Quinazoline compounds for inducing degradation of g12d mutant kras proteins

Abstract

The present invention relates to a quinazoline compound for inducing decomposition of G12D mutant KRAS protein. The present invention provides use of a quinazoline compound represented by the following formula (I) or a salt thereof in the manufacture of a medicament for treating pancreatic cancer. The present inventors also provide use of a pharmaceutical composition comprising a compound of formula (Ia) or a salt thereof and one or more pharmaceutically acceptable excipients in the manufacture of a medicament for treating pancreatic cancer. The quinazoline compound has excellent effects of inducing decomposition of G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, thereby completing the present invention. The quinazoline compound of the present invention or a salt thereof or the pharmaceutical composition can be used as a therapeutic agent for pancreatic cancer.

Description

[0001] This application is a divisional application of international application PCT / JP2022 / 005582, which entered the Chinese national phase on August 14, 2023, with application number 202280014815.8 and invention title "Quinazoline compound for inducing degradation of G12D mutant KRAS protein". Technical Field

[0002] This invention relates to pharmaceutical compositions, quinazoline compounds that have excellent effects in inducing the degradation of G12D mutant KRAS protein, are expected to be useful as G12D mutant KRAS inhibitors, and are useful, for example, as an active ingredient in pharmaceutical compositions for the treatment of pancreatic cancer. Background Technology

[0003] Pancreatic cancer, primarily ductal adenocarcinoma, is a cancer with a very poor prognosis, boasting a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, p.7-30), with approximately 460,000 new cases reported worldwide annually (CA Cancer J. Clin., 2018, 68, p.394-424). The most effective treatment for pancreatic cancer is surgery; however, due to the difficulty in early detection and the fact that most cases have already metastasized, the effectiveness of surgical intervention is often unreliable. Chemotherapy and radiation therapy are used when surgery is not performed, but survival rates are also not optimistic. Currently, FOLFRINOX therapy (a combination therapy of levolecithin and 5-FU, irinotecan, and oxaliplatin) is used as the standard treatment for pancreatic cancer. However, due to its high toxicity, this treatment is limited to patients with an ECOG Performance Status below 1, and patient selection requires careful consideration (J. Clin. Oncol., 2018, 36, p.2545-2556). Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, has been approved for use in combination with gemcitabine as a molecularly targeted therapy. However, the overall survival extension is only about two weeks compared to gemcitabine alone, indicating unsatisfactory treatment results. More effective treatments are still needed (J. Clin. Oncol., 2007, 25, p.1960-1966).

[0004] RAS proteins are low-molecular-weight guanosine triphosphate (GTP)-binding proteins of approximately 21 kDa, composed of 188-189 amino acids. There are four main proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) produced by three genes: KRAS, NRAS, and HRAS. RAS proteins exist in both an active GTP-binding form and an inactive GDP-binding form. RAS proteins are activated by exchanging GTP with guanosine diphosphate (GDP) through ligand stimulation of cell membrane receptors such as EGFR. The active RAS binds to up to 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signaling cascades. Conversely, the active RAS converts GTP to GDP through endogenous GTP hydrolysis (GTPase) activity, thus becoming the inactive form. This GTPase activity is enhanced by GTPase-activated proteins (GAPs). This indicates that RAS functions as an important "molecular switch" in intracellular signaling pathways such as EGFR, playing a crucial role in cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, p.761-774, Nature Rev. Drug Discov., 2014, 13, p.828-851, Nature Rev. Drug Discov., 2016, 15, p.771-785).

[0005] When amino acid substitutions occur due to mutations in the RAS gene, RAS becomes constantly activated due to decreased GTPase function and reduced response to GAP, continuously transmitting signals downstream. This excessive signaling leads to carcinogenesis and hyperproliferation of the cancer. Pancreatic ductal adenocarcinoma is generally believed to develop from a weak atypia stage through a strong atypia stage in pancreatic intraepithelial neoplasia (PanIN). KRAS gene mutations have been identified in the early stages of PanIN. Subsequently, abnormalities in tumor suppressor genes INK4A, p53, and SMAD4 occur, leading to malignancy (Nature Rev. Cancer, 2010, 10, p.683-695). Furthermore, KRAS gene mutations can be observed in more than 90% of pancreatic ductal adenocarcinomas, with point mutations at codon 12 of exon 2 of KRAS being the most common (Cancer Cell 2017, 32, p.185-203). This demonstrates that KRAS plays an important role in the carcinogenesis and progression of pancreatic cancer.

[0006] KRAS gene mutations include KRAS G12C and KRAS G12D mutations. G12C-mutated KRAS is highly frequent in non-small cell lung cancer, but occurs in a few percent of pancreatic cancers (Cancer Cell 2014, 25, p.272-281). Therapies targeting other KRAS mutations are hoped for. It has been reported that G12D-mutated KRAS can be identified in approximately 34% of pancreatic cancers, representing the highest proportion among KRAS mutations (Nat. Rev. Cancer, 2018, 18, p.767-777).

[0007] Patent documents 1, 2, and 3 disclose RAS inhibitors, and compounds represented by formulas (A) and (B) below are disclosed in patent documents 2 and 3, respectively. Patent documents 1, 2, and 3 describe their usefulness to cancers with mutations in codon 12 of KRAS, including, as one of them, the G12D mutation, but do not describe their effect on G12D-mutant KRAS cancers.

[0008]

[0009] (A)

[0010] (B)

[0011] (Please refer to the bulletin for the meaning of the symbols in the formula.)

[0012] In addition, patent documents 9, 10 and 11 disclose KRAS G12D inhibitors.

[0013] In recent years, as a technology for inducing the degradation of target proteins, difunctional compounds, collectively known as PROTAC (PROteolysis-TArgeting Chimera) and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), have been discovered, showing promise as a new drug development paradigm (Drug. Discov. Today Technol., 2019, 31, p15-27). These difunctional compounds promote the formation of a complex between the target protein and an E3 ligase within the cell, inducing the degradation of the target protein using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases recognize the protein to be degraded and ubiquitinate it, thereby initiating degradation within the proteasome.

[0014] There are over 600 types of E3 ligases in living organisms, broadly categorized into four types: HECT-domain E3s, U-box E3s, monomeric ring E3s, and multi-subunit E3s. Currently, E3 ligases are limited to those used in bifunctional catabolism inducers such as PROTAC and SNIPER. Representative examples include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). Notably, Patent Document 4 reports on VHL, and Patent Document 5 reports on CRBN.

[0015] Difunctional compounds are compounds formed by linking the ligand of the target protein and the ligand of the E3 ligase using a linker. Currently, difunctional compounds that degrade 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 are currently no reported difunctional compounds that target G12D mutant KRAS.

[0016] Existing technical documents

[0017] Patent documents

[0018] Patent Document 1: International Publication No. 2016 / 049565

[0019] Patent Document 2: International Publication No. 2016 / 049568

[0020] Patent Document 3: International Publication No. 2017 / 172979

[0021] Patent Document 4: International Publication No. 2013 / 106643

[0022] Patent Document 5: International Publication No. 2015 / 160845

[0023] Patent Document 6: U.S. Patent Application Publication No. 2018 / 0015087

[0024] Patent Document 7: International Publication No. 2019 / 195609

[0025] Patent Document 8: International Publication No. 2020 / 018788

[0026] Patent Document 9: International Publication No. 2021 / 041671

[0027] Patent Document 10: International Publication No. 2021 / 106231

[0028] Patent Document 11: International Publication No. 2021 / 107160

[0029] Patent Document 12: International Publication No. 2021 / 051034

[0030] Non-patent literature

[0031] Non-patent literature 1: Cell. Chem. Biol., 2020, 27, pp. 19-31

[0032] Non-patent literature 2: ACS Cent. Sci., 2020, 6, pp. 1367-1375 Summary of the Invention

[0033] The problem that the invention aims to solve

[0034] Quinazoline compounds are provided as active ingredients in pharmaceutical compositions, such as those that induce the degradation of G12D mutant KRAS protein, are of excellent quality, are expected to be useful as G12D mutant KRAS inhibitors, and are useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.

[0035] Methods for solving problems

[0036] The inventors conducted in-depth research on compounds useful as active ingredients in pharmaceutical compositions for the treatment of pancreatic cancer. As a result, they discovered that quinazoline compounds of formula (I), particularly the difunctional compounds of formula (I) characterized by the 8-position substituent of quinazoline being linked to the ligand of E3 ligase or the 8-position substituent of quinazoline being linked to the ligand of E3 ligase through a linker, have excellent inducing effects on the degradation of G12D mutant KRAS protein and inhibitory activity against G12D mutant KRAS, thus completing the present invention.

[0037] That is, the present invention relates to compounds of formula (I) or salts thereof, and pharmaceutical compositions containing compounds of formula (I) or salts thereof and one or more pharmaceutically acceptable excipients.

[0038]

[0039] (in the formula, R 1 It is a naphthyl group that can be substituted with OH or a group selected from the group consisting of formulas (II) and (III) below.

[0040] R 1a R 1bThey may be the same or different from each other, and can be H, methyl, F, or Cl. R 1c It can be F, Cl, methyl, or ethyl. R 2 H, halogens, and substituted C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is a 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms, either saturated or unsaturated. R 4 C can be replaced 1-6 Alkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or substituted 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms. R 5 C can be replaced 1-6 Alkyl groups, substituted C 3-6 Cycloalkyl groups or substituted 4- to 6-membered saturated heterocyclic groups containing one heteroatom selected from oxygen, sulfur, and nitrogen. R 6a R 6b The same or different from each other, for H or C that can be substituted. 1-6 Alkyl, or R 6a R 6b Together with the carbon atoms they are bonded to, they form substitutable C atoms. 3-6 Cycloalkyl or substituted 4- to 6-membered saturated heterocycles containing one heteroatom selected from oxygen, sulfur, and nitrogen. R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms, W can be a substituted phenyl group or a substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms. X represents a bond, CH2, O, S, or NR. 4x , R 4x For H or C 1-3 alkyl, Y is a phenylene or pyridinyl group, which may be substituted with F. L is -(L) 1 -L 2 -L 3 -L 4 )-, 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, R L1 For H or C 1-3 alkyl, Z is NH or a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. Alternatively, YLZ can be expressed as equation (XIII) below.

[0041] Furthermore, the present invention relates to compounds of formula (Ib) or salts thereof, and pharmaceutical compositions comprising compounds of formula (Ib) or salts thereof and one or more pharmaceutically acceptable excipients. Compounds of formula (Ib) are included in compounds of formula (I).

[0042]

[0043] (in the formula, R 1 For example, Equation (IIa) or Equation (IIIa) below.

[0044] R 1a R 1b If they are the same or different from each other, they are H or F. R 2 Halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is the following formula (IV),

[0045] R 4 C 1-3 Alkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl R 5 It is ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 6a R 6bThe same or different from each other, C is H or can be substituted by groups selected from the group consisting of F, OH and N(CH3)2. 1-3 Alkyl, or R 6a R 6b Together with the carbon atoms they are bonded to, they form cyclopropyl groups. R 7 It is H, a halogen, or a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX) below.

[0046] R 7a H or C that can be replaced by OH 1-3 alkyl, X is O. Y is a phenylene or pyridinyl dimethyl group. L stands for bond, C 1-3 Alkylene or C=O Z is NH or a group selected from the group consisting of formulas (X), (XI), and (XII) below.

[0047] Alternatively, YLZ can be expressed as equation (XIII) below.

[0048] It should be noted that, unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0049] Furthermore, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, particularly pharmaceutical compositions for the treatment of pancreatic cancer, particularly pharmaceutical compositions for the treatment of G12D-mutant KRAS-positive pancreatic cancer, particularly pharmaceutical compositions for the treatment of metastatic pancreatic cancer, particularly pharmaceutical compositions for the treatment of locally advanced pancreatic cancer, particularly pharmaceutical compositions for the treatment of recurrent or refractory pancreatic cancer, particularly pharmaceutical compositions for the treatment of pancreatic cancer in untreated and / or treated patients, particularly pharmaceutical compositions for the treatment of metastatic G12D-mutant KRAS-positive pancreatic cancer, particularly pharmaceutical compositions for the treatment of locally advanced G12D-mutant KRAS-positive pancreatic cancer, particularly pharmaceutical compositions for the treatment of recurrent or refractory G12D-mutant KRAS-positive pancreatic cancer, particularly pharmaceutical compositions for the treatment of G12D-mutant KRAS-positive pancreatic cancer in untreated and / or treated patients. It should be noted that the pharmaceutical composition includes therapeutic agents for pancreatic cancer, particularly G12D-mutant KRAS-positive pancreatic cancer, containing compounds of formula (I) or salts thereof.

[0050] Additionally, this invention relates to: compounds of formula (I) or salts thereof in the manufacture of pancreatic cancer, particularly G12D-mutated KRAS-positive pancreatic cancer, particularly metastatic pancreatic cancer, particularly locally advanced pancreatic cancer, particularly recurrent or refractory pancreatic cancer, particularly pancreatic cancer in untreated and / or treated patients, particularly metastatic G12D-mutated KRAS-positive pancreatic cancer, particularly locally advanced G12D-mutated KRAS-positive pancreatic cancer, particularly recurrent or refractory G12D-mutated KRAS-positive pancreatic cancer, particularly... Use in therapeutic pharmaceutical compositions for G12D-mutant KRAS-positive pancreatic cancer in untreated and / or treated patients; use of compounds of formula (I) or salts thereof in the treatment of pancreatic cancer, particularly G12D-mutant KRAS-positive pancreatic cancer; compounds of formula (I) or salts thereof for the treatment of pancreatic cancer, particularly G12D-mutant KRAS-positive pancreatic cancer; and treatment methods for pancreatic cancer, particularly G12D-mutant KRAS-positive pancreatic cancer, including the step of administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0051] In addition, the present invention also relates to compounds of formula (I) or salts thereof as G12D mutant KRAS protein degradation inducers and / or G12D mutant KRAS inhibitors, compounds of formula (I) or salts thereof for use as G12D mutant KRAS protein degradation inducers and / or G12D mutant KRAS inhibitors, and G12D mutant KRAS protein degradation inducers and / or G12D mutant KRAS inhibitors containing compounds of formula (I) or salts thereof.

[0052] It should be noted that "object" refers to a person or other animal that needs the treatment, or, as a means, to a person who needs the prevention or treatment.

[0053] Invention Effects

[0054] Compounds of formula (I) or their salts have the effect of inducing the degradation of G12D mutant KRAS protein and inhibiting G12D mutant KRAS, and can be used as therapeutic agents for pancreatic cancer, especially G12D mutant KRAS positive pancreatic cancer. Detailed Implementation

[0055] The present invention will now be described in detail.

[0056] In this specification, "can be substituted" means unsubstituted or having 1 to 5 substituents. Alternatively, it means unsubstituted or having 1 to 3 substituents. It should be noted that when there are two or more substituents, these substituents can be the same or different from each other.

[0057] “C 1-12"Alkyl" refers to alkyl groups with a straight or branched chain having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (The number of carbon atoms will be described similarly below). As a modifier, it is ethyl or dodecyl; as a modifier, it is C10. 1-6 Alkyl, in one manner, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl; in another manner, is methyl, ethyl, n-propyl, isopropyl, or sec-butyl; in another manner, is methyl, ethyl, isopropyl, or tert-butyl; in another manner, is methyl, ethyl, n-propyl, isopropyl, or n-butyl; in another manner, is C 1-3 Alkyl, as a form, is methyl, ethyl or isopropyl, as a form, is methyl or ethyl, as a form, is methyl or isopropyl, as a form, is methyl, as a form, is ethyl, as a form, isopropyl.

[0058] “C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and 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.

[0059] “C 1-3 "alkylene" refers to a straight-chain or branched C18 group. 1-3 Alkylenes, such as methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. As a form, they are either straight-chain or branched C24. 1-3 Alkylene, as a form, is methylene, ethylene, or trimethylene, as a form, is methylene or ethylene, as a form, is ethylene.

[0060] "Saturated or unsaturated 7- to 8-membered bridged heterocyclic groups" refers to saturated 7- to 8-membered monocyclic bridged heterocyclic groups containing 1 to 2 nitrogen atoms as cyclic atoms, or 7- to 8-membered monocyclic bridged heterocyclic groups with unsaturated bonds containing 1 to 2 nitrogen atoms as cyclic atoms. One type is a saturated 7- to 8-membered monocyclic bridged heterocyclic group containing 2 nitrogen atoms; another type is a saturated 7- to 8-membered monocyclic bridged heterocyclic group containing nitrogen atoms, where one of the two nitrogen atoms is bonded to one hydrogen atom. Examples include 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, and diazabicyclo[2.2.1]heptenyl. As one embodiment, it is 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 another embodiment, it is diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl or ... Azabicyclo[2.2.1]heptyl, in one mode being 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, in one mode being diazabicyclo[2.2.1]heptyl, in one mode being 2,5-diazabicyclo[2.2.1]heptyl, in one mode being 2,5-diazabicyclo[2.2.1]heptane-2-yl.

