective therapeutic drug is still needed (J. Clin. Oncol., 2007, 25, p. 1960-1966).

[0003] The RAS protein is a low molecular guanosine triphosphate (GTP)-binding protein of about 21 kDa consisting of 188-189 amino acids, and there are four major proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) produced from three genes, KRAS gene, NRAS gene, and HRAS gene. The RAS protein exists as a GTP-binding type as an active form and as a GDP-binding type as an inactive form. The RAS protein is activated by GTP exchange from guanosine diphosphate (GDP) by stimulation of a ligand to a cell membrane receptor such as EGFR or the like. The active RAS binds to as many as 20 effector proteins such as RAF, PI3K, RALGDS, and activates the downstream signal cascade. On the other hand, the active RAS is converted to the inactive form by endogenous GTP hydrolysis (GTPase) activity to convert GTP to GDP. This GTPase activity is enhanced by GTPase-activating protein (GAP). It is thus known that RAS assumes the function of an important "molecular switch" in the intracellular signal transduction pathway of EGFR or the like, and plays an important role in the processes of cell growth, proliferation, angiogenesis, and the like (Nature Rev. Cancer, 2011, 11, p. 761-774, Nature Rev. Drug Discov., 2014, 13, p. 828-851, Nature Rev. Drug Discov., 2016, 15, p. 771-785).

[0004] When an amino acid substitution occurs due to a mutation in the RAS gene, the RAS becomes a constant active state due to a decrease in the function as a GTPase and a decrease in the response to GAP, and continuously delivers signals to the downstream. This excess signal leads to carcinogenesis and hyperproliferation of cancer. It is generally considered that pancreatic ductal adenocarcinoma occurs from a weak dysplasia stage through a strong dysplasia stage in pancreatic intraepithelial neoplasia (PanIN), and a KRAS gene mutation is confirmed in the early stage PanIN. Thereafter, abnormalities in the tumor suppressor genes INK4A, p53, and SMAD4 occur, and the malignancy occurs (Nature Rev. Cancer, 2010, 10, p. 683-695). Furthermore, a mutation in the KRAS gene is observed in more than 90% of pancreatic ductal adenocarcinoma, and a point mutation at codon 12 of exon 2 of KRAS is the majority (Cancer Cell 2017, 32, p. 185-203). It is thus seen that KRAS plays an important role in the carcinogenesis and progression of pancreatic cancer.

[0005] As KRAS gene mutations, KRAS G12C mutation, KRAS G12D mutation, and the like are known, G12C mutation KRAS is high in frequency in non-small cell lung cancer, and on the other hand, is several percent in pancreatic cancer (Cancer Cell 2014, 25, p. 272-281), and a therapeutic drug against other KRAS mutations is desired. It is reported that G12D mutation KRAS is confirmed in about 34% of pancreatic cancer, which is the highest proportion among KRAS mutations (Nat. Rev. Cancer, 2018, 18, p. 767-777).

[0006] Patent Documents 1, 2, and 3 disclose RAS inhibitors, and the compounds represented by the following formula (A) and formula (B) are disclosed in Patent Documents 2 and 3, respectively. Patent Documents 1, 2, and 3 describe that cancers in which mutation of codon 12 of KRAS exists are useful, and as one of them, G12D mutation is included, but the effect on G12D mutation KRAS cancer is not described.

[0007]

[0008] (The meanings of the symbols in the formula are described in the publication)

[0009] In addition, Patent Documents 9, 10, and 11 disclose KRAS G12D inhibitors.

[0010] In recent years, as a technique for inducing the degradation of a target protein, bifunctional compounds collectively called PROTAC (PROteolysis-TArgeting Chimera), SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), and the like have been discovered, and are expected to become a new drug development model (Drug. Discov. Today Technol., 2019, 31, p15-27). The bifunctional compound promotes the formation of a complex of a target protein and an E3 ligase in a cell, and induces the degradation of the target protein by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms in a cell. A protein called E3 ligase recognizes a protein to be degraded and ubiquitinates it, thereby performing degradation in the proteasome.

[0011] There are more than 600 E3 ligases in vivo, which are roughly classified into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, E3 ligases used in bifunctional proteolysis-inducing agents such as PROTAC and SNIPER are limited, and as representatives, Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog (MDM2), and the like can be cited. In particular, Patent Literature 4 reports VHL, and Patent Literature 5 reports CRBN.

[0012] Bifunctional compounds are compounds in which a ligand for a target protein and a ligand for an E3 ligase are connected with a linker, and currently, bifunctional compounds that decompose KRAS protein have been reported (Non-Patent Literature 1, Non-Patent Literature 2, Patent Literature 6, Patent Literature 7, Patent Literature 8, Patent Literature 12). However, there is no report on bifunctional compounds targeting G12D mutant KRAS.

[0013] Prior Art Documents

[0014] Patent Literature

[0015] Patent Literature 1: International Publication No. 2016 / 049565

[0016] Patent Literature 2: International Publication No. 2016 / 049568

[0017] Patent Literature 3: International Publication No. 2017 / 172979

[0018] Patent Literature 4: International Publication No. 2013 / 106643

[0019] Patent Literature 5: International Publication No. 2015 / 160845

[0020] Patent Literature 6: U.S. Patent Application Publication No. 2018 / 0015087

[0021] Patent Literature 7: International Publication No. 2019 / 195609

[0022] Patent Literature 8: International Publication No. 2020 / 018788

[0023] Patent Literature 9: International Publication No. 2021 / 041671

[0024] Patent Literature 10: International Publication No. 2021 / 106231

[0025] Patent Literature 11: International Publication No. 2021 / 107160

[0026] Patent Literature 12: International Publication No. 2021 / 051034

[0027] Non-Patent Literature

[0028] Non-Patent Literature 1: Cell. Chem. Biol., 2020, 27, p19-31

[0029] Non-Patent Literature 2: ACS Cent. Sci., 2020, 6, p1367-1375 SUMMARY

[0030] PROBLEMS TO BE SOLVED BY THE INVENTION

[0031] To provide a quinazoline compound having an excellent effect of inducing G12D mutant KRAS protein degradation, which is useful as a G12D mutant KRAS inhibitor, and which is useful as an effective ingredient of a pharmaceutical composition for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.

[0032] METHOD FOR SOLVING THE PROBLEM

[0033] The present inventors have intensively studied a compound useful as an effective ingredient of a pharmaceutical composition for the treatment of pancreatic cancer, and as a result, have found that a quinazoline compound of the formula (I), particularly a bifunctional compound of the formula (I) characterized in that a substituent at the 8-position of the quinazoline is linked to a ligand of E3 ligase or a substituent at the 8-position of the quinazoline is linked to a ligand of E3 ligase through a linker, has an excellent effect of inducing G12D mutant KRAS protein degradation and G12D mutant KRAS inhibitory activity, thereby completing the present invention.

[0034] That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of the formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0035]

[0036] (In the formulae,

[0037] R 1 is a naphthyl group which can be substituted with OH or a group selected from the group consisting of the following formula (II) and formula (III),

[0038]

[0039] R 1a , R1b the same or different from each other, are H, methyl, F or CI,

[0040] R 1c is F, CI, methyl or ethyl,

[0041] R 2 is H, halogen, C 1-3 alkyl, cyclopropyl or vinyl,

[0042] R 3 is a saturated or unsaturated 7- to 8-membered bridged heterocyclic radical containing 1 to 2 nitrogen atoms,

[0043] R 4 is a C 1-6 alkyl, a 4- to 6-membered saturated heterocyclic radical which can be substituted, containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, a 5-membered heteroaryl radical which can be substituted, containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl radical which can be substituted, containing 1 to 3 nitrogen atoms,

[0044] R 5 is a C 1-6 alkyl, a C 3-6 cycloalkyl or a 4- to 6-membered saturated heterocyclic radical which can be substituted, containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen,

[0045] R 6a , R 6b the same or different from each other, are H or a C 1-6 alkyl which can be substituted, or R 6a , R 6b together with the carbon to which they are bonded form a C 3-6 cycloalkyl or a 4- to 6-membered saturated heterocyclic radical which can be substituted, containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen,

[0046] R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl, a 4- to 6-membered saturated heterocyclic radical which can be substituted, containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, a 5-membered heteroaryl radical which can be substituted, containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl radical containing 1 to 3 nitrogen atoms,

[0047] W is a phenyl radical which can be substituted or a 6-membered heteroaryl radical which can be substituted, containing 1 to 3 nitrogen atoms,

[0048] X is a bond, CH2, O, S or NR 4x ,

[0049] R 4xH or C 1-3 alkyl,

[0050] Y is phenylene or pyridinediyl, which phenylene can be substituted by F,

[0051] L is -(L 1 -L 2 -L 3 -L 4 )-,

[0052] L 1 , L 2 , L 3 , L 4 the same or different from each other, are a group selected from the group consisting of a bond, O, NR L1 , a pyrrolidinediyl which can be substituted, a piperidinediyl which can be substituted, a piperazinediyl which can be substituted, a C 1-3 alkylene and C=O,

[0053] R L1 is H or C 1-3 alkyl,

[0054] Z is NH or a 5-membered heteroarenetiyl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

[0055] Alternatively, Y-L-Z is the following formula (XIII).

[0056]

[0057] Further, the present application relates to a compound of the formula (Ib) or a salt thereof, and a pharmaceutical composition containing a compound of the formula (Ib) or a salt thereof and one or more pharmaceutically acceptable excipients. The compound of the formula (Ib) is included in the compound of the formula (I).

[0058]

[0059] (in the formula,

[0060] R 1 is the following formula (IIa) or formula (IIIa),

[0061]

[0062] R 1a , R 1b are the same or different from each other, and are H or F,

[0063] R 2 is halogen, C 1-3 alkyl, cyclopropyl or vinyl,

[0064] R 3for the following formula (IV),

[0065]

[0066] R 4 is C 1-3 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl which can be substituted, pyridyl which can be substituted, pyrimidinyl which can be substituted, pyrrolidinyl which can be substituted, or piperidinyl which can be substituted,

[0067] R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 cycloalkyl,

[0068] R 6a , R 6b are the same or different from each other, H or C 1-3 alkyl which can be substituted by a group selected from the group consisting of F, OH, and N(CH3)2, or R 6a , R 6b together with the carbon to which they are bonded form a cyclopropyl group,

[0069] R 7 is H, halogen, or a group selected from the group consisting of the following formula (VI), formula (VII), formula (VIII), and formula (IX),

[0070]

[0071] R 7a is H or C 1-3 alkyl which can be substituted by OH,

[0072] X is O,

[0073] Y is phenylene or pyridinediyl,

[0074] L is a bond, C 1-3 alkylene, or C=O,

[0075] Z is NH or a group selected from the group consisting of the following formula (X), formula (XI), and formula (XII),

[0076]

[0077] or, Y-L-Z is the following formula (XIII).

[0078]

[0079] Note that, unless otherwise specified, the same symbol in a certain chemical formula in this specification is used when it is used in other chemical formulas, and the same symbol indicates the same meaning.

[0080] In addition, the present application relates to a pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, particularly a pharmaceutical composition for the treatment of pancreatic cancer, particularly a pharmaceutical composition for the treatment of G12D mutant KRAS-positive pancreatic cancer, particularly a pharmaceutical composition for the treatment of metastatic pancreatic cancer, particularly a pharmaceutical composition for the treatment of locally advanced pancreatic cancer, particularly a pharmaceutical composition for the treatment of recurrent or refractory pancreatic cancer, particularly a pharmaceutical composition for the treatment of pancreatic cancer in a patient who has not been treated and / or has a history of treatment, particularly a pharmaceutical composition for the treatment of metastatic G12D mutant KRAS-positive pancreatic cancer, particularly a pharmaceutical composition for the treatment of locally advanced G12D mutant KRAS-positive pancreatic cancer, particularly a pharmaceutical composition for the treatment of recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, particularly a pharmaceutical composition for the treatment of G12D mutant KRAS-positive pancreatic cancer in a patient who has not been treated and / or has a history of treatment. Note that the pharmaceutical composition includes a therapeutic agent for pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer, containing the compound of formula (I) or a salt thereof.

[0081] In addition, the present application relates to: the use of the compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer, particularly metastatic pancreatic cancer, particularly locally advanced pancreatic cancer, particularly recurrent or refractory pancreatic cancer, particularly pancreatic cancer in a patient who has not been treated and / or has a history of treatment, particularly metastatic G12D mutant KRAS-positive pancreatic cancer, particularly locally advanced G12D mutant KRAS-positive pancreatic cancer, particularly recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer in a patient who has not been treated and / or has a history of treatment; the use of the compound of formula (I) or a salt thereof in the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer; the compound of formula (I) or a salt thereof for use in the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer; and a method for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer, comprising the step of administering to a subject an effective amount of the compound of formula (I) or a salt thereof.

[0082] In addition, the present application also relates to the compound of formula (I) or a salt thereof as a G12D mutant KRAS protein decomposition inducer and / or G12D mutant KRAS inhibitor, the compound of formula (I) or a salt thereof for use as a G12D mutant KRAS protein decomposition inducer and / or G12D mutant KRAS inhibitor, and a G12D mutant KRAS protein decomposition inducer and / or G12D mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof.

[0083] Note that the "subject" refers to a human or other animal in need of the treatment, as a mode, a human in need of the prevention or treatment.

[0084] Effects of the Invention

[0085] The compound of the formula (I) or a salt thereof has an effect of inducing decomposition of a G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer. DETAILED DESCRIPTION

[0086] The present application is described in detail below.

[0087] In the present specification, "may be substituted" means unsubstituted or having 1 to 5 substituents. As a mode, it means unsubstituted or having 1 to 3 substituents. Note that when having two or more substituents, the substituents can be the same or different from each other.

[0088] "C 1-12 "Alkyl" means a straight-chain or branched alkyl group having a carbon number of 1 to 12, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, dodecyl, and the like (the same applies hereinafter regarding the carbon number). As a mode, it is ethyl or dodecyl, as a mode, it is C 1-6 "Alkyl", as a mode, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl, as a mode, it is methyl, ethyl, n-propyl, isopropyl, or sec-butyl, as a mode, it is methyl, ethyl, isopropyl, or t-butyl, as a mode, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, as a mode, it is C 1-3 "Alkyl", as a mode, it is methyl, ethyl, or isopropyl, as a mode, it is methyl or ethyl, as a mode, it is methyl or isopropyl, as a mode, it is ethyl or isopropyl, as a mode, it is methyl, as a mode, it is ethyl, as a mode, it is isopropyl.

[0089] "C 3-6 "Cycloalkyl" means a cycloalkyl group having a carbon number of 3 to 6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. As a mode, it is cyclobutyl, cyclopentyl, or cyclohexyl, as a mode, it is cyclobutyl or cyclopentyl, as a mode, it is cyclopentyl or cyclohexyl, as a mode, it is cyclopropyl or cyclobutyl, as a mode, it is cyclopropyl, as a mode, it is cyclobutyl, as a mode, it is cyclopentyl, as a mode, it is cyclohexyl.

[0090] "C 1-3"Alkylene" means a straight-chain or branched C1-6alkylene group, for example methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one way, a straight-chain or branched C1-6alkylene group. 1-3 "Alkylene" means a straight-chain or branched C1-6alkylene group, for example methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one way, a straight-chain or branched C1-6alkylene group. 1-3 "Alkylene" means a straight-chain or branched C1-6alkylene group, for example methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. As one way, a straight-chain or branched C1-6alkylene group.

[0091] "Saturated or unsaturated 7- to 8-membered bridged heterocyclyl" means a saturated 7- to 8-membered monocyclic bridged heterocyclyl group having 1 to 2 nitrogen atoms as ring-forming atoms or a 7- to 8-membered monocyclic bridged heterocyclyl group having 1 to 2 nitrogen atoms as ring-forming atoms and having an unsaturated bond. As one way, a saturated 7- to 8-membered monocyclic bridged heterocyclyl group having 2 nitrogen atoms, as one way, a saturated 7- to 8-membered monocyclic bridged heterocyclyl group having a nitrogen atom and 1 of the 2 nitrogen atoms bonded to 1 hydrogen atom. For example, diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octenyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptenyl. As one way, diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]oct-6-enyl, diazabicyclo[3.2.1]oct-2-enyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]hept-5-enyl, as one way, diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl, or diazabicyclo[2.2.1]heptyl, as one way, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, or 2,5-diazabicyclo[2.2.1]heptyl, as one way, diazabicyclo[2.2.1]heptyl, as one way, 2,5-diazabicyclo[2.2.1]heptyl, as one way, 2,5-diazabicyclo[2.2.1]heptan-2-yl.

[0092] "4- to 6-membered saturated heterocyclyl group" means, for example, a 4- to 6-membered saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-forming atoms, and further, a sulfur atom contained in the heterocycle can be oxidized. As one way of the "4- to 6-membered saturated heterocyclyl group", it is a 4- to 6-membered saturated heterocyclyl group containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and further, a sulfur atom contained in the heterocycle can be oxidized. As one way, it is a 5- to 6-membered saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and further, a sulfur atom contained in the heterocycle can be oxidized, as one way, it is a 5-membered saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and further, a sulfur atom contained in the heterocycle can be oxidized, as one way, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidyl, moφholinyl, thiomorpholinyl or dioxothiomorpholinyl, as one way, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidyl, moφholinyl, thiomorpholinyl or dioxothiomorpholinyl, as one way, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidyl or moφholinyl, as one way, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidyl, as one way, it is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, as one way, it is pyrrolidinyl or piperidyl, as one way, it is oxetanyl, as one way, it is tetrahydrofuranyl, as one way, it is tetrahydropyranyl, as one way, it is pyrrolidinyl, as one way, it is piperidyl, as one way, it is moφholinyl, as one way, azetidinyl.

[0093] "5-membered heteroaryl group" means, for example, a 5-membered ring heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-forming atoms. As one way of the "5-membered heteroaryl group", it is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isothiazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, as one way, it is pyrazolyl, imidazolyl, triazolyl, oxazolyl or thiazolyl, as one way, it is pyrazolyl, imidazolyl, oxazolyl or thiazolyl, as one way, it is pyrazolyl, imidazolyl, triazolyl or isoxazolyl, oxazolyl, as one way, it is pyrazolyl, oxazolyl or thiazolyl, as one way, it is pyrazolyl, triazolyl or isoxazolyl, Oxazolyl, as one embodiment, is pyrazolyl or thiazolyl, as one embodiment, is pyrazolyl or triazolyl, as one embodiment, is pyrazolyl, as one embodiment, is imidazolyl, as one embodiment, is Oxazolyl, as one embodiment, is thiazolyl, as one embodiment, is triazolyl. Note that "5-membered heteroaromatic diradical" means a 2-valent radical formed by removing any 1 hydrogen from "5-membered heteroaryl".

[0094] "6-membered heteroaryl" means a heteroaryl group having a 6-membered ring containing, for example, 1 to 3 nitrogen atoms as ring-forming atoms. As one embodiment of "6-membered heteroaryl", pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl, as one embodiment, is pyridyl or pyridazinyl, as one embodiment, is pyridyl or pyrimidyl, as one embodiment, is pyridyl, as one embodiment, is pyrimidyl.

[0095] "halogen" means F, Cl, Br and I. As one embodiment, F, Cl or Br, as one embodiment, F or Cl, as one embodiment, F or Br, as one embodiment, F, as one embodiment, Cl, as one embodiment, Br.

[0096] As one embodiment of "C 1-6 alkyl" and "substitutable C 1-3 alkyl", one embodiment of an acceptable substituent is F, OH, OCH3, N(CH3)2, C 1-3 alkyl, hydroxymethyl, methoxymethyl, difluoroethyl, substitutable C 3-6Cycloalkyl, azabicyclo[3.3.0]octyl, or a substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen. In one embodiment, it is F, OH, OCH3, N(CH3)2, methyl, ethyl, hydroxymethyl, methoxymethyl, difluoroethyl, substituted cyclopropyl, tetrahydrofuranyl, substituted tetrahydropyranyl, morpholinyl, substituted pyrrolidinyl, substituted piperidinyl, or azabicyclo[3.3.0]octyl. In another embodiment, it is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, substituted cyclopropyl, tetrahydrofuranyl, substituted tetrahydropyranyl, morpholinyl, substituted pyrrolidinyl, or substituted cyclopropyl. pyrrolyl, piperidinyl or azabicyclo[3.3.0]octyl, as an example, is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolyl, methylpyrrolyl, piperidinyl or azabicyclo[3.3.0]octyl, as an example, is F, OH, OCH3, N(CH3)2, methyl, cyclo Propyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolyl, methylpyrrolyl or azabicyclo[3.3.0]octyl, as an example, OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, tetrahydrofuranyl, (methoxymethyl)cyclopropyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolyl, methylpyrrolyl or azabicyclo [3.3.0]Octyl, as a mode, is F, OH, OCH3, N(CH3)2, methyl, hydroxymethyl, methoxymethyl, cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolyl, methylpyrrolyl or azabicyclo[3.3.0]octyl, as a mode, is F, OH or OCH3, as a mode, is F, OH, OCH3 or N(CH3)2, as a mode, is F, OH or N(CH3)2, as a mode, is OH or OCH3, as a mode, is OH.

