Heterocyclic compound acting on G12D mutant KRAS protein

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer. The inventors have studied a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer, and found that a heterocyclic compound represented by formula (I) has an excellent activity of inducing G12D mutant KRAS proteolysis and / or an excellent activity of inhibiting G12D mutant KRAS, and can be used as a therapeutic agent for pancreatic cancer, thereby completing the present invention. The heterocyclic compound or a salt thereof according to the present invention can be used as a therapeutic agent for pancreatic cancer.

Description

Technical Field

[0001] The present invention relates to pharmaceutical compositions and heterocyclic compounds that are excellent in inducing degradation of G12D mutant KRAS protein and / or useful as G12D mutant KRAS inhibitors and are expected to be useful as active ingredients of pharmaceutical compositions for treating pancreatic cancer, for example. Background Art

[0002] Pancreatic cancer, primarily pancreatic ductal adenocarcinoma, has a very poor prognosis, with a five-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, p. 7-30). Approximately 460,000 new cases are reported worldwide each year (CA Cancer J. Clin., 2018, 68, p. 394-424). Surgery is the most effective treatment for pancreatic cancer, but early detection is difficult and often metastases have already occurred, making surgical treatment ineffective. Chemotherapy and radiotherapy are options for non-surgical treatment, but these treatments have poor survival rates. Currently, FOLFRINOX therapy (a multidrug combination therapy that adds levofolinate to the three chemotherapy drugs 5-FU, irinotecan, and oxaliplatin) is the standard treatment for pancreatic cancer. However, due to its high toxicity, it is only prescribed to patients with an ECOG performance status of 1 or lower, requiring careful patient selection (J. Clin. Oncol., 2018, 36, pp. 2545-2556). While the epidermal growth factor receptor (EGFR) inhibitor erlotinib combined with gemcitabine has been approved as a molecular targeted therapy, overall survival is only extended by approximately two weeks compared to gemcitabine alone, resulting in insufficient efficacy. More effective treatments are still needed (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] RAS protein is a low molecular weight guanosine triphosphate (GTP) binding protein of about 21kDa composed of 188-189 amino acids. There are four main proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) produced by three genes: KRAS gene, NRAS gene, and HRAS gene. RAS protein exists as an active GTP-binding type and an inactive GDP-binding type. RAS protein is activated by exchanging guanosine diphosphate (GDP) with GTP due to ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to up to 20 effector proteins such as RAF, PI3K, and RALGDS to activate downstream signaling cascades. On the other hand, active RAS converts GTP into GDP through endogenous GTP hydrolysis (GTPase) activity, thereby becoming inactive. This GTPase activity can be enhanced by GTPase activating protein (GAP). Therefore, RAS serves 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).

[0004] When amino acid substitutions occur due to mutations in the RAS gene, RAS's GTPase function decreases, reducing its response to GAPs and leading to a persistently activated state, continuously transmitting signals downstream. This excessive signaling leads to carcinogenesis and hyperplasia of the tumor. Pancreatic ductal adenocarcinoma is said to develop as pancreatic intraepithelial neoplasia (PanIN) progresses from a weaker stage of dysplasia to a more intense stage. KRAS gene mutations can be seen in PanIN in the early stages. Subsequently, abnormalities in the tumor suppressor genes INK4A, p53, and SMAD4 lead to malignant transformation (Nature Rev. Cancer, 2010, 10, pp. 683-695). Furthermore, mutations in the KRAS gene are found in over 90% of pancreatic ductal adenocarcinomas, with point mutations located at codon 12 of KRAS exon 2 accounting for the majority (Cancer Cell 2017, 32, pp. 185-203). Therefore, KRAS plays an important role in the carcinogenesis and progression of pancreatic cancer.

[0005] Known KRAS gene mutations include KRAS G12C and KRAS G12D. While G12C KRAS mutations are more common in non-small cell lung cancer, they are present in only a few percent of pancreatic cancers (Cancer Cell 2014, 25, pp. 272-281). There is a growing demand for therapeutic drugs targeting other KRAS mutations. G12D KRAS mutations are reported to be present in approximately 34% of pancreatic cancers, the highest rate among KRAS mutations (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0006] Patent Documents 1, 2, and 3 disclose RAS inhibitors, with Patent Documents 2 and 3 disclosing compounds represented by the following formulas (A) and (B), respectively. Patent Documents 1, 2, and 3 describe their effectiveness against cancers harboring KRAS codon 12 mutations, including the G12D mutation, but do not describe their effectiveness against G12D-mutated KRAS-positive cancers.

[0007]

[0008] In addition, Patent Documents 9, 10, 11, 12, 13, 14, 15, and 16 disclose KRAS G12D inhibitors.

[0009] In recent years, as a technology to induce the decomposition of target proteins, bifunctional compounds collectively referred to as PROTAC (PROteolysis-TArgeting Chimera, protein degradation targeting chimera), SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser, specific and non-genetic IAP-dependent protein eraser), etc. have been discovered, which are expected to be one of the new drug development models (Drug. Discov. Today Technol., 2019, 31, p15-27). Bifunctional compounds promote the formation of a complex between the target protein and the E3 ligase in the cell, and induce the decomposition of the target protein by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein decomposition mechanisms in the cell. Proteins called E3 ligases recognize proteins to be decomposed and ubiquitinate them, thereby promoting decomposition in the proteasome.

[0010] There are more than 600 E3 ligases in the body, which can be roughly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, there are limited E3 ligases used for bifunctional decomposition inducers such as PROTAC and SNIPER. Representative examples include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog 2 (mouse double minute 2 homolog, MDM2), etc. In particular, Patent Document 4 reports on VHL, and Patent Document 5 reports on CRBN.

[0011] Bifunctional compounds are compounds formed by linking a ligand of a target protein and a ligand of an E3 ligase with a linker. Bifunctional compounds that degrade KRAS proteins have been reported previously (Non-Patent Document 1, Non-Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 12, Patent Document 17). Furthermore, Patent Document 18 and Patent Document 19 report bifunctional compounds that reduce the level of G12D mutant KRAS protein, and Patent Document 20, Patent Document 21, and Patent Document 22 report quinazoline compounds for inducing the degradation of G12D mutant KRAS protein. However, at present, there are no reports suggesting that bifunctional compounds degrade G12D mutant KRAS protein except for Patent Documents 18 to 22.

[0012] Prior art literature

[0013] Patent Literature

[0014] Patent Document 1: International Publication No. 2016 / 049565

[0015] Patent Document 2: International Publication No. 2016 / 049568

[0016] Patent Document 3: International Publication No. 2017 / 172979

[0017] Patent Document 4: International Publication No. 2013 / 106643

[0018] Patent Document 5: International Publication No. 2015 / 160845

[0019] Patent Document 6: U.S. Patent Application Publication No. 2018 / 0015087

[0020] Patent Document 7: International Publication No. 2019 / 195609

[0021] Patent Document 8: International Publication No. 2020 / 018788

[0022] Patent Document 9: International Publication No. 2021 / 041671

[0023] Patent Document 10: International Publication No. 2021 / 106231

[0024] Patent Document 11: International Publication No. 2021 / 107160

[0025] Patent Document 12: International Publication No. 2022 / 002102

[0026] Patent Document 13: International Publication No. 2022 / 015375

[0027] Patent Document 14: International Publication No. 2022 / 098625

[0028] Patent Document 15: International Publication No. 2022 / 105855

[0029] Patent Document 16: International Publication No. 2022 / 031678

[0030] Patent Document 17: International Publication No. 2021 / 207172

[0031] Patent Document 18: International Publication No. 2022 / 148421

[0032] Patent Document 19: International Publication No. 2022 / 148422

[0033] Patent Document 20: International Publication No. 2022 / 173032

[0034] Patent Document 21: International Publication No. 2022 / 228576

[0035] Patent Document 22: International Publication No. 2023 / 280026

[0036] Non-patent literature

[0037] Non-patent literature 1: Cell. Chem. Biol., 2020, 27, pp. 19-31

[0038] Non-patent literature 2: ACS Cent. Sci., 2020, 6, p1367-1375 Summary of the Invention

[0039] Problems to be solved by the invention

[0040] Provided are pharmaceutical compositions, for example, heterocyclic compounds that have an excellent effect of inducing degradation of G12D mutant KRAS protein and / or are useful as G12D mutant KRAS inhibitors and are expected to be useful as active ingredients of pharmaceutical compositions for treating pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.

[0041] Methods used to solve problems

[0042] The present inventors have conducted intensive studies on compounds useful as active ingredients in pharmaceutical compositions for treating pancreatic cancer. As a result, they have discovered that heterocyclic compounds of formula (I), for example, bifunctional compounds of formula (I) characterized in that a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand for an E3 ligase via a linker, have excellent effects of inducing the degradation of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity, thereby completing the present invention.

[0043] That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0044]

[0045] (Where,

[0046] A is CR A or N,

[0047] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0048] Q is CR Q or N,

[0049] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0050] E is CH or N,

[0051] R 1 is selected from a C which may be substituted 1-3 a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV),

[0052]

[0053] R 1a 、R 1b and R 1cThe same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0054] R 2 -V 1 -V 2 or W,

[0055] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0056] R V1 H or substituted C 1-3 alkyl,

[0057] V 2 is the following formula (V) or formula (VI),

[0058]

[0059] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0060]

[0061] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0062] m is an integer from 0 to 2,

[0063] R 3 C can be substituted 1-6 an alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group,

[0064] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0065] R 4X H or substituted C 1-3 alkyl,

[0066] Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0067] R Y H or substituted C 1-3 alkyl,

[0068] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0069] The connecting group is Y 2 A group chemically bonded to EUB,

[0070] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0071] Furthermore, compounds having an effect of inducing the degradation of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity may be, for example, bifunctional compounds of formula (XXI) characterized in that a substituent at the 2-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand of an E3 ligase via a linking group.

[0072] That is, the present invention also relates to a compound of formula (XXI) or a salt thereof, and a pharmaceutical composition comprising the compound of formula (XXI) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0073]

[0074] (Where,

[0075] A is CR A or N,

[0076] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0077] Q is CR Q or N,

[0078] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0079] E is CH or N,

[0080] R 1 is selected from a C which may be substituted 1-3 a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV),

[0081]

[0082] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0083] R 2 -V 1 -V 2 or W,

[0084] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0085] R V1 H or substituted C 1-3 alkyl,

[0086] V 2 is the following formula (V) or formula (VI),

[0087]

[0088] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0089]

[0090] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0091] m is an integer from 0 to 2,

[0092] R 3P C can be substituted 1-6 an alkylene group, an optionally substituted heterocycloalkylene group, or an optionally substituted heteroarylene group,

[0093] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0094] R 4X H or substituted C 1-3 alkyl,

[0095] Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0096] R Y H or substituted C 1-3 alkyl,

[0097] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0098] R 5 H, CONR 6 R 7or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0099]

[0100] R 5a and R 5b The same or different, H, C which may be substituted 1-3 Alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, substituted oxazolyl, thiazolyl or pyrazinyl,

[0101] R 6 and R 7 The same or different, H or substituted C 1-6 Alkyl, or R 6 and R 7 Together with the nitrogen atom to which they are bonded, they form a 4- to 8-membered saturated heterocyclic ring, which may be substituted by a C 1-6 Alkyl substitution,

[0102] The connecting group is R 3P A group chemically bonded to EUB,

[0103] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0104] Furthermore, compounds having an effect of inducing the degradation of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity may be, for example, bifunctional compounds of formula (XXII) characterized in that a substituent at the 7-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand of an E3 ligase via a linking group.