[0061] "4- to 6-membered saturated heterocyclic groups" refer to, for example, 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as cyclic atoms, wherein the sulfur atom contained in the heterocycle can be oxidized. One type of "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocycle can be oxidized. Another type is a 5- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocycle can be oxidized. Yet another type is a 5-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, wherein the sulfur atom contained in the heterocycle can be oxidized. Other examples include oxoheterobutyl, tetrahydrofuranyl, tetrahydropyranyl, azaheterobutyl, pyrrolidinyl, and piperidinyl. Azolanic, imidazolanic, piperazine, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl, as one embodiment, oxetane, tetrahydrofuranyl, tetrahydropyranyl, azirnechiloyl, pyrrolinic, piperidinyl, piperazine, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl, as one embodiment, oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinic, piperidinyl, or morpholinyl, as one embodiment, oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinic, or piperidinyl, as one embodiment, oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinic, or piperidinyl, as one embodiment, oxetane, tetrahydrofuranyl, or tetrahydropyranyl, as one embodiment, pyrrolinic, or piperidinyl, as one embodiment, oxetane, tetrahydrofuranyl, tetrahydropyranyl, as one embodiment, pyrrolinic, as one embodiment, piperidinyl, as one embodiment, morpholinyl, as one embodiment, for Azolyl alkyl group.

[0062] "5-membered heteroaryl" refers to a heteroaryl group containing, for example, 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as cyclic atoms in a 5-membered ring. Examples of "5-membered heteroaryl" groups include pyrazolyl, imidazolyl, triazolyl, and tetrazolyl. azole group, iso azole group, thiazolyl group, isothiazolyl group, Diazole or thiadiazole, as an example, pyrazolyl, imidazole, triazole, Azolium or thiazolyl, as an example, pyrazolium, imidazole, The azole or thiazolyl group, in one mode, is pyrazolyl, imidazole, triazole, or iso-pyrazolyl. The azole group, as one way, is the pyrazol group. The azole or thiazolyl group, in one manner, is pyrazolyl, triazole, or iso-pyrazolyl. The azole group, as one mode, is pyrazolyl or thiazolyl, as one mode, pyrazolyl or triazolyl, as one mode, pyrazolyl, as one mode, imidazole, as one mode, and so on. The azole group, in one mode, is thiazolyl, and in another mode, it is triazolyl. It should be noted that "5-membered heteroaryl dimethyl" refers to a divalent group formed by removing any one hydrogen atom from a "5-membered heteroaryl".

[0063] "6-membered heteroaryl" refers to a heteroaryl group containing, for example, 1 to 3 nitrogen atoms as cyclic atoms in a 6-membered ring. One mode of "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0064] "Halogen" refers to F, Cl, Br, and I. As a form, it is F, Cl, or Br; as a form, it is F or Cl; as a form, it is F or Br; as a form, it is F; as a form, it is Cl; as a form, it is Br.

[0065] As "replaceable C" 1-6 "alkyl" and "substitutable C" 1-3 One acceptable substituent for "alkyl" is F, OH, OCH3, N(CH3)2, C. 1-3 Alkyl, hydroxymethyl, methoxymethyl, difluoroethyl, substituted 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.

[0066] 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 a means, C is substituted with groups selected from the group consisting of OH and OCH3. 1-3 Alkyl groups, as a means, are C groups that can be substituted with OH. 1-3 Alkyl groups, as a means, are C groups that can be substituted by OCH3. 1-3 Alkyl, as a form, for C 1-3 Alkyl, as a mode, is -SO2CH3, F, Cl, OH, methyl, or OCH3, as a mode, is F, Cl, OH, methyl, or OCH3, as a mode, is F, OH, or OCH3, as a mode, is -SO2CH3, F, Cl, or methyl, as a mode, is -SO2CH3, as a mode, is F, Cl, or methyl, as a mode, is methyl, ethyl, hydroxymethyl, or methoxymethyl, as a mode, is methyl, ethyl, or hydroxymethyl, as a mode, is C. 1-3 Alkyl, OCH3, or cyclopropyl, as an example, is methyl, ethyl, or cyclopropyl, as an example, is methyl, or ethyl, as an example, is methyl, or hydroxymethyl, as an example, is ethyl, or hydroxymethyl, as an example, is hydroxymethyl, or methoxymethyl, as an example, is methyl, as an example, is ethyl, as an example, is hydroxymethyl, as an example, is methoxymethyl. When formula (I) is formula (Ib), as an acceptable substituent among "substitutable pyrazolyl", "substitutable pyridyl", and "substitutable pyrimidinyl", it is C. 1-3 alkyl.

[0067] As one way to accept substituents among “substitutable 4- to 6-membered saturated heterocyclic groups,” “substitutable pyrrolidinyl,” “substitutable piperidinyl,” “substitutable oxobutyl,” “substitutable tetrahydrofuranyl,” and “substitutable tetrahydropyranyl,” C can be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 Alkyl, F, OH, OCH3, oxo- or oxetyl. As one form, it is F, OH, or OCH3; as another form, it is a C group that can be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 Alkyl, F, oxo, or oxehane butyl, as a means, is a C group that can be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 Alkyl or oxo group, as a means, is a C group that can be substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 Alkyl, as a form, for C that can be substituted by F. 1-3Alkyl groups, as a means, are C groups that can be substituted with OH. 1-3 Alkyl groups, as a means, are C groups that can be substituted by OCH3. 1-3 Alkyl, in one form, is OCH3, methyl, ethyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetyl; in another form, is methyl, hydroxymethyl, methoxymethyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetyl; in yet another form, is OCH3, methyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetyl; in yet another form, is methyl, difluoroethyl, hydroxyethyl, methoxyethyl, or oxetyl; in yet another form, is difluoroethyl, hydroxyethyl, or methoxyethyl; in yet another form, is methyl, ethyl, difluoroethyl, or... Oxycyclobutyl, as an example, is difluoroethyl or oxycyclobutyl, as an example, is methyl, ethyl, hydroxymethyl, methoxymethyl or oxoyl, as an example, is methyl or oxoyl, as an example, is hydroxymethyl or methoxymethyl, as an example, is 2,2-difluoroethyl, as an example, is oxycyclobutyl, as an example, is hydroxymethyl, as an example, is methoxymethyl, as an example, is methyl, as an example, is 2-hydroxyethyl, as an example, is 2-methoxyethyl, as an example, is OCH3, as an example, is oxoyl. When formula (I) is formula (Ib), as an acceptable substituent among "substitutable pyrrolidinyl" and "substitutable piperidinyl", it is an F-substituted C. 1-3 Alkyl or oxocyclic butyl.

[0068] As "substitutable pyrrolidine dimethyl", "substitutable piperidine dimethyl", "substitutable piperazine dimethyl", "substitutable C 1-3 One acceptable substituent for "alkylene" is F, OH, OCH3, or a substituted C. 1-3 Alkyl. In one form, it is F, OH, OCH3, methyl, ethyl, hydroxymethyl or methoxymethyl, in another form, it is F, OH, OCH3 or methyl.

[0069] As "C that can be replaced by F" 1-3One form of "alkyl" is a methyl group that can be substituted with F, or an ethyl group that can be substituted with F. Examples include methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl. Another form is methyl, ethyl, monofluoromethyl, difluoromethyl, or difluoroethyl.

[0070] As "C that can be replaced by OH" 1-3 One form of "alkyl" is a methyl group that can be substituted with one OH group or an ethyl group that can be substituted with one to two OH groups. For example, it is methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. Another form is methyl, ethyl, or hydroxymethyl; yet another form is methyl or hydroxymethyl; another form is hydroxymethyl or hydroxyethyl; yet another form is hydroxymethyl; yet another form is hydroxyethyl.

[0071] As "C that can be replaced by OCH3" 1-3 One form of "alkyl" is a methyl group that can be substituted with one OCH3 group or an ethyl group that can be substituted with one to two OCH3 groups. For example, it is methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl. Another form is methoxymethyl or methoxyethyl.

[0072] As "C that can be replaced by N(CH3)2" 1-3 One form of "alkyl" is a methyl group that can be substituted with one N(CH3)2 or an ethyl group that can be substituted with one N(CH3)2. Another form is methyl, ethyl, dimethylaminomethyl, or dimethylaminoethyl.

[0073] As a mode of "phenylene that can be substituted by F", it is a phenylene that can be substituted by 1 to 2 F. As a mode of "phenylene that can be substituted by 1 F", as a mode of "phenylene or fluorophenylene", as a mode of "phenylene", as a mode of "2-fluoro-1,4-phenylene", as a mode of "3-fluoro-1,4-phenylene".

[0074] The “G12D mutation” indicates a mutation in wild-type proteins in which the amino acid residue corresponding to the 12th position of the codon is changed from glycine to aspartic acid.

[0075] "G12D mutant KRAS" means a KRAS with the aforementioned "G12D mutation".

[0076] "Pancreatic cancer" refers to a malignant tumor that forms in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. Further, it can be classified as metastatic pancreatic cancer, locally advanced pancreatic cancer, recurrent or refractory pancreatic cancer, or pancreatic cancer in untreated and / or treated patients.

[0077] "G12D-mutated KRAS-positive pancreatic cancer" refers to pancreatic cancer that is positive for the G12D-mutated KRAS. For example, it includes pancreatic cancer with a KRAS G12D mutation, and pancreatic cancer with a high positivity rate for the G12D-mutated KRAS. Other examples include G12D-mutated KRAS-positive pancreatic ductal carcinoma and G12D-mutated KRAS-positive pancreatic ductal adenocarcinoma.

[0078] One manner in which a compound of formula (I) or a salt thereof of the present invention is shown below.

[0079] As one form of the above formula (I), it is a compound or a salt thereof as defined by the following formula (Ia).

[0080]

[0081] As one way to represent the above formulas (I) and (Ia), it is a compound or a salt thereof as defined by the following formula (Ib).

[0082]

[0083] The following describes one manner of the compounds of formula (I), formula (Ia) and formula (Ib) of the present invention or salts thereof.

[0084] (1-1)R 1 It is a naphthyl group that can be substituted with OH or a group selected from the group consisting of formulas (II) and (III) below.

[0085] R 1a R 1b They may be the same or different from each other, and can be H, methyl, F, or Cl. R 1c Compounds of F, Cl, methyl or ethyl or their salts.

[0086] (1-2)R 1 For example, Equation (IIa) or Equation (IIIa) below.

[0087] R 1a R 1b Compounds that are the same as or different from each other, and are H, methyl, F or Cl or their salts.

[0088] (1-3)R 1 For formula (IIa) or formula (IIIa), R 1a R 1b Compounds that are the same as or different from each other, and are H or F or their salts.

[0089] (1-4)R 1 For equation (IIa) or equation (IIIa), R 1a For F, R 1b Compounds containing H or their salts.

[0090] (1-5)R 1 For equation (IIa), R 1a Compounds of F or their salts.

[0091]

[0092] As R 1 Another way is R 1 For equation (II), R 1a For F, R 1c Compounds containing methyl groups or their salts. One way to represent this is R. 1 For equation (IIa), R 1a Compounds of H or F or their salts. In one manner, it is R. 1 For equation (IIa), R 1a Compounds of H or their salts. In one form, it is R. 1 For equation (IIIa), R 1a R 1b Compounds that are the same as or different from each other, and are H or F or their salts. As a way, it is R. 1 For equation (IIIa), R 1a R 1b All are compounds containing H or their salts. One way is R... 1 For equation (IIIa), R 1a For H, R 1b For compounds of F or their salts. In one manner, it is R. 1 For equation (IIIa), R 1a R 1b All are compounds of F or their salts. In one manner, it is R. 1 For equation (IIIa), R1a For F, R 1b Compounds containing H or their salts.

[0093] (2-1)R 2 H, halogens, and substituted C 1-3 Compounds of alkyl, cyclopropyl or vinyl groups or their salts.

[0094] (2-2)R 2 Halogen, C 1-3 Alkyl, cyclopropyl or vinyl and the C 1-3 Alkyl groups can be substituted for compounds or their salts, which are selected from the group consisting of OH and OCH3.

[0095] (2-3)R 2 Halogen, C 1-3 Compounds of alkyl, cyclopropyl or vinyl groups or their salts.

[0096] (2-4)R 2 It is a cyclopropyl compound or a salt thereof.

[0097] As R 2 Another way is R 2 It is a halogen compound or a salt thereof. In one way, it is R. 2 C 1-3 Alkyl compounds or their salts. One way is R... 2 Compounds of vinyl groups or their salts.

[0098] (3-1)R 3 It is a compound or its salt containing a saturated or unsaturated 7- or 8-membered bridged heterocyclic group with 1 to 2 nitrogen atoms.

[0099] (3-2)R 3 It is a compound or a salt thereof of 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.

[0100] (3-3)R 3 It is a compound of formula (IV) or a salt thereof.

[0101]

[0102] (4-1)R 4 C can be replaced 1-6Compounds or salts thereof containing alkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or substituted 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms.

[0103] (4-2)R 4 C can be replaced 1-6 Compounds of alkyl, substituted oxacyclobutyl, substituted tetrahydrofuran, substituted tetrahydropyran, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl or substituted piperidinyl, or salts thereof.

[0104] (4-3)R 4 C 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 Compounds of alkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl or substituted piperidinyl groups or their salts.

[0105] (4-4)R 4 C 1-3 Compounds of alkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl or substituted piperidinyl groups or their salts.

[0106] (4-5)R 4 C 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 Alkyl-substituted pyridyl groups, C groups that can be substituted by groups selected from the group consisting of F, OH, and OCH3 1-3 Alkyl-substituted pyrroleyl or C-substituted alkyl ... 1-3 Compounds of or salts thereof that are substituted with piperidinyl groups in the group consisting of alkyl and oxocyclic butyl groups.

[0107] (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.

[0108] (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.

[0109] 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... 4Compounds containing substituted pyridinyl groups or their salts. One way to represent this is R. 4 Compounds containing substituted pyrimidine groups or their salts. One way to represent this is R. 4 It is a substituted pyrrolidinyl compound or a salt thereof. As a way, it is R 4 Compounds containing substituted piperidinyl groups or their salts. One way to do this is R. 4 C can be replaced by F 1-3 Alkyl-substituted piperidinyl compounds or their salts. As a form, it is R... 4 It is a compound or a salt thereof that can be substituted with a piperidinyl group of difluoroethyl.

[0110] (5-1)R 5 C can be replaced 1-6 Alkyl groups, substituted C 3-6 Compounds or salts thereof that are cycloalkyl or contain a substituted 4- to 6-membered saturated heterocyclic group selected from oxygen, sulfur, and nitrogen.

[0111] (5-2)R 5 It is methyl, ethyl, isopropyl, tert-butyl or C 3-6 Cycloalkyl compounds or their salts.

[0112] (5-3)R 5 It is ethyl, isopropyl, tert-butyl or C 3-6 Cycloalkyl compounds or their salts.

[0113] (5-4)R 5 It is isopropyl or C 3-6 Cycloalkyl compounds or their salts.

[0114] (5-5)R 5 It is an isopropyl compound or a salt thereof.

[0115] As R 5 Another way is R 5 It is isopropyl, tert-butyl or C 3-6 Cycloalkyl compounds or their salts. As a way, it is R... 5 It is an isopropyl or tert-butyl compound or a salt thereof. As a form, it is R. 5 It is an isopropyl or cyclopropyl compound or a salt thereof. As a form, it is R. 5 It is a tert-butyl compound or a salt thereof. In one manner, it is R. 5 C 3-6 Cycloalkyl compounds or their salts.

[0116] (6-1)R 6a R 6b The same or different from each other, for H or C that can be substituted.1-6 Alkyl, or R 6a R 6b Together with the carbon atoms they are bonded to, they form substitutable C atoms. 3-6 Compounds or salts thereof that are cycloalkyl or contain a substituted 4- to 6-membered saturated heterocycle selected from oxygen, sulfur, and nitrogen.

[0117] (6-2) R 6a R 6b The same or different from each other, H or C 1-3 alkyl and the C 1-3 Alkyl groups can be substituted with groups selected from the group consisting of F, OH, OCH3, and N(CH3)2, or R. 6a R 6b Together with the carbon atoms they are bonded to, they form C 3-6 Cycloalkyl compounds or their salts.

[0118] (6-3)R 6a R 6b The same or different from each other, H or C 1-3 alkyl and the C 1-3 Alkyl groups can be substituted with groups selected from the group consisting of F, OH, and N(CH3)2, or R. 6a R 6b Together with the carbon atoms they are bonded to, they form cyclopropyl compounds or their salts.

[0119] (6-4)R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl compounds or their salts.

[0120] As R 6a R 6b Another way is R 6a R 6b The same or different from each other, C is H or can be substituted by groups selected from the group consisting of F, OH and N(CH3)2. 1-3 Alkyl compounds or their salts. One way is R... 6a R 6b The same or different from each other, C is a group that can be substituted by groups selected from the group consisting of F, OH and N(CH3)2. 1-3 Alkyl compounds or their salts. One way is R... 6a R 6b All are compounds containing H or their salts. One way is R... 6a For H, R 6b C is a group that can be substituted by groups selected from the group consisting of F, OH, and N(CH3)2. 1-3Alkyl compounds or their salts. One way is R... 6a For H, R 6b C can be replaced by F 1-3 Alkyl compounds or their salts. One way is R... 6a For H, R 6b C that can be replaced by N(CH3)2 1-3 Alkyl compounds or their salts. One way is R... 6a R 6b Together with the carbon atoms they are bonded to, they form cyclopropyl compounds or their salts.