[0097] As "substitutable 5-membered heteroaryl", "substitutable 6-membered heteroaryl", "substitutable C 3-6 One of the acceptable substituents among "cycloalkyl", "substituted pyrazolyl", "substituted pyridyl", "substituted pyrimidinyl", "substituted pyrimidinyl", "substituted phenyl", and "substituted cyclopropyl" is a C group that can be substituted with a group selected from the group consisting of OH and OCH3. 1-3alkyl, -SO2CH3, halogen, OH, OCH3, or C 3-6 cycloalkyl. As one mode, C 1-3 alkyl, as one mode, C 1-3 alkyl, as one mode, C 1-3 alkyl, as one mode, C 1-3 alkyl, as one mode, -SO2CH3, F, Cl, OH, methyl, or OCH3, as one mode, F, Cl, OH, methyl, or OCH3, as one mode, F, OH, or OCH3, as one mode, -SO2CH3, F, Cl, or methyl, as one mode, -SO2CH3, as one mode, F, Cl, or methyl, as one mode, methyl, ethyl, hydroxymethyl, or methoxymethyl, as one mode, methyl, ethyl, or hydroxymethyl, as one mode, C 1-3 alkyl, OCH3, or cyclopropyl, as one mode, methyl, ethyl, or cyclopropyl, as one mode, methyl or ethyl, as one mode, methyl or hydroxymethyl, as one mode, ethyl or hydroxymethyl, as one mode, hydroxymethyl or methoxymethyl, as one mode, methyl, as one mode, ethyl, as one mode, hydroxymethyl, as one mode, methoxymethyl. As one mode of the acceptable substituents of "pyrazolyl which can be substituted", "pyridyl which can be substituted", "pyrimidinyl which can be substituted" when formula (I) is formula (lb), C 1-3 alkyl.

[0098] As one mode of the acceptable substituents of "4- to 6-membered saturated heterocyclic group which can be substituted", "pyrrolidinyl which can be substituted", and "piperidinyl which can be substituted", "oxetanyl which can be substituted", "tetrahydrofuranyl which can be substituted", "tetrahydropyranyl which can be substituted", C 1-3 alkyl, F, OH, OCH3, oxo, or oxetanyl. As one mode, F, OH, or OCH3, as one mode, C 1-3 alkyl, F, oxo, or oxetanyl, as one mode, C 1-3 alkyl or oxo, as one mode, C 1-3 alkyl, as one mode, C 1-3alkyl, as one embodiment, is C 1-3 alkyl, as one embodiment, is C 1-3 alkyl, as one embodiment, is OCH3, methyl, ethyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetanyl, as one embodiment, is methyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetanyl, as one embodiment, is OCH3, methyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetanyl, as one embodiment, is methyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetanyl, as one embodiment, is difluoroethyl, hydroxyethyl, or methoxyethyl, as one embodiment, is methyl, ethyl, difluoroethyl, or oxetanyl, as one embodiment, is difluoroethyl or oxetanyl, as one embodiment, is methyl, ethyl, hydroxymethyl, methoxymethyl, or oxo, as one embodiment, is methyl or oxo, as one embodiment, is hydroxymethyl or methoxymethyl, as one embodiment, is 2,2-difluoroethyl, as one embodiment, is oxetanyl, as one embodiment, is hydroxymethyl, as one embodiment, is methoxymethyl, as one embodiment, is methyl, as one embodiment, is 2-hydroxyethyl, as one embodiment, is 2-methoxyethyl, as one embodiment, is OCH3, as one embodiment, is oxo. As one embodiment, of the substituents acceptable for "pyrrolidinyl which can be substituted" and "piperidinyl which can be substituted" when formula (I) is formula (lb), is C 1-3 alkyl or oxetanyl.

[0099] As one embodiment, of the substituents acceptable for "pyrrolidinyl which can be substituted" and "piperidinyl which can be substituted" when formula (I) is formula (lb), is C 1-3 alkylene", as one embodiment, is F, OH, OCH3, or C 1-3 alkyl which can be substituted. As one embodiment, is F, OH, OCH3, methyl, ethyl, hydroxymethyl, or methoxymethyl, as one embodiment, is F, OH, OCH3, or methyl.

[0100] As one embodiment, of the substituents acceptable for "C 1-3One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl.

[0101] One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl. 1-3 One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl.

[0102] One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl. 1-3 One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl.

[0103] One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl. 1-3 One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl.

[0104] One mode of "C1-6 alkyl which can be substituted by OH" is methyl which can be substituted by 1 OH or ethyl which can be substituted by 1 to 2 OHs. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. As one mode, methyl, ethyl or hydroxymethyl, as one mode, methyl or hydroxymethyl, as one mode, hydroxymethyl or hydroxyethyl, as one mode, hydroxymethyl, as one mode, hydroxyethyl.

[0105] "G12D mutation" means a mutation in which the amino acid residue corresponding to the 12th position of the codon is changed from glycine to aspartic acid in a wild-type protein.

[0106] "G12D mutant KRAS" means KRAS having the above-described "G12D mutation".

[0107] "Pancreatic cancer" means a malignant tumor formed in the pancreas. For example, it is pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, as one mode, it is pancreatic ductal carcinoma, as one mode, it is pancreatic ductal adenocarcinoma. Further, as one mode, it is metastatic pancreatic cancer, as one mode, it is locally advanced pancreatic cancer, as one mode, it is relapsed or refractory pancreatic cancer, as one mode, it is pancreatic cancer in a patient who has not been treated and / or has a history of treatment.

[0108] "G12D mutant KRAS-positive pancreatic cancer" means pancreatic cancer positive for G12D mutant KRAS. For example, it is pancreatic cancer in which a KRAS G12D mutation has occurred, it is pancreatic cancer in which the positive rate of G12D mutant KRAS is high. As one mode, it is G12D mutant KRAS-positive pancreatic ductal carcinoma, as one mode, it is G12D mutant KRAS-positive pancreatic ductal adenocarcinoma.

[0109] One mode of the compound of formula (I) or a salt thereof in the present application is shown below.

[0110] As one mode of the above-described formula (I), it is a compound or a salt thereof specified by the following formula (Ia).

[0111]

[0112] As one mode of the above-described formula (I) and formula (Ia), it is a compound or a salt thereof specified by the following formula (Ib).

[0113]

[0114] One mode of the compound of formula (I), formula (Ia), and formula (Ib) or a salt thereof in the present application is shown below.

[0115] (1-1)R 1 is a naphthyl group which can be substituted with OH or a group selected from the group consisting of the following formula (II) and formula (III),

[0116]

[0117] R 1a , R 1b are the same or different from each other, H, methyl, F, or Cl,

[0118] R 1c is a compound or a salt thereof in which R is F, Cl, methyl, or ethyl.

[0119] (1-2)R1 is a compound of the formula (IIa) or (IIIa),

[0120]

[0121] R 1a , R 1b are the same or different from each other and are H, methyl, F or CI.

[0122] (1-3) R 1 is a compound of the formula (IIa) or (IIIa),

[0123] R 1a , R 1b are the same or different from each other and are H or F.

[0124] (1-4) R 1 is a compound of the formula (IIa) or (IIIa), R 1a is F, R 1b is H.

[0125] (1-5) R 1 is a compound of the formula (IIa), R 1a is F.

[0126]

[0127] As another way of R 1 , R 1 is a compound of the formula (II), R 1a is F, R 1c is methyl. As one way, R 1 is a compound of the formula (IIa), R 1a is H or F. As one way, R 1 is a compound of the formula (IIa), R 1a is H. As one way, R 1 is a compound of the formula (IIIa), R 1a , R 1b are the same or different from each other and are H or F. As one way, R 1 is a compound of the formula (IIIa), R 1a , R 1b are both H. As one way, R 1 is a compound of the formula (IIIa), R 1a is H, R 1b is F. As one way, R 1 is a compound of the formula (IIIa), R 1a , R1b the compound or salt thereof is F. As one mode, R 1 is of formula (IIIa), R 1a is F, R 1b the compound or salt thereof is H.

[0128] (2-1) R 2 is H, halogen, C 1-3 alkyl, cyclopropyl or vinyl, or a salt thereof.

[0129] (2-2) R 2 is halogen, C 1-3 alkyl, cyclopropyl or vinyl, and the C 1-3 alkyl group can be substituted with a group selected from the group consisting of OH and OCH3, or a salt thereof.

[0130] (2-3) R 2 is halogen, C 1-3 alkyl, cyclopropyl or vinyl, or a salt thereof.

[0131] (2-4) R 2 is cyclopropyl, or a salt thereof.

[0132] As another mode of R 2 , R 2 is halogen, or a salt thereof. As one mode, R 2 is C 1-3 alkyl, or a salt thereof. As one mode, R 2 is vinyl, or a salt thereof.

[0133] (3-1) R 3 is a saturated or unsaturated 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms, or a salt thereof.

[0134] (3-2) 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, or a salt thereof.

[0135] (3-3) R 3 is a compound of the following formula (IV) or a salt thereof.

[0136]

[0137] (4-1) R 4 is a C 1-6a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms.

[0138] (4-2) R 4 is a substituted or unsubstituted C 1-6 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms.

[0139] (4-3) R 4 is a substituted or unsubstituted C 1-6 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms.

[0140] (4-4) R 4 is a substituted or unsubstituted C 1-3 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms.

[0141] (4-5) R 4 is a substituted or unsubstituted C 1-6 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms. 1-3 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms. 1-3 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms. 1-3 a compound or salt thereof, wherein A is a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 4- to 6-membered saturated heterocyclic group having 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, a substituted or unsubstituted 5-membered heteroaromatic group having 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or a substituted or unsubstituted 6-membered heteroaromatic group having 1 to 3 nitrogen atoms.

[0142] (4-6) R 4C is a group that can be substituted by a group selected from the group consisting of OH, OCH3, N(CH3)2, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, morpholinyl, pyrrolyl, methylpyrrolyl and azabicyclo[3.3.0]octyl. 1-6 Alkyl, oxetane butyl, tetrahydrofuranyl, tetrahydropyranyl, can be C 1-3 Compounds thereof, or salts thereof, of alkyl-substituted pyridyl groups, pyrrolidinyl groups substituted with groups selected from the group consisting of difluoroethyl, hydroxyethyl, and methoxyethyl, or piperidinyl groups substituted with groups selected from the group consisting of difluoroethyl and oxetyl.

[0143] (4-7)R 4 C that can be replaced by OCH3 1-6 Compounds of alkyl, tetrahydropyranyl or piperidinyl groups that may be substituted with difluoroethyl, or salts thereof.

[0144] As R 4 Another way is R 4 C can be replaced 1-6 Compounds of alkyl, oxetane-butyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl groups, or salts thereof. As a form, it is R. 4 It is a compound of tetrahydrofuranyl, tetrahydropyranyl, substituted pyrrolidinyl, or substituted piperidinyl, or a salt thereof. As a form, it is R. 4 It is a compound of tetrahydrofuranyl, tetrahydropyranyl, or a substituted piperidinyl group, or a salt thereof. As a form, it is R... 4 Compounds of tetrahydropyranyl or substituted piperidinyl groups, or salts thereof. As a form, it is R... 4 C can be replaced 1-6 Alkyl compounds or their salts. One way is R... 4 C that can be replaced by OCH3 1-6 Alkyl compounds or their salts. One way is R... 4 C 1-3 Alkyl compounds or their salts. One way is R... 4 It is an oxocyclic butyl compound or a salt thereof. As a way, it is R 4 It is a tetrahydrofuranyl compound or a salt thereof. As a form, it is R... 4 It is a tetrahydropyranyl compound or a salt thereof. As a form, it is R... 4 Compounds containing a substituted pyrazol group or a salt thereof. One way is R... 4or a salt thereof. As one mode, R 4 or a salt thereof. As one mode, R 4 or a salt thereof. As one mode, R 4 or a salt thereof. As one mode, R 4 or a salt thereof. As one mode, R 1-3 or a salt thereof. As one mode, R 4 or a salt thereof. As one mode, R

[0145] (5-1) R 5 or a salt thereof. As one mode, R 1-6 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R

[0146] (5-2) R 5 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R

[0147] (5-3) R 5 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R

[0148] (5-4) R 5 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R

[0149] (5-5) R 5 or a salt thereof. As one mode, R

[0150] As another mode of R 5 , R 5 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R 5 or a salt thereof. As one mode, R 5 or a salt thereof. As one mode, R 5 or a salt thereof. As one mode, R 5 or a salt thereof. As one mode, R 3-6 or a salt thereof. As one mode, R

[0151] (6-1) R 6a , R 6b are the same or different from each other, H or1-6 alkyl, or R 6a , R 6b together with the carbon to which they are bonded form a C 3-6 alkyl or a compound or salt thereof containing a 4- to 6-membered saturated heterocyclic ring having 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen.

[0152] (6-2) R 6a , R 6b are the same or different from each other, H or C 1-3 alkyl and the C 1-3 alkyl can be substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or R 6a , R 6b together with the carbon to which they are bonded form a C 3-6 cycloalkyl or a compound or salt thereof.

[0153] (6-3) R 6a , R 6b are the same or different from each other, H or C 1-3 alkyl and the C 1-3 alkyl can be substituted with a group selected from the group consisting of F, OH and N(CH3)2, or R 6a , R 6b together with the carbon to which they are bonded form a cyclopropyl group or a compound or salt thereof.

[0154] (6-4) R 6a is H, R 6b is C 1-3 alkyl which can be substituted with OH or a compound or salt thereof.

[0155] As another way of R 6a , R 6b , R 6a , R 6b are the same or different from each other, H or C 1-3 alkyl which can be substituted with a group selected from the group consisting of F, OH and N(CH3)2 or a compound or salt thereof. As one way, R 6a , R 6b are the same or different from each other, C 1-3 alkyl which can be substituted with a group selected from the group consisting of F, OH and N(CH3)2 or a compound or salt thereof. As one way, R 6a , R 6b are both H or a compound or salt thereof. As one way, R 6a is H, R 6b is C 1-3or a salt thereof. As one mode, it is R 6a is H, R 6b is C 1-3 alkyl or a salt thereof. As one mode, it is R 6a is H, R 6b is C 1-3 alkyl or a salt thereof. As one mode, it is R 6a , R 6b together with the carbon to which they bind form a cyclopropyl group or a salt thereof.

[0156] (7-1) R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl, a 4- to 6-membered saturated heterocyclic group optionally substituted with 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, a 5-membered heteroaryl group optionally substituted with 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms or a salt thereof.

[0157] (7-2) R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl or a group selected from the group consisting of the following formula (VI), formula (VII), formula (VIII), formula (IX), formula (XX), formula (XXI), formula (XXII), formula (XXIII) and formula (XXIV),

[0158]

[0159] R 7a , R 7b are the same or different from each other, H or C 1-3 alkyl optionally substituted with OH or a salt thereof.

[0160] (7-3) R 7 is H, halogen or a group selected from the group consisting of formula (VI), formula (VII), formula (VIII) and formula (IX),

[0161]

[0162] R 7a is H or C 1-3 alkyl optionally substituted with OH or a salt thereof.

[0163] (7-4) R 7 is H, halogen or a group selected from the group consisting of formula (VI), formula (VII), formula (VIII) and formula (IX), R7a is a C1-6alkyl group which can be substituted with OH; 1-3 or a salt thereof.

[0164] (7-5) R 7 is a group selected from the group consisting of Formula (VI), Formula (VII), Formula (VIII), and Formula (IX), R 7a is a C1-6alkyl group which can be substituted with OH; 1-3 or a salt thereof.

[0165] (7-6) R 7 or a salt thereof.

[0166] as R 7 Another way as R 7 is H, halogen, C1-6alkyl, or -SO2CH3. As one way, R 1-3 is H, halogen, C1-6alkyl, or -SO2CH3. As one way, R 7 is H, halogen, C1-6alkyl, or -SO2CH3. As one way, R 7 is H, halogen, C1-6alkyl, or -SO2CH3. As one way, R 7 is a group selected from the group consisting of Formula (VI), Formula (VII), Formula (VIII), and Formula (IX), R 7 is a group selected from the group consisting of Formula (VI), Formula (VII), Formula (VIII), and Formula (IX), R 7 is a compound of Formula (VI) or (VIII), or a salt thereof. As one way, R 7 is a compound of Formula (VI) or (IX), or a salt thereof. As one way, R 7 is a compound of Formula (VI), or a salt thereof. As one way, R 7 is a compound of Formula (VII), or a salt thereof. As one way, R 7 is a compound of Formula (VIII), or a salt thereof. As one way, R 7 is a compound of Formula (IX), or a salt thereof.

[0167] (7-8) R 7a is H or a C1-6alkyl group which can be substituted with OH; 1-3 or a salt thereof. As one way, R 7a or a salt thereof. As one way, R 7a is a C1-6alkyl group which can be substituted with OH; 1-3 or a salt thereof. As one way, R 7a is a C1-6alkyl group which can be substituted with OH; 1-3 or a salt thereof.

[0168] (8-1) A compound of the formula (I) wherein W is a phenyl group which can be substituted or a 6-membered heteroaryl group which can be substituted and contains 1 to 3 nitrogen atoms, or a salt thereof.

[0169] (8-2) W 1 is CH, W 2 is C-SO2CH3, or a salt thereof.

[0170] (8-3) W 1 , W 2 are the same or different from each other and are CH, CF, CCl, CCH3 or N, or a salt thereof.

[0171] (8-4) W 1 , W 2 are the same or different from each other and are CH, CF or N, or a salt thereof.

[0172] (8-5) W 1 is CH, W 2 is CH, or a salt thereof.

[0173] (9) W 1 , W 2 and R 7 :

[0174] i. W 1 is CH, W 2 is C-SO2CH3, R 7 is H, or

[0175] ii. W 1 , W 2 are the same or different from each other and are CH, CF, CCl, CCH3 or N, R 7 is H, halogen, C 1-3 alkyl, -SO2CH3, C 3-6 cycloalkyl or a group selected from the group consisting of the following formula (VI), formula (VII), formula (VIII), formula (IX), formula (XX), formula (XXI), formula (XXII), formula (XXIII) and formula (XXIV),

[0176]

[0177] R 7a , R 7b are the same or different from each other and are H or C 1-3 alkyl which can be substituted with OH, or a salt thereof.

[0178] (10-1) X is a bond, CH2, O, S or NR 4x , R4x For H or C 1-3 Alkyl compounds or their salts.

[0179] (10-2)X is O, S or NR 4x R 4x For H or C 1-3 Alkyl compounds or their salts.

[0180] (10-3)X is a compound of O or NH or its salt.

[0181] (10-4) Compounds in which X is O or its salts.

[0182] (11-1)Y is a phenylene or pyridinyl dimethyl compound or a salt thereof that can be substituted with F.

[0183] (11-2)Y is a compound of phenylene or pyridinium dimethyl or its salt.

[0184] (11-3)Y is a compound of phenylene that can be substituted by F or a salt thereof.

[0185] Another form of Y is a compound in which Y is 1,4-phenylene or 2,5-pyridinidinediyl, or a salt thereof. Another form of Y is a compound in which Y is phenylene, or a salt thereof. Another form of Y is a compound in which Y is 1,4-phenylene, or a salt thereof. Another form of Y is a compound in which Y is pyridinidinediyl, or a salt thereof. Another form of Y is a compound in which Y is 2,5-pyridinidinediyl, or a salt thereof.

[0186] (12-1)L is -(L) 1 -L 2 -L 3 -L 4 )-,

[0187] L 1 L 2 L 3 L 4 If they are the same or different from each other, select the free key, O, NR. L1 Substitutable pyrrolidine diel, substitutable piperidine diel, substitutable piperazine diel, substitutable C 1-3 Groups in the group consisting of alkylene and C=O,

[0188] R L1 For H or C 1-3 Alkyl compounds or their salts.