[0105] That is, the present invention also relates to a compound of formula (XXII) or a salt thereof, and a pharmaceutical composition comprising the compound of formula (XXII) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0106]

[0107] (Where,

[0108] A is CR A or N,

[0109] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0110] Q is CR Q or N,

[0111] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0112] E is CH or N,

[0113] R 1P is selected from a C which may be substituted 1-3 a naphthylene group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formulas (II-22A), (II-22B), (II-22C), (III-22A), (III-22B), (III-22C), and (III-22D),

[0114]

[0115] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0116] R 2 -V 1 -V 2 or W,

[0117] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0118] R V1 H or substituted C 1-3 alkyl,

[0119] V 2 is the following formula (V) or formula (VI),

[0120]

[0121] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0122]

[0123] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0124] m is an integer from 0 to 2,

[0125] R 3 C can be substituted 1-6 an alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group,

[0126] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0127] R 4X H or substituted C 1-3 alkyl,

[0128] Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0129] R Y H or substituted C 1-3 alkyl,

[0130] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0131] R 5 H, CONR 6 R 7 or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0132]

[0133] R 5a and R 5b The same or different, H, C which may be substituted 1-3 Alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, substituted oxazolyl, thiazolyl or pyrazinyl,

[0134] R 6 and R 7 The same or different, H or substituted C 1-6 Alkyl, or R 6 and R 7 Together with the nitrogen atom to which they are bonded, they form a 4- to 8-membered saturated heterocyclic ring, which may be substituted by a C 1-6 Alkyl substitution,

[0135] The connecting group is R 1P A group chemically bonded to EUB,

[0136] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0137] Furthermore, compounds having an effect of inducing the degradation of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity include, for example, bifunctional compounds of formula (XXIII) characterized by GDB-linker-EUB.

[0138] That is, the present invention also relates to a compound of formula (XXIII) or a salt thereof, and a pharmaceutical composition comprising the compound of formula (XXIII) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0139] GDB-Linker-EUB

[0140] (XXIII)

[0141] (Where,

[0142] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[0143] -Linking group -EUB is a group selected from the group consisting of the following formula (LE-1) to formula (LE-40).

[0144]

[0145]

[0146]

[0147]

[0148] It should be noted that, unless otherwise specified, when a symbol in a chemical formula in the present specification is used in another chemical formula, the same symbol has the same meaning.

[0149] In addition, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients; a pharmaceutical composition for treating pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating metastatic pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced pancreatic cancer as one embodiment; a pharmaceutical composition for treating relapsed or refractory pancreatic cancer as one embodiment; a pharmaceutical composition for treating pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment; a pharmaceutical composition for treating metastatic G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating relapsed or refractory G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment. It should be noted that the pharmaceutical composition containing the compound of formula (I) or its salt and one or more pharmaceutically acceptable excipients includes a therapeutic agent for pancreatic cancer, or G12D mutant KRAS-positive pancreatic cancer, containing the compound of formula (I) or its salt as one embodiment.

[0150] In addition, the present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for treating pancreatic cancer, as an embodiment, G12D mutant KRAS-positive pancreatic cancer, as an embodiment, metastatic pancreatic cancer, as an embodiment, locally advanced pancreatic cancer, as an embodiment, recurrent or refractory pancreatic cancer, as an embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment, as an embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, as an embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, as an embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, as an embodiment, and G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment. Use in a composition; Use of a compound of formula (I) or a salt thereof in the treatment of pancreatic cancer, as a mode of G12D mutation KRAS-positive pancreatic cancer, as a mode of metastatic pancreatic cancer, as a mode of locally advanced pancreatic cancer, as a mode of recurrent or refractory pancreatic cancer, as a mode of pancreatic cancer in patients who have not been treated and / or have a history of treatment, as a mode of metastatic G12D mutation KRAS-positive pancreatic cancer, as a mode of locally advanced G12D mutation KRAS-positive pancreatic cancer, as a mode of recurrent or refractory G12D mutation KRAS-positive pancreatic cancer, as a mode of G12D mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment; A compound of formula (I) or a salt thereof for treating pancreatic cancer, G12D mutant KRAS-positive pancreatic cancer as a mode, metastatic pancreatic cancer as a mode, locally advanced pancreatic cancer as a mode, recurrent or refractory pancreatic cancer as a mode, pancreatic cancer in patients who have not been treated and / or have a history of treatment as a mode, metastatic G12D mutant KRAS-positive pancreatic cancer as a mode, locally advanced G12D mutant KRAS-positive pancreatic cancer as a mode, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer as a mode, G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as a mode; and comprising administering an effective amount of A method for treating pancreatic cancer, as one embodiment, G12D mutant KRAS-positive pancreatic cancer, as one embodiment, metastatic pancreatic cancer, as one embodiment, locally advanced pancreatic cancer, as one embodiment, recurrent or refractory pancreatic cancer, as one embodiment, pancreatic cancer in untreated and / or treatment-history patients, as one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, as one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, as one embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, as one embodiment, and G12D mutant KRAS-positive pancreatic cancer in untreated and / or treatment-history patients, comprising administering a compound of formula (I) or a salt thereof to a subject.

[0151] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a G12D mutant KRAS protein decomposition inducer and / or a G12D mutant KRAS inhibitor; a compound of formula (I) or a salt thereof used as a G12D mutant KRAS protein decomposition inducer and / or a G12D mutant KRAS inhibitor; and a G12D mutant KRAS protein decomposition inducer and / or a G12D mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0152] In addition, the present invention relates to a pharmaceutical composition comprising a compound of Formula (XXI), Formula (XXII) or Formula (XXIII) or a salt thereof and one or more pharmaceutically acceptable excipients, a pharmaceutical composition for treating pancreatic cancer as one embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer as one embodiment, a pharmaceutical composition for treating metastatic pancreatic cancer as one embodiment, a pharmaceutical composition for treating locally advanced pancreatic cancer as one embodiment, a pharmaceutical composition for treating relapsed or refractory pancreatic cancer as one embodiment, a pharmaceutical composition for treating pancreatic cancer in untreated and / or previously treated patients as one embodiment, a pharmaceutical composition for treating metastatic G12D mutant KRAS-positive pancreatic cancer as one embodiment, a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer as one embodiment, a pharmaceutical composition for treating relapsed or refractory G12D mutant KRAS-positive pancreatic cancer as one embodiment, and a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer in untreated and / or previously treated patients as one embodiment. It should be noted that the pharmaceutical composition containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof and one or more pharmaceutically acceptable excipients includes a therapeutic agent for pancreatic cancer containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof, and as one embodiment, a therapeutic agent for G12D mutant KRAS-positive pancreatic cancer containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof.

[0153] In addition, the present invention also relates to the following solutions.

[0154] Use of a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof in the manufacture of a pharmaceutical composition for treating pancreatic cancer, as one embodiment, G12D mutant KRAS-positive pancreatic cancer, as one embodiment, metastatic pancreatic cancer, as one embodiment, locally advanced pancreatic cancer, as one embodiment, recurrent or refractory pancreatic cancer, as one embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment, as one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, as one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, as one embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, as one embodiment, and G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment;

[0155] Use of a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof for treating pancreatic cancer, G12D mutant KRAS-positive pancreatic cancer as a mode, metastatic pancreatic cancer as a mode, locally advanced pancreatic cancer as a mode, recurrent or refractory pancreatic cancer as a mode, pancreatic cancer in patients who have not been treated and / or have a history of treatment as a mode, metastatic G12D mutant KRAS-positive pancreatic cancer as a mode, locally advanced G12D mutant KRAS-positive pancreatic cancer as a mode, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer as a mode, G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as a mode;

[0156] A compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof for treating pancreatic cancer, G12D mutant KRAS-positive pancreatic cancer as one embodiment, metastatic pancreatic cancer as one embodiment, locally advanced pancreatic cancer as one embodiment, recurrent or refractory pancreatic cancer as one embodiment, pancreatic cancer in untreated and / or treatment-history patients as one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer as one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer as one embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer as one embodiment, G12D mutant KRAS-positive pancreatic cancer in untreated and / or treatment-history patients as one embodiment;

[0157] A method for treating pancreatic cancer, as an embodiment, G12D mutant KRAS-positive pancreatic cancer, as an embodiment, metastatic pancreatic cancer, as an embodiment, locally advanced pancreatic cancer, as an embodiment, recurrent or refractory pancreatic cancer, as an embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment, as an embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, as an embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, as an embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, as an embodiment, in patients who have not been treated and / or have a history of treatment, comprising administering an effective amount of a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof to a subject;

[0158] A compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof as an inducer of G12D mutant KRAS protein degradation and / or a G12D mutant KRAS inhibitor;

[0159] A compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof for use as an inducer of G12D mutant KRAS protein degradation and / or a G12D mutant KRAS inhibitor; and

[0160] A G12D mutant KRAS protein degradation inducer and / or a G12D mutant KRAS inhibitor containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof.

[0161] It should be noted that the term "subject" refers to a human or other animal in need of the treatment, and as an example, refers to a person in need of the prevention or treatment.

[0162] Effects of the Invention

[0163] The compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or their salts have the effect of inducing the decomposition of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity, and can be used as therapeutic agents for pancreatic cancer, especially G12D mutant KRAS-positive pancreatic cancer. DETAILED DESCRIPTION

[0164] The present invention is described in detail below.

[0165] In this specification, "may be substituted" means unsubstituted or having 1 to 5 substituents. In one embodiment, it means unsubstituted or having 1 to 3 substituents. When having two or more substituents, these substituents may be the same or different.

[0166] “C 1-12The term "alkyl" refers to a linear or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and dodecyl (hereinafter, the same applies to the number of carbon atoms). In one embodiment, it is ethyl or dodecyl.

[0167] Likewise, “C 1-6 The term “alkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl or sec-butyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl or tert-butyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl or n-butyl. In one embodiment, it is methyl, ethyl, n-propyl. In one embodiment, it is methyl and n-propyl. In one embodiment, it is methyl. In one embodiment, it is ethyl. In one embodiment, it is n-propyl.

[0168] Likewise, “C 1-3 “Alkyl” refers to a linear or branched alkyl group having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl or isopropyl. In one embodiment, it is methyl or ethyl. In one embodiment, it is n-propyl or isopropyl. In one embodiment, it is methyl or isopropyl. In one embodiment, it is methyl or n-propyl. In one embodiment, it is ethyl or isopropyl. In one embodiment, it is methyl. In one embodiment, it is ethyl. In one embodiment, it is isopropyl. In one embodiment, it is n-propyl.

[0169] “C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, it is cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, it is cyclobutyl or cyclopentyl. In another embodiment, it is cyclopentyl or cyclohexyl. In another embodiment, it is cyclopropyl or cyclobutyl. In another embodiment, it is cyclopropyl. In another embodiment, it is cyclobutyl. In another embodiment, it is cyclopentyl. In another embodiment, it is cyclohexyl.

[0170] “C 1-3 "Alkylene" refers to the above-mentioned "C 1-3 The carbon atom of the "alkyl" also has another divalent group connected by a bond. For example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. As a form, a straight chain or branched C 1-3 In one embodiment, the alkylene group is methylene, ethylene, or trimethylene. In one embodiment, it is methylene or ethylene. In one embodiment, it is methylene. In one embodiment, it is ethylene.