[0121] (7-1)R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Compounds or salts thereof containing cycloalkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms.

[0122] (7-2)R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups or groups selected from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV) below,

[0123] R 7a R 7b The same or different from each other, is H or C that can be replaced by OH. 1-3 Alkyl compounds or their salts.

[0124] (7-3)R 7 It is H, a halogen, or a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX) below.

[0125] R 7a H or C that can be replaced by OH 1-3 Alkyl compounds or their salts.

[0126] (7-4)R 7 R is H, a halogen, or a group selected from the group consisting of formulas (VI), (VII), (VIII), and (IX). 7a C that can be replaced by OH1-3 Alkyl compounds or their salts.

[0127] (7-5)R 7 To select groups from the group consisting of formulas (VI), (VII), (VIII), and (IX), R 7a C that can be replaced by OH 1-3 Alkyl compounds or their salts.

[0128] (7-6)R 7 Compounds containing H or their salts.

[0129] As R 7 Another way is R 7 H, halogen, C 1-3 Compounds of alkyl groups or -SO2CH3 groups or their salts. As a form, it is R... 7 It is a halogen compound or a salt thereof. In one way, it is R. 7 Compounds of -SO2CH3 or their salts. In one manner, it is R... 7 Compounds or salts thereof are selected from the group consisting of formulas (VI), (VII), (VIII), and (IX). As one method, it is R... 7 Compounds or salts thereof consisting of groups from the group consisting of formulas (VI), (VIII), and (IX). As a method, it is R... 7 It is a compound of formula (VI) or (VIII) or a salt thereof. As a form, it is R. 7 It is a compound of formula (VI) or (IX) or a salt thereof. As a form, it is R. 7 It is a compound of formula (VI) or a salt thereof. As a means, it is R. 7 It is a compound of formula (VII) or a salt thereof. In one manner, it is R. 7 It is a compound of formula (VIII) or a salt thereof. In one manner, it is R. 7 It is a compound of formula (IX) or a salt thereof.

[0130] (7-8)R 7a H or C that can be replaced by OH 1-3 Alkyl compounds or their salts. One way is R... 7a Compounds of H or their salts. In one form, it is R. 7a C that can be replaced by OH 1-3 Alkyl compounds or their salts. One way is R... 7a C 1-3 Alkyl compounds or their salts.

[0131] (8-1)W is a substituted phenyl group or a substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms of formula (I) or a salt thereof.

[0132] (8-2)W 1 For CH, W 2 Compounds of formula (Ia) of C-SO2CH3 or their salts.

[0133] (8-3)W 1 W 2 Compounds of formula (Ia) or salts thereof that are the same as or different from each other, and are CH, CF, CCl, CCH3 or N.

[0134] (8-4)W 1 W 2 Compounds of formula (Ia) or their salts that are the same as or different from each other, and are CH, CF or N.

[0135] (8-5)W 1 For CH, W 2 Compounds of formula (Ia) of CH or their salts.

[0136] (9)W 1 W 2 and R 7 : i. W 1 For CH, W 2 For C-SO2CH3, R 7 For H, or ii. W 1 W 2 The same or different from each other, namely CH, CF, CCl, CCH3 or N, R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups or groups selected from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV) below,

[0137] R 7a R 7b The same or different from each other, is H or C that can be replaced by OH. 1-3 Compounds of the alkyl group of formula (Ia) or their salts.

[0138] (10-1) X is a bond, CH2, O, S, or NR. 4x R 4x For H or C 1-3 Alkyl compounds or their salts.

[0139] (10-2) X is O, S or NR 4x R 4x For H or C 1-3 Alkyl compounds or their salts.

[0140] (10-3)X is a compound of O or NH or its salt.

[0141] (10-4) Compounds in which X is O or its salts.

[0142] (11-1)Y is a phenylene or pyridinyl dimethyl compound or a salt thereof that can be substituted with F.

[0143] (11-2)Y is a compound of phenylene or pyridinium dimethyl or its salt.

[0144] (11-3)Y is a compound of phenylene that can be substituted by F or a salt thereof.

[0145] 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.

[0146] (12-1)L is -(L 1 -L 2 -L 3 -L 4 )-, 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, R L1 For H or C 1-3 Alkyl compounds or their salts.

[0147] (12-2) L is the bond, C is the bond 1-3 Alkylene, C=O, or a group selected from the group consisting of formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX).

[0148] R L1For H or C 1-3 alkyl, R L2 R L3 They may be the same as or different from each other, and may be H, F, OH, OCH3, or substituted C. 1-3 alkyl, R L For CH or N, Compounds or their salts in which n is an integer from 1 to 2.

[0149] (12-3) L is the bond, C is the bond 1-3 Alkylene, C=O, or a group selected from the group consisting of formulas (XIV)-1, (XV)-1, (XVI)-1, (XVII)-1, (XVIII)-1, and (XIX)-1.

[0150] (in the formula) (This indicates a bond with Y.)

[0151] R L1 For H or C 1-3 alkyl, R L2 R L3 They may be the same as or different from each other, and may be H, F, OH, OCH3, or substituted C. 1-3 alkyl, R L For CH or N, Compounds or their salts in which n is an integer from 1 to 2.

[0152] (12-4) L is the bond, C is the bond 1-3 Alkylene, C=O, or a group selected from the group consisting of formulas (XIV) and (XVI) below.

[0153] R L1 C 1-3 alkyl, R L2 R L3 For H, Compounds or their salts where n is 1.

[0154] (12-5) L is the bond, C is the bond 1-3 Alkylene, C=O, or a group selected from the group consisting of formulas (XIV)-1 and (XVI)-1 below,

[0155] (in the formula) (This indicates a bond with Y.)

[0156] R L1 C 1-3 alkyl, R L2 R L3 For H, Compounds or their salts where n is 1.

[0157] (12-6) L is a bond, C=O, or a group selected from the group consisting of formulas (XIV) and (XVI), R L1 C 1-3 Alkyl, R L2 R L3 A compound or its salt in which H is n and n is 1.

[0158] (12-7) L is a bond, C=O, or a group selected from the group consisting of formula (XIV)-1 and formula (XVI)-1, R L1 C 1-3 Alkyl, R L2 R L3 A compound or its salt in which H is n and n is 1.

[0159] (12-8) L is C=O or a group selected from the group consisting of formulas (XIV) and (XVI), R L1 C 1-3 Alkyl, R L2 R L3 A compound or its salt in which H is n and n is 1.

[0160] (12-9)L is C=O or a group selected from the group consisting of formula (XIV)-1 and formula (XVI)-1, R L1 C 1-3 Alkyl, R L2 R L3 A compound or its salt in which H is n and n is 1.

[0161] (12-10) L is the bond, C is the bond 1-3 Alkylene or C=O compounds or their salts.

[0162] (12-11) Compounds or their salts for which L is a bond.

[0163] Another way to represent L is as a key or C. 1-3 Alkylene compounds or their salts. In one form, compounds with L as a bond or C=O, or their salts. In another form, compounds with L as C. 1-3 Alkylene compounds or their salts. In one form, it is a compound or its salt where L is C=O.

[0164] (13-1) Z is NH or a compound or its salt containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen in a 5-membered heteroaryl group.

[0165] (13-2) Z is NH or a group selected from the group consisting of the following formulas (V), (X), (XI) and (XII) or a salt thereof.

[0166]

[0167] (13-3) Z is NH or a compound or a salt thereof selected from the group consisting of formula (V)-1, formula (X)-1, formula (XI)-1 and formula (XII)-1.

[0168]

[0169] (in the formula) (This indicates a bond with L.)

[0170] (13-4) Z is NH or a compound or a salt thereof selected from the group consisting of the following formulas (X), (XI) and (XII).

[0171]

[0172] (13-5) Z is NH or a compound or a salt thereof selected from the group consisting of formula (X)-1, formula (XI)-1 and formula (XII)-1.

[0173]

[0174] (in the formula) (This indicates a bond with L.)

[0175] (13-6) Z is NH or a compound or a salt thereof selected from the group consisting of the following formulas (X) and (XI).

[0176]

[0177] (13-7) Z is NH or a compound or a salt thereof selected from the group consisting of the following formulas (X)-1 and (XI)-1.

[0178]

[0179] (in the formula) (This indicates a bond with L.)

[0180] (13-8) Z is a compound or a salt thereof selected from the group consisting of formula (X) and formula (XI).

[0181] (13-9)Z is a compound or a salt thereof selected from the group consisting of formula (X)-1 and formula (XI)-1.

[0182] (13-10) Z is a compound of NH or its salt.

[0183] (13-11) Z is a compound of formula (XI) or a salt thereof.

[0184]

[0185] (13-12) Z is a compound of formula (XI)-1 or a salt thereof.

[0186]

[0187] (in the formula) (This indicates a bond with L.)

[0188] Another form of Z is a compound or a salt thereof consisting of a group selected from the group consisting of formulas (X), (XI), and (XII). Another form of Z is a compound or a salt thereof consisting of a group selected from the group consisting of formulas (X)-1, (XI)-1, and (XII)-1. Another form of Z is a compound or a salt thereof consisting of formula (XI) or (XII). Another form of Z is a compound or a salt thereof consisting of formula (XI)-1 or (XII)-1. Another form of Z is a compound or a salt thereof consisting of formula (X). Another form of Z is a compound or a salt thereof consisting of formula (X)-1. Another form of Z is a compound or a salt thereof consisting of formula (XII). Another form of Z is a compound or a salt thereof consisting of formula (XII)-1.

[0189] (14-1)YLZ is a compound of formula (XIII) or a salt thereof.

[0190]

[0191] (14-2)YLZ is a compound of formula (XIII)-1 or a salt thereof.

[0192]

[0193] (where O-CH2) This indicates a carbon bond with O-CH2.

[0194] (15) A compound or its salt that is not contradictory to any two or more combinations of the methods described in (1-1) to (14-2) above.

[0195] As a combination described above (15), specifically, the following methods can be listed as examples.

[0196] (16-1) A compound of formula (I) or a salt thereof, which is a combination of (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), (11-1), (12-1) and (13-1) above, or a combination of (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1) and (14-1).

[0197] (16-2) A compound of formula (I) or a salt thereof, which is a combination of (1-1), (2-1), (3-2), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1), (11-1), (12-2) and (13-2) above, or a combination of (1-1), (2-1), (3-2), (4-1), (5-1), (6-1), (7-1), (8-1), (10-1) and (14-1).

[0198] (16-3) Formula (I) is Formula (Ia), a compound or its salt thereof, which is a combination of the above (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2), (11-1), (12-2) and (13-2) or a combination of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (9), (10-2) and (14-1)

[0199] Formula (I) is Formula (Ia), a compound or its salt thereof that is a combination 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) above or a combination of (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-5), (8-2), (10-2) and (14-1).

[0200] (16-3-ii) Formula (I) is Formula (Ia), a compound or a salt thereof that is a combination of the above (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 (1-2), (2-1), (3-3), (4-2), (5-2), (6-2), (7-2), (8-3), (10-2) and (14-1).

[0201] (16-4) Formula (I) is Formula (Ia), a compound or its salt thereof that is a combination of the above (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 above (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (9), (10-3) and (14-1).

[0202] Formula (I) is Formula (Ia), a compound or its salt thereof, which is a combination of the above (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 (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-5), (8-2), (10-3) and (14-1) forms.

[0203] (16-4-ii) Formula (I) is Formula (Ia), a compound or a salt thereof that is a combination 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) above, or a combination of (1-2), (2-2), (3-3), (4-3), (5-2), (6-2), (7-2), (8-3), (10-3) and (14-1).

[0204] Formula (I) is Formula (Ia), a compound or its salt in combination with the above combinations 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).

[0205] Formula (I) is Formula (Ib), a compound or its salt thereof, which is a combination of the above-mentioned (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4), (11-2), (12-10), and (13-4) arrangements, or a combination of the above-mentioned (1-3), (2-3), (3-3), (4-4), (5-3), (6-3), (7-3), (10-4), and (14-1) arrangements.

[0206] (16-7) Formula (I) is Formula (Ia), a compound or its salt in combination with the above combinations of (1-3), (2-4), (3-3), (4-6), (5-4), (6-3), (7-4), (8-4), (10-3), (11-1), (12-6) and (13-6).

[0207] Formula (I) (16-8) is Formula (Ia), a compound or its salt in combination with the above combinations 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).

[0208] (16-9) Formula (I) is Formula (Ia), a compound or its salt thereof, which is a combination of the above (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) in the manner described above, or a combination 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) in the manner described above.

[0209] (16-10) Equation (I) is Equation (Ia), R 1 For equation (IIa), R 1a For F, R 2 It is cyclopropyl, R 3 For equation (IV), R 4 C that can be replaced by OCH3 1-6 Alkyl, tetrahydropyranyl, or C that can be substituted by F 1-3 Alkyl-substituted piperidinyl, R 5 It is isopropyl, R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl, R 7 To select groups from the group consisting of free formulas (VI), (VII), (VIII), and (IX), R 7a C that can be replaced by OH 1-3 Alkyl, W 1 For CH, W 2 X is CH, Y is O, L is a phenylene that can be substituted by F, L is a bond, and Z is a compound of formula (XI) or a salt thereof.

[0210] (16-11) Equation (I) is Equation (Ia), R 1 For equation (IIa), R 1a For F, R 2 It is cyclopropyl, R3 For equation (IV), R 4 C that can be replaced by OCH3 1-6 Alkyl, tetrahydropyranyl, or piperidinyl that can be substituted with difluoroethyl, R 5 It is isopropyl, R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl, R 7 To select groups from the group consisting of free formulas (VI), (VII), (VIII), and (IX), R 7a C that can be replaced by OH 1-3 Alkyl, W 1 For CH, W 2 X is CH, Y is O, L is a phenylene that can be substituted by F, L is a bond, and Z is a compound of formula (XI) or a salt thereof.

[0211] (16-12) Equation (I) is Equation (Ia), R 1 For equation (IIa), R 1a For F, R 2 It is cyclopropyl, R 3 For equation (IV), R 4 C that can be replaced by OCH3 1-6 Alkyl, tetrahydropyranyl, or piperidinyl that can be substituted with difluoroethyl, R 5 It is isopropyl, R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl, R 7 To select groups from the group consisting of free formulas (VI), (VII), (VIII), and (IX), R 7a C that can be replaced by OH 1-3 Alkyl, W 1 For CH, W 2 X is CH, Y is O, L is a phenylene that can be substituted by F, L is a bond, and Z is a compound of formula (XI)-1 or its salt.

[0212] (16-13) Equation (I) is Equation (Ib), R 1 For equation (IIa), R 1a For F, R 2 It is cyclopropyl, R 3 For equation (IV), R 4 It is a tetrahydropyranyl or a substituted piperidinyl group, R 5 It is isopropyl, R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl, R 7 For equations (VI), (VIII), or (IX), R7a C that can be replaced by OH 1-3 Alkyl group, where X is O, Y is phenylene, L is a bond, and Z is a compound of formula (XI) or a salt thereof.

[0213] (16-14) Equation (I) is Equation (Ib), R 1 For equation (IIa), R 1a For F, R 2 It is cyclopropyl, R 3 For equation (IV), R 4 It is a tetrahydropyranyl group, R 5 It is isopropyl, R 6a For H, R 6b C that can be replaced by OH 1-3 Alkyl, R 7 For equation (VI) or (VIII), R 7a C 1-3 Alkyl group, where 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.

[0214] As examples of specific compounds included in this invention, the following compounds may be listed as an example.

[0215] Choose compounds or their salts from the group consisting of the following: (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]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, (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-] [3-yl]phenyl]ethyl}-L-prolineamide, (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-prolylamide, (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-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide, (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-{(2S)-2-[4-(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutane-2-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]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-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (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]-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, (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, and (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.

[0216] As examples of specific compounds included in this invention, the following compounds may be listed as an example.

[0217] Choose compounds or their salts from the group consisting of the following: (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-prolylamide, (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-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethyl]-L-prolylamide, (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-(2-oxo-1,3-] [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-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-prolylamide, (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-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide, (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutane-2-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-[({(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-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (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, (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 (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.

[0218] As examples of specific compounds included in this invention, the following compounds may be listed as an example.

[0219] Choose compounds or their salts from the group consisting of the following: (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, (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, (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-(2-oxo-1,3-] [3-yl]phenyl]ethyl}-L-prolineamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-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-prolylamide, (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-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide, (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide, (4R)-1-[(2S)-2-{4-[4-({[(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(2R,3R)-3-methoxybutane-2-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-[({(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-thiazolyl-5-yl)phenyl]ethyl}-L-prolylamide, (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]-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, (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolylamide, 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.

[0220] As examples of specific compounds included in this invention, the following compounds may be listed as an example.

[0221] Choose compounds or their salts from the group consisting of the following: (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]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, (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-] [3-yl]phenyl]ethyl}-L-prolineamide, (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-prolylamide, (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-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolineamide, and (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]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl]-4-hydroxy-L-prolineamide.

[0222] The compounds of formula (I) may contain tautomers and geometric isomers, depending on the type of substituents. In this specification, the compounds of formula (I) are sometimes described only in one form of isomer, but the present invention also includes other isomers, as well as isolated products of the isomers or mixtures thereof.