[0189] (12-2) L is the bond, C is the bond 1-3alkylene, C=0 or a group selected from the group consisting of the following formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII) and formula (XIX),

[0190]

[0191] R L1 is H or C 1-3 alkyl,

[0192] R L2 , R L3 are the same or different from each other, H, F, OH, OCH3or C 1-3 alkyl,

[0193] R L is CH or N,

[0194] an integer of 1 to 2.

[0195] (12-3) L is a bond, C 1-3 alkylene, C=0 or a group selected from the group consisting of the following formula (XIV)-1, formula (XV)-1, formula (XVI)-1, formula (XVII)-1, formula (XVIII)-1 and formula (XIX)-1,

[0196]

[0197] (in the formula, Y * represents bonding with Y.)

[0198] R L1 is H or C 1-3 alkyl,

[0199] R L2 , R L3 are the same or different from each other, H, F, OH, OCH3or C 1-3 alkyl,

[0200] R L is CH or N,

[0201] an integer of 1 to 2.

[0202] (12-4) L is a bond, C 1-3 alkylene, C=0 or a group selected from the group consisting of the following formula (XIV) and formula (XVI),

[0203]

[0204] R L1 is C 1-3 alkyl,

[0205] R L2 , R L3 is H,

[0206] the compound wherein n is 1 or a salt thereof.

[0207] (12-5) L is a bond, C 1-3 alkylene, C=0 or a group selected from the group consisting of formula (XIV)-1 and formula (XVI)-1,

[0208]

[0209] (in the formula, Y * represents a bond to Y.)

[0210] R L1 is C 1-3 alkyl,

[0211] R L2 , R L3 is H,

[0212] the compound wherein n is 1 or a salt thereof.

[0213] (12-6) L is a bond, C=0 or a group selected from the group consisting of formula (XIV) and formula (XVI), R L1 is C 1-3 alkyl, R L2 , R L3 is H, n is 1 or a salt thereof.

[0214] (12-7) L is a bond, C=0 or a group selected from the group consisting of formula (XIV)-1 and formula (XVI)-1, R L1 is C 1-3 alkyl, R L2 , R L3 is H, n is 1 or a salt thereof.

[0215] (12-8) L is C=0 or a group selected from the group consisting of formula (XIV) and formula (XVI), R L1 is C 1-3 alkyl, R L2 , R L3 is H, n is 1 or a salt thereof.

[0216] (12-9) L is C=0 or a group selected from the group consisting of formula (XIV)-1 and formula (XVI)-1, R L1 is C 1-3 alkyl, R L2 , R L3 is H, n is 1 or a salt thereof.

[0217] (12-10) L is a bond, C 1-3 alkylene or C=O, or a salt thereof.

[0218] (12-11) L is a bond, or a salt thereof.

[0219] As another mode of L, L is a bond or C 1-3 alkylene, or a salt thereof. As one mode, L is a bond or C=O, or a salt thereof. As one mode, L is C 1-3 alkylene, or a salt thereof. As one mode, L is C=O, or a salt thereof.

[0220] (13-1) Z is NH or a 5-membered heteroarenetwo group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a salt thereof.

[0221] (13-2) Z is NH or a group selected from the group consisting of the following formula (V), formula (X), formula (XI) and formula (XII), or a salt thereof.

[0222]

[0223] (13-3) Z is NH or a group selected from the group consisting of the following formula (V)-1, formula (X)-1, formula (XI)-1 and formula (XII)-1, or a salt thereof.

[0224]

[0225] (In the formula, L * represents bonding with L.)

[0226] (13-4) Z is NH or a group selected from the group consisting of the following formula (X), formula (XI) and formula (XII), or a salt thereof.

[0227]

[0228] (13-5) Z is NH or a group selected from the group consisting of the following formula (X)-1, formula (XI)-1 and formula (XII)-1, or a salt thereof.

[0229]

[0230] (In the formula, L * represents bonding with L.)

[0231] (13-6) Z is NH or a group selected from the group consisting of the following formula (X) and formula (XI), or a salt thereof.

[0232]

[0233] (13-7) Z is NH or a compound or salt thereof in which Z is a group selected from the group consisting of Formula (X)-1 and Formula (XI)-1.

[0234]

[0235] (In the formula, L * denotes bonding to L.)

[0236] (13-8) Z is a compound or salt thereof in which Z is a group selected from the group consisting of Formula (X) and Formula (XI).

[0237] (13-9) Z is a compound or salt thereof in which Z is a group selected from the group consisting of Formula (X)-1 and Formula (XI)-1.

[0238] (13-10) Z is NH or a salt thereof.

[0239] (13-11) Z is a compound or salt thereof in which Z is Formula (XI).

[0240]

[0241] (13-12) Z is a compound or salt thereof in which Z is Formula (XI)-1.

[0242]

[0243] (In the formula, L * denotes bonding to L.)

[0244] As another way of Z, Z is a compound or salt thereof in which Z is a group selected from the group consisting of Formula (X), Formula (XI), and Formula (XII). As one way, Z is a compound or salt thereof in which Z is a group selected from the group consisting of Formula (X)-1, Formula (XI)-1, and Formula (XII)-1. As one way, Z is a compound or salt thereof in which Z is Formula (XI) or Formula (XII). As one way, Z is a compound or salt thereof in which Z is Formula (XI)-1 or Formula (XII)-1. As one way, Z is a compound or salt thereof in which Z is Formula (X). As one way, Z is a compound or salt thereof in which Z is Formula (X)-1. As one way, Z is a compound or salt thereof in which Z is Formula (XII). As one way, Z is a compound or salt thereof in which Z is Formula (XII)-1.

[0245] (14-1) Y-L-Z is a compound or salt thereof in which Y-L-Z is Formula (XIII).

[0246]

[0247] (14-2) Y-L-Z is a compound or salt thereof in which Y-L-Z is Formula (XIII)-1.

[0248]

[0249] (in which O-CH2 * represents a carbon bond with O-CH2.

[0250] (15) A compound or a salt thereof according to any two or more of the modes described in (1-1) to (14-2) above, which are not contradictory.

[0251] As the combination described in (15) above, specifically, for example, the following modes can be given.

[0252] (16-1) A compound of the formula (I) or a salt thereof according to a combination of the modes described in (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) above, or a combination of the modes described in (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), and (14-1) above.

[0253] (16-2) A compound of the formula (I) or a salt thereof according to a combination of the modes described in (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) above, or a combination of the modes described in (1-1), (2-1), (3-2), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), and (14-1) above.

[0254] (16-3) A compound or a salt thereof according to a combination of the modes described in (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2), (11-1), (12-2), and (13-2) above, or a combination of the modes described in (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2), and (14-1) above, wherein the formula (I) is the formula (la).

[0255] (16-3-i) the compound of formula (I) is of formula (la), a combination of the manners 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 manners of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-5), (8-2), (10-2), and (14-1), or a salt thereof.

[0256] (16-3-ii) the compound of formula (I) is of formula (la), a combination of the manners 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 manners of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-2), (8-3), (10-2), and (14-1), or a salt thereof.

[0257] (16-4) the compound of formula (I) is of formula (la), a combination of the manners 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 manners of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (9), (10-3), and (14-1), or a salt thereof.

[0258] (16-4-i) the compound of formula (I) is of formula (la), a combination of the manners 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 manners of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-5), (8-2), (10-3), and (14-1), or a salt thereof.

[0259] (16-4-ii) the compound of formula (I) is of formula (la), a combination of the manners 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 manners of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-2), (8-3), (10-3), and (14-1), or a salt thereof.

[0260] (16-5) The compound or salt thereof according to any one of the above (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) in combination with the mode 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 the mode of (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4) and (14-1).

[0261] (16-6) The compound or salt thereof according to any one of the above (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4), (11-2), (12-10) and (13-4) in combination with the mode of (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4) and (14-1).

[0262] (16-7) The compound or salt thereof according to any one of the above (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) in combination with the mode 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).

[0263] (16-8) The compound or salt thereof according to any one of the above (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) in combination with the mode 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).

[0264] (16-9) The compound or salt thereof according to any one of the above (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) in combination with the mode 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).

[0265] (16-10) The compound or salt thereof according to any one of the above (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) in combination with the mode 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 the mode of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-11) and (13-8). 1 is formula (IIa), R 1a is F, R 2 is cyclopropyl, R 3 is formula (IV), R 4 is C 1-6 alkyl, tetrahydropyranyl or piperidinyl which can be substituted with C 1-3 alkyl which can be substituted with F, R​5 isopropyl, R 6a is H, R 6b is C 1-3 alkyl, R 7 is a group selected from the group consisting of formulae (VI), (VII), (VIII) and (IX), R 7a is C 1-3 alkyl, W 1 is CH, W 2 is CH, X is O, Y is phenylene which can be substituted by F, L is a bond, Z is a compound of formula (XI) or a salt thereof.

[0266] (16-11) Formula (I) is formula (la), R 1 is formula (IIa), R 1a is F, R 2 is cyclopropyl, R 3 is formula (IV), R 4 is C 1-6 alkyl, tetrahydropyranyl or piperidinyl which can be substituted by difluoroethyl, R 5 isopropyl, R 6a is H, R 6b is C 1-3 alkyl, R 7 is a group selected from the group consisting of formulae (VI), (VII), (VIII) and (IX), R 7a is C 1-3 alkyl, W 1 is CH, W 2 is CH, X is O, Y is phenylene which can be substituted by F, L is a bond, Z is a compound of formula (XI) or a salt thereof.

[0267] (16-12) Formula (I) is formula (la), R 1 is formula (IIa), R 1a is F, R 2 is cyclopropyl, R 3 is formula (IV), R 4 is C 1-6 alkyl, tetrahydropyranyl or piperidinyl which can be substituted by difluoroethyl, R 5 isopropyl, R 6a is H, R 6b is C 1-3 alkyl, R 7 is a group selected from the group consisting of formulae (VI), (VII), (VIII) and (IX), R 7a is C 1-3 alkyl, W1 is CH, W is 2 is CH, X is O, Y is phenylene which can be substituted with F, L is a bond, and Z is a compound of formula (XI)-1 or a salt thereof.

[0268] (16-13) Formula (I) is formula (lb), R 1 is formula (IIa), R 1a is F, R 2 is cyclopropyl, R 3 is formula (IV), R 4 is tetrahydropyranyl or piperidinyl which can be substituted, R 5 is isopropyl, R 6a is H, R 6b is C 1-3 alkyl which can be substituted with OH, R 7 is formula (VI), (VIII) or (IX), R 7a is C 1-3 alkyl which can be substituted with OH, X is O, Y is phenylene, L is a bond, and Z is a compound of formula (XI) or a salt thereof.

[0269] (16-14) Formula (I) is formula (lb), R 1 is formula (IIa), R 1a is F, R 2 is cyclopropyl, R 3 is formula (IV), R 4 is tetrahydropyranyl, R 5 is isopropyl, R 6a is H, R 6b is C 1-3 alkyl which can be substituted with OH, R 7 is formula (VI) or (VIII), R 7a is C 1-3 alkyl, X is O, Y is 1,4-phenylene, L is a bond, and Z is a compound of formula (XI)-1 or a salt thereof.

[0270] As examples of the specific compounds included in the present application, as one mode, the following compounds can be cited.

[0271] a compound selected from the group consisting of:

[0272] (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-indazol-4-yl)-2-( (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-indazol-4-yl)-2-[(

[0273] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0274] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0275] (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-indazol-4-yl)-2-[(

[0276] (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-indazol-4-yl)-2-[( (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0277] (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0278] (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0279] (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0280] (4R)-1 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl]-7- (6-fluoro-5-methyl-1 H-indol-4-yl)-2-[(2S)-2-hydroxypropoxy]quinazolin-8-yl}oxy)methyl] phenyl}-1 H-1,2,3-triazol-1 -yl]-3-methylbutanoyl]-4-hydroxy-N-{(1 R)-2-hydroxy-1 - [4-(1 -methyl-1 H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0281] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0282] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0283] As examples of the specific compounds included in the present application, as one mode, the following compounds can be cited.

[0284] a compound selected from the group consisting of:

[0285] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0286] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0287] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0288] (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-indazol-4-yl)-2-[(

[0289] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0290] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0291] (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-indazol-4-yl)-2-[(

[0292] (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-indazol-4-yl)-2-[(

[0293] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0294] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, and

[0295] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

[0296] As examples of specific compounds included in this invention, the following compounds may be listed as an example.

[0297] Choose compounds or their salts from the group consisting of the following:

[0298] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide,

[0299] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(

[0300] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[( (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[( (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(

[0301] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(

[0302] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[( (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(

[0303] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[( (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0304] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0305] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0306] (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7R)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0307] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

[0308] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0309] As examples of the specific compounds included in the present application, as one mode, the following compounds can be cited.

[0310] a compound selected from the group consisting of:

[0311] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0312] (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(

[0313] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0314] (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-indazol-4-yl)-2-[(

[0315] (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[(

[0316] (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-indazol-4-yl)-2-[( N- { (1R)-1- [4-( 1-ethyl- 1H- pyrazol-5-yl)phenyl] -2-hydroxyethyl} -4-hydroxy-L-prolinamide.

[0317] In the compound of formula (I), depending on the kind of substituent, there can be tautomers, geometric isomers. In the present specification, the compound of formula (I) is sometimes described in only one form of isomer, but the present application also includes isomers other than this, and includes isolated products of isomers or mixtures thereof.

[0318] In addition, in the compound of formula (I), there are sometimes asymmetric carbon atoms, axial asymmetry, and there can be diastereomers based thereon. The present application also includes isolated products of diastereomers of the compound of formula (I) or mixtures thereof.

[0319] Further, the present application also includes pharmaceutically acceptable prodrugs of the compound represented by formula (I). The pharmaceutically acceptable prodrug refers to a compound having a group which is decomposed by solvation or which is converted into an amino group, a hydroxyl group, a carboxyl group, or the like under physiological conditions. As the group forming the prodrug, there can be mentioned, for example, the groups described in Prog. Med., 1985, 5, p. 2157-2161 and "Development of Drugs", Vol. 7, Molecular Design, Kogyo Chosakai, 1990, p. 163-198.

[0320] In addition, the salt of the compound of formula (I) refers to a pharmaceutically acceptable salt of the compound of formula (I), and depending on the kind of substituent, there are sometimes acid addition salts or salts with bases. There can be mentioned, for example, the salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specifically, there can be mentioned: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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, dibenzoyltartaric acid, dimethylbenzoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like; salts with inorganic metals such as sodium, potassium, magnesium, calcium, aluminum, and the like; salts with organic bases such as methylamine, ethylamine, ethanolamine, and the like; salts with various amino acids and amino acid derivatives such as acetyl lysine, lysine, ornithine, and the like; ammonium salts, and the like.

[0321] Further, the present application also includes various hydrates, solvates, and polymorphs of the compound of formula (I) and salts thereof.

[0322] Furthermore, this invention includes all compounds of formula (I) or salts thereof labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of preferred isotopes for isotopic labeling of compounds of this 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 Isotopes of S, etc.

[0323] The compounds of this invention, labeled with isotopes, can be used in studies such as tissue distribution research of drugs and / or substrates. For example, from the perspective of ease of labeling and simplicity of detection, tritium ( 3 H), carbon-14 ( 14 C) Radioactive isotopes such as those used for this purpose.

[0324] Replace with a heavier isotope, for example, replacing hydrogen with deuterium. 2 H) Sometimes, improved metabolic stability can be therapeutically advantageous (e.g., increased half-life in vivo, reduced dosage, and reduced drug interactions).

[0325] Emit isotopes to positrons ( 11 C 18 F, 15 O and 13 The substitution of N (e.g.) can be used in positron emission tomography (PET) tests to test substrate-acceptor occupancy.

[0326] The isotopically labeled compounds of the present invention can generally be manufactured by existing methods known to those skilled in the art, or by using suitable isotopically labeled reagents instead of unlabeled reagents, and by the same manufacturing method as in the examples or manufacturing examples.

[0327] (Manufacturing method)

[0328] The compounds of the formula (I) and salts thereof can be produced using various publicly known synthesis methods based on the characteristics of their basic structures or the kinds of substituents. At this time, depending on the kinds of functional groups, the functional group is sometimes replaced with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from the starting material to the intermediate in advance, which is effective in the production technology. As such protecting groups, there can be cited, for example, the protecting groups described in "Greene's Protective Groups in Organic Synthesis" by P. G. M. Wuts and T. W. Greene, 5th edition, John Wiley & Sons Inc., 2014, and the like, and can be appropriately selected for use in accordance with their reaction conditions. In such a method, after the introduction of the protecting group and the reaction, the protecting group is removed as necessary, whereby the desired compound can be obtained.

[0329] In addition, the prodrugs of the compounds of the formula (I) can be produced by introducing a specific group at the stage from the starting material to the intermediate or further reacting the obtained compound of the formula (I) using the protecting groups described above. The reaction can be performed by applying publicly known methods such as esterification, amidation, dehydration, and the like, to those skilled in the art.

[0330] Hereinafter, representative production methods of the compounds of the formula (I) will be described. Each production method can also be performed with reference to the references attached in this description. Note that the production methods of the present application are not limited to the examples shown below.

[0331] In this specification, the following abbreviations are sometimes used.

[0332] DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, Pd / C: palladium on carbon.

[0333] (Production Method 1)

[0334]

[0335] (In the formula, PG 1 represents a protecting group of NH contained in R 3 2 represents a protecting group of NH contained in R 1 ​a protecting group of NH or OH contained in the compound (1) or a hydrogen atom. The same applies hereinafter)

[0336] The compound of the formula (I) can be obtained by subjecting the compound (1) to a deprotection reaction. Here, as examples of the protecting group which can be deprotected under acidic conditions, there can be mentioned tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl and the like.

[0337] This reaction is carried out usually with stirring for 0.1 hour to 5 days under cooling to heating reflux. As examples of the solvent to be used here, there are not particularly limited, and there can be mentioned alcohols such as MeOH, EtOH and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform and the like; ethers such as diethyl ether, THF, DOX, dimethoxyethane and the like; DMF, DMSO, MeCN or water; and mixtures of these. As examples of the deprotecting reagent, there are not particularly limited, and there can be mentioned hydrogen chloride (a DOX solution), trifluoroacetic acid, methanesulfonic acid and the like.

[0338] By selecting the protecting group, deprotection can also be carried out by catalytic hydrogenation. As examples of the protecting group, there can be mentioned benzyl, p-methoxybenzyl, benzyloxycarbonyl and the like. Further, deprotection can also be carried out using a source of fluoride ions such as tetra-n-butylammonium fluoride. As examples of the protecting group, there can be mentioned tert-butyl(dimethyl)silyl, (trimethylsilyl)ethoxymethyl and the like. Furthermore, as examples of the protecting group which can be deprotected under basic conditions, there can be mentioned acetyl, trifluoroacetyl, benzoyl and the like. Further, as examples of the protecting group which can be deprotected under acidic conditions, there can be mentioned tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl and the like. 1 2 By selecting the protecting group, deprotection can also be carried out by catalytic hydrogenation. As examples of the protecting group, there can be mentioned benzyl, p-methoxybenzyl, benzyloxycarbonyl and the like. Further, deprotection can also be carried out using a source of fluoride ions such as tetra-n-butylammonium fluoride. As examples of the protecting group, there can be mentioned tert-butyl(dimethyl)silyl, (trimethylsilyl)ethoxymethyl and the like. Furthermore, as examples of the protecting group which can be deprotected under basic conditions, there can be mentioned acetyl, trifluoroacetyl, benzoyl and the like. Further, as examples of the protecting group which can be deprotected under acidic conditions, there can be mentioned tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl and the like.

[0339] As a reference for this reaction, for example, the following literature can be referred to.

[0340] P.G.M. Wuts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014

[0341] Note that when the compound (1) as a starting material has an axis of asymmetry, this reaction can also be carried out using a stereoisomer obtained by temporarily separating the compound (1).

[0342] By subjecting the compound of the formula (I) to the following operation as a salt-forming reaction, the hydrochloride salt of the compound of the formula (I) can be obtained.

[0343] ​The compound of the formula (I) which is considered to form a salt with hydrochloric acid from its chemical structural characteristics is dissolved in CH2Cl2and MeOH, and hydrogen chloride (4M DOX solution, 10 equivalents) is added under ice cooling, and stirred for 30 minutes under ice cooling. The reaction mixture is concentrated under reduced pressure, and to the obtained residue, diethyl ether is added, and the resulting solid is filtered, and dried under reduced pressure to obtain the hydrochloride salt of the compound of the formula (I).