[0171] "Heterocycloalkyl" refers to a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and may contain an unsaturated bond in part. In addition, the sulfur atom as the ring-constituting atom of the saturated heterocyclic group may be oxidized. One embodiment of the "heterocycloalkyl" is "a 4- to 6-membered heterocycloalkyl group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms", one embodiment is "a 4- to 6-membered heterocycloalkyl group containing 1 to 2 oxygen atoms as ring-constituting atoms", one embodiment is "a 4- to 6-membered heterocycloalkyl group containing 1 oxygen atom as ring-constituting atom", one embodiment is "a 4- to 6-membered heterocycloalkyl group containing 1 nitrogen atom as ring-constituting atom", and one embodiment is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, in one embodiment, oxetanyl, tetrahydropyranyl or tetrahydrofuranyl, in one embodiment, tetrahydropyranyl or tetrahydrofuranyl, in one embodiment, tetrahydropyranyl, in one embodiment, tetrahydrofuranyl, in one embodiment, azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, in one embodiment, piperidinyl or piperazinyl, in one embodiment, piperidinyl, in one embodiment, piperazinyl.

[0172] "Heterocycloalkylene" refers to a divalent group in which the nitrogen atom or carbon atom constituting the ring in the above-mentioned "heterocycloalkyl" further has another connecting bond. One embodiment of the "heterocycloalkylene" is "a 4- to 6-membered heterocycloalkylene containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms", another embodiment is "a 4- to 6-membered heterocycloalkylene containing 1 to 2 oxygen atoms as ring-constituting atoms", another embodiment is "a 4- to 6-membered heterocycloalkylene containing 1 oxygen atom as ring-constituting atom", another embodiment is "a 4- to 6-membered heterocycloalkylene containing 1 nitrogen atom as ring-constituting atom", another embodiment is oxetanediyl, tetrahydrofurandiyl, tetrahydropyrandiyl, azetidinediyl, pyrrolidinediyl, piperidinediyl, Oxazolidinediyl, imidazolidinediyl, piperazinediyl, morpholinediyl, thiomorpholinediyl, dioxothiomorpholinediyl, in one embodiment, oxetanediyl, tetrahydropyrandiyl, or tetrahydrofurandiyl, in one embodiment, tetrahydropyrandiyl or tetrahydrofurandiyl, in one embodiment, tetrahydropyrandiyl, in one embodiment, tetrahydrofurandiyl, in one embodiment, azetidinediyl, pyrrolidinediyl, piperidinediyl, or piperazinediyl, in one embodiment, piperidinediyl or piperazinediyl, in one embodiment, piperidinediyl, in one embodiment, piperazinediyl.

[0173] "Bridged heterocycloalkyl" refers to a 7- to 9-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms as ring-constituting atoms. In one embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms as ring-constituting atoms. In another embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing 2 nitrogen atoms as ring-constituting atoms. In another embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing 2 nitrogen atoms as ring-constituting atoms, and in another embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing 2 nitrogen atoms as ring-constituting atoms, one of which is bonded to a hydrogen atom. Examples include diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl, and diazabicyclo[3.3.1]nonyl. In 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. In one embodiment, it is diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl or diazabicyclo[2.2. 1] heptyl group, one embodiment is diazabicyclo[2.2.1]heptyl or diazabicyclo[3.2.1]octyl, one embodiment is diazabicyclo[2.2.1]heptyl, one embodiment is diazabicyclo[3.2.1]octyl, one embodiment is 2,5-diazabicyclo[2.2.1]heptyl or 3,8-diazabicyclo[3.2.1]octyl, one embodiment is 2,5-diazabicyclo[2.2.1]heptyl, one embodiment is 3,8-diazabicyclo[3.2.1]octyl.

[0174] "Bridged heterocycloalkylene" refers to a divalent group in which the nitrogen or carbon atoms constituting the ring of the aforementioned "bridged heterocycloalkyl" further have another bond. In one embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkylene containing two nitrogen atoms. In another embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkylene containing two nitrogen atoms, one of which is bonded to a hydrogen atom. Examples include diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl, diazabicyclo[2.2.1]heptanediyl, and diazabicyclo[3.3.1]nonanediyl. In one embodiment, it is diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.2.1]oct-6-enediyl, diazabicyclo[3.2.1]oct-2-enediyl, diazabicyclo[3.1.1]heptanediyl, diazabicyclo[2.2.1]heptanediyl, diazabicyclo[2.2.1]hept-5-enediyl. In one embodiment, it is diazabicyclo[2.2.2]octanediyl, diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl or diazabicyclo[2.2.1 ]heptanediyl, as one embodiment, it is diazabicyclo[2.2.1]heptanediyl or diazabicyclo[3.2.1]octanediyl, as one embodiment, it is diazabicyclo[2.2.1]heptanediyl, as one embodiment, it is diazabicyclo[3.2.1]octanediyl, as one embodiment, it is 2,5-diazabicyclo[2.2.1]heptanediyl or 3,8-diazabicyclo[3.2.1]octanediyl, as one embodiment, it is 2,5-diazabicyclo[2.2.1]heptanediyl, as one embodiment, it is 3,8-diazabicyclo[3.2.1]octanediyl.

[0175] "Bridged piperazinyl" refers to a piperazinyl group having a bridge structure between carbon atoms in the ring, wherein the bridge structure is composed of carbon atoms. Examples include diazabicyclo[2.2.1]heptyl, diazabicyclo[3.2.1]octyl, and diazabicyclo[3.1.1]heptyl. In one embodiment, it is diazabicyclo[2.2.1]heptyl. In another embodiment, it is diazabicyclo[3.2.1]octyl. In another embodiment, it is diazabicyclo[3.1.1]heptyl. In another embodiment, it is 2,5-diazabicyclo[2.2.1]heptyl or 3,8-diazabicyclo[3.2.1]octyl. In another embodiment, it is 2,5-diazabicyclo[2.2.1]heptyl. In another embodiment, it is 3,8-diazabicyclo[3.2.1]octyl.

[0176] "Bridged piperazine diyl" refers to a divalent group in which the nitrogen atom constituting the ring of the aforementioned "bridged piperazine" further has another bond. Examples include diazabicyclo[2.2.1]heptanediyl, diazabicyclo[3.2.1]octanediyl, and diazabicyclo[3.1.1]heptanediyl. In one embodiment, it is diazabicyclo[2.2.1]heptanediyl. In another embodiment, it is diazabicyclo[3.2.1]octanediyl. In one embodiment, it is diazabicyclo[3.1.1]heptanediyl, in another embodiment, it is 2,5-diazabicyclo[2.2.1]heptanediyl or 3,8-diazabicyclo[3.2.1]octanediyl, in another embodiment, it is 2,5-diazabicyclo[2.2.1]heptanediyl, in another embodiment, it is 3,8-diazabicyclo[3.2.1]octanediyl.

[0177] "Spiroheterocycloalkyl" refers to a saturated 7- to 9-membered heterocyclic ring group containing 1 to 2 nitrogen atoms as ring-constituting atoms and a spiro atom. In one embodiment, it is a saturated 7- to 9-membered heterocyclic ring group containing 2 nitrogen atoms as ring-constituting atoms and a spiro atom. Examples include diazaspiro[3.3]heptyl, diazaspiro[3.4]octyl, diazaspiro[3.5]nonyl, and diazaspiro[4.4]nonyl. In one embodiment, it is 2,6-diazaspiro[3.4]octyl, and in another embodiment, it is 2,6-diazaspiro[3.3]heptyl.

[0178] "Spiroheterocycloalkylene" refers to a divalent group having two nitrogen atoms as ring-constituting atoms in the above-mentioned "spiroheterocycloalkyl" and each of which has a connecting bond. For example, it is 2,6-diazaspiro[3.3]heptanediyl, 2,6-diazaspiro[3.4]octanediyl, 2,7-diazaspiro[3.5]nonanediyl, and 2,7-diazaspiro[4.4]nonanediyl. As one embodiment, it is 2,6-diazaspiro[3.4]octanediyl, and as another embodiment, it is 2,6-diazaspiro[3.3]heptanediyl. In addition, "spiroheterocycloalkylene" can be a divalent group in which the nitrogen atom or carbon atom constituting the ring in the above-mentioned "spiroheterocycloalkyl" further has another connecting bond. That is, one embodiment of the "spiroheterocycloalkylene" is a saturated 7- to 9-membered spiroheterocycloalkylene group containing 1 to 2 nitrogen atoms, such as 2,6-diazaspiro[3.3]heptanediyl, 2,6-diazaspiro[3.4]octanediyl, 2,7-diazaspiro[3.5]nonanediyl, 2,7-diazaspiro[4.4]nonanediyl, 2-azaspiro[3.3]heptanediyl, 2-azaspiro[3.4]octanediyl, 6-azaspiro[3.4]octanediyl, 2-azaspiro[3.5]nonanediyl, 7-azaspiro[3.5]nonanediyl, 2-azaspiro[4.4]nonanediyl, and 7-azaspiro[4.4]nonanediyl. In one embodiment, it is 2,6-diazaspiro[3.4]octanediyl. In another embodiment, it is 2,6-diazaspiro[3.3]heptanediyl.

[0179] The "heterocycle" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0180] "5-membered heterocyclic ring" refers to a 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms. One embodiment of the "5-membered heterocyclic ring" is a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, Azole ring, iso Azole ring, thiazole ring, isothiazole ring, A diazole ring or a thiadiazole ring, as one embodiment, is a pyrazole ring, an imidazole ring, a triazole ring, Azole ring, iso Azole ring, thiazole ring, isothiazole ring, a diazole ring or a thiadiazole ring.

[0181] A "six-membered heterocycle" refers to a six-membered heterocycle containing 1 to 3 nitrogen atoms as ring-constituting atoms. One embodiment of the "six-membered heterocycle" is a six-membered heterocycle containing 1 to 3 nitrogen atoms as ring-constituting atoms, and one embodiment is a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, or a triazine ring.

[0182] "5- to 6-membered heterocycle" means a 5-membered heterocycle or a 6-membered heterocycle. One embodiment of the "5- to 6-membered heterocycle" is a 5-membered heterocycle, and another embodiment is a 6-membered heterocycle.

[0183] The term "heteroaryl" refers to a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. In one embodiment, it is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms as ring-constituting atoms. In one embodiment, it is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. In one embodiment, it is a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms as ring-constituting atoms. In one embodiment, it is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and in one embodiment, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, In one embodiment, oxadiazolyl and thiadiazolyl are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl.

[0184] "Heteroarylene" refers to a divalent group in which two different carbon atoms and / or nitrogen atoms constituting the ring in the above-mentioned "heteroaryl" are connected by a bond. One embodiment of the "heteroarylene" is a 5-membered heteroarylene containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms or a 6-membered heteroarylene containing 1 to 3 nitrogen atoms as ring-constituting atoms. Another embodiment is a 5-membered heteroarylene containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms. Another embodiment is a 6-membered heteroarylene containing 1 to 3 nitrogen atoms as ring-constituting atoms. Another embodiment is pyrazolediyl, imidazolediyl, triazolediyl, tetrazolyl, Azoles, isoxadiazoles oxadiazole, thiazole, isothiazole, oxadiazolediyl, thiadiazolediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl or triazinediyl, as one embodiment, pyrazoldiyl, imidazolediyl, triazolediyl, tetrazolediyl, Azoles, isoxadiazoles oxadiazole, thiazole, isothiazole, In one embodiment, the oxadiazolediyl group and the thiadiazolediyl group are pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl or triazinediyl.