[0223] Furthermore, compounds of formula (I) sometimes contain asymmetric carbon atoms or axial asymmetry, and diastereomers based thereon may exist. This invention also includes isolated products of diastereomers of compounds of formula (I) or mixtures thereof.

[0224] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of compounds represented by formula (I). A pharmaceutically acceptable prodrug is a compound having groups that can be decomposed by solvent addition or converted into amino, hydroxyl, carboxyl, or other groups under physiological conditions. Examples of groups forming prodrugs include those described in Prog. Med., 1985, 5, pp. 2157-2161 and "Pharmaceutical Development," Volume 7, Molecular Design, Hirokawa Shoten, 1990, pp. 163-198.

[0225] Furthermore, salts of compounds of formula (I) refer to pharmaceutically acceptable salts of compounds of formula (I), which, depending on the type of substituent, sometimes form acid addition salts or salts with bases. Examples of such salts can be cited in P. Heinrich Stahl's *Handbook of Pharmaceutical Salts Properties, Selection, and Use*, Wiley-VCH, 2008. Specifically, examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, xyleneformyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine; and ammonium salts.

[0226] Furthermore, the present invention also includes various hydrates, solvates, and polymorphs of compounds of formula (I) and their salts.

[0227] 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 such as S.

[0228] 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.

[0229] Replace with a heavier isotope, for example, replacing hydrogen with deuterium. 2H) Sometimes, improved metabolic stability can be therapeutically advantageous (e.g., increased half-life in vivo, reduced dosage, and reduced drug interactions).

[0230] 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.

[0231] 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.

[0232] (Manufacturing method)

[0233] Compounds of formula (I) and their salts can be manufactured using various known synthetic methods based on their basic structure or the types of substituents. In this case, depending on the type of functional group, it is sometimes technically efficient to pre-replace the functional group with a suitable protecting group (a group that can be easily converted to the functional group) during the stage from the starting material to the intermediate. Examples of such protecting groups include those described in PGM Wuts and TW Greene's "Greene's Protective Groups in Organic Synthesis," 5th edition, John Wiley & Sons Inc., 2014, which can be appropriately selected based on their reaction conditions. In such methods, after introducing the protecting group and reacting, the protecting group is removed as needed, thereby obtaining the desired compound.

[0234] Furthermore, the prodrug of the compound of formula (I) can be manufactured in the same manner as the protecting group described above, by introducing a specific group during the process from the starting material to the intermediate, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying conventional methods known to those skilled in the art, such as esterification, amidation, and dehydration.

[0235] The following describes representative methods for manufacturing compounds of formula (I). Each manufacturing method may also be described with reference to the appended references. It should be noted that the manufacturing methods of the present invention are not limited to the examples shown below.

[0236] The following abbreviations are sometimes used in this manual.

[0237] DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf) CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Dichloromethane adduct, Pd / C: Palladium on carbon.

[0238] (Manufacturing Method 1)

[0239] (where PG) 1 R represents 3 The protecting group of NH contained in it, PG 2 R represents 1 The NH or OH protecting groups or hydrogen atoms contained therein. (The same applies below.)

[0240] The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction. Examples of protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl, etc.

[0241] This reaction is carried out by stirring, typically from cooling to heating under reflux, for 0.1 hours to 5 days. Examples of solvents used herein, without particular limitation, include: alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, or chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, or water; and mixtures thereof. Examples of deprotecting agents, without particular limitation, include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, and methanesulfonic acid.

[0242] Deprotection can also be achieved through catalytic hydrogenation by selecting a protecting group. Examples of protecting groups include benzyl, p-methoxybenzyl, and benzyloxycarbonyl. Alternatively, deprotection can be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl. Furthermore, examples of protecting groups capable of deprotection under basic conditions include acetyl, trifluoroacetyl, and benzoyl. Additionally, as for PG... 1 PG 2Alternatively, protective groups that can be deprotected under different deprotection conditions can be selected separately, and deprotection can be carried out in stages.

[0243] For example, the following references may be consulted as references for this reaction.

[0244] PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014

[0245] It should be noted that when the compound (1) used as a raw material has axial asymmetry, the stereoisomer obtained by temporarily separating the compound (1) can also be used to carry out this reaction.

[0246] The hydrochloride salt of the compound of formula (I) can be obtained by applying the following operation as a salt-forming reaction to the compound of formula (I).

[0247] Based on its chemical structure, the compound of formula (I), which is considered to be capable of forming a salt with hydrochloric acid, was dissolved in CH2Cl2 and MeOH. Hydrogen chloride (4M DOX solution, 10 equivalents) was added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the resulting residue. The resulting solid was filtered off and dried under reduced pressure to obtain the hydrochloride salt of the compound of formula (I).

[0248] The hydrochloride salt of the compound of formula (I) can be obtained by applying the following operation as a desalting reaction to obtain the compound of formula (I).

[0249] The hydrochloride salt of the compound of formula (I) was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target compound was collected, made alkaline with saturated sodium bicarbonate aqueous solution, and then extracted with CHCl3 / MeOH (5 / 1). The combined organic layers were dried with anhydrous sodium sulfate, the solution was concentrated under reduced pressure, the resulting solid was washed with diethyl ether, and dried under reduced pressure to obtain the compound of formula (I).

[0250] (Raw Material Synthesis 1)

[0251] (where Y) 1 Indicates CH, CF, or N. (The same applies below.)

[0252] This manufacturing method is a first method for manufacturing compound (1)-1 contained in raw material compound (1).

[0253] (First step)

[0254] This step describes a method for producing compound (1)-1 by cyclization addition reaction of compound (2) and compound (3).

[0255] In this reaction, compounds (2) and (3) are used in equal or excess amounts, and the mixture thereof is preferably stirred for 0.1 hours to 5 days in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or in the absence of a solvent, under cooling to reflux, preferably at 0°C to 100°C. Examples of solvents used herein are not particularly limited, but include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and mixtures thereof. Copper salts include CuI, CuSO4, and CuOTf. Reducing agents include sodium ascorbate. The presence of substances such as TEA, DIPEA, N-methylmorpholine (NMM), 2,6-dimethylpyridine, and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) can sometimes be advantageous in facilitating the reaction.

[0256] [literature]

[0257] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599.

[0258] It should be noted that the PG of compound (2) can also be used. 2 The reaction is first carried out on the compound obtained by the deprotection reaction.

[0259] (Raw Material Synthesis 2)

[0260] (In the formula, R represents C) 1-3 Alkyl group. (The same applies below)

[0261] This manufacturing method is a second method for manufacturing compound (1)-1 contained in raw material compound (1).

[0262] (First step)

[0263] This step is a method for producing compound (5) by cyclization addition reaction of compound (2) and compound (4).

[0264] The reaction conditions are the same as those in the first step of the synthesis of starting material 1.

[0265] (Second Step)

[0266] This step is a method for producing compound (6) by hydrolyzing compound (5).

[0267] This reaction is carried out by stirring compound (5) under cooling to reflux for 0.1 hours to 5 days. Examples of solvents used herein are not particularly limited, but include alcohols, acetone, N,N-dimethylformamide, tetrahydrofuran, etc. Furthermore, a mixture of the above solvents and water is sometimes preferred for the reaction. Examples of hydrolysis reagents are not particularly limited, but include aqueous solutions of sodium hydroxide, aqueous solutions of potassium hydroxide, trimethyltin hydroxide, etc.

[0268] For example, the following references may be consulted as references for this reaction.

[0269] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[0270] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0271] (Step 3)

[0272] This step is a method for producing compound (1)-1 by amidation reaction of compound (6) and compound (7).

[0273] In this reaction, compounds (6) and (7) are used in equal or excess amounts, and their mixture is stirred for 0.1 hours to 5 days in the presence of a condensing agent, in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 60°C. Examples of solvents, without particular limitation, include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; alcohols; N,N-dimethylformamide, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of condensing agents include hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidine. PyBOP, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenyl azidophosphate (DPPA), etc. The use of additives (e.g., 1-hydroxybenzotriazole) is sometimes preferred for the reaction. The presence of organic bases such as TEA, DIPEA, or NMM, or inorganic bases such as potassium carbonate, sodium carbonate, or potassium hydroxide, is sometimes advantageous in facilitating the reaction.

[0274] Alternatively, an acylation reaction can be performed after converting compound (6) into a reactive derivative. Examples of reactive derivatives of carboxylic acids include acyl halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, and active esters obtained by condensation with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with compound (7) can be carried out in solvents that are inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, under cooling to heating, preferably -20°C to 120°C.

[0275] [literature]

[0276] S.R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Volume 1, Academic Press Inc., 1991.

[0277] "Lectures on Experimental Chemistry (5th Edition)" edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen)

[0278] (Raw Material Synthesis 3)

[0279] (where PG) 3 LG represents the protecting group of OH. 1 The term "leaving group" indicates that the borate group, pinacol borate ester group, or other borate group protected by a borate protecting group (hereinafter sometimes referred to as borate group, etc.) is a leaving group. Examples of leaving groups shown here include Cl, Br, methanesulfonyl, p-toluenesulfonyl, etc.

[0280] This manufacturing method is the first method for manufacturing raw material compound (2).

[0281] (First step)

[0282] This step is a method for producing compound (10) by in-situ substitution reaction of compound (8) and compound (9).

[0283] In this reaction, compounds (8) and (9) are used in equal or one in excess, and their mixture is stirred for 0.1 hours to 5 days in a solvent inert to the reaction or in the absence of solvent, under cooling to reflux, preferably from 0°C to 80°C. Examples of solvents used herein are not particularly limited, but include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, and MeCN; and mixtures thereof. The presence of organic bases such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), and tBuOK, and inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate, can sometimes be advantageous in facilitating the reaction.

[0284] Alternatively, compound (10) can be prepared by catalytic hydrogenation of the compound obtained by the Gou-Heck reaction of compound (8) and compound (9).

[0285] (Second Step)

[0286] This step is a method for producing compound (12) by in-situ substitution reaction of compound (10) and compound (11).

[0287] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0288] Alternatively, compound (12) can be manufactured by coupling the hydrogen atoms of compound (11) to halogens with the root of compound (10).

[0289] (Step 3)

[0290] This step involves reacting compound (12) with PG. 3 A method for producing compound (13) by in-situ substitution reaction of -OH.

[0291] As used here, PG 3 Examples of -OH include benzyl alcohol and p-methoxybenzyl alcohol.

[0292] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0293] (Fourth step)

[0294] This step involves reacting compound (13) with R... 2-A method for producing compounds (14) by the Suzuki-Miyaura coupling reaction of boric acid derivatives composed of boric acid groups, etc. Examples of boric acid groups, etc. used herein are not particularly limited, and may include boric acid groups, borate ester groups, borate pinacol ester groups, triol borate ester salt groups and trifluoroborate groups.

[0295] In this reaction, compound (13) and R are used in equal or excess amounts. 2 Boric acid derivatives composed of boric acid groups, etc., are stirred in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, at room temperature to reflux, preferably 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents used herein, without particular limitation, include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropanol, butanol, and pentanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolin-2-one, and water; and mixtures thereof. Inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide can be included. Examples of palladium catalysts include tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. Dichloromethane adducts, (1E,4E)-1,5-diphenylpentan-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, etc. The presence of ligands such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, and 1,1'-bis(diphenylphosphino)ferrocene can sometimes facilitate the reaction. Additionally, heating the mixture by microwave irradiation can sometimes facilitate the reaction.

[0296] [literature]

[0297] J. Am. Chem. Soc., 2005, 127, p.4685-4696

[0298] Org. Lett. 2011, 13, p.3948-3951

[0299] Org. Lett. 2012, 14, p.1278-1281

[0300] R 2When the atom is hydrogen, compound (14) can be produced by the catalytic hydrogenation reaction of compound (13).

[0301] (Step 5)

[0302] This step is a method for producing compound (16) by the Suzuki-Miyaura coupling reaction of compound (14) and compound (15).

[0303] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0304] It should be noted that when compound (16) is axially asymmetric, it is obtained as a mixture of diastereomers, and the individual diastereomers can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0305] (Step Six)

[0306] This step is a method for producing compound (17) by deprotection through the catalytic hydrogenation reaction of compound (16).

[0307] This reaction can be carried out by stirring compound (16) under a hydrogen atmosphere, at atmospheric pressure to under pressure, in a solvent that is inert to the reaction, such as MeOH, EtOH, or ethyl acetate, in the presence of a metal catalyst, under cooling to heating, preferably at room temperature for 1 hour to 5 days. As a metal catalyst, palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plates and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel are used.

[0308] (Seventh Step)

[0309] This step is a method for producing compound (2) by reacting compound (17) with compound (18).

[0310] This reaction is carried out by using compounds (17) and (18) in equal or excess amounts and by reacting a mixture thereof in the presence of a base, in a solvent inert to the reaction, under cooling to reflux, preferably at 0°C to 80°C, typically for 0.1 hours to 5 days. The solvent used herein is not particularly limited, but examples include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, and MeCN; and mixtures thereof. Examples of bases are not particularly limited, but examples include: organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The reaction can sometimes be carried out in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride.

[0311] For example, the following references may be consulted as references for this reaction.

[0312] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 14, Maruzen, 2005

[0313] It should be noted that compound (2) sometimes exhibits axial asymmetry and is obtained as a mixture of diastereomers, which can be used to make PG 2 Compound (2) with a protecting group or compound (2) is given a deprotection reaction, and the resulting compound is subjected to conventional resolution operations, such as resolution by ODS column chromatography or silica gel column chromatography, thereby isolating the individual diastereomers.

[0314] The deprotection reaction conditions used here are the same as those described in manufacturing method 1.

[0315] Additionally, for compound (18), it will be combined with LG 1 A significant portion of hydroxyl compounds are halogenated, which allows for the production of LG. 1 The compound is a halogenated compound. Examples of halogenating agents used herein are not particularly limited, but may include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, etc.

[0316] For example, the following references may be consulted as references for this reaction.

[0317] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 13, Maruzen, 2004

[0318] Furthermore, for compound (18), it will be related to LG 1A significant portion of hydroxyl compounds can be sulfonated in the presence of a base, thereby producing LG. 1 Compounds with a sulfonyl group. Examples of sulfonating agents used herein are not particularly limited, but may include, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. Examples of bases are not particularly limited, but may include, for example, TEA, DIPEA, pyridine, and tetramethylethylenediamine.

[0319] For example, the following references may be consulted as references for this reaction.

[0320] Synthesis 1999, 9, p.1633-1636

[0321] (Raw Material Synthesis 4)

[0322] (where R is in the formula) LG Indicate C 1-12 Alkyl group, n indicates 1 or 2.

[0323] This manufacturing method is a second method for manufacturing the raw material compound (16).

[0324] (First step)

[0325] This step involves reacting compound (10) with R. LG A method for producing compound (19) by in-situ substitution reaction of -SH. As used herein, R... LG Examples of -SH can be listed in C. 1-12 Alkyl mercaptans, such as ethanethiol and dodecyl mercaptan.

[0326] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0327] (Second Step)

[0328] This step involves reacting compound (19) with PG. 3 A method for producing compound (20) by in-situ substitution reaction of -OH. As used herein, PG 3 Examples of -OH include benzyl alcohol and p-methoxybenzyl alcohol.

[0329] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0330] (Step 3)

[0331] This step involves reacting compound (20) with R... 2 A method for producing compound (21) by the Suzuki-Miyaura coupling reaction of boric acid derivatives composed of boric acid groups, etc.

[0332] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0333] R 2 When the atom is hydrogen, compound (21) can be produced by the catalytic hydrogenation reaction of compound (20).

[0334] (Fourth step)

[0335] This step is a method for producing compound (22) by the Suzuki-Miyaura coupling reaction of compound (21) and compound (15).

[0336] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0337] (Step 5)

[0338] This step is a method for producing compound (23) by oxidation reaction of compound (22).

[0339] In this reaction, compound (22) is treated with an equal or excess amount of oxidant in a solvent inert to the reaction, under cooling to heating, preferably -20°C to 80°C, typically for 0.1 hours to 3 days. In this reaction, oxidation with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferred. Examples of solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidants include cumene hydrogen peroxide, potassium persulfate (Oxone), activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, etc.

[0340] [literature]

[0341] Edited by the Chemical Society of Japan, "Lectures on Experimental Chemistry", 5th edition, Volume 17, Maruzen, 2004

[0342] (Step Six)

[0343] This step is a method for producing compound (16) by in-situ substitution reaction of compound (23) and compound (24).

[0344] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0345] It should be noted that when compound (16) is axially asymmetric, it is obtained as a mixture of diastereomers, and each diastereomer can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography.

[0346] (Raw Material Synthesis 5)

[0347] This manufacturing method is a second method for manufacturing raw material compound (2).

[0348] (First step)

[0349] This step is a method for producing compound (25) by deprotection through the catalytic hydrogenation reaction of compound (23).

[0350] The reaction conditions are the same as those in step six of the synthesis of starting material 3.

[0351] (Second Step)

[0352] This step is a method for producing compound (26) by reacting compound (25) with compound (18).

[0353] The reaction conditions are the same as those in step seven of the synthesis of starting material 3.

[0354] (Step 3)

[0355] This step is a method for producing compound (2) by in-situ substitution reaction of compound (26) and compound (24).

[0356] The reaction conditions are the same as those in the first step of the synthesis of raw materials 3.