[0344] The hydrochloride salt of the compound of the formula (I) can be obtained as the compound of the formula (I) by applying the following operation as a desalting reaction.

[0345] The hydrochloride salt of the compound of the formula (I) is purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and the fraction containing the target is collected, and after making it alkaline with saturated sodium bicarbonate aqueous solution, extracted with CHCl3 / MeOH (5 / 1). The combined organic layer is dried with anhydrous sodium sulfate, and the solution is concentrated under reduced pressure, and the obtained solid is washed with diethyl ether, and dried under reduced pressure to obtain the compound of the formula (I).

[0346] (Synthesis of raw material 1)

[0347]

[0348] (In the formula, Y 1 represents CH, CF or N. The same applies hereafter)

[0349] This production method is a first method of producing the compound (1)-1 included in the raw material compound (1).

[0350] (First step)

[0351] This step is a method of producing the compound (1)-1 by a cycloaddition reaction of the compound (2) and the compound (3).

[0352] In this reaction, an equal amount or an excess amount of compound (2) and compound (3) is used, and a mixture thereof is preferably allowed to react in the presence of a copper salt, further preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or without a solvent, under cooling to heating under reflux, preferably at 00C to 1000C, usually with stirring for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, and the like; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and a mixture of these. As the copper salt, CuI, CuSO4, CuOTf, and the like. As the reducing agent, sodium ascorbate and the like can be exemplified. The reaction is sometimes advantageously performed in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, tris[(l-benzyl-lH-l,2,3-triazol-4-yl)methyl]amine (TBTA), and the like, in terms of smooth progress of the reaction.

[0353] [Documents]

[0354] Angew. Chem. Int. Ed. 2002, 41, p. 2596-2599.

[0355] Note that PG 2 The compound obtained by the deprotection reaction is subjected to this reaction first.

[0356] (Synthesis of raw material compound 2)

[0357]

[0358] (In the formula, R represents C 1-3 alkyl. The same applies hereafter)

[0359] This production method is a second method for producing compound (1)-1 included in raw material compound (1).

[0360] (First step)

[0361] This step is a method for producing compound (5) by a cycloaddition reaction of compound (2) with compound (4).

[0362] The reaction conditions are the same as those in the first step of Synthesis of raw material compound 1.

[0363] (Second step)

[0364] This step is a method for producing compound (6) by hydrolysis of compound (5).

[0365] This reaction is carried out by usually stirring the compound (5) under cooling to under heating reflux for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and alcohols, acetone, N,N-dimethylformamide, tetrahydrofuran, and the like can be given. Further, it is sometimes preferable for the reaction to be carried out as a mixed solvent of the above solvent and water. Examples of the hydrolysis reagent are not particularly limited, and aqueous sodium hydroxide, aqueous potassium hydroxide, trimethyltin hydroxide, and the like can be given.

[0366] As a reference for this reaction, for example, the following literature can be referred to.

[0367] "Experimental Chemistry Course (5th Edition)", Vol. 16 (2005) (Maruzen)

[0368] Angew. Chem. Int. Ed. 2005, 44, p. 1378-1382.

[0369] (Third step)

[0370] This step is a method for producing the compound (1)-1 by an amidation reaction of the compound (6) with the compound (7).

[0371] In this reaction, the compound (6) and the compound (7) are used in equal amounts or one is used in excess, and their mixture is usually stirred in the presence of a condensing agent in a solvent inert to the reaction, under cooling to heating, preferably at -20°C to 60°C, for 0.1 hour to 5 days. Examples of the solvent are not particularly limited, and aromatic hydrocarbons such as toluene; ethers such as THF, DOX; halogenated hydrocarbons such as dichloromethane; alcohols; N,N-dimethylformamide, DMSO, ethyl acetate, MeCN; and mixtures of these can be given. Examples of the condensing agent can be given as hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), and the like. It is sometimes preferable for the reaction to be carried out in the presence of an additive such as 1-hydroxybenzotriazole. It is sometimes advantageous in terms of smoothly carrying out the reaction to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide.

[0372] ​Alternatively, a method in which compound (6) is converted into a reactive derivative and then subjected to acylation can also be used. As examples of the reactive derivative of carboxylic acid, acyl halide obtained by reacting with a halogenating agent such as phosphorous oxychloride or thionyl chloride, mixed anhydride obtained by reacting with isobutyl chloroformate or the like, active ester obtained by condensing with 1-hydroxybenzotriazole or the like, and the like can be given. The reaction of these reactive derivatives with compound (7) can be carried out in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like, at cooling to heating, preferably at -20°C to 120°C.

[0373] [Documents]

[0374] S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd Ed., Vol. 1, Academic Press Inc., 1991

[0375] "Experimental Chemistry Course (5th Ed.)", Vol. 16 (2005) (Maruzen), edited by The Chemical Society of Japan

[0376] (Synthesis of starting material 3)

[0377]

[0378] (In the formula, PG 3 represents a protecting group for OH, LG 1 represents a leaving group, and BLG represents a boronic acid group, a pinacol ester of boronic acid group, or a trifluoroborate group (hereinafter sometimes referred to as a boronic acid group or the like) protected with a boronic acid protecting group. As examples of the leaving group shown herein, Cl, Br, methanesulfonyl group, p-toluenesulfonyl group, and the like can be given.)

[0379] This production method is a first method for producing the starting material compound (2).

[0380] (First step)

[0381] This step is a method for producing compound (10) by in situ substitution reaction of compound (8) with compound (9).

[0382] In this reaction, an equal amount or an excess amount of compound (8) and compound (9) is used, and the mixture thereof is usually stirred at 0°C to 80°C under cooling to heating reflux in a solvent inert to the reaction or without a solvent for 0.1 hour to 5 days. As the solvent used here, there is no particular limitation, and examples of the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, and the like; DMF, DMAc, DMSO, ethyl acetate, MeCN; and a mixture of these can be given. The reaction is sometimes advantageously carried out in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, and the like, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, and the like, inorganic bases.

[0383] Alternatively, compound (10) can also be produced by subjecting the compound obtained by the Grignard-Henry reaction of compound (8) and compound (9) to a catalytic hydrogenation reaction.

[0384] (Second step)

[0385] This step is a method for producing compound (12) by an in situ substitution reaction of compound (10) and compound (11).

[0386] The reaction conditions are the same as those in the first step of the synthesis of the starting material 3.

[0387] Alternatively, compound (12) can also be produced by subjecting the compound obtained by the Grignard-Henry reaction of compound (8) and compound (9) to a catalytic hydrogenation reaction.

[0388] (Third step)

[0389] This step is a method for producing compound (13) by an in situ substitution reaction of compound (12) and PG 3 -OH.

[0390] As examples of PG 3 -OH used here, benzyl alcohol and p-methoxybenzyl alcohol can be given.

[0391] The reaction conditions are the same as those in the first step of the synthesis of the starting material 3.

[0392] (Fourth step)

[0393] This step is a method for producing compound (13) by an in situ substitution reaction of compound (12) and PG 2- a method of producing the compound (14) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a boronic acid group. As examples of the boronic acid group and the like used here, there are no particular limitations, and boronic acid group, boronic ester group, pinacol boronic ester group, triol borate group, and trifluoroborate group can be listed.

[0394] In this reaction, the compound (13) and the compound (14) are used in equal amounts or one in excess. 2 - a boronic acid derivative such as a boronic acid group, and mixtures thereof are usually stirred for 0.1 hour to 5 days at room temperature to heating reflux, preferably 20°C to 140°C, in the presence of a base and a palladium catalyst in a solvent inert to the reaction. As examples of the solvent used here, there are no particular limitations, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, and the like; alcohols such as MeOH, EtOH, isopropanol, butanol, pentanol, and the like; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water; and mixtures of these can be listed. As the base, inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and the like can be listed. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one / palladium(3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and the like can be listed. The reaction is sometimes favorably performed in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, and the like. In addition, the mixture is sometimes favorably heated by microwave irradiation.

[0395] [Documents]

[0396] J. Am. Chem. Soc, 2005, 127, p. 4685-4696

[0397] Org. Lett. 2011, 13, p. 3948-3951

[0398] Org. Lett. 2012, 14, p. 1278-1281

[0399] R 2 When R is a hydrogen atom, the compound (14) can be produced by catalytic hydrogenation of the compound (13).

[0400] (Fifth Step)

[0401] This step is a method for producing compound (16) by Suzuki-Miyaura coupling reaction of compound (14) and compound (15).

[0402] The reaction conditions are the same as those in the fourth step of the synthesis of the starting material 3.

[0403] Note that when compound (16) has an axial asymmetry, it is obtained as a mixture of diastereomers, and each diastereomer can be isolated by performing a conventional resolution operation, such as resolution using an ODS column chromatography, silica gel column chromatography.

[0404] (Sixth Step)

[0405] This step is a method for producing compound (17) by deprotection through catalytic hydrogenation of compound (16).

[0406] This reaction can be performed by stirring compound (16) in a hydrogen atmosphere, at normal pressure to pressurized, in a solvent inert to the reaction, such as MeOH, EtOH, ethyl acetate, etc., 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, a palladium catalyst such as Pd / C, palladium black, a platinum catalyst such as platinum plate, platinum oxide, a nickel catalyst such as reduced nickel, Raney nickel, etc. is used.

[0407] (Seventh Step)

[0408] This step is a method for producing compound (2) by reaction of compound (17) and compound (18).

[0409] This reaction is performed by using compound (17) and compound (18) in equal amounts or one in excess and allowing their mixture to react in the presence of a base, in a solvent inert to the reaction, under cooling to heating reflux, preferably at 0°C to 80°C, usually for 0.1 hour to 5 days. As the solvent used here, there is no particular limitation, and examples that can be listed include: aromatic hydrocarbons such as benzene, toluene, xylene, etc.; alcohols such as MeOH, EtOH, etc.; ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, etc.; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, etc.; DMF, DMSO, ethyl acetate, MeCN; and mixtures of these. As examples of the base, there is no particular limitation, and examples that can be listed include: organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, tBuOK, etc.; inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, etc. It is sometimes advantageous to perform the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.

[0410] As a reference for this reaction, for example, the following literature can be referred to.

[0411] The Chemical Society of Japan, "Experimental Chemistry Course", 5th edition, Vol. 14, Maruzen, 2005

[0412] Note that compound (2) sometimes has an axis of asymmetry, and is obtained as a mixture of diastereomers, and PG 2 Compound (2) or compound (2) is subjected to a deprotection reaction, and the obtained compound is subjected to a conventional resolution operation, for example, resolution using an ODS column chromatography, a silica gel column chromatography, whereby each diastereomer is isolated.

[0413] The reaction conditions of the deprotection reaction used here are the same as those described in the step of Production Method 1.

[0414] In addition, for compound (18), a compound in which the portion corresponding to LG 1 is a hydroxyl group is halogenated, whereby a compound in which LG 1 is a halogen can be produced. As examples of the halogenating agent used here, there is no particular limitation, and examples include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, and the like.

[0415] As a reference for this reaction, for example, the following literature can be referred to.

[0416] The Chemical Society of Japan, "Experimental Chemistry Course", 5th edition, Vol. 13, Maruzen, 2004

[0417] In addition, for compound (18), a compound in which the portion corresponding to LG 1 is a hydroxyl group is sulfonylated in the presence of a base, whereby a compound in which LG 1 is a sulfonyl group can be produced. As examples of the sulfonylating agent used here, there is no particular limitation, and examples include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and the like. As examples of the base, there is no particular limitation, and examples include TEA, DIPEA, pyridine, tetramethylethylenediamine, and the like.

[0418] As a reference for this reaction, for example, the following literature can be referred to.

[0419] Synthesis 1999, 9, p. 1633-1636

[0420] (Synthesis of starting material 4)

[0421]

[0422] (In the formula, R LG represents a C 1-12alkyl, n represents 1 or 2.

[0423] This production method is a second method for producing the starting material compound (16).

[0424] (First step)

[0425] This step is a method for producing compound (19) by an in situ substitution reaction of compound (10) with R LG -SH. As R LG -SH used here, C 1-12 alkyl mercaptans such as ethanethiol and dodecanethiol can be exemplified.

[0426] The reaction conditions are the same as those of the first step of the starting material synthesis 3.

[0427] (Second step)

[0428] This step is a method for producing compound (20) by an in situ substitution reaction of compound (19) with PG 3 -OH. As PG 3 -OH used here, benzyl alcohol and p-methoxybenzyl alcohol can be exemplified.

[0429] The reaction conditions are the same as those of the first step of the starting material synthesis 3.

[0430] (Third step)

[0431] This step is a method for producing compound (21) by a Suzuki-Miyaura coupling reaction of compound (20) with a boronic acid derivative composed of R 2 -boric acid group or the like.

[0432] The reaction conditions are the same as those of the fourth step of the starting material synthesis 3.

[0433] When R 2 is a hydrogen atom, compound (21) can be produced by a catalytic hydrogenation reaction of compound (20).

[0434] (Fourth step)

[0435] This step is a method for producing compound (22) by a Suzuki-Miyaura coupling reaction of compound (21) with compound (15).

[0436] The reaction conditions are the same as those of the fourth step of the starting material synthesis 3.

[0437] (Fifth step)

[0438] This step is a method for producing compound (23) by an oxidation reaction of compound (22).

[0439] In this reaction, compound (22) is treated with an equivalent or excess amount of an oxidizing agent in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 80°C, usually for 0.1 hours to 3 days. In this reaction, oxidation using meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is preferred. As examples of the solvent, aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and a mixture of these can be given. As examples of other oxidizing agents, cumene hydroperoxide, monopersulfate (Oxone), active manganese dioxide, chromic acid, potassium permanganate, sodium periodate and the like can be given.

[0440] [Documents]

[0441] The Chemical Society of Japan, "Lecture Notes on Experimental Chemistry", 5th edition, Vol. 17, Maruzen, 2004

[0442] (Sixth step)

[0443] This step is a method for producing compound (16) by an in situ substitution reaction of compound (23) with compound (24).

[0444] The reaction conditions are the same as those in the first step of the synthesis of the starting material 3.

[0445] Note that when compound (16) has an axial asymmetry, it is obtained as a mixture of diastereomers, and each diastereomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography, silica gel column chromatography.

[0446] (Synthesis of the starting material 5)

[0447]

[0448] This production method is a second method for producing the starting material compound (2).

[0449] (First step)

[0450] This step is a method for producing compound (25) by deprotection through a catalytic hydrogenation reaction of compound (23).

[0451] The reaction conditions are the same as those in the sixth step of the synthesis of the starting material 3.

[0452] (Second step)

[0453] This step is a method for producing compound (26) by a reaction of compound (25) with compound (18).

[0454] The reaction conditions are the same as those in the seventh step of the synthesis of the starting material 3.

[0455] (Third step)

[0456] This step is a method for producing compound (2) by an in situ substitution reaction of compound (26) with compound (24).

[0457] The reaction conditions are the same as those in the first step of the synthesis of the starting material 3.

[0458] Note that compound (2) sometimes has axial asymmetry and is obtained as a mixture of diastereomers, and each diastereomer can be isolated by subjecting compound (2) as a protecting group or compound (2) to a deprotection reaction and then performing a conventional resolution operation, such as resolution using an ODS column chromatography or a silica gel column chromatography. 2 The reaction conditions of the deprotection reaction used here are the same as those described in the steps of Production Method 1.

[0459] The reaction conditions of the deprotection reaction used here are the same as those described in the steps of Production Method 1.

[0460] (Synthesis of the starting material 6)

[0461]

[0462] (In the formula, PG 4 , PG 5 represents a protecting group.)

[0463] This production method is a method for producing the starting material compound (3).

[0464] (First step)

[0465] This step is a method for producing compound (28) by an amidation reaction of compound (7) with compound (27).

[0466] The reaction conditions are the same as those in the third step of the synthesis of the starting material 2.

[0467] (Second step)

[0468] This step is a method for producing compound (29) by subjecting compound (28) to a deprotection reaction.

[0469] The reaction conditions are the same as those described in the steps of Production Method 1.

[0470] (Third step)

[0471] This step is a method for producing compound (31) by an amidation reaction of compound (29) with compound (30).

[0472] The reaction conditions are the same as those in the third step of the synthesis of the starting material 2.

[0473] (Fourth step)

[0474] This step is a method for producing compound (32) by subjecting compound (31) to a deprotection reaction.

[0475] The reaction conditions are the same as those described in the step of Production Method 1.

[0476] (Fifth step)

[0477] This step is a method for producing compound (3) by reacting compound (32) with a diazo transfer reagent.

[0478] In this reaction, compound (32) is treated with an equivalent or excess amount of a diazo transfer reagent in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to 50°C, usually for 0.1 hours to 3 days. As examples of the diazo transfer reagent, there are no particular limitations, and examples include trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or a salt thereof, 2-azido-1,3-dimethylimidazole hexafluorophosphate (ADMP), and the like. It is sometimes advantageous to perform the reaction in the presence of an organic base such as TEA, 4-dimethylaminopyridine (DMAP), 2,6-dimethylpyridine, and a catalytic amount of a copper salt such as CuSO4. As examples of the solvent, there are halogenated hydrocarbons such as THF, dichloromethane, MeCN, alcohols, water, and a mixture of these.

[0479] [Documents]

[0480] J. Org. Chem. 2012, 77, p. 1760-1764

[0481] Nature 2019, 574, p. 86-89

[0482] Org. Biomol. Chem. 2014, 12, p. 4397-4406

[0483] (Synthesis of starting material 7)

[0484]

[0485] (In the formula, LG 2 represents a leaving group, and PG 6 represents a protecting group of NH.)

[0486] This production method is a method for producing a starting material compound (1)-2 or a starting material compound (1)-3 included in the starting material compound (1). Here, a production method when L 2 is NR L1 , pyrrolidinediyl, piperidinediyl, or piperazinediyl is shown.

[0487] (First step)

[0488] This step is a method for producing compound (2)-1 by reacting compound (17) with compound (33).

[0489] The reaction conditions are the same as those in the seventh step of the synthesis of 3 from the starting material.

[0490] (Second step)

[0491] This step is a method for producing compound (2)-2 by hydrolyzing compound (2)-1.

[0492] The reaction conditions are the same as those in the second step of the synthesis of 2 from the starting material.

[0493] (Third step)

[0494] This step is a method for producing compound (1)-2 by amidation of compound (32) with compound (2)-2.

[0495] The reaction conditions are the same as those in the third step of the synthesis of 2 from the starting material.

[0496] (Fourth step)

[0497] This step is a method for producing compound (35) by amidation of compound (32) with compound (34).

[0498] The reaction conditions are the same as those in the third step of the synthesis of 2 from the starting material.

[0499] (Fifth step, sixth step)

[0500] This step is a method for producing compound (1)-3 by amidation of a compound obtained by performing a deprotection reaction of compound (35) with compound (2)-2.

[0501] The reaction conditions of the deprotection reaction are the same as those in the steps described in Production Method 1.

[0502] The reaction conditions of the amidation reaction are the same as those in the third step of the synthesis of 2 from the starting material.

[0503] (Synthesis of starting material 8)

[0504]

[0505] (In the formula, in the case where Z is NH, A 1 represents a hydrogen atom and A 2 represents a halogen, Z is a 5-membered heteroarene diradical containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and A 1 is a group selected from the group consisting of Cl, Br, and I, A 2 represents a boronic acid group or the like, and A 1 is a boronic acid group or the like, A2 R represents a group selected from the group consisting of CI, Br and I.

[0506] This production method is a method for producing the starting material compound (1)-4.

[0507] (First step)

[0508] This step is a method for producing compound (38) by an in situ reaction or Borchardt-Hartwig amination reaction of compound (36) with compound (37) when Z is NH.

[0509] The reaction conditions of the in situ reaction are the same as those of the first step of the starting material synthesis 3.

[0510] As a reference for the Borchardt-Hartwig amination reaction, for example, the following literature can be referred to.

[0511] J. Am. Chem. Soc., 2020, 142, p. 15027-15037

[0512] In addition, this step is a method for producing compound (38) by a Suzuki-Miyaura coupling reaction of compound (36) with compound (37) when Z is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0513] The reaction conditions are the same as those of the fourth step of the starting material synthesis 3.

[0514] Here, as a reference for the reaction when Z is formula (V), for example, the following literature can be referred to.

[0515] J. Org. Chem., 2000, 65, p. 1516-1524

[0516] Chemical Communications 2014, 50, p. 1867-1870

[0517] Bioorg. Med. Chem. Lett., 2001, 11, p. 2061-2065

[0518] (Second step)

[0519] This step is a method for producing compound (39) by a reaction of compound (38) with compound (17).