[0185] "4- to 8-membered saturated heterocyclic ring" refers to a 4- to 8-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, which may partially contain an unsaturated bond, may have a bridge, or may form a spirocycle. Furthermore, the sulfur atom contained in the heterocyclic ring may be oxidized. In one embodiment, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, azepane, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, azabicyclo[2.2.1]heptane, diazabicyclo[2.2.1]heptane, azaspiro[3.3]heptane, azaspiro[3.4]octane, oxazaspiro[3.3]heptane or diazaspiro[3.3]heptane, as one embodiment, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, Piperidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, azaspiro[3.3]heptane or oxazaspiro[3.3]heptane, as an embodiment, azetidine, tetrahydropyran, morpholine or oxazaspiro[3.3]heptane, as an embodiment, azetidine or tetrahydropyran, as an embodiment, morpholine or oxazaspiro[3.3]heptane, as an embodiment, tetrahydropyran.

[0186] As "heterocycloalkyl which may be substituted", "heterocycloalkylene which may be substituted", "C 1-6 One form of acceptable substituents in "alkylene" is C 1-3 Alkyl, -O(C 1-3 alkyl), C=O, halogen, OH, as one embodiment, C 1-3 Alkyl, -O(C 1-3 Alkyl), halogen, as one embodiment, -O(C 1-3 Alkyl), halogen, as a mode, C 1-3 Alkyl group is, as an example, OH, as an example, F, as an example, methyl, as an example, ethyl.

[0187] As a "replaceable C 1-6 Alkyl", "substituted C 1-3 Alkyl", "substituted C 1-3 One form of acceptable substituents in "alkylene" is C 1-3 Alkyl, -O(C 1-3 alkyl), C=O, halogen, OH, as one embodiment, C 1-3 Alkyl, -O(C 1-3 Alkyl), halogen, as one embodiment, -O(C 1-3 Alkyl), halogen, as a mode, C 1-3Alkyl group is, as an example, OH, as an example, F, as an example, methyl, as an example, ethyl.

[0188] One embodiment of the acceptable substituents for "optionally substituted heteroarylene", "optionally substituted phenylene" and "optionally substituted heteroaryl" is C 1-3 Alkyl, -O(C 1-3 Alkyl), halogen, OH, as a way, for C 1-3 Alkyl, -O(C 1-3 Alkyl), halogen, as a mode, C 1-3 In one embodiment, the alkyl group is methyl, in another embodiment, the ethyl group, in another embodiment, the halogen group, in another embodiment, the F group.

[0189] As a "replaceable One form of acceptable substituents in "oxazolyl" is C 1-3 Alkyl is, as an example, methyl or isopropyl, as an example, methyl, as an example, isopropyl.

[0190] "Halogen" refers to F, Cl, Br and I. In one embodiment, it is F, Cl or Br, in one embodiment, it is F or Cl, in one embodiment, it is F or Br, in one embodiment, it is F, in one embodiment, it is Cl, in one embodiment, it is Br.

[0191] "EUB" refers to a group capable of binding to an E3 ubiquitin ligase. In one embodiment, it is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. In one embodiment, it is a group capable of binding to parahydroxycerebroside, IAP, or MDM2. In another embodiment, it is a group capable of binding to parahydroxycerebroside. Those skilled in the art will understand this by referring to the following literature, but are not limited to these.

[0192] [literature]

[0193] Current Research in Chemical Biology.,2022,2,100020

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[0203] ACS Cham.Biol.,2019,14,2822

[0204] "GDB" refers to a group capable of binding to the G12D mutant KRAS protein and is not limited to the example compounds described in the following literature.

[0205] [literature]

[0206] International Publication No. 2021 / 041671

[0207] International Publication No. 2021 / 106231

[0208] International Publication No. 2021 / 107160

[0209] International Publication No. 2022 / 002102

[0210] International Publication No. 2022 / 105855

[0211] International Publication No. 2022 / 161443

[0212] International Publication No. 2022 / 171013

[0213] International Publication No. 2022 / 171147

[0214] International Publication No. 2022 / 184178

[0215] International Publication No. 2022 / 187528

[0216] International Publication No. 2022 / 194066

[0217] International Publication No. 2022 / 199586

[0218] International Publication No. 2022 / 246092

[0219] International Publication No. 2022 / 266069

[0220] The "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon position 12 in the wild-type protein is converted from glycine to aspartic acid.

[0221] “G12D mutant KRAS” means KRAS having the above-mentioned “G12D mutation”.

[0222] "Pancreatic cancer" refers to a malignant tumor that develops in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. In one embodiment, pancreatic ductal carcinoma is present. In another embodiment, pancreatic ductal adenocarcinoma is present. Furthermore, in another embodiment, metastatic pancreatic cancer is present. In another embodiment, locally advanced pancreatic cancer is present. In another embodiment, recurrent or refractory pancreatic cancer is present. In another embodiment, pancreatic cancer is present in patients who have not undergone treatment and / or have a history of treatment.

[0223] "G12D mutation KRAS-positive pancreatic cancer" refers to pancreatic cancer that is G12D mutation KRAS-positive. For example, this refers to pancreatic cancer that has the KRAS G12D mutation, or a pancreatic cancer with a high G12D mutation KRAS positive rate. In one embodiment, this refers to G12D mutation KRAS-positive pancreatic ductal carcinoma, or in another embodiment, to G12D mutation KRAS-positive pancreatic ductal adenocarcinoma.

[0224] “Z N1 " refers to a compound selected from the following formula (Z N1 -1) to (Z N1 -15) in a group ( *LGZ Indicates that LG Z or the bonding portion of the linking group, R Z1’ The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 alkyl)2, n' is an integer from 0 to 2, R Z2’ 、R Z3’ and R Z4‘ The same or different, H or substituted C 1-6 Alkyl, Ring B1' is a benzene ring or a 6-membered heterocyclic ring, wherein RZ1’ and- *LGN Forms a bond with the carbon atom constituting ring B1'.)

[0225]

[0226]

[0227] “Z N2 " refers to a compound selected from the following formula (Z N2 -1) to (Z N2 -15) in a group ( *LGZ Indicates that LG Z or the bonding portion of the linking group, R Z1’ The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 alkyl)2, n' is an integer from 0 to 2, R Z2’ and R Z3’ The same or different, H or substituted C 1-6 Alkyl, Ring B1' is a benzene ring or a 6-membered heterocyclic ring, wherein R Z1’ and- *LGN Forms a bond with the carbon atom constituting ring B1'.)

[0228]

[0229]

[0230] “Z C " refers to a compound selected from the following formula (Z C -16) to (Z C -27) in a group ( *LGZ Indicates that LG Z or the bonding portion of the linking group, R Z1’ The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 alkyl)2, n' is an integer from 0 to 2, R Z2’ 、R Z4’ and R Z5’The same or different, H or substituted C 1-6 Alkyl, M' is a bond, -O-, -S-, -N(R M’ )- or C which may be substituted 1-3 Alkylene, R M’ H or substituted C 1-3 Alkyl, ring B2' is a benzene ring or a 5- to 6-membered heterocyclic ring, wherein R Z1’ and- *LGC Forming a bond with the carbon atom constituting ring B1', M', R Z1’ and- *LGC Forms a bond with the carbon atom constituting ring B2'. ).

[0231]

[0232]

[0233] One embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.

[0234] (1-1)A is CR A or N,

[0235] R A H, C which can be substituted 1-3 Alkyl or cyano compounds or salts thereof.

[0236] (1-2) The compound or a salt thereof, wherein A is CH or N.

[0237] (1-3) The compound wherein A is CH or a salt thereof.

[0238] (1-4) The compound wherein A is N or a salt thereof.

[0239] (2-1)Q is CR Q or N,

[0240] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 A cycloalkyl or vinyl compound or a salt thereof.

[0241] (2-2)Q is CR Q ,

[0242] R Q C 3-6 A cycloalkyl compound or a salt thereof.

[0243] (2-3)Q is CR Q ,

[0244] R Q A compound or a salt thereof which is a cyclopropyl group.

[0245] (3-1) The compound or a salt thereof, wherein E is CH or N.

[0246] (3-2) The compound wherein E is CH or a salt thereof.

[0247] (4-1)R 1 is selected from a C which may be substituted 1-3 a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV),

[0248]

[0249] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen compounds or salts thereof.

[0250] (4-2)R 1 is the following formula (II),

[0251]

[0252] R 1a and R 1c Same or different from each other, C 1-3 Alkyl or halogen compound or salt thereof.

[0253] (4-3)R 1 is the following formula (II),

[0254]

[0255] R 1a is halogen, R 1c C 1-3 An alkyl compound or a salt thereof.

[0256] (4-4)R 1 It is a compound of the following formula (II-2) or a salt thereof.

[0257]

[0258] (5-1)R 2 -V 1 -V 2 or W,

[0259] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0260] R V1 H or substituted C 1-3 alkyl,

[0261] V 2 is the following formula (V) or formula (VI),

[0262]

[0263] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0264]

[0265] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0266] A compound or a salt thereof, wherein m is an integer of 0 to 2.

[0267] (5-2)R 2 -V 1 -V 2 or W,

[0268] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0269] R V1 Can be selected from C 3-6 C substituted with one of the groups consisting of cycloalkyl, halogen and -OH 1-3 alkyl,

[0270] V 2 is the following formula (V-2) or (VI-2),

[0271]

[0272] W is a compound or a salt thereof selected from the group consisting of the following formulae (VII-3), (VII-4), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV).

[0273]

[0274] (5-3)R2 -V 1 -V 2 or W,

[0275] V 1 is a bond, -O- or -N(R V1 )-,

[0276] R V1 C 1-3 alkyl,

[0277] V 2 is the following formula (VI-2),

[0278]

[0279] W is a compound represented by the following formula (XII) or a salt thereof.

[0280]

[0281] (5-4)R 2 -V 1 -V 2 or W,

[0282] V 1 is -O- or -N(CH3)-,

[0283] V 2 is the following formula (VI-2),

[0284]

[0285] W is a compound represented by the following formula (XII) or a salt thereof.

[0286]

[0287] (5-5)R 2 -V 1 -V 2 or W,

[0288] V 1 For -O-,

[0289] V 2 is the following formula (VI-2),

[0290]

[0291] W is a compound represented by the following formula (XII) or a salt thereof.

[0292]

[0293] (5-6)R 2 -V1 -V 2 or W,

[0294] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0295] R V1 Can be selected from C 3-6 C substituted with one of the groups consisting of cycloalkyl, halogen and -OH 1-3 alkyl,

[0296] V 2 is the following formula (V-2) or (VI-2),

[0297]

[0298] W is a compound or a salt thereof which is one group selected from the group consisting of the following formulae (VII-4), (XI) and (XII).

[0299]

[0300] (5-6-2)R 2 -V 1 -V 2 or W,

[0301] V 1 -O- or -N(R V1 )-,

[0302] R V1 C 1-3 alkyl,

[0303] V 2 is the following formula (V-2) or (VI-2),

[0304]

[0305] W is a compound or a salt thereof which is one group selected from the group consisting of the following formulae (VII-4), (XI) and (XII).

[0306]

[0307] (5-7)R 2 -V 1 -V 2 or W,

[0308] V 1 is -O- or -N(CH3)-,

[0309] V 2is the following formula (VI-2),

[0310]

[0311] W is a compound represented by the following formula (VII-4) or (XII) or a salt thereof.

[0312]

[0313] (6-1)R 3 C can be substituted 1-6 A compound or a salt thereof containing an alkyl group, an optionally substituted heterocycloalkyl group or an optionally substituted heteroaryl group.

[0314] (6-2)R 3 Can be selected from -O-(C 1-6 Alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 C substituted by one of the groups consisting of alkyl)2 and heterocycloalkyl 1-6 An alkyl or optionally substituted heterocycloalkyl compound or a salt thereof.