[0357] It should be noted that compound (2) sometimes exhibits axial asymmetry and is obtained as a mixture of diastereomers, which can be used to make PG 2 Compound (2) with a protecting group or compound (2) is given a deprotection reaction, and the resulting compound is subjected to conventional resolution operations, such as resolution by ODS column chromatography or silica gel column chromatography, thereby isolating the individual diastereomers.

[0358] The deprotection reaction conditions used here are the same as those described in manufacturing method 1.

[0359] (Raw Material Synthesis 6)

[0360] (where PG) 4 PG 5 (This indicates a protective base.)

[0361] This manufacturing method is a method for manufacturing raw material compound (3).

[0362] (First step)

[0363] This step is a method for producing compound (28) by amidation reaction of compound (7) and compound (27).

[0364] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0365] (Second Step)

[0366] This step is a method for producing compound (29) by subjecting compound (28) to a deprotection reaction.

[0367] The reaction conditions are the same as those described in manufacturing method 1.

[0368] (Step 3)

[0369] This step is a method for producing compound (31) by amidation reaction of compound (29) and compound (30).

[0370] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0371] (Fourth step)

[0372] This step is a method for producing compound (32) by subjecting compound (31) to a deprotection reaction.

[0373] The reaction conditions are the same as those described in manufacturing method 1.

[0374] (Step 5)

[0375] This step is a method for producing compound (3) by reacting compound (32) with a diazo transfer reagent.

[0376] In this reaction, compound (32) is treated with an equal or excess diazo transfer reagent in a solvent inert to the reaction, under cooling to heating, preferably from 0°C to 50°C, typically for 0.1 hours to 3 days. Examples of diazo transfer reagents are not particularly limited, but include, for example, trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or its salts, and 2-azido-1,3-dimethylimidazole. Examples of solvents include hexafluorophosphate (ADMP). Reactions can sometimes be carried out in the presence of organic bases such as TEA, 4-dimethylaminopyridine (DMAP), and 2,6-dimethylpyridine, and catalytic amounts of copper salts such as CuSO4. Examples of solvents include THF, halogenated hydrocarbons such as dichloromethane, MeCN, alcohols, water, and mixtures thereof.

[0377] [literature]

[0378] J. Org. Chem. 2012, 77, p.1760-1764

[0379] Nature 2019, 574, pp. 86-89

[0380] Org. Biomol. Chem. 2014, 12, p.4397-4406

[0381] (Raw Material Synthesis 7)

[0382] (where LG) 2 PG represents the leaving group. 6 (This represents the protecting group of NH.)

[0383] This manufacturing method is a method for manufacturing raw material compound (1)-2 or raw material compound (1)-3 contained in raw material compound (1). Here, L in the raw material compound (1)-3 is shown. 2 For NR L1 Methods for manufacturing pyrrolidine dimethyl, piperidine dimethyl, or piperazine dimethyl.

[0384] (First step)

[0385] This step is a method for producing compound (2)-1 by reacting compound (17) with compound (33).

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

[0387] (Second Step)

[0388] This step is a method for producing compound (2)-2 by hydrolyzing compound (2)-1.

[0389] The reaction conditions are the same as those in the second step of the synthesis of starting material 2.

[0390] (Step 3)

[0391] This step is a method for producing compound (1)-2 by amidation reaction of compound (32) with compound (2)-2.

[0392] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0393] (Fourth step)

[0394] This step is a method for producing compound (35) by amidation reaction of compound (32) and compound (34).

[0395] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0396] (Step 5, Step 6)

[0397] This step is a method for producing compound (1)-3 by reacting the compound obtained by the deprotection reaction of compound (35) with the amidation reaction of compound (2)-2.

[0398] The reaction conditions for the deprotection reaction are the same as those described in manufacturing method 1.

[0399] The reaction conditions for the amidation reaction are the same as those for the third step of the synthesis of starting material 2.

[0400] (Raw Material Synthesis 8)

[0401] (where Z is NH, A) 1 Represents a hydrogen atom and A 2 In the case where Z represents a halogen and A is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, then A represents a halogen. 1 When choosing groups from the group consisting of Cl, Br, and I, A 2 Indicating borate groups, etc., A 1 When it is a borate group, etc., A 2 This indicates a group selected from the group consisting of Cl, Br, and I.

[0402] This manufacturing method is a method for manufacturing raw material compound (1)-4.

[0403] (First step)

[0404] This step is a method for producing compound (38) by in-situ reaction of compound (36) and compound (37) or by Buchwald-Hartwig amination reaction when Z is NH.

[0405] The reaction conditions for the in-situ reaction are the same as those for the first step of the synthesis of raw materials 3.

[0406] For references regarding the Buchwald-Hartwig amination reaction, see, for example, the following literature.

[0407] J. Am. Chem. Soc., 2020, 142, p.15027-15037

[0408] In addition, this step is a method for producing compound (38) by the Suzuki-Miyaura coupling reaction of compound (36) and compound (37) when Z is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0409] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0410] Here, as a reference for the reaction when Z is Equation (V), for example, the following literature may be consulted.

[0411] J. Org. Chem., 2000, 65, p.1516-1524

[0412] Chemical Communications 2014, 50, p.1867-1870

[0413] Bioorg. Med. Chem. Lett., 2001, 11, p.2061-2065

[0414] (Second Step)

[0415] This step is a method for producing compound (39) by reacting compound (38) with compound (17).

[0416] The reaction conditions are the same as those in step seven of the synthesis of starting material 3.

[0417] Alternatively, this step can also produce compound (39) through the photoelongation reaction of compound (38) and compound (17).

[0418] For example, the following literature may be consulted as a reference for the photoelongation reaction.

[0419] Chem. Asian J. 2007, 2, p.1340 - 1355

[0420] (Step 3)

[0421] This step is a method for producing compound (40) by hydrolyzing compound (39).

[0422] The reaction conditions are the same as those in the second step of the synthesis of starting material 2.

[0423] (Fourth step)

[0424] This step is a method for producing compound (1)-4 by amidation reaction of compound (40) and compound (29).

[0425] The reaction conditions are the same as those in the third step of the synthesis of starting material 2.

[0426] (Raw Material Synthesis 9)

[0427] (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.)

[0428] 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).

[0429] (First step)

[0430] 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).

[0431] In this reaction, compounds (42) and (41) are used in equal or excess amounts, and their mixture is stirred for 0.1 hours to 5 days in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, at room temperature to reflux, preferably 20°C to 140°C. Examples of solvents used herein are not particularly limited, including ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolin-2-one, ethyl acetate, water, and mixtures thereof. Examples of bases include potassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Examples of palladium catalysts include tetratetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. Dichloromethane adducts, (1E,4E)-1,5-diphenylpentan-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, etc. Additionally, heating the mixture by microwave irradiation can sometimes be advantageous in facilitating the reaction.

[0432] For example, the following literature can be consulted as a reference for the reaction.

[0433] Synthesis 2020, 52, p.2521-2527

[0434] PNAS 2016, 113, pp. 7124-7129

[0435] Alternatively, for example, a method for producing compound (45) by reacting compound (42), which is a group selected from the group consisting of formulas (IX), (XX), (XXI), (XXII), and (XXIV), with compound (41) via a Ullman reaction.

[0436] For example, the following literature can be consulted as a reference for the reaction.

[0437] Angew. Chem. Int. Ed., 2003, 42, p.5400-5449

[0438] Additionally, this step is for A 3 When it is a carboxyl group, it is obtained through, for example, R 7 A method for producing compound (45) by decarbonation coupling reaction of compound (42) of formula (VII) and compound (41).

[0439] For example, the following literature can be consulted as a reference for the reaction.

[0440] Science, 2006, 313, pp. 662-664

[0441] 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).

[0442] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0443] (Second Step)

[0444] This step is a method for producing compound (43) by replacing the bromine group of compound (41) with a borate group or the like.

[0445] For example, the following literature can be consulted as a reference for the reaction.

[0446] Eur. J. Med. Chem., 2019, 162, p.407-422

[0447] J. Org. Chem. 2020, 85, 16, p.10966-10972

[0448] J. Am. Chem. Soc., 2010, 132, p.17701-17703

[0449] (Step 3)

[0450] 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.

[0451] The reaction conditions are the same as those in the fourth step of the synthesis of raw materials 3.

[0452] 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).

[0453] For example, the following literature can be consulted as a reference for the reaction.

[0454] Adv. Synth. Catal. 2020, 362, p.3311-3331.

[0455] (Fourth step)

[0456] This step is a method for preparing compound (7) by subjecting compound (45) to a deprotection reaction.

[0457] The reaction conditions are the same as those described in manufacturing method 1.

[0458] Compounds of formula (I) can be isolated and purified as free compounds, their salts, hydrates, solvates, or polymorphs or amorphous solids. Salts of compounds of formula (I) can also be prepared by salt-forming reactions using conventional methods.

[0459] Separation and purification can be carried out using common chemical operations such as extraction, fractional crystallization, and various fractionation chromatography.

[0460] Various isomers can be produced by selecting appropriate starting material compounds, or they can be separated by utilizing the differences in physicochemical properties between the isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., stepwise crystallization guided by diastereomeric salts of optically active bases or acids, chromatography using chiral columns, etc.), or they can be produced from appropriate optically active starting material compounds.

[0461] In addition, compounds of formula (I) or their intermediates sometimes have axial asymmetry and are obtained as a mixture of diastereomers, which can be isolated by conventional resolution operations, such as resolution using octadecylsilane (ODS) column chromatography or silica gel column chromatography.

[0462] The pharmacological activity of the compounds of formula (I) was confirmed by the following tests.

[0463] Example 1-1 Evaluation of KRAS degradation in human G12D mutant KRAS-positive pancreatic cancer cell line AsPC-1

[0464] The expression level of KRAS G12D was determined by sandwich ELISA to evaluate the KRAS decomposition effect of the tested compound.

[0465] AsPC-1 cells (ATCC, CRL-1682) were planted at a density of 1.8 x 10⁻⁶ cells per well. 4 90 μL of cells were seeded in each well of a 96-well plate (IWAKI). Cell culture conditions were performed at 37°C in the presence of 5% CO2 using RPMI 1640 medium (Merck) containing 10% fetal bovine serum (Cytiva).

[0466] The following day, the compound to be tested (final concentration in the range of 10 μM to 0.3 nM, 10 spots) was diluted 100-fold with fresh culture medium, and 10 μL was added to each well. The same treatment was performed on 4 wells each time. In addition, when preparing sandwich ELISA plates, 20 μL of capture antibody (anti-KRAS antibody, LS Bio) diluted 1000-fold in phosphate-buffered saline [PBS; Fujifilm and Koden Chemical Co., Ltd.] was added to each well of a MaxiSorp 384-well plate (Thermo Scientific), sealed, and incubated overnight at 4°C.

[0467] Twenty-four hours after treatment with the test compound, the culture supernatant was discarded, and 50 μL of cell lysis buffer (prepared by adding 1 / 100 and 1 / 500 of a Halt protease phosphatase inhibitor mixture [Thermo Scientific] and Benzonase nuclease [Merck] to RIPA buffer [Thermo Scientific]) was quickly added to each well to lyse the cells. The four wells treated in the same way were then combined into one well to prepare a total of 200 μL of cell lysate sample. For KRAS assay, MaxiSorp 384-well plates treated with capture antibodies from the previous day were washed twice with PBS (Thermo Scientific; 20x PBS Tween-20 diluted 20-fold with deionized water) containing 0.05% Tween-20 (25 μL each time). After treatment with blocking buffer (Intercept Blocking Buffer; LI-CORBiosciences) for 60 minutes, 20 μL of cell lysate sample was added to each well. In the β-actin assay, 20 μL of cell lysate sample was added directly to each well of a MaxiSorp 384-well plate, sealed, and left to stand overnight at 4°C.

[0468] The following day, after washing the KRAS detection plate with PBS containing 0.05% Tween-20, 20 μL of anti-Ras (G12D Mutant Specific) antibody (Cell Signaling Technology) diluted 1000-fold with blocking solution was added to each well, and the plate was incubated at room temperature for 5 hours. Afterward, the plate was centrifuged to remove the supernatant (using a centrifuge-type dehydrator; the supernatant was removed using the same method below). After washing with PBS containing 0.05% Tween-20, 20 μL of anti-rabbit IgG HRP binding antibody (Cell Signaling Technology) diluted 1000-fold with blocking solution was added to each well, and the plate was incubated at room temperature for 1 hour. After centrifuging the plates to remove the supernatant, the plates were washed with PBS containing 0.05% Tween-20. 20 μL of BM chemiluminescent ELISA substrate (Merck) was added to each well, and the luminescence intensity was measured using a 2103 EnVision (PerkinElmer) scanner. Separately, the β-actin detection plates were washed with PBS containing 0.05% Tween-20 and treated with blocking solution for 60 minutes. 20 μL of anti-β-actin antibody (Abcam) diluted 1000-fold with blocking solution was added to each well as the detection antibody, and the plates were incubated at room temperature for 5 hours. Afterward, the plates were centrifuged to remove the supernatant, washed with PBS containing 0.05% Tween-20, and 20 μL of anti-mouse IgG HRP binding antibody (Cell Signaling Technology) diluted 1000-fold with blocking solution was added to each well as the secondary antibody, and the plates were incubated at room temperature for 1 hour. Afterwards, the plate was centrifuged to remove the supernatant, washed with PBS containing 0.05% Tween-20, and 20 μL of BM chemiluminescent ELISA substrate was added to each well. The luminescence intensity was measured using EnVision.

[0469] The signal value corrected for β-actin levels upon DMSO addition was set to 100%, and the signal value upon addition of 10 μM of the compound in Example No. 7 was set to 0%. The 50% decomposition value (DC) of KRAS was calculated using a sigmoid-Emax model nonlinear regression analysis. 50 The molecular weight of the tested compound was calculated in the form of the molecular weight of the non-salt-forming free body, as described in Example No. 22: dihydrochloride, Examples No. 2-7, 9-12 and 14-18: trihydrochloride, Example No. 19: tetrahydrochloride, Example No. 21: pentahydrochloride, and other Example No.: free body without salt formation.

[0470] The results for several compounds tested using formula (I) are shown in Table 1.

[0471] [Table 1]

[0472] Experimental Examples 1-2: Evaluation of KRAS degradation in human G12D mutant KRAS-positive pancreatic cancer cell line AsPC-1

[0473] The expression level of KRAS G12D was measured by cell ELISA to evaluate the KRAS degradation effect of the tested compound.

[0474] AsPC-1 cells were spaced at 2.0 x 10⁶ cells per well. 4 20 μL of cells were seeded in each well of a 384-well plate (Greiner bio-one). Cell culture conditions were performed using RPMI 1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[0475] The following day, the test compound (final concentration in the range of 10 μM to 0.3 nM, 10 spots), the compound of Example No. 26 (Example No. 8 in Examples No. 74 and 75) with a final concentration of 10 μM as a positive control, and the solvent DMSO of the test compound as a negative control were diluted 500 times with fresh culture medium. 20 μL was added to each well and incubated overnight.

[0476] The following day, after removing the culture supernatant, 20 μL of 4% paraformaldehyde phosphate buffer (Fujifilm and Koden Chemical Co., Ltd.) was added to each well, and the cells were fixed by incubation at room temperature for 30 minutes. Then, the supernatant was removed, and 20 μL of PBS containing 0.1% Triton X-100 (Amersham Biosciences) was added to each well. After incubation at room temperature for 10 minutes, the supernatant was removed, and 25 μL of PBS was added to each well, followed by washing. This washing process was repeated twice. Next, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) was added to each well. After incubation at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifuge-type dehydrator; the same method was used to remove the supernatant below), and 25 μL of PBS was added to each well, followed by washing. This washing process was repeated twice. Remove the supernatant by centrifugation, and add 20 μL of the blocking buffer to each well. After standing at room temperature for 30 minutes, remove the supernatant by centrifugation, and add 20 μL of the solution containing the anti-Ras (G12D Mutant Specific) antibody and anti-β-actin antibody diluted 1000-fold with the blocking buffer to each well. Incubate overnight at 4°C.

[0477] The following day, the plate was centrifuged to remove the supernatant. 25 μL of PBS was added to each well, and the supernatant was removed again to wash each well. This washing process was repeated twice. After centrifugation to remove the supernatant, 20 μL of a blocking solution containing donkey anti-mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) and goat anti-rabbit IgG H&L (IRDye 800CW) (Li-COR Biosciences) diluted 1000-fold was added to each well. After standing at room temperature for 1 hour, the supernatant was removed. 25 μL of PBS was added to each well, and the supernatant was removed again to wash each well. This washing process was repeated twice. After centrifugation to remove the supernatant, the plate was air-dried at room temperature for at least 2 hours. Fluorescence signals at 700 nm and 800 nm were measured using an Aerius microscope (Li-COR Biosciences).

[0478] The signal value corrected for β-actin with the addition of DMSO was set to 100%, and the signal value with the addition of 10 μM of the compound in Example No. 26 was set to 0%. The 50% decomposition value (DC) of KRAS was calculated by nonlinear regression analysis using the Sigmoid-Emax model. 50The molecular weight of the tested compounds was calculated in the form of the molecular weight of Example No. 30: trihydrochloride, Example No. 46: tetrahydrochloride, and other Example Nos.: free bodies that did not form salts. The results for several tested compounds of formula (I) are shown in Table 2.