[0520] The reaction conditions are the same as those of the seventh step of the starting material synthesis 3.

[0521] In addition, this step can also produce compound (39) by a Mitsunobu reaction of compound (38) with compound (17).

[0522] For example, the following literature may be consulted as a reference for the photoelongation reaction.

[0523] Chem.Asian J.2007,2,p.1340-1355

[0524] (Step 3)

[0525] This step is a method for producing compound (40) by hydrolyzing compound (39).

[0526] The reaction conditions are the same as those in the second step of the synthesis of starting material 2.

[0527] (Fourth step)

[0528] This step is a method for producing compound (1)-4 by amidation reaction of compound (40) and compound (29).

[0529] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0530] (Raw Material Synthesis 9)

[0531]

[0532] (where PG) 7 Indicates a protective base, PG 8 PG 9 PG 10 Same or different, indicating hydrogen atoms or protecting groups, A 3 A represents hydrogen atoms, carboxyl groups, or borate groups, etc. 4 BLG represents a hydrogen atom or a group selected from the group consisting of Cl, Br, and I. 1 (This indicates borate groups, etc.)

[0533] This manufacturing method is used to manufacture R. 7 A method for selecting a starting compound (7) from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII) and (XXIV).

[0534] (First step)

[0535] This step is in A 3 When it is a hydrogen atom, it is obtained through, for example, R 7 A method for producing compound (45) by a grooving-Heck reaction of compound (42) of formula (VI) and compound (41).

[0536] In the reaction, an equimolar amount or an excess of one of compound (42) and compound (41) is used, and a mixture thereof is usually stirred at room temperature to heating reflux, preferably at 20°C to 140°C, for 0.1 hour to 5 days in a solvent inert to the reaction in the presence of a base and a palladium catalyst. Examples of the solvent used herein are not particularly limited, and ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, ethyl acetate, water, and a mixture of these can be given. As the base, an alkali such as potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, and the like can be given. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-diene-3-one / palladium(3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and the like can be given. In addition, a method in which the mixture is heated by microwave irradiation is sometimes advantageous in the smooth progress of the reaction.

[0537] As a reference for the reaction, for example, the following literature can be referred to.

[0538] Synthesis 2020, 52, p. 2521-2527

[0539] PNAS 2016, 113, p. 7124-7129

[0540] Alternatively, for example, a method in which compound (45) is produced by Ullmann reaction of compound (42) which is a compound selected from the group consisting of formula (IX), formula (XX), formula (XXI), formula (XXII), and formula (XXIV) and compound (41).

[0541] As a reference for the reaction, for example, the following literature can be referred to.

[0542] Angew. Chem. Int. Ed., 2003, 42, p. 5400-5449

[0543] In addition, the present step is a decarboxylation reaction of compound (42) which is a compound of formula (VII) and compound (41). 3 When R is a carboxyl group, for example, R 7 A method in which compound (45) is produced by decarboxylative coupling reaction of compound (42) which is a compound of formula (VII) and compound (41).

[0544] As a reference for the reaction, for example, the following literature can be referred to.

[0545] Science, 2006, 313, pp. 662-664

[0546] Therefore, this step is to... 3 When it is a borate group, etc., it is obtained through, for example, R 7 A method for producing compound (45) by a Suzuki-Miyaura coupling reaction of compound (42) consisting of groups selected from the group consisting of formulas (VI), (VIII) and (XXIII) with compound (41).

[0547] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0548] (Second Step)

[0549] This step is a method for producing compound (43) by replacing the bromine group of compound (41) with a borate group or the like.

[0550] For example, the following literature can be consulted as a reference for the reaction.

[0551] Eur.J.Med.Chem.,2019,162,p.407-422

[0552] J.Org.Chem.2020,85,16,p.10966-10972

[0553] J.Am.Chem.Soc.,2010,132,p.17701-17703

[0554] (Step 3)

[0555] This step is in A 4 A method for producing compound (45) by a Suzuki-Miyaura coupling reaction of compound (44) and compound (43) when selecting groups from the group consisting of Cl, Br and I.

[0556] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0557] Additionally, this step is in A 4 A method for producing compound (45) by Chan-Lam-Evans coupling reaction of compound (44) with compound (43) when the hydrogen atom is, for example, a group selected from the group consisting of formulas (IX), (XX), (XXI), (XXII) and (XXIV).

[0558] For example, the following literature can be consulted as a reference for the reaction.

[0559] Adv.Synth.Catal.2020,362,p.3311-3331.

[0560] (Fourth step)

[0561] This step is a method for producing compound (7) by subjecting compound (45) to a deprotection reaction.

[0562] The reaction conditions are the same as those described in the step of Production Method 1.

[0563] The compound of the formula (I) is isolated, purified in the form of a free compound, a salt thereof, a hydrate, a solvate, or a polymorph or amorphous solid substance. The salt of the compound of the formula (I) can also be produced by subjecting to a salt formation reaction of a conventional method.

[0564] The isolation and purification can be performed by applying usual chemical operations such as extraction, fractional crystallization, various types of chromatography, and the like.

[0565] The various isomers can be produced by selecting an appropriate starting compound, or can be separated by utilizing the difference in physical and chemical properties between the isomers. For example, the optical isomers can be obtained by a usual optical resolution method of a racemate (e.g., fractional crystallization into a diastereomeric salt with an optically active base or acid, chromatography using a chiral column, and the like), and in addition, can be produced from an appropriate optically active starting compound.

[0566] In addition, the compound of the formula (I) or an intermediate thereof sometimes has axial asymmetry, is obtained in the form of a mixture of diastereomers, and each diastereomer can be isolated by performing a usual resolution operation such as resolution using an octadecylsilyl (ODS) column chromatography, silica gel column chromatography.

[0567] The pharmacological activity of the compound of the formula (I) is confirmed by the following test.

[0568] Test Example 1-1 Evaluation of KRAS decomposition effect on human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1

[0569] The amount of KRAS G12D expression was measured by a sandwich ELISA method, whereby the KRAS decomposition effect by the test compound was evaluated.

[0570] AsPC-1 cells (ATCC, CRL-1682) were each inoculated at 90 μL in a 96-well plate (IWAKI Corporation) at 1.8 x 10 4 Regarding the cell culture conditions, RPMI1640 medium (Merck) containing 10% fetal bovine serum (Cytiva) was used and was performed at 37°C in the presence of 5% CO2.

[0571] The next day, the test compound (final concentration ranging from 10 μΜ to 0.3 nM, 10 points) was diluted 100-fold with fresh culture medium, and 10 μL was added to each well. Four wells each were treated identically. In addition, when the sandwich ELISA plate was prepared, 20 μL of the capture antibody (anti-KRAS antibody, LS Bio) diluted 1000-fold in phosphate buffered saline (PBS; Fuji Photo Film and Otsuka Pharmaceutical) and mixed was added to each well of a MaxiSorp 384-well plate (Thermo Scientific), and after sealing, it was left standing at 4°C for 1 night.

[0572] After 24 hours of test compound treatment, the culture supernatant was discarded, and 50 μL of a cell lysis solution (prepared by adding 1 / 100 and 1 / 500 amounts of Halt protease phosphatase inhibitor cocktail (Thermo Scientific) and Benzonase nuclease (Merck), respectively, to RIPA buffer (Thermo Scientific)) was quickly added to each well, and the cells were lysed. After that, four wells each that had been identically treated were combined into one well, and a cell lysate sample of a total of 200 μL was prepared. In the KRAS detection, the MaxiSorp 384-well plate that had been treated with the capture antibody from the previous day was washed with PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 was diluted 20-fold with ion exchange water and used) (25 μL each, 2 times), and treated with a blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) for 60 minutes, and then 20 μL of the cell lysate sample was added to each well. In the β-actin detection, 20 μL of the cell lysate sample was directly added to each well of a MaxiSorp 384-well plate, and after sealing, it was left standing at 4°C for 1 night.

[0573] The next day, after washing the plate for KRAS detection with PBS containing 0.05% Tween-20, 20 μL of anti-Ras(G12D Mutant Specific) antibody (Cell Signaling Technology) diluted 1000-fold with the blocking solution was added to each well as a detection antibody, and left to stand for 5 hours at room temperature. After that, the plate was centrifuged to remove the supernatant (dehydration device was used. Hereinafter, the supernatant was removed by the same method), washed with PBS containing 0.05% Tween-20, and 20 μL of anti-rabbit IgG HRP-conjugated antibody (Cell Signaling Technology) diluted 1000-fold with the blocking solution was added to each well as a secondary antibody, and left to stand for 1 hour at room temperature. The plate was centrifuged to remove the supernatant, washed with PBS containing 0.05% Tween-20, and 20 μL of BM chemiluminescence ELISA substrate (Merck) was added to each well, and the amount of luminescence was measured using 2103 EnVision (PerkinElmer). In addition, after washing the plate for β-actin detection with PBS containing 0.05% Tween-20 and treating with the blocking solution for 60 minutes, 20 μL of anti-β-actin antibody (Abeam) diluted 1000-fold with the blocking solution was added to each well as a detection antibody, and left to stand for 5 hours at room temperature. After that, the plate was centrifuged to remove the supernatant, washed with PBS containing 0.05% Tween-20, and 20 μL of anti-mouse IgG HRP-conjugated antibody (Cell Signaling Technology) diluted 1000-fold with the blocking solution was added to each well as a secondary antibody, and left to stand for 1 hour at room temperature. After that, the plate was centrifuged to remove the supernatant, washed with PBS containing 0.05% Tween-20, and 20 μL of BM chemiluminescence ELISA substrate was added to each well, and the amount of luminescence was measured using EnVision.

[0574] The signal value at the time of addition of DMSO was corrected by the amount of β-actin and was set to 100%, and the signal value at the time of addition of 10 μM of the compound of Example No. 7 was set to 0%, and the 50% decomposition value (DC50) of the amount of KRAS was calculated by nonlinear regression analysis of the Sigmoid-Emax model. 50 The molecular weight of the compound to be tested was calculated as the molecular weight of the free form not forming a salt in the case of Example No. 22: dihydrochloride, Example Nos. 2 to 7, 9 to 12, and 14 to 18: trihydrochloride, Example No. 19: tetrahydrochloride, Example No. 21: penta- hydrochloride, and the like.

[0575] The results of several compounds to be tested of the formula (I) are shown in Table 1.

[0576] [Table 1]

[0577] Ex DC 50 (nM) Ex DC 50 (nM) Ex DC 50 (nM) 1 123 11 178 21 72 2 598 12 136 22 62 3 140 13 151 23 34 4 897 14 221 24 103 5 153 15 95 25 44 6 103 16 188 26 24 7 46 17 92 27 55 8 37 18 74 28 45 9 77 19 139 29 33 10 124 20 100

[0578] Evaluation of KRAS decomposition effect on human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1 in Test Example 1-2

[0579] The KRAS G12D expression amount was measured by cell ELISA, and the KRAS decomposition effect by the test compound was evaluated.

[0580] AsPC-1 cells were seeded at 2.0 x 10 4 cells per well in 384-well plates (Greiner bio-one) in 20 μL each. As for the cell culture conditions, RPMI1640 medium containing 10% fetal bovine serum was used, and the culture was performed in the presence of 5% CO2 at 37°C.

[0581] The next day, the test compound (in the range of a final concentration of 10 μM to 0.3 nM, 10 points), the compound of Example No. 26 (Example No. 8 in Example Nos. 74 and 75) as a positive control at a final concentration of 10 μM, and DMSO as a solvent of the test compound were each added to each well in 20 μL after being diluted 500 times with fresh medium, and the culture was performed overnight.

[0582] The next day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (Fuji Photo Film Co., Ltd. and Light Pure Chemicals Corp.) was added to each well, and the cells were fixed by standing at room temperature for 30 minutes. Thereafter, the supernatant was removed, and 20 μL of PBS containing 0.1% Triton X-100 (Amersham Biosciences Corp.) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed, 25 μL of PBS was added to each well, the supernatant was removed, and each well was washed. The washing was performed a total of 2 times. Then, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen Corp.) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation (dehydration was performed using a centrifugal dehydration device. Hereinafter, the supernatant was removed by the same method), 25 μL of PBS was added to each well, the supernatant was removed, and each well was washed. The washing was performed a total of 2 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, the supernatant was removed by centrifugation, and 20 μL of a solution in which an anti-Ras (G12D Mutant Specific) antibody and an anti-β-actin antibody were diluted 1000-fold with the blocking solution was added to each well as a primary antibody, and the plate was left standing at 4°C overnight.

[0583] The next day, the plate was centrifuged to remove the supernatant, 25 μL of PBS was added to each well, the supernatant was removed, and each well was washed. The washing was performed a total of 2 times. The supernatant was removed by centrifugation, and 20 μL of a solution in which a donkey anti-mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences Corp.) and a goat anti-rabbit IgG H&L (IRDye 800CW) (Li-COR Biosciences Corp.) were diluted 1000-fold with the blocking solution was added to each well as a secondary antibody. After standing at room temperature for 1 hour, the supernatant was removed, 25 μL of PBS was added to each well, the supernatant was removed, and each well was washed. The washing was performed a total of 2 times. After the supernatant was removed by centrifugation of the plate, the plate was directly air-dried at room temperature for 2 hours or more, and the fluorescence signals at 700 nm and 800 nm were measured using an Aerius (LI-COR Biosciences Corp.).

[0584] The signal value at the time of addition of DMSO corrected with the signal value of β-actin was set to 100%, and the signal value at the time of addition of 10 μM of the compound of Example No. 26 was set to 0%, and the 50% decomposition value (DC50) of the amount of KRAS was calculated by nonlinear regression analysis of the Sigmoid-Emax model. 50). As for the molecular weight of the test compound, the molecular weight of the free form of the compound not forming a salt was calculated. The results of several test compounds of formula (I) are shown in Table 2.

[0585] [Table 2]

[0586] Ex DC 50 ((nM)]]> Ex DC 50 (nM) Ex DC 50 (nM) 30 157 45 15 60 102 31 138 46 37 61 21 32 139 47 13 62 10 33 30 48 4 63 70 34 24 49 15 64 48 35 84 50 11 65 14 36 17 51 11 66 250 37 25 52 10 67 840 38 53 53 8 68 1393 39 6 54 8 69 31 40 5 55 24 70 14 41 9 75 5886 71 35 42 6 57 134 72 16 43 10 58 37 73 134 44 111 59 45 74 1000

[0587] Evaluation of the inhibitory effect of test example 2 on the phosphorylation of ERK in human G12D mutant KRAS-positive pancreatic cancer strain AsPC-1

[0588] The phosphorylation of threonine at position 202 (Thr202) and tyrosine at position 204 (Tyr204) of ERK located downstream of KRAS signal was measured by cell ELISA, whereby the inhibitory effect of the test compound on the phosphorylation of ERK was evaluated.

[0589] AsPC-1 cells were seeded at 2.0 x 10 4 cells per well in 36 μL / well in a 384-well plate (Greiner bio-one). As for the cell culture conditions, RPMI1640 medium containing 10% fetal bovine serum was used, and the culture was performed in the presence of 5% CO2 at 37°C.

[0590] Next day, after 4 μL of each of the test compound (final concentration ranging from 10 μM to 3.0 nM, 6 points), the positive control of trametinib (MEK inhibitor) at a final concentration of 1 μM, and the negative control of the solvent DMSO of the test compound were added to each well by diluting 100-fold with fresh culture medium, the cells were incubated for 24 hours. After the incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque Co.] diluted with PBS) was added to each well, and the cells were fixed by standing for 90 minutes at room temperature. Thereafter, the plate was centrifuged to remove the supernatant (dehydration device was used. Hereinafter, the supernatant was removed by the same method), and 20 μL of PBS containing 0.1% Triton X-100 was added to each well. After standing for 10 minutes at room temperature, the supernatant was removed by centrifugation, and the same operation was repeated. Then, 20 μL of PBS containing 0.5% SDS was added to each well, and after standing for 30 minutes at room temperature, the supernatant was removed by centrifugation. Next, 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well, and the plate was allowed to stand for 1 hour at room temperature. The supernatant was removed by centrifugation, and 10 or 15 μL of phospho-ERK (Thr202 / Tyr204) antibody (Phospho-p44 / 42 MAPK (Erkl / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology Co.) diluted 2500-fold with the blocking solution was added to each well, and the plate was allowed to stand overnight at 4°C.

[0591] Next day, after 4 μL of each of the test compound (final concentration ranging from 10 μM to 3.0 nM, 6 points), the positive control of trametinib (MEK inhibitor) at a final concentration of 1 μM, and the negative control of the solvent DMSO of the test compound were added to each well by diluting 100-fold with fresh culture medium, the cells were incubated for 24 hours. After the incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque Co.] diluted with PBS) was added to each well, and the cells were fixed by standing for 90 minutes at room temperature. Thereafter, the plate was centrifuged to remove the supernatant (dehydration device was used. Hereinafter, the supernatant was removed by the same method), and 20 μL of PBS containing 0.1% Triton X-100 was added to each well. After standing for 10 minutes at room temperature, the supernatant was removed by centrifugation, and the same operation was repeated. Then, 20 μL of PBS containing 0.5% SDS was added to each well, and after standing for 30 minutes at room temperature, the supernatant was removed by centrifugation. Next, 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well, and the plate was allowed to stand for 1 hour at room temperature. The supernatant was removed by centrifugation, and 10 or 15 μL of phospho-ERK (Thr202 / Tyr204) antibody (Phospho-p44 / 42 MAPK (Erkl / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology Co.) diluted 2500-fold with the blocking solution was added to each well, and the plate was allowed to stand overnight at 4°C.

[0592] The signal value when DMSO was added was set to 100%, and the signal value when 1 μM of trametinib was added was set to 0%, and the 50% inhibition value (IC 50). As for the molecular weight of the test compound, the molecular weight of the free form of the dihydrochloride salt of Example No. 22, the trihydrochloride salt of Example Nos. 2 to 7, 9 to 12, 14 to 18, and 30, the tetrahydrochloride salt of Example Nos. 19 and 46, the penta- hydrochloride salt of Example No. 21, and the molecular weight of the free form of the compound of the other examples were calculated. The results of several test compounds of Formula (I) are shown in Table 3.

[0593] [Table 3]

[0594] Ex IC 50 (nM) Ex IC 50 (nM) Ex IC 50 (nM) 1 89 11 39 21 19 2 779 12 37 22 12 3 62 13 29 23 10 4 522 14 63 24 25 5 97 15 22 25 15 6 58 16 67 26 8 7 17 17 36 27 27 8 15 18 28 28 12 9 18 19 51 29 15 10 26 20 36 30 185 45 11 60 50 31 194 46 22 61 24 32 92 47 18 62 15 33 32 48 8 63 72 34 26 49 21 64 80 35 55 50 10 65 11 36 31 51 14 66 114 37 18 52 11 67 758 38 28 53 10 68 2209 39 6 54 18 69 17 40 7 55 38 70 12 41 17 71 38 42 22 57 65 72 16 43 11 58 25 73 133 44 95 59 26

[0595] Evaluation of the Inhibition of Adhesion-Independent Cell Proliferation of the Test Compound on the Human G12D Mutant KRAS-Positive Pancreatic Cancer Cell Line AsPC-1

[0596] The Inhibition of Adhesion-Independent Cell Proliferation by the Test Compound was evaluated by spherical three-dimensional culture.

[0597] AsPC-1 cells were seeded at 5 x 10 2 cells per well in 36 μL / well in a cell low-attachment U-bottom 384-well plate (PrimeSurface: Sumitomo Bakelite Co., Ltd.). The cell culture was performed under the same conditions as in Test Example 2.

[0598] The next day, the test compound (in the range of a final concentration of 10 μM to 3.0 nM, 6 points) and the solvent DMSO of the test compound as a negative control were each added to each well at 4 μL after being diluted 100-fold with fresh medium. After incubation for 6 days in the presence of 5% CO2 at 37°C, 20 μL of CellTiter-Glo 2.0 (Promega Co.) was added to each well. After stirring for 1 hour at room temperature using a plate mixer (FINEPCR Co.), the luminescent signal was measured using an ARVO X3 (PerkinElmer Co.).