[0315] (6-3)R 3 Can be selected from -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl substituted with one of the following groups: 1-6 A compound or a salt thereof containing an alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl radical.

[0316] (6-4)R 3 C may be substituted by -OCH3 or tetrahydrofuran 1-3 alkyl, tetrahydrofuryl or tetrahydropyranyl compounds or salts thereof.

[0317] (6-5)R 3 A compound or a salt thereof which is an n-propyl group or a tetrahydropyranyl group which may be substituted with -OCH3.

[0318] (7-1) X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0319] R 4X H or substituted C 1-3 An alkyl compound or a salt thereof.

[0320] (7-2) X is -O- or -NR 4X -,

[0321] R 4X C 1-3 An alkyl compound or a salt thereof.

[0322] (7-3) The compound or a salt thereof, wherein X is -O-.

[0323] (8-1)Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0324] R Y H or substituted C 1-3 An alkyl compound or a salt thereof.

[0325] (8-2)Y 1 -O-(C 1-3 alkylene)- *Y2 or -(C 1-3 Alkylene)-O- *Y2 ( *Y2 Indicates that Y 2 ) or a salt thereof.

[0326] (8-3)Y 1 -O-(C 1-3 alkylene)- *Y2 ( *Y2 Indicates that Y 2 ) or a salt thereof.

[0327] (8-4)Y 1 -O-(methylene)- *Y2 ( *Y2 Indicates that Y 2 ) or a salt thereof.

[0328] (9-1)Y 2is a bond, an optionally substituted phenylene group or an optionally substituted heteroarylene group, or a salt thereof.

[0329] (9-2)Y 2 A compound or a salt thereof which is a phenylene group or a pyridinediyl group.

[0330] (9-3)Y 2 A compound or a salt thereof which is a phenylene group which may be substituted with fluorine.

[0331] (9-4)Y 2 A compound containing phenylene or a salt thereof.

[0332] (9-5)Y 2 A compound or a salt thereof which is a phenylene group or a pyridinediyl group which may be substituted.

[0333] (10-1) The connecting group is Y 2 A compound containing a group chemically bonded to EUB or a salt thereof.

[0334] (10-2) The connecting group is -(L 1 -L 2 -L 3 -L 4 )-,

[0335] L 1 , L 2 , L 3 and L 4 The same or different from each other, is selected from a free bond, C=O, -O-, -S-, -SO2-, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7-membered to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7-membered to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-6 A group in the group consisting of an alkylene group,

[0336] R L H or C 1-6 An alkyl compound or a salt thereof.

[0337] (10-3) The connecting group is -(L 1 -L 2 -L 3 -L 4 )-,

[0338] L 1 is C=O,

[0339] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl,

[0340] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0341] L 4 For the bond, -N(R L4 )-, -O- or C 1-3 Alkylene,

[0342] R L3 H or C 1-3 alkyl,

[0343] R L4 H or C 1-3 An alkyl compound or a salt thereof.

[0344] (10-3-2) The connecting group is -(L 1 -L 2 -L 3 -L 4 )-,

[0345] L 1 is C=O,

[0346] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl,

[0347] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0348] L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene,

[0349] R L3 H or C 1-3 alkyl,

[0350] R L4 H or C 1-3 An alkyl compound or a salt thereof.

[0351] (10-4) The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7),

[0352] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) 2 Forming bonds,

[0353]

[0354] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[0355] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[0356] R L2 H or C 1-3 An alkyl compound or a salt thereof.

[0357] (10-5) The connecting group is -(L 1 -L 2 -L 3 -L 4 )-,

[0358] L 1 is C=O,

[0359] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl,

[0360] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0361] L 4 For the bond, -N(R L4 )-, -O- or C 1-3 Alkylene,

[0362] R L3 H or C 1-3 alkyl,

[0363] R L4 H or C 1-3 An alkyl compound or a salt thereof.

[0364] (10-5-2) The linking group is -(L 1 -L 2 -L 3 -L 4 )-,

[0365] L 1 is C=O,

[0366] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl,

[0367] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0368] L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene,

[0369] R L3 H or C 1-3 alkyl,

[0370] R L4 H or C 1-3 An alkyl compound or a salt thereof.

[0371] (10-6)

[0372] The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7),

[0373] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) 2 Forming bonds,

[0374]

[0375] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[0376] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[0377] R L2 H or C 1-3 An alkyl compound or a salt thereof.

[0378] (10-7) The linking group is a compound represented by the following formula (L-5A) or (L-7A) or a salt thereof.

[0379]

[0380] (11-1) EUB is a compound or a salt thereof having a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0381] (11-2) A compound or a salt thereof in which EUB is a group capable of binding to parahydroxycerebroside.

[0382] (11-3)EUB is the following formula (XV),

[0383]

[0384] G is CR G or N,

[0385] R G H or C 1-6 alkyl,

[0386] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0387] Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), Ring B1 and Ring B2 form a bond with a linking group,

[0388] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0389]

[0390]

[0391] R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2,

[0392] n is an integer from 0 to 2,

[0393] R Z2 、R Z3 and R Z4 The same or different, H or substituted C 1-6 alkyl,

[0394] M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene,

[0395] R M H or substituted C 1-3 alkyl,

[0396] Ring B1 is a benzene ring or a 6-membered heterocyclic ring,

[0397] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0398] Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring,

[0399] Here, M, R Z1 A compound or a salt thereof in which a linking group forms a bond with a carbon atom constituting ring B2.

[0400] (11-3-2) EUB is a group capable of binding to parahydroxycerebroside. The group capable of binding to parahydroxycerebroside is represented by the following formula (XV):

[0401]

[0402] G is CR G or N,

[0403] R G H or C 1-6 alkyl,

[0404] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0405] Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), Ring B1 and Ring B2 form a bond with a linking group,

[0406] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0407]

[0408]

[0409] R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2,

[0410] n is an integer from 0 to 2,

[0411] R Z2 、R Z3 and R Z4 The same or different, H or substituted C 1-6 alkyl,

[0412] M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene,

[0413] R M H or substituted C 1-3 alkyl,

[0414] Ring B1 is a benzene ring or a 6-membered heterocyclic ring,

[0415] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0416] Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring,

[0417] Here, M, R Z1 A compound or a salt thereof in which a linking group forms a bond with a carbon atom constituting ring B2.

[0418] (11-4)EUB is the following formula (XV),

[0419]

[0420] G is CH or N,

[0421] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23),

[0422] Here, in the formulas (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22), and (Z-23), ring B1 and ring B2 form a bond with a linking group,

[0423] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23),

[0424]

[0425] R Z1 C 1-6 Alkyl or halogen,

[0426] n is an integer of 0 or 1,

[0427] R Z2 and R Z4 Same or different from each other, H or C 1-6 alkyl,

[0428] M is a bond or C 1-3 Alkylene,

[0429] Ring B1 is a benzene ring or a pyridine ring,

[0430] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0431] Ring B2 is a benzene ring or a pyridine ring,

[0432] Here, M, R Z1 A compound or a salt thereof in which a linking group forms a bond with a carbon atom constituting ring B2.

[0433] (11-5)EUB is the following formula (XV),

[0434]

[0435] G is CH or N,

[0436] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23),

[0437] Here, the ring B1 and the ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group,

[0438] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-20), (Z-22) and (Z-23),

[0439]

[0440] R Z1 C 1-3 Alkyl or halogen,

[0441] n is an integer from 0 to 1,

[0442] R Z2 C 1-3 alkyl,

[0443] M is a bond or C 1-3 Alkylene,

[0444] Ring B1 is a benzene ring or a pyridine ring,

[0445] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0446] Ring B2 is a benzene ring or a pyridine ring,

[0447] Here, M, R Z1 A compound or a salt thereof in which a linking group forms a bond with a carbon atom constituting ring B2.

[0448] (11-6)EUB is the following formula (XV),

[0449]

[0450] G is CH or N,

[0451] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F),

[0452] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group,

[0453] Wherein, when G is N, Z is a compound or a salt thereof selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F).

[0454]

[0455] (11-7)EUB is the following formula (XV),

[0456]

[0457] G is CH,

[0458] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C) and (Z-15A),

[0459] Here, the compound or its salt in which the benzene ring or 6-membered heterocyclic ring in the formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C) and (Z-15A) forms a bond with a connecting group.

[0460]

[0461] (11-8)EUB is the following formula (XV),

[0462]

[0463] G is CH or N,

[0464] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A),

[0465] Here, the benzene ring or 6-membered heterocyclic ring in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with the linking group.

[0466] When G is N, Z is the compound (Z-16A) or (Z-22A) or a salt thereof.

[0467]

[0468] EUB is the following formula (XV),

[0469]

[0470] G is CR G or N,

[0471] R G H or C 1-6 alkyl,

[0472] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27),

[0473] Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27), Ring B1 and Ring B2 form a bond with a linking group,

[0474] wherein, when G is N, Z is a group selected from the group consisting of formulae (Z-1), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27),

[0475]

[0476]

[0477] R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2,

[0478] n is an integer from 0 to 2,

[0479] R Z2 、R Z3 、R Z4 and R Z5 The same or different, H or substituted C 1-6 alkyl,

[0480] M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene,

[0481] R M H or substituted C 1-3 alkyl,

[0482] Ring B1 is a benzene ring or a 6-membered heterocyclic ring,

[0483] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0484] Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring,

[0485] Here, M, R Z1 A compound or a salt thereof in which a linking group forms a bond with a carbon atom constituting ring B2.

[0486] (11-10)EUB is the following formula (XV),

[0487]

[0488] G is CH or N,

[0489] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A),

[0490]

[0491]

[0492] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group, and the benzene ring in (Z-24A) forms a bond with a linking group.

[0493] Wherein, when G is N, Z is a compound or a salt thereof selected from the group consisting of (Z-1A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A).

[0494] (12) Compounds or salts thereof that are combinations of two or more compounds in the embodiments described in (1-1) to (11-10) that are not inconsistent with each other. For example, the following combinations can be mentioned, but are not limited to these.

[0495] (12-1) A compound of formula (I) or a salt thereof.

[0496]

[0497] (Where,

[0498] A is CR A or N,

[0499] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0500] Q is CR Q or N,

[0501] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0502] E is CH or N,

[0503] R 1 is selected from a C which may be substituted 1-3 a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV),

[0504]

[0505] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0506] R 2 -V 1 -V 2 or W,

[0507] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0508] R V1 H or substituted C 1-3 alkyl,

[0509] V 2 is the following formula (V) or formula (VI),

[0510]

[0511] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0512]

[0513] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0514] m is an integer from 0 to 2,

[0515] R 3 C can be substituted 1-6 an alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group,

[0516] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0517] R 4X H or substituted C 1-3 alkyl,

[0518] Y1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0519] R Y H or substituted C 1-3 alkyl,

[0520] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0521] The connecting group is Y 2 A group chemically bonded to EUB,

[0522] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0523] (12-2) The compound or a salt thereof according to (12-1), wherein EUB is a group capable of binding to parahydroxycerebroside.