[0479] [Table 2]

[0480] Example 2: Evaluation of the inhibitory effect on ERK phosphorylation in the human G12D mutant KRAS-positive pancreatic cancer cell line AsPC-1

[0481] The phosphorylation of threonine (Thr202) and tyrosine (Tyr204) at position 202 of ERK, located downstream of the KRAS signal, was measured by cell ELISA to evaluate the inhibitory effect of the tested compound on ERK phosphorylation.

[0482] AsPC-1 cells were spaced at 2.0 x 10⁶ cells per well. 4 Cells were seeded at 36 μL / well in 384-well plates (Greinerbio-one). Culture conditions were performed using RPMI 1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[0483] The following day, the test compound (final concentration ranging from 10 μM to 3.0 nM, 6 spots), trametinib (MEK inhibitor) at a final concentration of 1 μM as a positive control, and DMSO as a solvent for the test compound as a negative control were diluted 100-fold with fresh culture medium. 4 μL of each solution was added to each well, and the cells were incubated for 24 hours. Immediately after incubation, 30 μL of 30% glyoxal solution (prepared by diluting 40% glyoxal [Nacalai Tesque] with PBS) was added to each well, and the cells were fixed by incubation at room temperature for 90 minutes. The plates were then centrifuged to remove the supernatant (using a centrifugal dehydrator; the same method was used to remove the supernatant below). 20 μL of PBS containing 0.1% Triton X-100 was added to each well. After incubation at room temperature for 10 minutes, the supernatant was removed by centrifugation, and this process was repeated. Next, add 20 μL of PBS containing 0.5% SDS to each well, incubate at room temperature for 30 minutes, and then centrifuge to remove the supernatant. Then, add 20 μL of blocking buffer to each well and incubate at room temperature for 1 hour. Remove the supernatant by centrifugation, and add 10 or 15 μL of the phosphorylated antibody (Phospho-p44 / 42MAPK(Erk1 / 2)(Thr202 / Tyr204)(D13.14.4E)XP rabbit mAb; Cell Signaling Technology) diluted 2500-fold with blocking buffer to each well, and incubate overnight at 4°C.

[0484] The following day, the plate was centrifuged to remove the supernatant. 50 μL of PBS containing 0.05% Tween-20 was added to each well, and the supernatant was removed by centrifugation. This washing process was repeated three times. After washing, 15 μL of goat anti-rabbit IgG H&L (IRDye 800CW), diluted 1000 times with blocking solution, was added to each well as the secondary antibody. The plate was incubated at room temperature for 1 hour. The plate was centrifuged to remove the supernatant. The primary antibody was reacted with PBS containing 0.05% Tween-20, and the wells were washed three times in the same manner. After centrifugation to remove the supernatant, the plate was air-dried at room temperature for at least 3 hours. The fluorescence signal at 800 nm was measured using Aerius.

[0485] The signal value when DMSO was added was set to 100%, and the signal value when 1 μM trametinib was added was set to 0%. The 50% inhibition value (IC50) was calculated using a sigmoid-Emax model nonlinear regression analysis. 50The molecular weight of the tested compounds was calculated in the form of molecular weight for Example No. 22: dihydrochloride, Examples No. 2-7, 9-12, 14-18 and 30: trihydrochloride, Examples No. 19 and 46: tetrahydrochloride, Example No. 21: pentahydrochloride, and other Example No.: free bodies without salt formation. The results for several tested compounds of Formula (I) are shown in Table 3.

[0486] [Table 3]

[0487] Example 3: Evaluation of the cell adhesion-independent inhibitory effect on the human G12D mutant KRAS-positive pancreatic cancer cell line AsPC-1.

[0488] The adhesion-independent cell proliferation inhibition effect of the tested compound was evaluated by spherical three-dimensional culture.

[0489] AsPC-1 cells were spaced at 5 x 10 cells per well. 2 Cells were seeded at 36 μL / well in 384-well U-shaped plates with low cell adsorption (PrimeSurface: Sumitomo Bakelite Co., Ltd.). Cell culture was performed under the same conditions as in Experiment 2.

[0490] The following day, the test compound (final concentration ranging from 10 μM to 3.0 nM, 6 spots) and the solvent DMSO (used as a negative control) were diluted 100-fold with fresh culture medium, and 4 μL was added to each well. After incubation at 37°C in the presence of 5% CO2 for 6 days, 20 μL of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring for 1 hour at room temperature using a plate mixer (FINEPCR), the luminescence signal was measured using ARVO X3 (PerkinElmer).

[0491] The signal value during DMSO treatment was set to 100%, and the signal value in the absence of cells and culture medium alone was set to 0%. The 50% inhibition value (IC50) was calculated using nonlinear regression analysis with the Sigmoid-Emax model. 50 The molecular weight of the tested compounds was calculated in the form of molecular weights for Example No. 22: dihydrochloride, Examples No. 2-7, 9-12, 14-18 and 30: trihydrochloride, Examples No. 19 and 46: tetrahydrochloride, Example No. 21: pentahydrochloride, and other Example No.: free bodies without salt formation. The results for several tested compounds of Formula (I) are shown in Table 4.

[0492] [Table 4]

[0493] Example 4: Evaluation of the antitumor effect of human G12D mutant KRAS-positive pancreatic cancer cell line PK-59 in tumor-bearing mice.

[0494] PK-59 cells (RIKEN BRC, RCB1901) were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. PK-59 cells were recovered, resuspended in PBS, and an equal volume of Matrigel (Becton, Dickinson, and Company) was added to prepare 1.0 x 10⁻⁶ cells. 7 ~2.0x10 7 Cells / mL, the resulting cell suspension was implanted into 4-6 week old male nude mice (CAnN.Cg-Foxn1) at a volume of 100 μL. nu / CrlCrlj (nu / nu), Charles River Laboratories Japan) Subcutaneous implantation. Approximately 2 weeks after implantation, the tumors were grouped in a manner where the tumor volume and body weight were approximately the same across groups, and the test compound was administered starting the following day. The experiment was conducted with 5 mice in each of the solvent group and the test compound administration group. The compounds of Examples 8, 48, and 70 were dissolved in a solvent with a volume ratio of 4:84.4:1.1:1:9:0.5, consisting of ethanol (Fujifilm and Koichi Chemical), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Chemical), 50% (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) aqueous solution (ROQUETTE), HCO-40 (Nikko Chemical), and 1M sodium hydroxide aqueous solution (Kanto Chemical). The compounds of Examples 22 and 26 were dissolved in a solvent containing propylene glycol (Fujifilm and Koichi Chemical), Tween 80 (Nacalai Tesque), and Otsuka saline (Otsuka Pharmaceutical) at a volume ratio of 6.7:3.3:90. The compound of Example 39 was dissolved in a solvent containing propylene glycol, ethanol, 50% HP-βCD aqueous solution, HCO-40, and 5% glucose solution at a volume ratio of 10:8:10:10:62. The test compound or solvent dissolved in each solvent was administered intravenously via the tail vein. Administration was twice weekly. Tumor diameter and body weight were measured twice weekly. Tumor volume was calculated using the following formula.

[0495] Tumor volume (mm) 3 [[Tumor's long diameter (mm)] x [Tumor's short diameter (mm)]] 2 x 0.5

[0496] The tumor proliferation inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound administration group one day before the start of administration to 100% inhibition and the tumor volume of the solvent group two weeks after the first administration to 0% inhibition. Additionally, when the tumor volume of the test compound administration group was lower than the tumor volume one day before the start of administration, the tumor volume one day before the start of administration was set to 0% shrinkage, and 0% tumor volume was set to 100% shrinkage, and the tumor shrinkage rate (%) of the test compound was calculated. The molecular weight of the test compound was calculated in the form of the molecular weight of Example No. 22: dihydrochloride, and Example Nos. other than those mentioned above: free bodies without salt formation. The results for several test compounds of formula (I) are shown in Table 5.

[0497] [Table 5]

[0498] Example 5: Evaluation of the inhibitory effect of KRAS G12D / SOS / c-Raf complex formation.

[0499] Using recombinant human KRAS G12D, SOS, and c-Raf proteins, the inhibitory effect of the tested compounds on the formation of complexes of these proteins was investigated by time-resolved fluorescence resonance energy transfer (TR-FRET).

[0500] Add 400 nM (2.5 μL) of biotinylated AviTag-KRAS G12D (amino acid regions 1-185, GDP) dissolved in analytical buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, pH 7.0) and the target compound to a 384-well plate (Corning) at a volume of 2.5 μL. Then add c-Raf (amino acid regions 51-131) GST (2.5 μL; 130 nM) containing Son of Sevenless (SOS) (amino acid regions 564-1049, 2.5 μL; 1.3 μM) and GTP (Sigma-Aldrich, 2 μM) to the plate and incubate at room temperature for 1 hour. Subsequently, a mixture (10 μL) of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (PerkinElmer; 100 ng / mL) was added, and the fluorescence intensity at 620 nm and 665 nm was measured using an EnVision 2104 (PerkinElmer) at an excitation wavelength of 337 nm. After normalizing the values ​​to the fluorescence intensity at a reference wavelength of 620 nm, the signal value during solvent treatment was set as 0% inhibition, and the signal value without GTP was set as 100% inhibition. The 50% inhibition concentration (IC50) was calculated using a sigmoid-Emax model nonlinear regression analysis. 50 ).

[0501] The results of the above experiments confirmed the G12D mutant KRAS degradation effect on several compounds of formula (I) (Examples 1-1 and 1-2). Furthermore, the G12D mutant KRAS inhibitory effect was confirmed (Example 5). Moreover, the phosphorylation inhibition effect of ERK, located downstream of the KRAS signal, was confirmed on several compounds of formula (I) (Example 2). Additionally, the cell proliferation inhibition effect on human G12D mutant KRAS-positive pancreatic cancer cells was confirmed on several compounds of formula (I) (Example 3), and the antitumor effect in tumor-bearing mice with human G12D mutant KRAS-positive pancreatic cancer cells was confirmed (Example 4). Therefore, compounds of formula (I) can be used for the treatment of pancreatic cancer, especially G12D mutant KRAS-positive pancreatic cancer.

[0502] Pharmaceutical compositions containing one or more of the compounds of formula (I) or their salts as active ingredients can be prepared by commonly used methods using excipients, pharmaceutical excipients or pharmaceutical carriers, etc., commonly used in the art.

[0503] Administration can be performed orally using tablets, pills, capsules, granules, powders, liquids, etc., or via non-oral methods such as intra-articular, intravenous, intramuscular, or intra-articular administration, including injections, transmucosal agents, inhalers, etc.

[0504] As a solid composition for oral administration, tablets, powders, granules, etc., can be used. In such a solid composition, one or more active ingredients are mixed with at least one inert excipient. The composition may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar coating or a film of gastric-soluble or enteric-soluble substances as needed.

[0505] Liquid compositions intended for oral administration contain pharmaceutically acceptable emulsifiers, solutions, suspending agents, syrups, or elixirs, and contain commonly used inert diluents such as purified water or EtOH ethanol. In addition to inert diluents, the liquid composition may also contain solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0506] Injectable preparations intended for non-oral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as EtOH. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. They are sterilized, for example, by filtration through a bacterial trap, by the addition of a bactericide, or by irradiation. Alternatively, they can be formulated as sterile solid compositions and dissolved or suspended in sterile water or sterile solvents for injection before use.

[0507] Inhalers or nasal inhalers, or other mucosal preparations, can be made from solid, liquid, or semi-solid substances and can be manufactured using conventionally known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., can be appropriately added. Administration can be performed using suitable inhalation or blowing devices. For example, known devices or nebulizers, such as metered-dose inhalers, can be used to administer the compound alone or as a powder forming a mixture of formulations, or in combination with a pharmaceutically acceptable carrier in the form of a solution or suspension. Dry powder inhalers, etc., can be single- or multiple-dose inhalers that utilize dry powder or powder-containing capsules. Alternatively, they can be administered via pressurized aerosol sprays using suitable propellants, such as chlorofluorocarbons or carbon dioxide.

[0508] When administered orally, the daily dose is typically approximately 0.001–100 mg / kg, preferably 0.1–30 mg / kg, and more preferably 0.1–10 mg / kg per unit of body weight, administered once or divided into 2–4 doses. When administered intravenously, the daily dose is typically approximately 0.0001–10 mg / kg per unit of body weight, administered once daily or divided into multiple doses. Additionally, as a mucosal agent, the dose is typically approximately 0.001–100 mg / kg per unit of body weight, administered once daily or divided into multiple doses. The dosage can be appropriately determined considering symptoms, age, sex, etc., and according to individual circumstances.

[0509] Although the dosage form, administration site, type of excipient or additive may vary, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, or in one manner, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0510] The compound of formula (I) can be used in combination with various therapeutic or preventative agents for diseases for which the compound of formula (I) is believed to be effective. This combination may be administered simultaneously, or separately, continuously, or at desired intervals. Simultaneously administered formulations may be combination agents or separately formulated.

[0511] Example

[0512] The method for manufacturing compounds of formula (I) will be further described in detail below based on examples. It should be noted that the present invention is not limited to the compounds described in the following examples. Furthermore, the methods for manufacturing the starting material compounds are shown in the manufacturing examples. In addition, the method for manufacturing compounds of formula (I) is not limited to the manufacturing methods of the specific examples shown below; compounds of formula (I) can also be manufactured by combinations of these manufacturing methods or by methods obvious to those skilled in the art.

[0513] It should be noted that in this specification, the naming of compounds sometimes uses naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[0514] In addition, for convenience, the concentration in mol / L is expressed as M. For example, 1M sodium hydroxide aqueous solution means a 1 mol / L sodium hydroxide aqueous solution.

[0515] The “amorphous solid morphology” described in this specification includes two types: morphologies that do not show peaks in powder X-ray diffraction (XRD) patterns and morphologies with low crystallinity.

[0516] XRD was performed using Empyrean on a Cu tube with a tube current of 40 mA, a tube voltage of 45 kV, a step size of 0.013°, and a wavelength of [missing information]. The diffraction angle range (2θ) was measured under the condition of 2.5 to 40°.

[0517] Manufacturing Example 1

[0518] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was ice-cooled, and then DIPEA (240 mL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (48 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was 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 volume of approximately 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered off, and (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (123 g) was obtained in solid form.

[0519] Manufacturing Example 2

[0520] To a mixture of (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL), and DABCO (1.15 g), cesium carbonate (50.3 g) was added while stirring at room temperature, and the mixture was stirred overnight at room temperature under an argon atmosphere. Approximately 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was washed with water while filtering, and dried under reduced pressure overnight to obtain (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (32.8 g).

[0521] Manufacturing Example 5

[0522] Under an argon gas flow and ice cooling, the (1S,4S)-5-{7-bromo-8-fluoro-6-iodine-2-[( A mixture of 11.9 g of tert-butyl heptane-2-carboxylic acid, benzyl alcohol (2.37 g), and THF (40 mL) was added to tBuOK (2.54 g), and the mixture was stirred at this temperature for 1.5 hours. Ice water and a saturated aqueous solution of ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixture of hexane / ethyl acetate (6 / 1) was added to the resulting residue and stirred briefly. The precipitated solid was filtered off and dried to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodide-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (11.8 g).

[0523] Manufacturing Example 8

[0524] Under an argon atmosphere, (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodide-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropylboronic acid (1.27 g), potassium phosphate (5.67 g), PdCl2 (dppf) The mixture of CH2Cl2 (600 mg) was stirred at 100 °C for 3 hours. After the reaction mixture was allowed to cool naturally to room temperature, the solution was concentrated under reduced pressure. A saturated aqueous sodium chloride solution was added to the resulting residue, and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (3.8 g).

[0525] Manufacturing Example 11

[0526] (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (3.15 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-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 g) The mixture (mL) was degassed and purged with argon at room temperature with stirring, and then stirred at 100°C for 2.5 hours under an argon atmosphere. Water (approximately 150 mL) was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was 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) to obtain fractions containing (1) a mixture of low-polarity diastereomers (peak-1 and 2, with the same axial asymmetry) and (2) a mixture of high-polarity diastereomers (peak-3 and 4, with the same axial asymmetry). The fractions containing low-polarity diastereomer mixtures (peak-1,2, with the same axial asymmetry) were collected and obtained as foamy solids as (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 (1.42 g). Additionally, fractions containing a mixture of highly polar diastereomers (peak-3,4, with the same axial asymmetry) were collected and given as foamy solids as (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( [Alkyl-4-yl]oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.37 g). A mixture of low-polarity diastereomers was used in the subsequent reaction.

[0527] Manufacturing Example 14

[0528] (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-2-[( [2.2.1]-Heptane-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).

[0529] Manufacturing Example 22

[0530] 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).

[0531] Manufacturing Example 32

[0532] 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 (358 mg containing approximately 30% water) 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).

[0533] Manufacturing Example 34

[0534] 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 added to a solution of cesium carbonate (1.9 g) and DABCO (160 mg) 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).