[0599] The signal value at the time of DMSO treatment was set to 100%, and the signal value at the time of the absence of cells, only medium was set to 0%, and the 50% inhibition value (IC 50 ) was calculated by non-linear regression analysis of the Sigmoid-Emax model. As for the molecular weight of the test compound, the molecular weight of the free form of the dihydrochloride salt of Example No. 22, the trihydrochloride salt of Example Nos. 2 to 7, 9 to 12, 14 to 18, and 30, the tetrahydrochloride salt of Example Nos. 19 and 46, the penta- hydrochloride salt of Example No. 21, and the molecular weight of the free form of the compound of the other examples were calculated. The results of several test compounds of Formula (I) are shown in Table 4.

[0600] [Table 4]

[0601] Ex IC 50 (nM) Ex IC 50 (nM) Ex IC 50 (nM) 1 190 11 128 21 47 2 1412 12 112 22 27 3 108 13 74 23 21 4 670 14 153 24 55 5 169 15 64 25 66 6 100 16 185 26 20 7 31 17 104 27 103 8 23 18 70 28 37 9 96 19 138 29 42 10 114 20 79 30 323 45 20 60 127 31 321 46 56 61 61 32 186 47 22 62 34 33 42 48 20 63 133 34 33 49 46 64 245 35 43 50 21 65 45 36 24 51 27 66 360 37 19 52 31 67 975 38 27 53 23 68 1627 39 18 54 24 69 64 40 20 55 76 70 21 41 31 71 51 42 46 57 90 72 26 43 16 58 80 73 112 44 266 59 70

[0602] Evaluation of antitumor effect of test example 4 on human G12D mutant KRAS-positive pancreatic cancer strain PK-59 tumor-bearing mice

[0603] PK-59 cells (RIKEN BRC, RCB1901) were cultured in RPMI1640 medium containing 10% fetal bovine serum in the presence of 5% CO2 at 37°C. The PK-59 cells were recovered, suspended with PBS, and added with an equal amount of Matrigel (Becton, Dickinson and Company) to prepare 1.0 x 10 7 ~2.0 x 10 7 cells / mL, and the resulting cell suspension was implanted into the subcutis of 4- to 6-week-old male nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj(nu / nu), Charles River Laboratories Japan) at a volume of 100 μL. About 2 weeks after the implantation, the mice were grouped in such a manner that the tumor volumes and body weights were approximately the same among the groups, and the test compound was administered from the next day. The test was performed with 5 mice in the solvent group and the test compound administration group. The compounds of Example 8, Example 48, and Example 70 were dissolved in a solvent in which ethanol (Fuji Photo Film and Otsuka Pharmaceutical), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Chemical), 50% (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) aqueous solution (ROQUETTE), HCO-40 (Chroma), and 1M sodium hydroxide aqueous solution (Kanto Chemical) were set at a liquid volume ratio of 4:84.4:1.1:1:9:0.5. The compounds of Example 22 and Example 26 were dissolved in a solvent in which propylene glycol (Fuji Photo Film and Otsuka Pharmaceutical) and Tween 80 (Nacalai Tesque), Otsuka physiological saline (Otsuka Pharmaceutical) were set at a liquid volume ratio of 6.7:3.3:90. The compound of Example 39 was dissolved in a solvent in which propylene glycol, ethanol, 50% HP-βCD aqueous solution, HCO-40, and 5% glucose solution were set at a liquid volume ratio of 10:8:10:10:62. The test compound or solvent dissolved with each solvent was administered into the tail vein. The administration was performed twice at an interval of one week. The measurement of the tumor diameters and body weights was performed twice every 1 week. The tumor volume was calculated using the following formula.

[0604] [Tumor volume (mm 3 )] = [Long diameter of tumor (mm)] x [Short diameter of tumor (mm)] x 0.5 2

[0605] ​The tumor growth inhibition rate (%) by the test compound was calculated by setting the tumor volume of the test compound administration group on the day before administration was started at 100% inhibition, and setting the tumor volume of the solvent group 2 weeks after the first administration at 0% inhibition. In addition, when the tumor volume of the test compound administration group was lower than the tumor volume on the day before administration was started, the tumor volume on the day before administration was started was set at 0% regression, and the tumor volume of 0 was set at 100% regression, to calculate the tumor regression rate (%) of the test compound. Regarding the molecular weight of the test compound, the calculation was performed in the form of the molecular weight of the free form of the salt not formed in the example number 22: dihydrochloride salt, and the example numbers other than the above. The results of several test compounds of formula (I) are shown in Table 5.

[0606] [Table 5]

[0607] Ex Dose (mg / kg) Antitumor effect two weeks after the first administration 8 10 98% inhibition 22 10 93% inhibition 26 10 94% inhibition 39 10 13% regression 48 10 32% regression 70 10 42% regression

[0608] Evaluation of KRAS G12D / SOS / c-Raf complex formation inhibitory effect of test compound

[0609] Using human recombinant KRAS G12D, SOS, and c-Raf proteins, the inhibitory effect of the test compound on the complex formation of these proteins was investigated by time-resolved fluorescence resonance energy transfer (TR-FRET) method.

[0610] To a 384-well plate (Corning), 40000 nM to 40 nM of biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 μL; 400 nM) and a test compound dissolved in an assay buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, pH 7.0) were added in a liquid amount of 2.5 μL. 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), GTP (Sigma-Aldrich; 2 μM) were added, and left standing at room temperature for 1 hour. Thereafter, a mixture (10 μL) of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (PerkinElmer; 100 ng / mL) was added, and the fluorescence intensity at 620 nm and 665 nm was measured using EnVision 2104 (PerkinElmer) under excitation at 337 nm. After the value was normalized with the fluorescence intensity at the reference wavelength 620 nm, the signal value upon solvent treatment was set as 0% inhibition, and the signal value in the absence of GTP was set as 100% inhibition, and the 50% inhibition concentration (IC 50 ) was calculated by nonlinear regression analysis of Sigmoid-Emax model.

[0611] As a result of the above test, the G12D mutant KRAS decomposition action was confirmed for several compounds of the formula (I) (Test Example 1-1 and Test Example 1-2). In addition, the G12D mutant KRAS inhibitory action was confirmed (Test Example 5). Furthermore, the phosphorylation inhibitory action of ERK located downstream of KRAS signal was confirmed for several compounds of the formula (I) (Test Example 2). In addition, the cell proliferation inhibitory action on human G12D mutant KRAS positive pancreatic cancer strain (Test Example 3), the antitumor action in tumor-bearing mice of human G12D mutant KRAS positive pancreatic cancer strain (Test Example 4) were confirmed for several compounds of the formula (I). Therefore, the compound of the formula (I) can be used for the treatment of pancreatic cancer, particularly G12D mutant KRAS positive pancreatic cancer, and the like.

[0612] A pharmaceutical composition containing one or two or more of the compounds of the formula (I) or salts thereof as an effective ingredient can be prepared by a generally used method using an excipient, i.e., a pharmaceutical excipient or a pharmaceutical carrier, and the like, which are generally used in the art.

[0613] The administration can be any of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or non-oral administration such as intra-articular, intravenous, intramuscular, etc., using injections, transmucosal agents, inhalants, etc.

[0614] As a solid composition for oral administration, tablets, powders, granules, etc. can be used. In such a solid composition, one or two or more effective components are mixed with at least one inert excipient. The composition can contain inert additives such as lubricants, disintegrants, stabilizers, dissolution aids according to a conventional method. The tablets or pills can be coated with sugar or a film of a stomach- soluble or enteric substance as needed.

[0615] A liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, etc., containing an inert diluent commonly used such as purified water or EtOH ethanol. In this liquid composition, in addition to the inert diluent, auxiliary agents such as solubilizers, wetting agents, suspending agents, sweeteners, flavorings, aromatics, preservatives can be contained.

[0616] An injection for non-oral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion. As an aqueous solvent, for example, distilled water for injection or physiological saline is contained. As a non-aqueous solvent, for example, an alcohol such as EtOH is contained. Such a composition can also contain an isotonic agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizer or a dissolution aid. They are sterilized, for example, by filtration through a bacteria-retaining filter, by the incorporation of a sterilizing agent or by irradiation. In addition, they can also be manufactured as a sterile solid composition and dissolved or suspended in sterile water or a sterile injection solvent before use.

[0617] Inhalants or transmucosal agents, etc. can use a solid, liquid or semi-solid substance, and can be manufactured according to a method known in the past. For example, a known excipient, and a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickening agent, etc. can be appropriately added. The administration can use an apparatus for appropriate inhalation or blowing. For example, a known apparatus such as a metered-dose inhaler or a nebulizer can be used, and the compound can be administered as a powder alone or as a mixture forming a formulation, or in the form of a solution or a suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler, etc. can be an inhaler for one or more administrations, and can use a dry powder or a powder-containing capsule. Alternatively, it can be a pressurized aerosol spray or the like using an appropriate propellant such as chlorofluorocarbon or carbon dioxide or the like appropriate gas.

[0618] In the case of oral administration, the amount to be administered per day is preferably about 0.001 to 100 mg / kg, more preferably 0.1 to 30 mg / kg, and even more preferably 0.1 to 10 mg / kg per unit of body weight, which is administered once or divided into two to four times. In the case of intravenous administration, the amount to be administered per day is preferably about 0.0001 to 10 mg / kg per unit of body weight, which is administered once or divided into multiple times. In addition, as a transmucosal agent, the amount to be administered per day is about 0.001 to 100 mg / kg per unit of body weight, which is administered once or divided into multiple times. The amount to be administered can be appropriately determined in consideration of symptoms, age, sex, and the like, and according to the respective conditions.

[0619] The pharmaceutical composition of the present application contains 0.01 to 100% by weight, and as one mode, 0.01 to 50% by weight of one or more compounds of the formula (I) or salts thereof as an effective ingredient, although it varies depending on the administration route, dosage form, administration site, and kind of excipient or additive.

[0620] The compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases in which the compound of the formula (I) is considered to exhibit effectiveness. The combination can be simultaneous administration, or administration separately and continuously or at an interval. The simultaneous administration preparation can be a combined preparation, or a preparation in which administration is separately performed.

[0621] Examples

[0622] The production method of the compound of the formula (I) is further described below based on Examples. Note that the present application is not limited to the compounds described in the following Examples. In addition, the production method of the raw material compound is shown in the Production Examples. Furthermore, the production method of the compound of the formula (I) is not limited only to the production method of the specific Examples shown below, and the compound of the formula (I) can also be produced by a combination of these production methods or a method obvious to those skilled in the art.

[0623] Note that in the present specification, the naming of the compounds sometimes uses a naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[0624] In addition, for convenience, the concentration mol / L is expressed as M. For example, 1M aqueous sodium hydroxide solution means 1 mol / L aqueous sodium hydroxide solution.

[0625] The "amorphous solid form" described in the present specification includes both a form that does not show a peak in a powder X-ray diffraction (XRD) pattern and a form having low crystallinity.

[0626] XRD was performed using Empyrean with tube sphere: Cu, tube current: 40 mA, tube voltage: 45 kV, step: 0.013°, wavelength: 1.5418 A. The diffraction angle range (2 theta) was measured under the conditions of 2.5 to 40°.

[0627] Production Example 1

[0628] To a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), THF (500 mL) was added DIPEA (240 mL), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) under ice cooling, and stirred at room temperature overnight. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a total amount of the solution of about 400 mL. To the resulting solution was added a mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL), and stirred at room temperature. The precipitated solid was filtered, and (1S,4S)-tert-butyl 5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (123 g) was obtained as a solid.

[0629] Production Example 2

[0630] To a mixture of (1S,4S)-tert-butyl 5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL), DABCO (1.15 g) was added cesium carbonate (50.3 g) under stirring at room temperature under argon atmosphere, and stirred at room temperature overnight. To the reaction mixture was added about 1 kg of ice water, and stirred at room temperature for 6 hours. The precipitated solid was filtered while washing with water, and dried under reduced pressure overnight to obtain (1S,4S)-tert-butyl 5-{7-bromo-8-fluoro-6-iodo-2-[tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (32.8 g) as a solid.

[0631] Production Example 5

[0632] To a mixture of (1S,4S)-tert-butyl 5-{7-bromo-8-fluoro-6-iodo-2-[tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (32.8 g), DMF (320 mL), THF (200 mL), DABCO (3.2 g) was added cesium carbonate (128 g) under stirring at room temperature under argon atmosphere, and stirred at room temperature overnight. To the reaction mixture was added about 1 kg of ice water, and stirred at room temperature for 6 hours. The precipitated solid was filtered while washing with water, and dried under reduced pressure overnight to obtain (1S,4S)-tert-butyl 5-{7-bromo-8-fluoro-2-[tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (32.8 g) as a solid. ​To a mixture of (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H- pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- butyl ester (11.9 g), benzyl alcohol (2.37 g), THF (40 mL) was added tBuOK (2.54 g) and stirred at the temperature for 1.5 hours. To the reaction mixture was added ice water and saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, to the resulting residue was added a mixed solvent of hexane / ethyl acetate (6 / 1) and stirred for a while, the precipitated solid was filtered, dried, and obtained as a solid (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g). (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g).

[0633] Production Example 8

[0634] To a mixture of (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H- pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- butyl ester (11.9 g), benzyl alcohol (2.37 g), THF (40 mL) was added tBuOK (2.54 g) and stirred at the temperature for 1.5 hours. To the reaction mixture was added ice water and saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, to the resulting residue was added a mixed solvent of hexane / ethyl acetate (6 / 1) and stirred for a while, the precipitated solid was filtered, dried, and obtained as a solid (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g). (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g). (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g).

[0635] Production Example 11

[0636] To a mixture of (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H- pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert- butyl ester (11.9 g), benzyl alcohol (2.37 g), THF (40 mL) was added tBuOK (2.54 g) and stirred at the temperature for 1.5 hours. To the reaction mixture was added ice water and saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, to the resulting residue was added a mixed solvent of hexane / ethyl acetate (6 / 1) and stirred for a while, the precipitated solid was filtered, dried, and obtained as a solid (lS,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[l-(tetrahydro-2H-pyran-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.8 g). A mixture of tert-butyl 5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl- 1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-4-yl]-2-[2-(4-oxazol-2-yl-phenyl)- ethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (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)-1 H-indazole (1.92 g), potassium phosphate (4.1 g), dicyclohexyl(2',6'-diisopropoxy-[1,1 '-biphenyl]-2-yl)phosphine (0.12 g), (2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '-biphenyl)[2-(2'-amino-1,1 '- biphenyl)]palladium(II) methanesulfonate (0.2 g), DOX (40 mL), water (8 mL) was stirred at room temperature under argon atmosphere after degassing and argon replacement. To the cooled reaction mixture to room temperature, water (about 150 mL) was added and extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified with silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give fractions containing (1 ) a mixture of low polar diastereomers (peak-1 and 2. peak-1, 2 are the same axial asymmetric) and (2) a mixture of high polar diastereomers (peak-3 and 4. peak-3, 4 are the same axial asymmetric). The fraction containing a mixture of low polar diastereomers (peak-1, 2, the same axial asymmetric) was collected to give (1 S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-4-yl]-2-[2-(4-oxazol-2-yl-phenyl)-ethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.42 g) as a foam-like solid. In addition, the fraction containing a mixture of high polar diastereomers (peak-3, 4, the same axial asymmetric) was collected to give (1 S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-4-yl]-2-[2-(4-oxazol-2-yl-phenyl)-ethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.37 g) as a foam-like solid. The mixture of low polar diastereomers was used in the next reaction.

[0637] Preparation Example 14

[0638] ​​​​(1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (10 g) was added to a MeOH (200 mL) solution containing 10% Pd / C (50% water, 2 g). The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The resulting reaction mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (8.11 g).

[0639] Manufacturing Example 22

[0640] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[( In a mixture of tert-butyl 2-heptane-2-carboxylic acid (7.48 g), DMF (70 mL), and 1-(chloromethyl)-4-ethynylbenzene (1.9 g), cesium carbonate (6.2 g) was added while stirring at room temperature, and the mixture was stirred at 60 °C for 2 hours under an argon atmosphere. Ice water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, which had cooled naturally to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and the resulting solid was filtered off as a foamy solid to give (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (8.12 g).

[0641] Manufacturing Example 32

[0642] To (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylthio)-7-[6-fluoro-5-methyl-1-( In a CH2Cl2 (13 mL) solution of 1.3 g of tert-butyl heptane-2-carboxylic acid (1.3 g), m-chloroperbenzoic acid (approximately 30% water, 358 mg) was added under ice-cooling, and the mixture was stirred at this temperature for 2 hours. A 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture under ice-cooling. The aqueous and organic layers were separated, and the resulting aqueous layer was extracted with ethyl acetate. The resulting organic layers were mixed and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (1.32 g).

[0643] Manufacturing Example 34

[0644] To (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-( A mixture of tert-butyl heptane-2-carboxylic acid (1.32 g), DMAc (15 mL), and 4-ethyl-3-hydroxypyridine (525 mg) was prepared, and cesium carbonate (1.9 g) and DABCO (160 mg) were added at room temperature. The mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere, followed by stirring at 100 °C for 2 hours. After naturally cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-[(4-ethylpyridin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (774 mg).

[0645] Manufacturing Example 36

[0646] To (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( In a mixture of [2.2.1]heptane-2-carboxylic acid tert-butyl ester (10 g) and CH2Cl2 (150 mL), m-chloroperbenzoic acid (approximately 30% water, 3.3 g) was added under ice cooling, and the mixture was stirred at this temperature for 3 hours. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture under ice cooling and stirred briefly. The aqueous and organic layers were separated, and the resulting aqueous layer was extracted with CH2Cl2. The resulting organic layers were mixed and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the resulting solution was concentrated under reduced pressure to obtain an oxide as a foamy solid. The obtained bubbly solid was dissolved in THF (100 mL), and under an argon atmosphere and cooling with an ice / MeOH bath, 4.17 g of 2-(trimethylsilyl)ethyl 4-hydroxypiperidine-1-carboxylic acid 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 to separate the aqueous layer. 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 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 mixture of low-polarity diastereomers (peak-1 and 2, peak-1 and 2 are of the same axis asymmetry) and (2) a mixture of high-polarity diastereomers (peak-3 and 4, peak-3 and 4 are of the same axis asymmetry). The fractions containing low-polarity diastereomer mixtures (peak-1,2, with the same axial asymmetry) were collected and given as oils as (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [3.77 g]-2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. Additionally, fractions containing a mixture of highly polar diastereomers (peak-3,4, with the same axial asymmetry) were collected to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [1.75 g]-2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. A mixture of low-polarity diastereomers was used in the subsequent reaction.

[0647] Manufacturing Example 37

[0648] Under an argon atmosphere, the (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethanesulfinyl)-7-[6-fluoro-5-methyl-1-( A mixture of (2.2.1)-heptan-2-carboxylic acid tert-butyl ester (935 mg), (3S)-oxapentane-3-ol (163 μL), and THF (10 mL) was added to tBuOK (269 mg) under ice / MeOH bath cooling, and stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added under ice cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The drying agent 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 fractions containing (1) a mixture of low-polarity diastereomers (peak-1 and 2, peak-1 and 2 having the same axial asymmetry) and (2) a mixture of high-polarity diastereomers (peak-3 and 4, peak-3 and 4 having the same axial asymmetry). The fraction containing the low-polarity diastereomers (peak-1 and 2, having the same axial asymmetry) was collected and given as a solid (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(3S)-2-yl)-1H-indazol-4-yl]-2-{[(3S)-oxapran-3-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (346 mg). Additionally, fractions containing a mixture of highly polar diastereomers (peak-3,4, with the same axial asymmetry) were collected to give (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(3S)-oxapran-3-yl]-2-{[(3S)-oxapran-3-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (329 mg). A mixture of low-polarity diastereomers was used in the subsequent reaction.

[0649] Manufacturing Example 40

[0650] To (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( A mixture of (4R)-1-[(2S)-2-azido-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazo-5-yl)phenyl]ethyl}-L-prolyl ester (4.24 g), sodium ascorbate (1.45 g), tert-butanol (35 mL), THF (35 mL), and water (35 mL) was stirred at room temperature with anhydrous copper(II) (389 mg) for 2.5 hours. Ethyl acetate and water were added to separate the aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (5.62 g).

[0651] Manufacturing Example 51

[0652] Under an argon atmosphere, the (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy} A mixture of tert-butyl heptane-2-carboxylic acid (1.1 g), THF (22 mL), and tetrabutylammonium fluoride (1 M HF solution, 2.57 mL) was added to acetic acid (90 μL) at room temperature and stirred at 60 °C for 15 hours. After naturally cooling to room temperature, ethyl acetate and saturated ammonium chloride aqueous solution were added for separation. The aqueous layer was extracted with ethyl acetate / methanol (10 / 1), and the combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [Alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (951 mg).