[0524] (12-3) The compound or a salt thereof according to (12-2), wherein

[0525] EUB is the following formula (XV),

[0526]

[0527] G is CR G or N,

[0528] R G H or C 1-6 alkyl,

[0529] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0530] Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), Ring B1 and Ring B2 form a bond with a linking group,

[0531] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),

[0532]

[0533]

[0534] R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2,

[0535] n is an integer from 0 to 2,

[0536] R Z2 、R Z3 and R Z4 The same or different, H or substituted C 1-6 alkyl,

[0537] M is a bond, -O-, -S-, -N(RM )- or C which may be substituted 1-3 Alkylene,

[0538] R M H or substituted C 1-3 alkyl,

[0539] Ring B1 is a benzene ring or a 6-membered heterocyclic ring,

[0540] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0541] Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring,

[0542] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0543] (12-4) The compound or a salt thereof according to (12-3), wherein

[0544] EUB is the following formula (XV),

[0545]

[0546] G is CH or N,

[0547] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23),

[0548] Here, in the formulas (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22), and (Z-23), ring B1 and ring B2 form a bond with a linking group,

[0549] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23),

[0550]

[0551]

[0552] R Z1 C 1-6 Alkyl or halogen,

[0553] n is an integer of 0 or 1,

[0554] R Z2 and R Z4 The same or different, H or C 1-6 alkyl,

[0555] M is a bond or C 1-3 Alkylene,

[0556] Ring B1 is a benzene ring or a pyridine ring,

[0557] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0558] Ring B2 is a benzene ring or a pyridine ring,

[0559] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0560] (12-5) The compound or a salt thereof according to (12-4), wherein

[0561] A is CH or N,

[0562] Q is CR Q ,

[0563] R Q C 3-6 Cycloalkyl,

[0564] E is CH,

[0565] R 1 is the following formula (II),

[0566]

[0567] R 1a and R 1c Same or different from each other, C 1-3 Alkyl or halogen,

[0568] R 2 -V 1 -V 2 or W,

[0569] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0570] R V1 Can be selected from C 3-6 C substituted with one of the groups consisting of cycloalkyl, halogen and -OH 1-3 alkyl,

[0571] V 2is the following formula (V-2) or (VI-2),

[0572]

[0573] W is a group selected from the group consisting of the following formulae (VII-3), (VII-4), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV),

[0574]

[0575] R 3 Can be selected from -O-(C 1-6 Alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 C substituted by one of the groups consisting of alkyl)2 and heterocycloalkyl 1-6 an alkyl group or an optionally substituted heterocycloalkyl group,

[0576] X is -O- or -NR 4X -,

[0577] R 4X C 1-3 alkyl,

[0578] Y 1 -O-(C 1-3 alkylene)- *Y2 or -(C 1-3 Alkylene)-O- *Y2 ( *Y2 Indicates that Y 2 bonding part. ), Y 2 is phenylene or pyridinediyl,

[0579] The linking group is -(L 1 -L 2 -L 3 -L 4 )-,

[0580] L 1 , L 2 , L 3 and L 4 The same or different from each other, is selected from a free bond, C=O, -O-, -S-, -SO2-, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7-membered to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7-membered to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-6 A group in the group consisting of an alkylene group,

[0581] R L H or C 1-6 alkyl.

[0582] (12-6) The compound or a salt thereof according to (12-5), wherein

[0583] R 1 is the following formula (II),

[0584]

[0585] R 1a is halogen, R 1c C 1-3 alkyl,

[0586] R 2 -V 1 -V 2 or W,

[0587] V 1 is a bond, -O- or -N(R V1 )-,

[0588] R V1 C 1-3 alkyl,

[0589] V 2 is the following formula (VI-2),

[0590]

[0591] W is the following formula (XII),

[0592]

[0593] R 3 Can be selected from -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl substituted with one of the following groups: 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl,

[0594] X is -O-,

[0595] Y 1 -O-(C 1-3 alkylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0596] Y 2 is phenylene,

[0597] The linking group is -(L 1-L 2 -L 3 -L 4 )-,

[0598] L 1 is C=O,

[0599] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl,

[0600] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0601] L 4 For the bond, -N(R L4 )-, -O- or C 1-3 Alkylene,

[0602] R L3 H or C 1-3 alkyl,

[0603] R L4 H or C 1-3 alkyl,

[0604] EUB is the following formula (XV),

[0605]

[0606] G is CH or N,

[0607] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23),

[0608] Here, the ring B1 and the ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group,

[0609] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-20), (Z-22) and (Z-23),

[0610]

[0611] R Z1 C 1-3 Alkyl or halogen,

[0612] n is an integer of 0 or 1,

[0613] R Z2 C 1-3 alkyl,

[0614] M is a bond or C 1-3 Alkylene,

[0615] Ring B1 is a benzene ring or a pyridine ring,

[0616] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0617] Ring B2 is a benzene ring or a pyridine ring,

[0618] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0619] (12-6-2) The compound or a salt thereof according to (12-5), wherein

[0620] R 1 is the following formula (II),

[0621]

[0622] R 1a is halogen, R 1c C 1-3 alkyl,

[0623] R 2 -V 1 -V 2 or W,

[0624] V 1 is a bond, -O- or -N(R V1 )-,

[0625] R V1 C 1-3 alkyl,

[0626] V 2 is the following formula (VI-2),

[0627]

[0628] W is the following formula (XII),

[0629]

[0630] R3 Can be selected from -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl substituted with one of the following groups: 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl,

[0631] X is -O-,

[0632] Y 1 -O-(C 1-3 alkylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0633] Y 2 is phenylene,

[0634] The linking group is -(L 1 -L 2 -L 3 -L 4 )-,

[0635] L 1 is C=O,

[0636] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl,

[0637] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0638] L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene,

[0639] R L3 H or C 1-3 alkyl,

[0640] R L4 H or C 1-3 alkyl,

[0641] EUB is the following formula (XV),

[0642]

[0643] G is CH or N,

[0644] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23),

[0645] Here, the ring B1 and the ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group,

[0646] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-20), (Z-22) and (Z-23),

[0647]

[0648] R Z1 C 1-3 Alkyl or halogen,

[0649] n is an integer of 0 or 1,

[0650] R Z2 C 1-3 alkyl,

[0651] M is a bond or C 1-3 Alkylene,

[0652] Ring B1 is a benzene ring or a pyridine ring,

[0653] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0654] Ring B2 is a benzene ring or a pyridine ring,

[0655] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0656] (12-7) The compound or a salt thereof according to (12-6), wherein

[0657] Q is CR Q ,

[0658] R Q is cyclopropyl,

[0659] R 1 is the following formula (II-2),

[0660]

[0661] R2 -V 1 -V 2 or W,

[0662] V 1 is -O- or -N(CH3)-,

[0663] V 2 is the following formula (VI-2),

[0664]

[0665] W is the following formula (XII),

[0666]

[0667] R 3 C may be substituted by -OCH3 or tetrahydrofuran 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl,

[0668] Y 1 -O-(methylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0669] The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7),

[0670] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) 2 Forming bonds,

[0671]

[0672] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[0673] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[0674] R L2 H or C 1-3 alkyl,

[0675] EUB is the following formula (XV),

[0676]

[0677] G is CH or N,

[0678] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F),

[0679] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group,

[0680] Wherein, when G is N, Z is a group selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F).

[0681]

[0682]

[0683] (12-8) A compound of formula (I) or a salt thereof that is a combination of the above-mentioned modes (1-2), (2-3), (3-2), (4-4), (5-5), (6-5), (7-3), (8-4), (9-4), (10-7), and (11-8).

[0684] (12-9) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-3), (5-2), (6-3), (7-2), (8-2), (9-3), (10-5), and (11-4).

[0685] (12-10) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-2), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), and (11-4).

[0686] (12-11) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-1), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), and (11-4).

[0687] (12-12) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-1), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), and (11-6).

[0688] (12-13) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-4), (9-4), (10-5), and (11-5).

[0689] (12-14) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), and (11-5).

[0690] (12-15) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), and (11-6).

[0691] (12-16) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-3), and (11-5).

[0692] (12-17) A compound of formula (I) or a salt thereof that is a combination of the above-mentioned modes (1-2), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-4), and (11-6).

[0693] (12-18) A compound of formula (I) or a salt thereof that is a combination of the above-mentioned modes (1-3), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), and (11-5).

[0694] (12-19) A compound of formula (I) or a salt thereof that is a combination of the above-mentioned modes (1-4), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), and (11-5).

[0695] (12-20) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-3), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), and (11-6).

[0696] (12-21) A compound of formula (I) or a salt thereof as a combination of the above-mentioned modes (1-4), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), and (11-6).

[0697] (12-22) The compound or salt thereof according to (12-7), wherein

[0698] R 2 -V 1 -V 2 or W,

[0699] V 1 For -O-,

[0700] V 2 is the following formula (VI-2),

[0701]

[0702] W is the following formula (XII),

[0703]

[0704] R 3 is n-propyl or tetrahydropyranyl which may be substituted by -OCH3,

[0705] The linking group is the following formula (L-5A) or (L-7A),

[0706]

[0707] EUB is the following formula (XV),

[0708]

[0709] G is CH or N,

[0710] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A),

[0711]

[0712] Here, the benzene ring or 6-membered heterocyclic ring in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with the linking group.

[0713] When G is N, Z is (Z-16A) or (Z-22A).

[0714] (12-23) The compound or salt thereof according to (12-2), wherein

[0715] EUB is the following formula (XV),

[0716]

[0717] G is CR G or N,

[0718] R G H or C 1-6 alkyl,

[0719] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27),

[0720] Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27), Ring B1 and Ring B2 form a bond with a linking group,

[0721] wherein, when G is N, Z is a group selected from the group consisting of formulae (Z-1), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27),

[0722]

[0723]

[0724] R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (which may be substituted C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2,

[0725] n is an integer from 0 to 2,

[0726] R Z2 、R Z3 、R Z4 and R Z5 The same or different, H or substituted C 1-6 alkyl,

[0727] M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene,

[0728] R M H or substituted C 1-3 alkyl,

[0729] Ring B1 is a benzene ring or a 6-membered heterocyclic ring,

[0730] Here, R Z1and the linking group forms a bond with the carbon atom constituting ring B1,

[0731] Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring,

[0732] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0733] (12-24) The compound or a salt thereof according to (12-23), wherein

[0734] A is CH or N,

[0735] Q is CR Q ,

[0736] R Q is cyclopropyl,

[0737] R 1 is the following formula (II-2),

[0738]

[0739] R 2 -V 1 -V 2 or W,

[0740] V 1 is -O- or -N(CH3)-,

[0741] V 2 is the following formula (VI-2),

[0742]

[0743] W is the following formula (VII-4) or (XII),

[0744]

[0745] R 3 C may be substituted by -OCH3 or tetrahydrofuran 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl,

[0746] X is -O-,

[0747] Y 1 -O-(methylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0748] Y 2 is phenylene,

[0749] The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7),

[0750] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) 2 Forming bonds,

[0751]

[0752] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[0753] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[0754] R L2 H or C 1-3 alkyl,

[0755] EUB is the following formula (XV),

[0756]

[0757] G is CH or N,

[0758] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A),

[0759]

[0760]

[0761] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group, and the benzene ring in (Z-24A) forms a bond with a linking group.

[0762] Wherein, when G is N, Z is a group selected from the group consisting of (Z-1A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A).

[0763] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0764] A compound or a salt thereof selected from the group consisting of:

[0765] 5-[(8-{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]benzoyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione,

[0766] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0767] 3-(5-{[(3S)-4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0768] 3-[5-({(3S)-4-[4-({[6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{[(3S)-pyrrolidin-3-yl]oxy}quinolin-8-yl]oxy}methyl)benzoyl]-3-methylpiperazin-1-yl}methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione,

[0769] 1-(6-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione,

[0770] 3-(5-{[(3S)-4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0771] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and

[0772] 1-(7-{[(3S)-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-[( [1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione.