[0535] Manufacturing Example 36

[0536] To (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( In a mixture of 10 g of tert-butyl 2-heptane-2-carboxylic acid and 150 mL of CH2Cl2, m-chloroperbenzoic acid (containing approximately 30% water, 3.3 g) was added under ice cooling, and the mixture was stirred at this temperature for 3 hours. Saturated aqueous solutions of sodium thiosulfate and 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 over 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 resulting 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, a saturated aqueous solution of ammonium chloride, 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 a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain fractions containing (1) a mixture of low-polarity diastereomers (peak-1 and 2, with the same axial asymmetry) and (2) a mixture of high-polarity diastereomers (peak-3 and 4, with the same axial 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.

[0537] Manufacturing Example 37

[0538] 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 being of the same axial asymmetry) and (2) a mixture of high-polarity diastereomers (peak-3 and 4, peak-3 and 4 being of the same axial asymmetry). The fraction containing the low-polarity diastereomers (peak-1 and 2, of 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)-oxapentane-3-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (346 mg). Additionally, fractions containing highly polar diastereomers (peak-3,4, 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.

[0539] Manufacturing Example 40

[0540] 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-prolylamide (2.30 g), sodium ascorbate (1.45 g), tert-butanol (35 mL), THF (35 mL), and water (35 mL) was stirred at room temperature 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).

[0541] Manufacturing Example 51

[0542] Under an argon atmosphere, the (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [2.2.1]-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-[(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 (1.1 g), THF (22 mL), tetrabutylammonium fluoride (1M THF solution, 2.57 g / mL) In a mixture of mL, acetic acid (90 μL) was added at room temperature, and the mixture was stirred at 60 °C for 15 hours. After naturally cooling to room temperature, ethyl acetate and a 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 a 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).

[0543] Manufacturing Example 52

[0544] 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 added to a mixture of 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).

[0545] Manufacturing Example 53

[0546] To (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [2,2,1]-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 (250 mg), 2,2-difluoroethyl trifluoromethanesulfonic acid (124 mg), and MeCN (3 mL) were mixed, and DIPEA (99 μL) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The residue was concentrated under reduced pressure, and purified by 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-( [196 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}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester.

[0547] Manufacturing Example 54

[0548] To a solution of (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-methylbutyrate (190 mg) in CH2Cl2 (12 mL), thionyl chloride (500 μL) was added under an argon atmosphere and ice-cooled, and the mixture was stirred at this temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and DMF (7 mL) and (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [alkyl-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[( [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).

[0549] Manufacturing Example 56

[0550] 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 with an aqueous sodium hydroxide solution (1 M, 2.5 mL), and stirred at room temperature for 3 days. After neutralization with hydrochloric acid (1 M, 2.5 mL) under ice-cooling, CHCl3 and water were added for separation, and the aqueous layer was extracted with CHCl3. The combined organic layers were dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the solution was 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).

[0551] Manufacturing Example 61

[0552] 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-(methoxycarbonyl)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 (3.97 g) was added to a solution of 1,2-dichloroethane (60 mL) at room temperature with trimethyltin hydroxide (IV) (3.35 g) and stirred at 80 °C for 18 hours. After naturally cooling to room temperature, hydrochloric acid (1 M, 60 mL) was added, and the mixture was extracted with CHCl3 / MeOH (9 / 1). The organic layer was washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-L-proline (3.26 g).

[0553] Manufacturing Example 63

[0554] To (4R)-1-[(2S)-2-(4-{4-[({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]phenyl]-1H-1,2,3-triazol-1-yl]-3-methylbutyryl]-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).

[0555] Manufacturing Example 66

[0556] (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).

[0557] Manufacturing Example 67

[0558] Add (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 (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'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.15 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate (0.27 g) and DOX (20 mL), water (4 The reaction mixture was stirred at room temperature for 5 hours at 90°C under an argon atmosphere, followed by degassing and argon purging. Then, it was stirred at 100°C for 7 hours. The reaction mixture, cooled to room temperature, was diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and 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 (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-[( [2.2.1]heptan-2-carboxylic acid tert-butyl ester (360 mg). The low-polarity diastereomer was used in the subsequent reaction.

[0559] Manufacturing Example 68

[0560] Under a nitrogen atmosphere, the (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[( In a DMF (5 mL) solution of [2.2.1]heptan-2-carboxylic acid tert-butyl ester (250 mg), cesium carbonate (180 mg) and chloro(methoxy)methane (35 μL) were added under ice cooling and stirred at room temperature for 15 hours.

[0561] Cesium carbonate (260 mg) and chloro(methoxy)methane (50 μL) were added under ice-cooling conditions, and the mixture was stirred further at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the mixture was concentrated under reduced pressure.

[0562] The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[3-fluoro-5-(methoxymethoxy)-2-methylphenyl]-2-[( [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (186 mg).

[0563] Manufacturing Example 69

[0564] Under an argon atmosphere, PdCl2 (dppf) was added to a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl ester (4.43 g), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (4.67 g), potassium carbonate (3.87 g), DOX (80 mL), and water (8 mL). CH2Cl2 (1.14 g) was stirred at 100 °C for 16 hours. After naturally cooling to room temperature, ethyl acetate was added, filtered through diatomaceous earth, 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) in solid form.

[0565] Manufacturing Example 71

[0566] Hydrogen chloride (4M DOX solution, 25.6 mL) was added to a solution of {(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl} tert-butyl carbamate (3.34 g) in CH2Cl2 (25 mL) and MeOH (25 mL) while cooling to -20 to -10 °C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]ethane-1-ol n hydrochloride (3.06 g) as a solid.

[0567] Manufacturing Example 73

[0568] To a mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethane-1-ol n-hydrochloride (3.43 g), (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.81 g), and DMF (40 mL), DIPEA (7.8 mL) was added under ice-cooling, followed by the addition of HATU (4.5 g) in small increments under ice-cooling. The mixture was stirred for 1 hour under ice-cooling and then at room temperature for 1 hour. Water, a saturated aqueous sodium chloride solution, and ethyl acetate were added under ice-cooling to separate the aqueous layer. The aqueous layer was extracted with ethyl acetate, followed by extraction with ethyl acetate / isopropanol (9 / 1). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5.01 g) as an oil.

[0569] Manufacturing Example 76

[0570] To a solution of (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5.01 g) in CH2Cl2 (35 mL) and MeOH (30 mL), hydrogen chloride (4M DOX solution, 28 mL) was added while cooling to -20 to -10 °C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazole-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolineamide n hydrochloride (4.71 g) as a solid.

[0571] Manufacturing Example 79

[0572] DIPEA (6.2 mL) was added to a mixture of (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (3.81 g), N-(tert-butoxycarbonyl)-L-valine (2.16 g), and DMF (45 mL). Then, HATU (3.61 g) was added in small increments under ice-cooling conditions, and the mixture was stirred for 1 hour under ice-cooling conditions, followed by stirring at room temperature for 1 hour. Water, a saturated aqueous sodium chloride solution, and ethyl acetate were added under ice-cooling conditions to separate the aqueous layer. The aqueous layer was extracted with ethyl acetate, followed by extraction with ethyl acetate / isopropanol (9 / 1). 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 give N-(tert-butoxycarbonyl)-L-valine-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-proline (4.43 g) as a solid.

[0573] Manufacturing Example 83

[0574] To a solution of N-(tert-butoxycarbonyl)-L-valinel-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide (4.43 g) in CH2Cl2 (35 mL) and MeOH (35 mL), hydrogen chloride (4M DOX solution, 20 mL) was added while cooling to -20 to -15 °C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give L-valinel-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolineamide n hydrochloride (4.21 g) as a solid.

[0575] Manufacturing Example 88

[0576] To a mixture of L-valinel-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}-L-prolinen hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), and MeCN (20 mL), 2-azido-1,3-dimethylimidazole was added dropwise over 10 minutes at a time while ice-cooled. A solution of hexafluorophosphate (1.06 g) in MeCN (5 mL) was stirred at ice temperature for 5 hours. Water, a saturated aqueous sodium chloride solution, and ethyl acetate were added to separate the aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (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-prolineamide (1.07 g) as a solid.

[0577] Manufacturing Example 93

[0578] To a mixture of L-valine methyl ester hydrochloride (1.96 g), MeCN (45 mL), and DIPEA (5 mL), methyl 4-bromo-2-(bromomethyl)benzoate (3.00 g) was added under water cooling. The mixture was slowly heated to 80 °C and stirred at 80 °C for 2 days. After naturally cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride 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 (CHCl3 / ethyl acetate) to give methyl (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-methylbutyrate (2.86 g) as a solid.

[0579] Manufacturing Example 94

[0580] Under an argon atmosphere, methyl (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-methylbutyrate (600 mg), potassium (2-trimethylsilyl)-ethoxymethyltrifluoroborate (876 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (151 mg), sodium carbonate (390 mg), DOX (9 mL), and water (1.8 mL) were added to palladium acetate (41 mg) at room temperature, and the mixture was stirred at 130 °C for 4 hours under microwave irradiation. After natural cooling to room temperature, ethyl acetate was added, and the mixture was filtered through diatomaceous earth and washed with ethyl acetate. Water was added to the filtrate, and the mixture was separated. The organic layer was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give the coupling reaction product (600 mg). Trifluoroacetic acid (2.1 mL) was added to a CH2Cl2 solution of the coupling reaction product under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give methyl (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-methylbutyrate (190 mg) as a solid.

[0581] Manufacturing Example 95

[0582] Under an argon atmosphere, ethyl 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol-1-yl]butyrate (190 mg), 4-bromobenzyl alcohol (100 mg), and PdCl2 (dppf) were added. A mixture of CH2Cl2 (45 mg) and potassium phosphate (227 mg) was added to a solution of DOX (2 mL) and water (0.4 mL), and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give ethyl 2-{4-[4-(hydroxymethyl)phenyl]-1H-pyrazol-1-yl}-3-methylbutyrate (157 mg) as an oil.

[0583] Manufacturing Example 96

[0584] Under an argon atmosphere, a solution of 4.4 mL of tetramethylpiperidine in 80 mL of THF was added dropwise with 15.2 mL of 1.57 M hexane solution under dry ice-MeOH refrigerant (-78 °C), and the mixture was stirred for 1 hour under ice-cooling. For the reaction mixture, a solution of 5.21 g of (3-bromo-5-fluorophenoxy)(tert-butyl)di(methyl)silane in 20 mL of THF was added under dry ice-MeOH refrigerant, and the mixture was stirred for 1 hour at this temperature. Iodomethane (2.2 mL) was added dropwise to the reaction mixture, and the mixture was stirred for 1 hour at this temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was stirred while heating to room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was extracted. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (5.13 g) as an oil.

[0585] Manufacturing Example 97

[0586] To a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl] tert-butyl carbamate (500 mg), N-methyl-2-nitrobenzenesulfonamide (376 mg), tri-n-butylphosphine (0.51 mL), and THF (7 mL), 1,1'-azobis(N,N-dimethylformamide) (353 mg) was added in small amounts at ice-cooled conditions, and the mixture was stirred at room temperature for 8 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give tert-butyl {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl} carbamate (667 mg) as a solid.

[0587] Manufacturing Example 98

[0588] Under an argon atmosphere, palladium acetate (29 mg) was added to a mixture of {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl} tert-butyl carbamate (665 mg), 4-methyl-1,3-thiazole (235 μL), potassium acetate (253 mg), and DMAc (13 mL), and the mixture was stirred at 100 °C for 16 hours. After naturally cooling to room temperature, ethyl acetate and water were added, and the insoluble matter was filtered through diatomaceous earth. The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl carbamate {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamate (268 mg) in solid form.

[0589] Manufacturing Example 99

[0590] Under an argon atmosphere, tert-butyl carbamate (130 mg), potassium carbonate (84 mg), and DMF (1.3 mL) were mixed with 4-tert-butylbenzenethiol (82 μL) at room temperature and stirred for 3 hours at room temperature. 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 water and a saturated 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 give tert-butyl carbamate (60 mg) as an oil.

[0591] Manufacturing Example 100

[0592] To a mixture of {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl} tert-butyl carbamate (55 mg) and THF (1 mL), formaldehyde (37% aqueous solution, 26 μL) was added under ice-cooling, and the mixture was stirred for 10 minutes under the same conditions. Sodium triacetoxyborohydride (67 mg) was then added, and the mixture was stirred at room temperature for 1 hour. After dilution with CHCl3, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was stirred briefly to separate the aqueous layer. The aqueous layer was extracted with CHCl3 / MeOH (5 / 1), and the combined organic layers were dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to give {(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl} tert-butyl carbamate (75 mg) as an oil.

[0593] Manufacturing Example 102

[0594] A mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl ester (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (2.05 g), potassium acetate (1.91 g), DOX (40 mL), and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred overnight at 100 °C under an argon atmosphere. The reaction solution, cooled naturally to room temperature, was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl carbamate {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]ethyl} as an oil (3.21 g).

[0595] Manufacturing Example 103

[0596] Under an argon atmosphere, palladium acetate (200 mg) was added to a mixture of {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]ethyl}carbamate (3.21 g), methyl 5-bromo-1,3-thiazolyl-4-carboxylic acid (2.6 g), potassium phosphate (3.8 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (730 mg), DOX (30 mL), and water (6 mL) at room temperature, and the mixture was stirred at 100 °C for 3 hours. After naturally cooling to room temperature, ethyl acetate was added, and the mixture was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazol-4-carboxylic acid (1.48 g) as a solid.

[0597] Manufacturing Example 104

[0598] Under a nitrogen atmosphere, diisobutylaluminum hydride (1M toluene solution, 11 mL) was added dropwise to a CH2Cl2 solution of methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazol-4-carboxylic acid (1.01 g) in 20 mL of nitrogen, and the mixture was stirred for 1 hour under ice-cooling. The reaction was stopped by adding MeOH under ice-cooling, followed by the addition of 60 mL of 10% sodium potassium tartrate aqueous solution and CHCl3, and stirring overnight. The aqueous layer was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. Water was added, and the mixture was extracted with CHCl3. The organic layer was 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 (CHCl3 / MeOH) to give [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazolyl-5-yl]phenyl}ethyl] tert-butyl carbamate (588 mg) in solid form.

[0599] Manufacturing Example 106

[0600] Boron trifluoride was added to a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl ester (1 g), 2,2-dimethoxypropane (3.3 mL), and acetone (15 mL). The diethyl ether complex (26 μL) was stirred at room temperature for 1 hour. TEA (66 μL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- tert-butyl 3-carboxylic acid ester (1.09 g).

[0601] Manufacturing Example 107

[0602] (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- tert-butyl 3-carboxylate (300 mg), 1,3- In a DOX (1.69 mL) solution of 183 mg of oxazolidin-2-one, copper iodide (I) (32 mg), racemic (1R,2R)-cyclohexane-1,2-diamine (20 μL), and potassium carbonate (290 mg) were added at room temperature. The mixture was stirred at 140 °C for 2 h under microwave irradiation, followed by stirring at 150 °C for 1 h. Ethyl acetate and water were added, and the mixture was filtered through diatomaceous earth. The solution was 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-]into-solid form. [[3-yl)phenyl]-1,3- tert-butyl 3-carboxylic acid ester (120 mg).

[0603] Manufacturing Example 109

[0604] To a THF (27 mL) solution of 1-(4-bromophenyl)-2-fluoroethyl ketone (2.7 g) and (S)-2-methylpropane-2-sulfinamide (3.03 g), tetraisopropyl titanate (11.1 g) was added, and the mixture was stirred at 40°C for 12 hours. BH3 was then added under ice-cooled conditions (0–5°C). The THF complex (1 M THF solution, 18.4 mL) was stirred for 2 hours. After the reaction was stopped by adding water, the mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give (S)-N-[(1R)-1-(4-bromophenyl)-2-fluoroethyl]-2-methylpropane-2-sulfinamide (3.2 g) as an oil.

[0605] Manufacturing Example 156

[0606] Under a nitrogen atmosphere, DIPEA (200 μL) was added to an ice-cooled CH2Cl2 solution (110 mg) of (4-ethynyl-3-fluorophenyl)methanol (2 mL), followed by methanesulfonyl chloride (80 μL). The reaction mixture was stirred overnight at room temperature, then water was added, and the mixture was extracted with CHCl3. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to give 4-(chloromethyl)-1-ethynyl-2-fluorobenzene (122 mg) as an oil.

[0607] Manufacturing Example 189

[0608] To a mixture of (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-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), (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-prolineamide (33 mg), copper iodide (I) (7 mg), and sodium ascorbate (21 mg) were added at room temperature, and the mixture was stirred at 50 °C for 3 hours. Ice, a 2% aqueous solution of disodium ethylenediaminetetraacetate, and a saturated aqueous solution of sodium chloride were injected into the reaction vessel. The mixture was extracted three times with CH2Cl2, and the combined organic layers were dried with anhydrous magnesium 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 obtain (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2-hydroxyethyl)amino]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (62) mg).

[0609] Manufacturing Example 238

[0610] Under an argon atmosphere, bis(tri-tert-butylphosphine)palladium(0) (18 mg) was added to 4-methyl-1,3- Azoxyl-5-carboxylic acid (178 mg), tetra-n-butylammonium chloride (195 mg), (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- A mixture of tert-butyl 3-carboxylate (250 mg), cesium carbonate (344 mg), and DMF (2.5 mL) was stirred at 170 °C for 30 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with ethyl acetate, and the insoluble matter was removed by filtration through diatomaceous earth. The filtrate was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-]into-solid form. [Azol-5-yl)phenyl]-1,3- tert-butyl 3-carboxylic acid ester (215 mg).