[0653] Manufacturing Example 52

[0654] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (250 mg), oxetane-3-one (43 mg), CH2Cl2 (3 mL) were mixed with sodium triacetoxyborohydride (122 mg) at room temperature and stirred for 16 hours at room temperature.] Add saturated sodium bicarbonate aqueous solution and stir for 10 minutes at room temperature. Extract with CHCl3 / MeOH (5 / 1), and dry the combined organic layers with anhydrous sodium sulfate. Filter off the insoluble matter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (CHCl3 / MeOH) to give (1S,4S)-5-(6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [220 mg]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-{[1-(oxetane-3-yl)piperidin-4-yl]oxy}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (220 mg).

[0655] Manufacturing Example 53

[0656] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl 2-[(piperidin-4-yl)oxy]-8-{[4-(1-{(2S)-1-[(2S,4R)-4- hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1- yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}quinazolin-4-yl}-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg), 2,2-difluoroethyl trifluoromethanesulfonate (124 mg), MeCN (3 mL) was added DIPEA (99 μL) at room temperature and stirred at room temperature for 16 hours. Concentrated under reduced pressure, the residue was purified with silica gel column chromatography (CHCl3 / MeOH) to give (1S,4S)-5-(6-cyclopropyl-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-[6-fluoro-5-methyl-1-( tert-Butyl 2-[(piperidin-4-yl)oxy]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (196 mg).

[0657] Preparation Example 54

[0658] To a solution of methyl (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-indol-2-yl]-3- methylbutanoate (190 mg) in CH2Cl2(12 mL) was added thionyl chloride (500 μL) under argon atmosphere at ice cooling, and stirred at the temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to the resulting residue was added DMF (7 mL), (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-oxo-1,3-dihydro-2H-indol-2-yl]-1,3- dihydro-2H-indol-1-yl}-1,3-dioxo-1,3-dihydro-2H-inden-2-carboxylic acid (100 mg) at ice cooling, and stirred at the temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified with silica gel column chromatography (CHCl3 / MeOH) to give (1S,4S)-5-{6-cyclopropyl-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-indol-2-yl]-3- methylbutyl}-1,3-dioxo-1,3-dihydro-2H-inden-2-carboxylic acid (100 mg). tert-Butyl 2-[(piperidin-4-yl)oxy]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (196 mg). [2.2.1]heptan-2-carboxylic acid tert-butyl ester (450 mg) and cesium carbonate (260 mg) were stirred overnight at 60 °C under an argon atmosphere. The reaction solution was filtered through diatomaceous earth, and the residue on the diatomaceous earth was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [2-[(2S)-1-methoxy-3-methyl-1-oxobutane-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methoxy)-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (670 mg).

[0659] Manufacturing Example 56

[0660] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [2-[(2S)-1-methoxy-3-methyl-1-oxobutane-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methoxy)-2-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (670 mg) was added to a MeOH solution (7 mL) under ice-cooling conditions, followed by the addition of 1 M, 2.5 mL of aqueous sodium hydroxide solution, and stirred at room temperature for 3 days. After neutralization with 1 M, 2.5 mL of hydrochloric acid under ice-cooling conditions, CHCl3 and water were added for separation. The aqueous layer was extracted with CHCl3. The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH), and then purified again by silica gel column chromatography (alkaline silica gel, CHCl3 / MeOH) to obtain (2S)-2-{5-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-3-methylbutyric acid (372 mg).

[0661] Production Example 61

[0662] To a solution of (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alk-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2- (methoxycarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3- triazol-4-yl)phenyl]methoxy}-2-[( alk-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (3.97 g) in 1,2-dichloroethane (60 mL) was added trimethyltin hydroxide (IV) (3.35 g) at room temperature and stirred at 80°C for 18 hours. After natural cooling to room temperature, hydrochloric acid (1M, 60 mL) was added and extracted with CHCl3 / MeOH (9 / 1). The organic layer was washed with 1M hydrochloric acid and dried over anhydrous sodium sulfate. The insoluble matter was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (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-( alk-2-yl)-1H-indazol-4-yl]-2-[( alk-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (3.26 g).

[0663] Production Example 63

[0664] To a solution of (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-( alk-2-yl)-1H-indazol-4-yl]-2-[( alk-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (150 mg), 3-{4-[(1R)-1-amino-2-hydroxyethyl]phenyl}-1,3- In a mixture of 2-oxazolidinone N-hydrochloride (60 mg), DIPEA (70 μL), and DMF (3 mL), HATU (70 mg) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. Water, a saturated sodium chloride aqueous solution, and ethyl acetate were added to separate the aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3- [(-3-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (173 mg).

[0665] Manufacturing Example 66

[0666] (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[( A mixture of tert-butyl 2-heptane-2-carboxylic acid (6.5 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (7.6 g), triphenylphosphine (0.53 g), potassium acetate (4.9 g), DOX (120 mL), and palladium acetate (0.23 g) was degassed and replaced with argon gas, and stirred overnight at 115 °C. The reaction solution, naturally cooled to room temperature, was filtered through diatomaceous earth while being washed with a small amount of dioxane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[( [Alkyl-4-yl)oxy]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (5.47 g).

[0667] Manufacturing Example 67

[0668] Add (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (1.52 g), (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (0.84 g), potassium phosphate (1.85 g), dicyclohexyl(2',6'-diisopropyl) Oxy-[1,1'-biphenyl]-2-yl)phosphine (0.15 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.27 g), DOX (20 mL), and water (4 mL) were stirred at room temperature and degassed and purged with argon. The mixture was then stirred at 90 °C for 5 hours under an argon atmosphere. Subsequently, the mixture was stirred at 100 °C for 7 hours. The reaction solution was naturally cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution 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 (peak-1) and (2) a high-polarity diastereomer (peak-2). The fraction containing the low-polarity diastereomer (peak-1) was recovered and obtained as a foam solid as (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (580 mg). Additionally, fractions containing the highly polar diastereomer (peak-2) were collected as foam solids to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[( [Alkyl-4-yl]oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (360 mg). The low-polarity diastereomer was used in the subsequent reaction.

[0669] Manufacturing Example 68

[0670] Under a nitrogen atmosphere, the (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[( To a solution of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg) in DMF (5 mL) was added cesium carbonate (180 mg) and chloro(methoxy)methane (35 μL) under ice-cooling, and the mixture was stirred for 15 hours at room temperature.

[0671] To the reaction mixture was further added cesium carbonate (260 mg) and chloro(methoxy)methane (50 μL) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and filtered, and concentrated under reduced pressure.

[0672] The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.00 g) as an oil. tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (186 mg).

[0673] Production Example 69

[0674] To a mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (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 added PdCl2(dppf)-CH2Cl2(1.14 g) under argon atmosphere, and the mixture was stirred for 16 hours at 100°C. After natural cooling to room temperature, ethyl acetate was added, and filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.74 g) as a solid.

[0675] Production Example 71

[0676] To a solution of tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2- hydroxyethyl}carbamate (3.34 g) in CH2Cl2(25 mL), MeOH (25 mL), hydrogen chloride (4 M DOX solution, 25.6 mL) was added under cooling to -20 to -10 °C, and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol n hydrochloride (3.06 g) as a solid.

[0677] Production Example 73

[0678] To a mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol n hydrochloride (3.43 g), (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.81 g) and DMF (40 mL), DIPEA (7.8 mL) was added under ice cooling, followed by the addition of HATU (4.5 g) in small portions under ice cooling, and stirred at ice cooling for 1 hour and at room temperature for 1 hour. Water, saturated aqueous sodium chloride solution and ethyl acetate were added under ice cooling, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate / isopropanol (9 / 1), and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (5.01 g) as an oil.

[0679] Production Example 76

[0680] To a solution of tert-butyl (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (5.01 g) in CH2Cl2(35 mL), MeOH (30 mL), hydrogen chloride (4 M DOX solution, 28 mL) was added under cooling to -20 to -10 °C, and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide n hydrochloride (4.71 g) as a solid.

[0681] Production Example 79

[0682] To a mixture of (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide n hydrochloride (3.81 g), N-(tert- butoxycarbonyl)-L-valine (2.16 g) and DMF (45 mL) was added DIPEA (6.2 mL) followed by HATU (3.61 g) in small portions at a time under ice cooling, stirred for 1 hour under ice cooling and stirred for 1 hour at room temperature. Water, saturated aqueous sodium chloride solution and ethyl acetate were added under ice cooling, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, extracted with ethyl acetate / isopropanol (9 / 1), and the combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide as a solid (4.43 g).

[0683] Production Example 83

[0684] To a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (4.43 g) in CH2Cl2(35 mL), MeOH (35 mL) was added hydrogen chloride (4 M DOX solution, 20 mL) under cooling to -20 to -15°C, and stirred for 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure to obtain L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide n hydrochloride as a solid (4.21 g).

[0685] Production Example 88

[0686] To a mixture of L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide n hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), MeCN (20 mL) was added 2-azido-1,3-dimethylimidazole A solution of hexafluorophosphate (1.06 g) in MeCN (5 mL) was stirred under ice cooling for 5 hours. Water, saturated aqueous 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 layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide (1.07 g) as a solid.

[0687] Production Example 93

[0688] To a mixture of L-valine methyl ester hydrochloride (1.96 g), MeCN (45 mL), DIPEA (5 mL) was added methyl 4-bromo-2-(bromomethyl)benzoate (3.00 g) under water cooling, and slowly warmed to 80°C, and stirred at 80°C for 2 days. After natural cooling to room temperature, ethyl acetate and water were added, and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / ethyl acetate) to give methyl (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-methylbutanoate (2.86 g) as a solid.

[0689] Production Example 94

[0690] To a mixture of (2S)-2-(5-bromo-l-oxo-l,3-dihydro-2H-isoindol-2-yl)-3- methylbutyric acid methyl ester (600 mg), potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate (876 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (151 mg), sodium carbonate (390 mg), DOX (9 mL) and water (1.8 mL) under argon atmosphere, palladium acetate (41 mg) was added at room temperature, and stirred under microwave irradiation at 130°C for 4 hours. After natural cooling to room temperature, diethyl ether acetate was added, and filtered with celite, and washed with diethyl ether acetate. To the obtained filtrate, water was added, and partitioned, and the organic layer was washed with saturated aqueous sodium chloride solution. After drying the organic layer with anhydrous sodium sulfate, the insoluble matter was filtered off, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain a coupled reaction product (600 mg). To a solution of the obtained coupled 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. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (2S)-2-[5-(hydroxymethyl)-l-oxo-l,3-dihydro-2H-isoindol-2-yl]-3- methylbutyric acid methyl ester as a solid (190 mg).

[0691] Production Example 95

[0692] To a mixture of 3-methyl-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl]butyric acid ethyl ester (190 mg), 4-bromobenzyl alcohol (100 mg), PdCl2(dppf)CH2Cl2(45 mg), potassium phosphate (227 mg) under argon atmosphere, DOX (2 mL), water (0.4 mL) was added, and stirred at 100°C for 12 hours. After cooling the reaction mixture to room temperature, filtered with celite, and washed the celite with diethyl ether acetate. The filtrate was diluted with diethyl ether acetate, washed with water and saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The insoluble matter was filtered off, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-{4-[4-(hydroxymethyl)phenyl]-lH-pyrazol-l-yl}-3-methylbutyric acid ethyl ester as an oil (157 mg).

[0693] Production Example 96

[0694] To a solution of 2,2,6,6-tetramethylpiperidine (4.4 mL) in THF (80 mL) under argon, was added dropwise n-butyllithium (1.57 M in hexanes, 15.2 mL) with cooling under a dry ice-MeOH coolant (-78 °C) and stirred for 1 hour with cooling under ice. To the reaction mixture was added a solution of (3-bromo-5-fluorophenoxy)(tert-butyl)di(methyl)silane (5.21 g) in THF (20 mL) with cooling under a dry ice-MeOH coolant and stirred for 1 hour at this temperature. To the reaction mixture was added iodomethane (2.2 mL) dropwise and stirred for 1 hour at this temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution and stirred while warming to room temperature. To the reaction mixture was added ethyl acetate and extracted, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The insolubles were filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (5.13 g) as an oil.

[0695] Production Example 97

[0696] To a mixture of N-[(lR)-l-(4-bromophenyl)-2-hydroxyethyl]carbamic acid tert-butyl ester (500 mg), N-methyl-2-nitrobenzenesulfonamide (376 mg), tri-n-butylphosphine (0.51 mL) and THF (7 mL) was added 1,1'-azobis(N,N-dimethylformamide) (353 mg) in small portions with cooling under ice and stirred for 8 hours at room temperature. Diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give {(lR)-l-(4-bromophenyl)-2-[methyl(2-nitrobenzene-l-sulfonyl)amino]ethyl}carbamic acid tert-butyl ester (667 mg) as a solid.

[0697] Production Example 98

[0698] To a mixture of {(lR)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]-2-[methyl(2- nitrophenyl-l-sulfonyl)amino]ethyl}aminoformic acid tert-butyl ester (130 mg), potassium carbonate (84 mg) and DMF (1.3 mL) was added 4-tert-butylbenzenethiol (82 μL) under argon atmosphere at room temperature, and stirred at room temperature for 3 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering off the insoluble matter, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain {(lR)-2-(methylamino)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}aminoformic acid tert-butyl ester (60 mg) as an oil.

[0699] Production Example 99

[0700] To a mixture of {(lR)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]-2-[methyl(2- nitrophenyl-l-sulfonyl)amino]ethyl}aminoformic acid tert-butyl ester (130 mg), potassium carbonate (84 mg) and DMF (1.3 mL) was added 4-tert-butylbenzenethiol (82 μL) under argon atmosphere at room temperature, and stirred at room temperature for 3 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering off the insoluble matter, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain {(lR)-2-(methylamino)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}aminoformic acid tert-butyl ester (60 mg) as an oil.

[0701] Production Example 100

[0702] To a mixture of tert-butyl {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}carbamate (55 mg), THF (1 mL) was added, under ice cooling, formaldehyde (37% aqueous solution, 26 μL), and stirred for 10 minutes under the same condition. To this was added sodium triacetoxyborohydride (67 mg), and stirred for 1 hour at room temperature. After dilution with CHCl3, saturated aqueous sodium bicarbonate solution was added, stirred for a while, and the aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH (5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and concentrated under reduced pressure to give tert-butyl {(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl}carbamate (75 mg) as an oil.

[0703] Production Example 102

[0704] A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL), and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred at 100°C under argon atmosphere overnight. To the reaction solution, which was naturally cooled to room temperature, was added ethyl acetate for dilution, and filtered with celite. The filtrate was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g) as an oil.

[0705] Production Example 103

[0706] To a mixture of tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g), 5-bromo-1,3-thiazole-4- carboxylic acid methyl ester (2.6 g), potassium phosphate (3.8 g), dicyclohexyl(2',6'- dimethoxybiphenyl-2-yl)phosphine (730 mg), DOX (30 mL), and water (6 mL) was added palladium acetate (200 mg) at room temperature under argon, and stirred at 100°C for 3 hours. After natural cooling to room temperature, ethyl acetate was added, and washed with water and saturated aqueous sodium chloride solution. After drying the organic layer over anhydrous magnesium sulfate, insoluble matter was filtered off, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3- thiazole-4-carboxylic acid methyl ester (1.48 g) as a solid.

[0707] Production Example 104

[0708] To a solution of 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3- thiazole-4-carboxylic acid methyl ester (1.01 g) in CH2Cl2(20 mL) was added diisobutylaluminum hydride (1 M solution in toluene, 11 mL) dropwise under ice cooling, and stirred for 1 hour under ice cooling. The reaction was stopped by adding MeOH under ice cooling, and 10% aqueous sodium potassium tartrate solution (60 mL) and CHCl3were added, and stirred overnight. The mixture was partitioned, and the aqueous layer was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice cooling, and stirred for 1 hour under ice cooling. Water was added, and extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]carbamate (588 mg) as a solid.

[0709] Production Example 106

[0710] To a mixture of tert-butyl N-[(1 R)-1 -(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g), 2,2-dimethoxypropane (3.3 mL) and acetone (15 mL) was added boron trifluoride diethyl ether complex (26 μL) and stirred at room temperature for 1 hour. TEA (66 μL) was added and stirred at room temperature for 10 minutes. Concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- oxazolidine-3-carboxylic acid tert-butyl ester (1.09 g) as a solid. tert-butyl oxazolidine-3-carboxylate (1.09 g).

[0711] Manufacturing Example 107

[0712] To a solution of (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- oxazolidine-3-carboxylic acid tert-butyl ester (300 mg), 1,3- oxazolidine-2-one (183 mg) in DOX (1.69 mL) was added copper (I) iodide (32 mg), rac-(1 R,2R)-cyclohexane-1,2-diamine (20 μL), potassium carbonate (290 mg) at room temperature. Stirred under microwave irradiation at 140 °C for 2 hours and at 150 °C for 1 hour. Added ethyl acetate and water and filtered through celite. Concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (120 mg) as a solid. tert-butyl oxazolidine-3-carboxylate (1.09 g). tert-butyl oxazolidine-3-carboxylate (1.09 g). tert-butyl oxazolidine-3-carboxylate (1.09 g). tert-butyl oxazolidine-3-carboxylate (1.09 g).

[0713] Manufacturing Example 109

[0714] To a solution of 1 -(4-bromophenyl)-2-fluoroethanone (2.7 g), (S)-2- methylpropane-2-sulfinamide (3.03 g) in THF (27 mL) was added tetraisopropyl orthotitanate (1 1.1 g) and stirred at 40 °C for 12 hours. BH3-THF complex (1 M THF solution, 18.4 mL) was added under ice cooling (0-5 °C) and stirred for 2 hours. After the reaction was quenched by the addition of water, the mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give (S)-N-[(1 R)-1 -(4-bromophenyl)-2-fluoroethyl]-2- methylpropane-2-sulfinamide (3.2 g) as an oil.

[0715] Manufacturing Example 156

[0716] To a solution of (4-ethynyl-3-fluorophenyl)methanol (110 mg) in CH2Cl2(2 mL) under nitrogen was added DIPEA (200 μL) followed by methanesulfonyl chloride (80 μL). After the reaction mixture was stirred at room temperature overnight, water was added and extracted with CHCl3. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. The insoluble material was filtered off and concentrated under reduced pressure to give 4-(chloromethyl)-l-ethynyl-2-fluorobenzene (122 mg) as an oil.

[0717] Production Example 189

[0718] To a mixture of (lS,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-2-[(2-hydroxyethyl)amino]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1] heptane-2-carboxylic acid tert-butyl ester (49 mg), tBuOH (0.5 mL), THF (0.5 mL) and water (0.5 mL) was added (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (33 mg), copper (I) iodide (7 mg) and sodium ascorbate (21 mg) at room temperature and stirred at 50°C for 3 hours. Ice, 2% ethylenediaminetetraacetic acid disodium salt aqueous solution and saturated aqueous sodium chloride solution were poured into the reaction vessel, extracted with CH2Cl2three times, and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give (lS,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2- hydroxyethyl)amino]-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}-lH-l,2,3- triazol-4-yl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (62 mg) as a solid.

[0719] Production Example 238

[0720] Under argon atmosphere, bis(tri-tert-butylphosphine)palladium(0) (18 mg) was added to a mixture of 4-methyl-l,3- thiazol-5-ylboronic acid (20 mg), 2-bromo-5-fluoropyridine (20 mg), potassium carbonate (20 mg) and 2-methyl-2-butene (0.5 mL) in 1,4-dioxane (0.5 mL) and water (0.1 mL) at room temperature. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was poured into water and extracted with CH2Cl2three times, and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give 5-(5-fluoro-2-pyridyl)-4-methyl-l,3-thiazol-2-ylboronic acid (20 mg) as a solid. oxazole-5-carboxylic acid (178 mg), tetra-n-butylammonium chloride (195 mg), (4R)-4- (4-bromophenyl)-2,2-dimethyl-1,3-oxazinan-3-one (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) were stirred under microwave irradiation at 170 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and the insoluble material was removed by filtration through celite. The filtrate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazinan-3-one as a solid. A mixture of tert-butyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) was stirred under microwave irradiation at 170 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and the insoluble material was removed by filtration through celite. The filtrate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazinan-3-one as a solid. A mixture of tert-butyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) was stirred under microwave irradiation at 170 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and the insoluble material was removed by filtration through celite. The filtrate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazinan-3-one as a solid. A mixture of tert-butyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) was stirred under microwave irradiation at 170 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and the insoluble material was removed by filtration through celite. The filtrate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazinan-3-one as a solid.