[0773] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0774] A compound or a salt thereof selected from the group consisting of:

[0775] 5-[(8-{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]benzoyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione,

[0776] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0777] 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0778] 3-[5-({(3S)-4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{[(3S)-pyrrolidin-3-yl]oxy}quinolin-8-yl]oxy}methyl)benzoyl]-3-methylpiperazin-1-yl}methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione,

[0779] 1-(6-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione,

[0780] 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0781] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and

[0782] 1-(7-{[(3S)-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-[( [1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione.

[0783] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0784] A compound or a salt thereof selected from the group consisting of:

[0785] 5-[(8-{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]benzoyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione,

[0786] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0787] 3-(5-{[(3S)-4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0788] 3-[5-({(3S)-4-[4-({[(7P)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{[(3S)-pyrrolidin-3-yl]oxy}quinolin-8-yl]oxy}methyl)benzoyl]-3-methylpiperazin-1-yl}methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione,

[0789] 1-(6-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione,

[0790] 3-(5-{[(3S)-4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione,

[0791] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and

[0792] 1-(7-{[(3S)-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-[( [1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione.

[0793] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0794] A compound selected from the group consisting of:

[0795] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-2,6-dione n phosphate,

[0796] 3-(5-{[(3S)-4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione n-phosphate.

[0797] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0798] A compound selected from the group consisting of:

[0799] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-2,6-dione n phosphate,

[0800] 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione n-phosphate.

[0801] As examples of specific compounds encompassed by the present invention, the following compounds can be cited as one embodiment.

[0802] A compound selected from the group consisting of:

[0803] 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-2,6-dione n phosphate,

[0804] 3-(5-{[(3S)-4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione n-phosphate.

[0805] One embodiment of the compound of formula (XXI) or a salt thereof in the present invention is shown below.

[0806] (21-1) A compound of the formula (XXI) or a salt thereof.

[0807]

[0808] (Where,

[0809] A is CR A or N,

[0810] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0811] Q is CR Q or N,

[0812] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0813] E is CH or N,

[0814] R 1 is selected from a C which may be substituted 1-3a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV),

[0815]

[0816] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0817] R 2 -V 1 -V 2 or W,

[0818] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0819] R V1 H or substituted C 1-3 alkyl,

[0820] V 2 is the following formula (V) or formula (VI),

[0821]

[0822] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0823]

[0824] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0825] m is an integer from 0 to 2,

[0826] R 3P C can be substituted 1-6 an alkylene group, an optionally substituted heterocycloalkylene group, or an optionally substituted heteroarylene group,

[0827] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0828] R 4X H or substituted C 1-3 alkyl,

[0829] Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0830] R Y H or substituted C 1-3 alkyl,

[0831] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0832] R 5 H, CONR 6 R 7 or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0833]

[0834] R 5a and R 5b The same or different, H, C which may be substituted 1-3 Alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, substituted oxazolyl, thiazolyl or pyrazinyl,

[0835] R 6 and R 7 The same or different, H or substituted C 1-6 Alkyl, or R 6 and R 7 Together with the nitrogen atom to which they are bonded, they form a 4- to 8-membered saturated heterocyclic ring, which may be substituted by a C 1-6 Alkyl substitution,

[0836] The connecting group is R 3P A group chemically bonded to EUB,

[0837] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0838] (21-2) The compound or a salt thereof according to (21-1), wherein

[0839] A is CH or N,

[0840] Q is CR Q ,

[0841] R Q C 3-6 Cycloalkyl,

[0842] E is CH,

[0843] R 1 is the following formula (II),

[0844]

[0845] R 1a is halogen, R 1c C 1-3 alkyl,

[0846] R 2 -V 1 -V 2 or W,

[0847] V 1 is a bond, -O- or -N(R V1 )-,

[0848] R V1 C 1-3 alkyl,

[0849] V 2 is the following formula (VI-2),

[0850]

[0851] W is the following formula (XII),

[0852]

[0853] R 3P Can be selected from -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl substituted with one of the following groups: 1-6 Alkylene, oxetanediyl, tetrahydrofurandiyl or tetrahydropyrandiyl,

[0854] R 5 is H or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0855]

[0856] R 5a and R 5b The same or different, H, C which may be substituted 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl,

[0857] X is -O-,

[0858] Y 1 -O-(C 1-3 alkylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion.)

[0859] Y 2 is phenylene,

[0860] The linking group is -(L 1 -L 2 -L 3 -L 4 )-,

[0861] L 1 is C=O,

[0862] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl,

[0863] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0864] L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene,

[0865] R L3 H or C 1-3 alkyl,

[0866] R L4 H or C 1-3 alkyl,

[0867] EUB is a group capable of binding to parahydroxycerebroside. The group capable of binding to parahydroxycerebroside is represented by the following formula (XV):

[0868]

[0869] G is CH or N,

[0870] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23),

[0871] Here, the ring B1 and the ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group,

[0872] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-20), (Z-22) and (Z-23),

[0873]

[0874] R Z1 C 1-3 Alkyl or halogen,

[0875] n is an integer from 0 to 1,

[0876] R Z2 C 1-3 alkyl,

[0877] M is a bond or C 1-3Alkylene,

[0878] Ring B1 is a benzene ring or a pyridine ring,

[0879] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0880] Ring B2 is a benzene ring or a pyridine ring,

[0881] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0882] (21-3) The compound or a salt thereof according to (21-2), wherein

[0883] A is CH or N,

[0884] Q is CR Q ,

[0885] R Q is cyclopropyl,

[0886] E is CH,

[0887] R 1 is the following formula (II-2),

[0888]

[0889] R 2 -V 1 -V 2 or W,

[0890] V 1 is -O- or -N(CH3)-,

[0891] V 2 is the following formula (VI-2),

[0892]

[0893] W is the following formula (XII),

[0894]

[0895] R 3P To be -O(C 1-3 Alkyl) substituted C 1-6 Alkylene,

[0896] R 5 For H,

[0897] X is -O-,

[0898] Y 1-O-(methylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0899] Y 2 is phenylene,

[0900] The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7),

[0901] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) 2 Forming bonds,

[0902]

[0903] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[0904] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[0905] R L2 H or C 1-3 alkyl,

[0906] EUB is a group capable of binding to parahydroxycerebroside. The group capable of binding to parahydroxycerebroside is represented by the following formula (XV):

[0907]

[0908] G is CH or N,

[0909] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F),

[0910] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group,

[0911] Wherein, when G is N, Z is a group selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F).

[0912]

[0913]

[0914] One embodiment of the compound of formula (XXII) or a salt thereof in the present invention is shown below.

[0915] (22-1) A compound of formula (XXII) or a salt thereof.

[0916]

[0917] (Where,

[0918] A is CR A or N,

[0919] R A H, C which can be substituted 1-3 Alkyl or cyano,

[0920] Q is CR Q or N,

[0921] R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl,

[0922] E is CH or N,

[0923] R 1P is selected from a C which may be substituted 1-3a naphthylene group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formulas (II-22A), (II-22B), (II-22C), (III-22A), (III-22B), (III-22C), and (III-22D),

[0924]

[0925] R 1a 、R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen,

[0926] R 2 -V 1 -V 2 or W,

[0927] V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-,

[0928] R V1 H or substituted C 1-3 alkyl,

[0929] V 2 is the following formula (V) or formula (VI),

[0930]

[0931] W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

[0932]

[0933] R 2a The same or different from each other, OH, OCH3, F or C which may be substituted 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2),

[0934] m is an integer from 0 to 2,

[0935] R 3 C can be substituted 1-6 an alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group,

[0936] X is a bond, -CH2-, -O-, -S- or -NR 4X -,

[0937] R 4X H or substituted C 1-3 alkyl,

[0938] Y 1 -O-(which may be substituted C 1-3 alkylene)- *Y2 、-S-(C 1-3 alkylene)- *Y2 、-SO2-(can be substituted C 1-3 alkylene)- *Y2 、-NR Y -(C 1-3 alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0939] R Y H or substituted C 1-3 alkyl,

[0940] Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted,

[0941] R 5 H, CONR 6 R 7 or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0942]

[0943] R 5a and R 5b The same or different, H, C which may be substituted 1-3Alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, substituted oxazolyl, thiazolyl or pyrazinyl,

[0944] R 6 and R 7 The same or different, H or substituted C 1-6 Alkyl, or R 6 and R 7 Together with the nitrogen atom to which they are bonded, they form a 4- to 8-membered saturated heterocyclic ring, which may be substituted by a C 1-6 Alkyl substitution,

[0945] The connecting group is R 1P A group chemically bonded to EUB,

[0946] EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0947] (22-2) The compound or a salt thereof according to (22-1), wherein

[0948] A is CH or N,

[0949] Q is CR Q ,

[0950] R Q C 3-6 Cycloalkyl,

[0951] E is CH,

[0952] R 1P is selected from a C which may be substituted 1-3 a naphthylene group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formulas (II-22A), (II-22B), and (II-22C),

[0953]

[0954] R 1a is halogen, R 1c C 1-3 alkyl,

[0955] R 2 -V 1 -V 2 or W,

[0956] V1 is a bond, -O- or -N(R V1 )-,

[0957] R V1 C 1-3 alkyl,

[0958] V 2 is the following formula (VI-2),

[0959]

[0960] W is the following formula (XII),

[0961]

[0962] R 3 C can be substituted 1-6 an alkyl group, an optionally substituted heterocycloalkyl group, or an optionally substituted heteroaryl group,

[0963] R 5 is H or a group selected from the group consisting of the following formulae (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV),

[0964]

[0965] R 5a and R 5b The same or different, H, C which may be substituted 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl,

[0966] X is -O-,

[0967] Y 1 -O-(C 1-3 alkylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[0968] Y 2 is phenylene,

[0969] The linking group is -(L 1 -L 2 -L 3 -L 4 )-,

[0970] L 1 is C=O,

[0971] L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl,

[0972] L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl,

[0973] L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene,

[0974] R L3 H or C 1-3 alkyl,

[0975] R L4 H or C 1-3 alkyl,

[0976] EUB is a group capable of binding to parahydroxycerebroside. The group capable of binding to parahydroxycerebroside is represented by the following formula (XV):

[0977]

[0978] G is CH or N,

[0979] Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23),

[0980] Here, the ring B1 and the ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group,

[0981] Wherein, when G is N, Z is a group selected from the group consisting of free formulas (Z-16), (Z-20), (Z-22) and (Z-23),

[0982]

[0983]

[0984] R Z1 C 1-3 Alkyl or halogen,

[0985] n is an integer from 0 to 1,

[0986] R Z2 C 1-3 alkyl,

[0987] M is a bond or C 1-3 Alkylene,

[0988] Ring B1 is a benzene ring or a pyridine ring,

[0989] Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1,

[0990] Ring B2 is a benzene ring or a pyridine ring,

[0991] Here, M, R Z1 and the linking group forms a bond with the carbon atom constituting ring B2.

[0992] (22-3) The compound or a salt thereof according to (22-2), wherein

[0993] A is CH or N,

[0994] Q is CR Q ,

[0995] R Q is cyclopropyl,

[0996] E is CH,

[0997] R 1P is selected from a C which may be substituted 1-3 a naphthylene group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group, and a halogen group, or a group selected from the group consisting of the following formulas (II-22A), (II-22B), and (II-22C),

[0998]

[0999] R 1a F, R 1c is methyl,

[1000] R 2 -V 1 -V 2 or W,

[1001] V 1 is -O- or -N(CH3)-,

[1002] V 2 is the following formula (VI-2),

[1003]

[1004] W is the following formula (XII),

[1005]

[1006] R 3 C may be substituted by -OCH3 or tetrahydrofuran 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl,

[1007] R 5 For H,

[1008] X is -O-,

[1009] Y 1 -O-(methylene)- *Y2 ( *Y2 Indicates that Y 2 bonding portion. ),

[1010] Y 2 is phenylene,

[1011] The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7),

[1012] Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) 2 Forming bonds,

[1013]

[1014] L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 Alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl,

[1015] L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-,

[1016] R L2 H or C 1-3 alkyl,

[1017] EUB is a group capable of binding to parahydroxycerebroside. The group capable of binding to parahydroxycerebroside is represented by the following formula (XV):

[1018]

[1019] G is CH or N,

[1020] Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F),

[1021] Here, the benzene ring or 6-membered heterocyclic ring in the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group,

[1022] Wherein, when G is N, Z is a group selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F).