[0611] Manufacturing Example 239

[0612] (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- 858 mg of tert-butyl 3-carboxylic acid, 500 mg of 2-methyl-1H-imidazolium, 95 mg of copper iodide (I), 138 mg of quinoline-8-ol, and 670 mg of potassium carbonate were suspended in 10 mL of DMSO and reacted at 150 °C for 3 hours under argon atmosphere and microwave irradiation. 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 sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (4R)-2,2-dimethyl-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1,3- tert-butyl 3-carboxylic acid ester (500 mg).

[0613] Manufacturing Example 245

[0614] To a mixture of 235 g of 4-bromo-6-fluoro-1H-indazole, 183 mL of TEA, and 1880 mL of CH2Cl2, 335 g of 1,1',1''-(chloromethanetriyl)triphenyl (335 g) was added at room temperature, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was then poured into ice water (1.5 L), and the organic and aqueous layers were separated. The aqueous layer was extracted three times with CH2Cl2 (400 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was pulverized by adding 550 mL of petroleum ether (0°C, 2 hours), filtered, and dried under reduced pressure to give 508.98 g of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole as a solid.

[0615] Manufacturing Example 246

[0616] To a mixture of 100 g of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole and 100 mL of 2-methyltetrahydrofuran, lithium diisopropylamino (2 M THF solution, 214.28 mL) was added at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 h. Iodomethane (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 h. The reaction was stopped by adding water (2000 mL), and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was pulverized by adding ethyl acetate (50 mL) / petroleum ether (50 mL), filtered, and dried under reduced pressure to obtain 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) in solid form.

[0617] Manufacturing Example 247

[0618] Palladium acetate (4.52 g) was added to a mixture of 100 g of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole, 61.42 g of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (61.42 g), 10.57 g of triphenylphosphine, 59.34 g of potassium acetate, and 1000 mL of DOX at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and nitrogen-filled three times each, and then stirred at 100 °C for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added, and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layers were dried over anhydrous sodium sulfate, and insoluble matter was filtered off. Activated carbon (50 g) was added to the resulting solution, and the mixture was stirred at 20 °C for 1 hour, filtration occurring while washing three times with ethyl acetate (50 mL). The filtrate was concentrated, and methanol (200 mL) was added to the resulting residue to pulverize it. The residue was filtered and dried under reduced pressure to obtain 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) in solid form.

[0619] Manufacturing Example 248

[0620] (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethanesulfonyl)-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), and N-methyl-2-pyrrolidone (2 mL) were mixed and reacted at 130 °C for 30 min under microwave irradiation. The reaction solution was diluted with ice water and saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-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) in solid form.

[0621] Manufacturing Example 249

[0622] (1S,4S)-5-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [(2R,3R)-3-hydroxybutane-2-yl]oxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (75 mg) was mixed with 2 mL of dehydrated THF. Sodium hydride (55% mineral oil dispersion, 20 mg) was added while cooling and stirring in an ice-methanol bath under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. Iodomethane (20 μL) was added again while cooling and stirring in an ice-methanol bath, and the mixture was stirred overnight at room temperature using an argon-filled balloon in a sealed container. Ice and a saturated ammonium chloride aqueous solution were injected into the reaction vessel, and the mixture was extracted twice with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-(6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [(2R,3R)-3-methoxybutane-2-yl]-2-{[(2R,3R)-3-methoxybutane-2-yl]oxy}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (74 mg).

[0623] Manufacturing Example 252

[0624] MeOH (3 mL) was added to (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (211 mg). Then, 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added while stirring at room temperature, and the mixture was stirred for 1 hour at room temperature under an argon atmosphere. Ice and a saturated aqueous sodium bicarbonate solution were added to the reaction vessel, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (87) as a low-polarity diastereomer. (mg), in solid form, was obtained as the highly polar diastereomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (59 mg). The low-polarity diastereomer was used in subsequent reactions.

[0625] Manufacturing Example 281

[0626] DMF (25 mL) and triethylamine (3 mL) were added to (3R)-pyrrolidine-3-ol (1.7 g). 1-({[2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (4.5 g) was added in small amounts each time under an argon atmosphere and while cooling and stirring in an ice / methanol bath. The mixture was then stirred at this temperature under cooling and an argon atmosphere for 2 hours. The reaction mixture was diluted with ice water and extracted twice with ethyl acetate. The combined organic layers were washed successively with 1 M hydrochloric acid / ice water (1 / 1), water, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give (3R)-3-hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (3.6 g) as an oil.

[0627] 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.

[0628] Example 8

[0629] 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 tert-butyl heptane-2-carboxylic acid [2.2.1]heptane-2-carboxylic acid 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). 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 (3.01 g).

[0630] Example 7

[0631] The (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 (1.04 g) was dissolved in CH2Cl2 (9 mL) and MeOH (9 mL), and then hydrogen chloride (4M DOX solution, 3 mL) was added under ice cooling. The mixture was stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the resulting residue. The precipitated solid was filtered off and dried under reduced pressure to give (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 n hydrochloride (1.04 g).

[0632] Example 20

[0633] 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-(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-[( A mixture of [2.2.1]heptane-2-carboxylic acid tert-butyl ester (170 mg), CH2Cl2 (2 mL), and MeOH (2 mL) was added with hydrogen chloride (4 M DOX solution, 0.988 mL) under ice cooling, and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and CHCl3 and saturated sodium bicarbonate aqueous solution were added. After stirring briefly, the aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH (5 / 1), and the combined organic layers were dried over anhydrous sodium sulfate. After filtering off insoluble matter, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH), followed by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target analyte was collected, made alkaline with saturated sodium bicarbonate aqueous solution, and extracted twice with CHCl3 / MeOH (5 / 1). The combined organic layers were dried with anhydrous sodium sulfate. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure. The resulting solid was washed with diethyl 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]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-] [3-yl]phenyl]ethyl}-L-proline amide (74 mg).

[0634] Example 18

[0635] Under a nitrogen atmosphere, the (4R)-1-[(2S)-2-(4-{4-[({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-[( 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 (4M DOX solution, 0.5 mL) was added under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. 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).

[0636] Example 49

[0637] Under a nitrogen atmosphere, the following reaction is performed: (1S,4S)-5-(6-cyclopropyl-8-{[3-fluoro-4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazolyl-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-yl]-3-methyl-1-oxobutane-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]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 (158 mg) was dissolved in EtOH (2 mL) solution, and methanesulfonic acid (100 μL) was added at room temperature. The mixture was stirred at 50 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fraction containing the target analyte was added to a 5% sodium bicarbonate aqueous solution and extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layers were dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The process of adding EtOH to the residue to dissolve it and then concentrating it under reduced pressure was repeated twice. Add diethyl ether, filter out the resulting solid, wash with diethyl ether, and dry 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-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 (50 mg).

[0638] The manufacturing methods of the embodiments shown above were performed in the same manner to manufacture the compounds of the embodiments shown in Tables 102 to 126 below. Furthermore, the manufacturing methods and physicochemical data of each compound of the embodiments are shown in Tables 127 to 131 below.

[0639] Additionally, the following abbreviations are sometimes used in the tables described below.

[0640] PEx: Manufacturing example number, Ex: Example number, PSyn: Manufacturing example number manufactured by the same method, Syn: Example number manufactured by the same method (e.g., Syn: 8 indicates manufacturing by the same method as Example 8, Syn: 18# indicates desalting reaction as described in manufacturing method 1 on the hydrochloride obtained by the same method as Example 18), Str: Chemical structural formula (chemical structural formula containing " The "" indicates that the compound's axial asymmetry or central asymmetry is unique. n HCl: n hydrochloride (indicating that compounds with manufacturing example numbers are mono- to tri-hydrochloride, and compounds with example numbers are mono- to penta-hydrochloride), DAT: physicochemical data, ESI+: m / z value in mass spectrometry (ionization ESI, [M+H] if not declared). + ESI-: m / z value in mass spectrometry (ionization ESI, [MH] if not declared). - NMR: DMSO-d6 1 δ value (ppm) of the peak in H-NMR (500 MHz), NMR (100℃): DMSO-d6 at 100℃ 1 δ values ​​(ppm) of H-NMR (500 MHz) peaks, s: singlet (spectrum), d: doublet (spectrum), dd: doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum) (e.g., br s).

[0641]

[0642] Furthermore, as examples of specific compounds of formula (I) included in this invention, compounds having any of the structures described below are shown. These compounds can be manufactured by the representative manufacturing methods, manufacturing examples and embodiments shown above, or combinations of these manufacturing methods, or by methods obvious to those skilled in the art.

[0643] Furthermore, these compounds exhibit excellent ability to induce the degradation of G12D mutant KRAS protein and are expected to be useful as G12D mutant KRAS inhibitors, and can be used as active ingredients in pharmaceutical compositions, such as therapeutic pharmaceutical compositions for pancreatic cancer.

[0644]

[0645] Industrial availability

[0646] The compounds of the present invention or their salts have excellent effects in inducing the degradation of G12D mutant KRAS protein, are useful as G12D mutant KRAS inhibitors, and can be used as active ingredients in pharmaceutical compositions, such as therapeutic pharmaceutical compositions for pancreatic cancer.

Claims

1. Use of a compound of formula (I) or a salt thereof in the preparation of a medicament for the treatment of pancreatic cancer, In formula (I), R 1 The naphthyl group can be substituted with OH or a group selected from the group consisting of formulas (II) and (III) below: R 1a R 1b They may be the same or different from each other, and can be H, methyl, F, or Cl. R 1c It can be F, Cl, methyl, or ethyl. R 2 H, halogens, and substituted C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is a 7- to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms, either saturated or unsaturated. R 4 C can be replaced 1-6 Alkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or substituted 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms. R 5 C can be replaced 1-6 Alkyl groups, substituted C 3-6 Cycloalkyl groups or substituted 4- to 6-membered saturated heterocyclic groups containing one heteroatom selected from oxygen, sulfur, and nitrogen. R 6a R 6b The same or different from each other, for H or C that can be substituted. 1-6 Alkyl, or R 6a R 6b Together with the carbon atoms they are bonded to, they form substitutable C atoms. 3-6 Cycloalkyl or substituted 4- to 6-membered saturated heterocycles containing one heteroatom selected from oxygen, sulfur, and nitrogen. R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups, substituted 4- to 6-membered saturated heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen, substituted 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or 6-membered heteroaryl groups containing 1 to 3 nitrogen atoms, W can be a substituted phenyl group or a substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms. X represents a bond, CH2, O, S, or NR. 4x , R 4x For H or C 1-3 alkyl, Y is a phenylene or pyridinyl group, which may be substituted with F. L is -(L) 1 -L 2 -L 3 -L 4 )-, 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, R L1 For H or C 1-3 alkyl, Z is NH or a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. Alternatively, YLZ can be expressed as follows (XIII): 。 2. The use according to claim 1, wherein in formula (I), R 3 It is 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, L stands for bond, C 1-3 Alkylene, C=O, or a group selected from the group consisting of the following formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX): R L1 For H or C 1-3 alkyl, R L2 R L3 They may be the same as or different from each other, and may be H, F, OH, OCH3, or substituted C. 1-3 alkyl, R L For CH or N, n is an integer from 1 to 2. Z is NH or a group selected from the group consisting of the following formulas (V), (X), (XI), and (XII): 。 3. The use according to claim 2, wherein, Equation (I) is the same as the following equation (Ia): R 1 For example, the following formula (IIa) or formula (IIIa): R 1a R 1b They may be the same or different from each other, and can be H, methyl, F, or Cl. R 2 H, halogens, and substituted C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is the following formula (IV): R 4 C can be replaced 1-6 Alkyl, substituted oxetyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl R 5 It is methyl, ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 6a R 6b The same or different from each other, H or C 1-3 Alkyl, the C 1-3 Alkyl groups can be substituted with groups selected from the group consisting of F, OH, OCH3, and N(CH3)2, or R. 6a R 6b Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl, W 1 W 2 and R 7 : i. W 1 For CH, W 2 For C-SO2CH3, R 7 For H, or ii. W 1 W 2 The same or different from each other, namely CH, CF, CCl, CCH3 or N, R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups or groups selected from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV): R 7a R 7b The same or different from each other, is H or C that can be replaced by OH. 1-3 alkyl, X is O, S, or NR 4x , R 4x For H or C 1-3 alkyl, Y is a phenylene or pyridinyl group, which may be substituted with F. L stands for bond, C 1-3 Alkylene, C=O, or a group selected from the group consisting of the following formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX): R L1 For H or C 1-3 alkyl, R L2 R L3 They may be the same as or different from each other, and may be H, F, OH, OCH3, or substituted C. 1-3 alkyl, R L For CH or N, n is an integer from 1 to 2. Z is NH or a group selected from the group consisting of the following formulas (V), (X), (XI), and (XII): Alternatively, YLZ can be expressed as follows (XIII): 。 4. The use according to claim 3, wherein in formula (I), R 2 Halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, the C 1-3 Alkyl groups can be substituted from groups selected from the group consisting of OH and OCH3. R 4 C 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, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl X is either O or NH. L stands for bond, C 1-3 Alkylene, C=O, or a group selected from the group consisting of the following formulas (XIV) and (XVI): R L1 C 1-3 alkyl, R L2 R L3 For H, n is 1.

5. The use according to claim 4, wherein in formula (Ia), R 1 It is the following formula (IIa): R 1a For F, R 2 It is cyclopropyl. R 4 C that can be replaced by OCH3 1-6 Alkyl, tetrahydropyranyl, or piperidinyl that can be substituted with difluoroethyl, R 5 It is isopropyl. R 6a For H, R 6b C that can be replaced by OH 1-3 alkyl, R 7 The groups selected are those from the group consisting of the following formulas (VI), (VII), (VIII), and (IX): R 7a C that can be replaced by OH 1-3 alkyl, W 1 For CH, W 2 For CH, X is O. Y is a phenylene that can be substituted by F. L stands for bond. Z is the following expression (XI): 。 6. The use according to claim 1, wherein, Equation (I) is the same as the following equation (Ib): R 1 For example, the following formula (IIa) or formula (IIIa): R 1a R 1b If they are the same or different from each other, they are H or F. R 2 Halogen, C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is the following formula (IV): R 4 C 1-3 Alkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl R 5 It is ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 6a R 6b The same or different from each other, C is H or can be substituted by groups selected from the group consisting of F, OH and N(CH3)2. 1-3 Alkyl, or R 6a R 6b Together with the carbon atoms they are bonded to, they form cyclopropyl groups. R 7 It is H, a halogen, or a group selected from the group consisting of the following formulas (VI), (VII), (VIII), and (IX): R 7a H or C that can be replaced by OH 1-3 alkyl, X is O. Y is a phenylene or pyridinyl dimethyl group. L stands for bond, C 1-3 Alkylene or C=O Z is NH or a group selected from the group consisting of the following formulas (X), (XI), and (XII): Alternatively, YLZ can be expressed as follows (XIII): 。 7. Use of a pharmaceutical composition comprising a compound of formula (Ia) or a salt thereof and one or more pharmaceutically acceptable excipients in the preparation of a medicament for the treatment of pancreatic cancer. in, In the following formula (Ia): R 1 For example, Equation (IIa) or Equation (IIIa) below. R 1a R 1b They may be the same or different from each other, and can be H, methyl, F, or Cl. R 2 H, halogens, and substituted C 1-3 Alkyl, cyclopropyl, or vinyl, R 3 It is the following formula (IV), R 4 C can be replaced 1-6 Alkyl, substituted oxetyl, substituted tetrahydrofuranyl, substituted tetrahydropyranyl, substituted pyrazolyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrrolidinyl, or substituted piperidinyl R 5 It is methyl, ethyl, isopropyl, tert-butyl or C 3-6 cycloalkyl, R 6a R 6b The same or different from each other, H or C 1-3 Alkyl, the C 1-3 Alkyl groups can be substituted with groups selected from the group consisting of F, OH, OCH3, and N(CH3)2, or R. 6a R 6b Together with the carbon atoms they are bonded to, they form C 3-6 cycloalkyl, W 1 W 2 and R 7 : i. W 1 For CH, W 2 For C-SO2CH3, R 7 For H, or ii. W 1 W 2 The same or different from each other, namely CH, CF, CCl, CCH3 or N, R 7 H, halogen, C 1-3 Alkyl group, -SO2CH3, C 3-6 Cycloalkyl groups or groups selected from the group consisting of formulas (VI), (VII), (VIII), (IX), (XX), (XXI), (XXII), (XXIII), and (XXIV) below, R 7a R 7b The same or different from each other, is H or C that can be replaced by OH. 1-3 alkyl, X is O, S, or NR 4x , R 4x For H or C 1-3 alkyl, Y is a phenylene or pyridinyl group, which may be substituted with F. L stands for bond, C 1-3 Alkylene, C=O, or a group selected from the group consisting of formulas (XIV), (XV), (XVI), (XVII), (XVIII), and (XIX). R L1 For H or C 1-3 alkyl, R L2 R L3 They may be the same as or different from each other, and may be H, F, OH, OCH3, or substituted C. 1-3 alkyl, R L For CH or N, n is an integer from 1 to 2. Z is NH or a group selected from the group consisting of formulas (V), (X), (XI), and (XII). Alternatively, YLZ can be expressed as equation (XIII) below. 。

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