[0721] Preparation 239

[0722] A mixture of (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazinan-3-one (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) was stirred under microwave irradiation at 170 °C for 30 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate and the insoluble material was removed by filtration through celite. The filtrate was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazinan-3-one as a solid. A mixture of tert-butyl oxazolidine-3-carboxylate (858 mg), 2-methyl-1H-imidazole (500 mg), copper (I) iodide (95 mg), quinolin-8-ol (138 mg), potassium carbonate (670 mg) was suspended in DMSO (10 mL) and reacted under microwave irradiation at 150 °C for 3 hours under 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 layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (basic silica gel, hexane / ethyl acetate) to give (4R)-2,2-dimethyl-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1,3-oxazinan-3-one as an oil. A mixture of tert-butyl oxazolidine-3-carboxylate (858 mg), 2-methyl-1H-imidazole (500 mg), copper (I) iodide (95 mg), quinolin-8-ol (138 mg), potassium carbonate (670 mg) was suspended in DMSO (10 mL) and reacted under microwave irradiation at 150 °C for 3 hours under 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 layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (basic silica gel, hexane / ethyl acetate) to give (4R)-2,2-dimethyl-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1,3-oxazinan-3-one as an oil.

[0723] Preparation 245

[0724] To a mixture of 4-bromo-6-fluoro-lH-indazole (235 g), TEA (183 mL), CH2Cl2(1880 mL) was added l,l',l"-(chloromethanetriyl)triphenyl (335 g) at room temperature and stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1.5 L) and the organic layer and the aqueous layer were separated, the aqueous layer was extracted with CH2Cl2(400 mL) three times. The combined organic layer was dried over anhydrous sodium sulfate, filtered off the insoluble material and the filtrate was concentrated under reduced pressure. To the obtained residue was added petroleum ether (550 mL) to powder (0°C, 2 hours) and filtered off, dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

[0725] Preparation Example 246

[0726] To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) in 2- methyltetrahydrofuran (1000 mL) was added lithium diisopropylamide (2M THF solution, 214.28 mL) at -78°C under nitrogen atmosphere and the mixture was stirred at -78°C for 2.5 hours. Iodomethane (26.68 mL) was added at -78°C and stirred at 25°C for 2.5 hours. The reaction was quenched by adding water (2000 mL) and extracted with ethyl acetate (800 mL) twice. The combined organic layer was dried over anhydrous sodium sulfate, filtered off the insoluble material and the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (50 mL) / petroleum ether (50 mL) to powder and filtered off, dried under reduced pressure to obtain 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) as a solid.

[0727] Preparation Example 247

[0728] To 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), DOX (1000 mL) was added palladium acetate (4.52 g) under nitrogen atmosphere at room temperature. After degassing and nitrogen filling of the reaction mixture were carried out each 3 times, it was stirred under nitrogen atmosphere at 100°C for 12 hours. After cooling, water (1500 mL) was added and extracted with ethyl acetate (900 mL) 3 times. After drying the combined organic layers over anhydrous sodium sulfate, insoluble materials were filtered off. To the resulting solution was added activated carbon (50 g) and stirred at 20°C for 1 hour, filtered while washing 3 times with ethyl acetate (50 ml). The filtrate was concentrated, the resulting residue was powdered by adding methanol (200 mL), filtered and dried under reduced pressure to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0729] Preparation Example 248

[0730] A mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (350 mg), 2-aminoethanol (1 mL), N-methyl-2-pyrrolidone (2 mL) was reacted under microwave irradiation at 130°C for 30 minutes. The reaction solution was diluted with ice water, saturated aqueous ammonium chloride solution, and extracted with ethyl acetate 2 times. After washing the combined organic layers with saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. Insoluble materials were filtered off, and 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 give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2-hydroxyethyl)amino]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (198 mg) as a solid.

[0731] Preparation Example 249

[0732] To a mixture of (1S,4S)-5-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1- To tert-butyl [2-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5- methyl- l-(2-methyl- 1H-imidazol-4-yl)- lH-indol-3-yl]- 1H-indol- 1-yl)ethoxy]acetate (75 mg) was added dry THF (2 mL) and sodium hydride (55% dispersion in mineral oil, 20 mg) was added with stirring under an argon atmosphere while cooling in an ice-methanol bath. After stirring at room temperature for 1 h, iodomethane (20 μL) was added while cooling in an ice-methanol bath and the reaction was stirred at room temperature overnight under an argon atmosphere in a balloon. The reaction vessel was filled with ice, saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The collected organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl [2-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl- l-(2-methyl- lH-imidazol-4-yl)- lH-indol-3-yl]- lH-indol- 1 -yl)ethoxy]acetate (75 mg) as a white solid. tert-Butyl [2-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl- l-(2-methyl- lH-imidazol-4-yl)- lH-indol-3-yl]- lH-indol- 1 -yl)ethoxy]acetate (75 mg).

[0733] Preparation Example 252

[0734] To (lS,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2- (trityl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2. l]heptane-2-carboxylic acid tert-butyl ester (211 mg) was added MeOH (3 mL) and after stirring at room temperature was added 4-methylbenzene-1 -sulfonic acid monohydrate (48 mg) and stirred at room temperature under argon atmosphere for 1 hour. To the reaction vessel was added ice and saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were 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 give (lS,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl- 1 H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylic acid tert-butyl ester as the less polar diastereomer as a solid (87 mg) and (lS,4S)-5-{6- cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1 H-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as the more polar diastereomer as a solid (59 mg). The less polar diastereomer was used in the next reaction.

[0735] Manufacturing Example 281

[0736] To (3R)-pyrrolidin-3-ol (1.7 g) was added DMF (25 mL), triethylamine (3 mL) and after stirring with cooling in an ice / methanol bath was added 1-({[2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (4.5 g) in small portions and stirred at this temperature with cooling under argon atmosphere for 2 hours. To the reaction mixture was added ice water for dilution and extracted twice with ethyl acetate. The combined organic layers were washed successively with 1M hydrochloric acid / ice water (1 / 1), water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were filtered off and the filtrate was concentrated under reduced pressure to give (3R)-3-hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (3.6 g) as an oil.

[0737] The same manufacturing method as the manufacturing examples shown above was used to manufacture the compounds shown in Tables 6 to 101. Furthermore, the manufacturing methods, structures, and physicochemical data of the compounds in each manufacturing example are shown in Tables 6 to 101.

[0738] Example 8

[0739] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[( A mixture of 5.61 g of [alkyl-4-yl]oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and 60 mL of CH2Cl2 was added under cooling (internal temperature: below -5 °C), followed by stirring at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and the residue was extracted three times with CHCl3 / MeOH (5 / 1) by adding saturated aqueous sodium bicarbonate solution. The combined organic layers were dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the crude product was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target analyte was extracted three times with CHCl3 / MeOH (5 / 1). The combined organic layers were 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 product, and the mixture was stirred at 80 °C for 10 minutes, followed by overnight stirring at room temperature. Hexane (70 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered off, washed with isopropyl acetate / hexane (1 / 1), and dried overnight at 40 °C under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide (3.01g).

[0740] Example 7

[0741] (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[( (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[( (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[(

[0742] Example 20

[0743] (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[( (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[( (1.04 g) in CH2Cl2(9 mL), MeOH (9 mL) was added hydrogen chloride (4 M DOX solution, 3 mL) under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and the resulting residue was added with diethyl ether, and the precipitated solid was filtered 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-indazol-4-yl)-2-[( A mixture of tert-butyl (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-indazol-4-yl}-2-[( alk-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-(2-oxo-1,3- oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide (74 mg).

[0744] Example 18

[0745] To a mixture of (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-( alk-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-(2-oxo-1,3- A mixture of (2R)-2-amino-2-{4-[4-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethane-1-ol n-hydrochloride (25 mg) and DMF (1 mL) was added sequentially to DIPEA (50 μL) and HATU (35 mg) under ice-cooling, and 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 solution and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-{[(1R)-2-hydroxy-1-{4-[4-[4-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethyl]carbamoyl}pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (59 mg). Next, the obtained compound was dissolved in CH2Cl2 (0.5 mL) and MeOH (0.5 mL), and hydrogen chloride (4 M DOX solution, 0.5 mL) was added under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. Ether was added to the resulting residue, the precipitated solid was filtered off, washed with ether, and dried under reduced pressure to give (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-indazol-4-yl)-2-[( Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethyl]-L-prolylamide n hydrochloride (43 mg).

[0746] Example 49

[0747] To a solution of (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-indazol-4-yl)-2-[( alk-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl] ethyl}-L-prolinamide (50 mg) was prepared similarly to the production method of the examples shown above. In addition, the production method and the physicochemical data of each example compound are shown in Tables 127 to 131 described later. alk-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl] ethyl}-L-prolinamide (50 mg) was prepared similarly to the production method of the examples shown above. In addition, the production method and the physicochemical data of each example compound are shown in Tables 127 to 131 described later. alk-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3- methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl] ethyl}-L-prolinamide (50 mg) was prepared similarly to the production method of the examples shown above. In addition, the production method and the physicochemical data of each example compound are shown in Tables 127 to 131 described later.

[0748] The example compounds shown in Tables 102 to 126 described later were produced similarly to the production method of the examples shown above. In addition, the production method and the physicochemical data of each example compound are shown in Tables 127 to 131 described later.

[0749] In addition, in the tables described later, the following abbreviations are sometimes used.

[0750] PEx: manufacturing example number, Ex: example number, PSyn: manufacturing example number manufactured by the same method, Syn: example number manufactured by the same method (for example, Syn: 8 indicates manufactured by the same method as Example 8, Syn: 18# indicates that the hydrochloride salt manufactured by the same method as Example 18 is subjected to the desalting reaction described in Manufacturing Method 1), Str: chemical structure (in the chemical structure, the compound with "*" indicates that the compound has only one axial or central asymmetry), n HCl: n hydrochloride (indicates that the compound with the manufacturing example number is a monohydrochloride to a trihydrochloride, and the compound with the example number is a monohydrochloride to a penta- hydrochloride), DAT: physical and chemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] + when not stated), ESI-: m / z value in mass spectrometry (ionization method ESI, [M-H] - when not stated), NMR: δ value (ppm) of the peak in 1 H-NMR (500 MHz), NMR (100°C): δ value (ppm) of the peak in 1 H-NMR (500 MHz) at 100°C in DMSO-d6, s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad (spectrum) (example: br s).

[0751] [Table 6]

[0752] [Table 7]

[0753]

[0754] [Table 8]

[0755]

[0756] [Table 9]

[0757]

[0758] [Table 10]

[0759]

[0760] [Table 11]

[0761]

[0762] [Table 12]

[0763]

[0764] [table 13]

[0765]

[0766] [table 14]

[0767]

[0768] [table 15]

[0769]

[0770] [table 16]

[0771]

[0772] [table 17]

[0773]

[0774] [table 18]

[0775]

[0776] [table 19]

[0777] [table 20]

[0778]

[0779] [table 21]

[0780]

[0781] [table 22]

[0782]

[0783] [table 23]

[0784]

[0785] [table 24]

[0786]

[0787] [table 25]

[0788]

[0789] [table 26]

[0790]

[0791] [table 27]

[0792]

[0793] [Table 28]

[0794]

[0795] [Table 29]

[0796]

[0797] [Table 30]

[0798]

[0799] [Table 31]

[0800]

[0801] [Table 32]

[0802]

[0803] [Table 33]

[0804]

[0805] [Table 34]

[0806]

[0807] [Table 35]

[0808]

[0809] [Table 36]

[0810]

[0811] [Table 37]

[0812]

[0813] [Table 38]

[0814]

[0815] [Table 39]

[0816]

[0817] [Table 40]

[0818]

[0819] [Table 41]

[0820]

[0821] [Table 42]

[0822]

[0823] [Table 43]

[0824]

[0825] [Table 44]

[0826]

[0827] [Table 45]

[0828]

[0829] [Table 46]

[0830]

[0831] [Table 47]

[0832]

[0833] [Table 48]

[0834]

[0835] [Table 49]

[0836]

[0837] [Table 50]

[0838]

[0839] [Table 51]

[0840]

[0841] [Table 52]

[0842]

[0843] [Table 53]

[0844]

[0845] [Table 54]

[0846]

[0847] [Table 55]

[0848]

[0849] [table 56]

[0850]

[0851] [table 57]

[0852]

[0853] [table 58]

[0854]

[0855] [table 59]

[0856]

[0857] [table 60]

[0858]

[0859] [table 61]

[0860]

[0861] [table 62]

[0862]

[0863] [table 63]

[0864]

[0865] [table 64]

[0866]

[0867] [table 65]

[0868]

[0869] [table 66]

[0870]

[0871] [table 67]

[0872]

[0873] [table 68]

[0874]

[0875] [table 69]

[0876]

[0877] [table 70]

[0878]

[0879] [table 71]

[0880]

[0881] [table 72]

[0882]

[0883] [table 73]

[0884]

[0885] [table 74]

[0886]

[0887] [table 75]

[0888]

[0889] [table 76]

[0890]

[0891] [table 77]

[0892]

[0893] [table 78]

[0894]

[0895] [table 79]

[0896]

[0897] [table 80]

[0898]

[0899] [table 81]

[0900]

[0901] [table 82]

[0902]

[0903] [table 83]

[0904]

[0905] [table 84]

[0906]

[0907] [table 85]

[0908]

[0909] [table 86]

[0910]

[0911] [table 87]

[0912]

[0913] [table 88]

[0914]

[0915] [table 89]

[0916]

[0917] [table 90]

[0918]

[0919] [table 91]

[0920] [table 92]

[0921]

[0922] [table 93]

[0923]

[0924] [table 94]

[0925]

[0926] [table 95]

[0927]

[0928] [table 96]

[0929]

[0930] [table 97]

[0931]

[0932] [table 98]

[0933]

[0934] [table 99]

[0935]

[0936] [table 100]

[0937]

[0938] [table 101]

[0939]

[0940] [table 102]

[0941]

[0942] [table 103]

[0943]

[0944] [table 104]

[0945]

[0946] [table 105]

[0947]

[0948] [table 106]

[0949]

[0950] [table 107]

[0951]

[0952] [table 108]

[0953]

[0954] [table 109]

[0955]

[0956] [table 110]

[0957]

[0958] [table 111]

[0959]

[0960] [table 112]

[0961]

[0962] [table 113]

[0963]

[0964] [table 114]

[0965]

[0966] [table 115]

[0967]

[0968] [table 116]

[0969]

[0970] [table 117]

[0971]

[0972] [table 118]

[0973]

[0974] [table 119]

[0975]

[0976] [table 120]

[0977] [table 121]

[0978]

[0979] [table 122]

[0980]

[0981] [table 123]

[0982]

[0983] [table 124]

[0984]

[0985] [table 125]

[0986]

[0987] [table 126]

[0988]

[0989] [Table 127]

[0990]

[0991] [Table 128]

[0992]

[0993] [Table 129]

[0994]

[0995] [Table 130]

[0996]

[0997] [Table 131]

[0998]

[0999] In addition, as examples of the specific compounds of formula (I) included in the present application, compounds having any one of the following structures are shown. These compounds can be produced by the representative production method, the production examples and the examples shown above, or a combination of these production methods, or a method obvious to those skilled in the art.

[1000] Further, these compounds are excellent in the action of inducing the degradation of G12D mutant KRAS protein, are useful as G12D mutant KRAS inhibitors, and can be used as effective ingredients of pharmaceutical compositions, for example, pharmaceutical compositions for the treatment of pancreatic cancer.

[1001]

[1002]

[1003] Industrial applicability

[1004] The compound of the present application or a salt thereof is excellent in the action of inducing the degradation of G12D mutant KRAS protein, is useful as a G12D mutant KRAS inhibitor, and can be used as an effective ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the treatment of pancreatic cancer.

Claims

1. A compound or a salt thereof selected from the group consisting of: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-] [(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolyamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

2. The compound according to claim 1 or a salt thereof, which is a compound selected from the group consisting of: (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2 (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

3. The compound according to claim 1 or a salt thereof, which is a compound selected from the group consisting of: (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methyl-butyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

4. The compound according to claim 1 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [Alkyl-4-yl]oxy]quinazolin-8-yl}oxy]methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide.

5. The compound according to claim 1, which is (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-indazol-4-yl)-2-[ (R)-2-hydroxy-1-phenylethyl]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, or a salt thereof.

5. The compound according to claim 1, which is (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-indazol-4-yl)-2-[ (R)-2-hydroxy-1-phenylethyl]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, or a salt thereof.

6. The compound according to claim 1 or a salt thereof, which is (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-indazol-4-yl)-2-[( alk-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-(2-oxo-1,3- azolidin-3-yl)phenyl]ethyl}-L-prolinamide.

7. The compound or salt thereof according to claim 1, which is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

8. The compound according to claim 1 or a salt thereof, which is (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-indazol-4-yl)-2-[ (8 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[ (8 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[ (8 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[ (8 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[ (8 -[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1] 9. The compound according to claim 1, which is (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-indazol-4-yl)-2-[ (9 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-indazol-4-yl)-2-[ (9 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-indazol-4-yl)-2-[ (9 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-indazol-4-yl)-2-[ (9 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-indazol-4-yl)-2-[ (9 1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2 10. The compound or salt thereof according to claim 1, which is (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

11. The compound or salt thereof according to claim 1, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

12. The compound according to claim 1 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide.

13. The compound according to claim 1 or a salt thereof, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

14. The compound or a salt thereof according to claim 1, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

15. The compound according to claim 2 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [Alkyl-4-yl]oxy]quinazolin-8-yl}oxy]methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide.

16. The compound according to claim 2 or a salt thereof, which is (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ 17. The compound according to claim 2, which is (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-indazol-4-yl)-2-[ (2S)-2-oxo-3-oxazolidinyl]ethyl}oxy)methyl]phenyl}-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, or a salt thereof.

17. The compound according to claim 2, which is (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-indazol-4-yl)-2-[ (2S)-2-oxo-3-oxazolidinyl]ethyl}oxy)methyl]phenyl}-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3- oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, or a salt thereof.

17. The compound according to claim 2, which is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6- cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept 18. The compound according to claim 2 or a salt thereof, which is (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)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

19. The compound according to claim 2 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [Alkyl-4-yl]oxy]quinazolin-8-yl}oxy]methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide.

20. The compound according to claim 2 or a salt thereof, which is (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ 21. The compound according to claim 2 or a salt thereof, which is (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

22. The compound according to claim 2 or a salt thereof, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

23. The compound according to claim 2 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide.

24. The compound or salt thereof according to claim 2, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

25. The compound or a salt thereof according to claim 2, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

26. The compound according to claim 3 or a salt thereof, which is (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-indazol-4-yl)-2-[( (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-indazol-4-yl)-2-[ 27. The compound according to claim 3 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethyl]-L-prolylamide.

28. The compound according to claim 3, which is (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-indazol-4-yl)-2-[( -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-(2-oxo-1,3- -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-(2-oxo-1,3- 29. The compound or salt thereof according to claim 3, which is (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)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

30. The compound according to claim 3 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [Alkyl-4-yl]oxy]quinazolin-8-yl}oxy]methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide.

31. The compound according to claim 3 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [Alkyl-4-yl]oxy]quinazolin-8-yl]oxy]methyl]phenyl]-1H-1,2,3-triazol-1-yl]-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl]-4-hydroxy-L-prolineamide.

32. The compound or salt thereof according to claim 3, which is (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-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutan-2-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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

33. The compound or salt thereof according to claim 3, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]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-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

34. The compound according to claim 3 or a salt thereof, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[( [Alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-2-fluorophenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide.

35. The compound according to claim 3, which is (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-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, or a salt thereof.

36. The compound or a salt thereof according to claim 3, wherein the compound is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Azolium-5-yl)phenyl]ethyl}-L-prolineamide.

37. A pharmaceutical composition comprising the compound according to any one of claims 1 to 36, or a salt thereof, and one or more pharmaceutically acceptable excipients.

38. Use of the pharmaceutical composition according to claim 37 for the manufacture of a medicament for the treatment of pancreatic cancer.

39. Use of the compound according to any one of claims 1 to 36, or a salt thereof, for the manufacture of a medicament for the treatment of pancreatic cancer.

40. The use according to claim 39, wherein the pancreatic cancer is G12D mutant KRAS positive pancreatic cancer.

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