[1023]

[1024] One embodiment of the compound of formula (XXIII) or a salt thereof in the present invention is shown below.

[1025] (23-1) A compound of formula (XXIII) or a salt thereof.

[1026] GDB-Linker-EUB

[1027] (XXIII)

[1028] (Where,

[1029] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[1030] -Linking group -EUB is a group selected from the group consisting of the following formula (LE-1) to formula (LE-37).

[1031]

[1032]

[1033]

[1034]

[1035] (23-2) The compound or a salt thereof according to (23-1), wherein

[1036] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[1037] -Linking group-EUB is a group selected from the group consisting of the following formula (LE-5), formula (LE-8), formula (LE-10), formula (LE-20) or (LE-23).

[1038]

[1039] (23-3) The compound or a salt thereof according to (23-2), wherein

[1040] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[1041] -Linking group-EUB is represented by the following formula (LE-10).

[1042]

[1043] (23-4) A compound of formula (XXIII) or a salt thereof.

[1044] GDB-Linker-EUB

[1045] (XXIII)

[1046] (Where,

[1047] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[1048] -Linking group -EUB is a group selected from the group consisting of the following formula (LE-1) to formula (LE-40).

[1049]

[1050]

[1051]

[1052]

[1053] (23-5) The compound or a salt thereof according to (23-4), wherein

[1054] GDB is a group that has the ability to bind to the G12D mutant KRAS protein.

[1055] -Linking group-EUB is a group selected from the group consisting of the following formula (LE-5), formula (LE-8), formula (LE-10), formula (LE-15) or formula (LE-23).

[1056]

[1057] The compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may exist as tautomers or geometric isomers depending on the types of substituents. In this specification, the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may be described as only one isomer, but the present invention also includes other isomers, isolated products of isomers, or mixtures thereof.

[1058] In addition, compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may have asymmetric carbon atoms or axial asymmetry, and diastereomers based on these may exist. The present invention also includes isolated products of diastereomers of compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or mixtures thereof.

[1059] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of compounds represented by formula (I), formula (XXI), formula (XXII), or formula (XXIII). Pharmaceutically acceptable prodrugs refer to compounds having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of prodrug-forming groups include those described in Prog. Med., 1985, 5, p. 2157-2161 and "Drug Development," Volume 7, Molecular Design, Hirokawa Shoten, 1990, p. 163-198.

[1060] In addition, salts of compounds of formula (I), (XXI), (XXII), or (XXIII) refer to pharmaceutically acceptable salts of the compounds of formula (I), which may form acid addition salts or salts with bases depending on the types of substituents. Examples include salts described 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; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric 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 acetyleucine, lysine, and ornithine; and ammonium salts.

[1061] Furthermore, the present invention also includes various hydrates, solvates and polymorphs of the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) and salts thereof.

[1062] In addition, the present invention includes all compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or their salts which are labeled with one or more radioactive or non-radioactive isotopes acceptable in pharmaceutical sciences. Examples of preferred isotopes for isotope labeling of the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O. 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), sulfur ( 35 S, etc.) isotopes.

[1063] The compounds of the present invention that are labeled with isotopes can be used in studies such as tissue distribution of drugs and / or substrates. For example, tritium ( 3 H), carbon 14 ( 14C) and other radioactive isotopes are used for this purpose.

[1064] Replacement with a heavier isotope, such as replacement of hydrogen with deuterium ( 2 H) Sometimes, due to the improved metabolic stability, it is therapeutically advantageous (e.g., increased half-life in vivo, reduced dosage, reduced drug interactions).

[1065] Positron-emitting isotopes ( 11 C. 18 F. 15 O and 13 N, etc.) can be used in positron emission tomography (PET) experiments to test substrate receptor occupancy.

[1066] The isotope-labeled compounds of the present invention can generally be produced by conventional methods known to those skilled in the art or by the same production methods as in the Examples or Production Examples using an appropriate isotope-labeled reagent instead of an unlabeled reagent.

[1067] (Manufacturing Method)

[1068] Compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) and salts thereof can utilize the feature based on the kind of its basic structure or substituent, and various known synthetic methods are applied to manufacture.At this moment, according to the kind of functional group, sometimes in advance, the functional group is replaced with suitable protecting group (the group that can be easily converted into the functional group) in the stage from raw material to intermediate, and this is effective in manufacturing technology.As such protecting group, the protecting group etc. recorded in, for example, PGM Wuts and TW Greene can be enumerated, " Greene's Protective Groups in Organic Synthesis ", the 5th edition, John Wiley & Sons Inc., 2014 can be suitably selected to use according to their reaction conditions.In such method, after importing this protecting group to react, removing protecting group as required, thus can obtain desired compound.

[1069] In addition, the prodrug of the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) can be produced by introducing a specific group at the stage from the raw material to the intermediate, or by further reacting the obtained compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII), in the same manner as the above-mentioned protecting groups. The reaction can be carried out by applying methods well known to those skilled in the art such as conventional esterification, amidation, and dehydration.

[1070] Hereinafter, representative production methods of compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) are described. Each production method can also be carried out with reference to the references attached in this description. It should be noted that the production method of the present invention is not limited to the examples shown below.

[1071] In this specification, the following abbreviations may be used.

[1072] DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidino Hexafluorophosphoric acid, iPr2O: diisopropyl ether, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2]octane, TfOH: trifluoromethanesulfonic acid, COMU: N-[({[(1Z)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethanamine hexafluorophosphate, NMM: N-methylmorpholine, CDI: 1,1'-carbonyldiimidazole, NMO: N-methylmorpholine N-oxide, LHMDS: lithium bis(trimethylsilyl)amide, NHMDS: sodium bis(trimethylsilyl)amide, DMEDA: N,N'-dimethylethylenediamine, Triton B: benzyltrimethylammonium hydroxide, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[1073] (First Manufacturing Method)

[1074] This production method is a first method for producing the compound of formula (I) or a salt thereof.

[1075]

[1076] (where PG1 -R 11 For R 1 The NH or OH contained therein is bonded with PG as a protecting group 1 Group, PG 2 -R 21 For R 2 The NH or OH contained therein is bonded with PG as a protecting group 2 The same applies below)

[1077] The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction under acidic conditions. Examples of protecting groups that can be deprotected under acidic conditions include tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl.

[1078] In this reaction, the deprotecting agent is used in an equivalent amount or an excess amount to compound (1) in a solvent inert to the reaction, and the reaction is carried out under cooling or heating under reflux, usually with stirring for 0.1 hour to 5 days. Examples of the deprotecting agent used here are not particularly limited, and include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. Examples of the solvent used here are not particularly limited, and include alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, or chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, TfOH, or water; and mixtures thereof.

[1079] In addition, by selecting a protecting group, deprotection can also be carried out by catalytic hydrogenation or under alkaline conditions. As examples of protecting groups that can be deprotected by catalytic hydrogenation, benzyl, p-methoxybenzyl, benzyloxycarbonyl, etc. can be listed. In addition, deprotection can also be carried out using fluoride ion sources such as tetra-n-butylammonium fluoride. As examples of protecting groups, tert-butyl (dimethyl) silyl, (trimethylsilyl) ethoxymethyl, etc. can be listed. As examples of protecting groups that can be deprotected under alkaline conditions, acetyl, trifluoroacetyl, benzoyl, etc. can be listed. In addition, as PG1 and PG2, protecting groups that can be deprotected under different deprotection conditions can also be selected respectively, and deprotection can be carried out in stages.

[1080] As references for this reaction, for example, the following documents can be referred to.

[1081] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis (5th ed., 2014)”.

[1082] When the compound (1) as a starting material has axial asymmetry, the present reaction can also be carried out using stereoisomers obtained by temporarily separating the compound (1).

[1083] (Second Manufacturing Method)

[1084] This production method is a second method for producing a salt of the compound of formula (I).

[1085]

[1086] The compound of formula (I) or a salt thereof can be obtained by subjecting compound (1) to a deprotection reaction under acidic conditions, followed by treatment under alkaline conditions to isolate the compound as a free form, and then subjecting the compound to a salt-forming reaction. Examples of protecting groups that can be deprotected under acidic conditions include tert-butyloxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl.

[1087] In this reaction, a deprotecting agent in an equivalent amount or an excess amount to compound (1) is used, and the mixture is stirred in a solvent inert to the reaction, usually for 0.1 hour to 5 days under cooling or heating under reflux, and then treated with an alkaline aqueous solution to isolate the compound in its free form. Subsequently, an acidic agent in an equivalent amount or an excess amount is used, and the mixture is stirred in a solvent inert to the reaction, usually for 0.1 hour to 5 days under cooling or heating under reflux. Examples of the deprotecting agent used here are not particularly limited, and include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. Examples of the solvent used here are not particularly limited, and include alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, or chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, TfOH, or water; and mixtures thereof. Examples of the acidic reagent used here include acids such as hydrogen chloride (DOX solution), phosphoric acid, and p-toluenesulfonic acid. Examples of the alkaline aqueous solution used here are not particularly limited, but include sodium bicarbonate aqueous solution.

[1088] In addition, by selecting a protecting group, deprotection can also be carried out by catalytic hydrogenation or under alkaline conditions. As examples of protecting groups that can be deprotected by catalytic hydrogenation, benzyl, p-methoxybenzyl, benzyloxycarbonyl, etc. can be listed. In addition, deprotection can also be carried out using fluoride ion sources such as tetra-n-butylammonium fluoride. As examples of protecting groups, tert-butyl (dimethyl) silyl, (trimethylsilyl) ethoxymethyl, etc. can be listed. As examples of protecting groups that can be deprotected under alkaline conditions, acetyl, trifluoroacetyl, benzoyl, etc. can be listed. In addition, as PG1 and PG2, protecting groups that can be deprotected under different deprotection conditions can also be selected respectively, and deprotection can be carried out in stages.

[1089] As references for this reaction, for example, the following documents can be referred to.

[1090] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis (5th ed., 2014)”.

[1091] When the compound (1) as a starting material has axial asymmetry, the present reaction can also be carried out using stereoisomers obtained by temporarily separating the compound (1).

[1092] (Raw Material Manufacturing Method 1)

[1093] The present production method is a method for producing compound (1)-1 contained in compound (1) which is a raw material of the first production method and the second production method.

[1094]

[1095] (Where, L 2A Indicates that it can be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, R LG Indicates C 1-12 Alkyl. Same below)

[1096] (First step)

[1097] This step is a step of obtaining compound (3) by subjecting compound (2) to hydrolysis conditions.

[1098] In this reaction, the same amount of a hydrolysis reagent as compound (2) or an excess amount of a hydrolysis reagent is used, and the reaction is carried out in a solvent inert to the reaction, under cooling or heating under reflux, usually with stirring for 1 hour to 5 days. Examples of the hydrolysis reagent used here are not particularly limited, and include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous lithium hydroxide solution, trimethyltin hydroxide, etc. Examples of the solvent are not particularly limited, and include alcohols such as methanol, ethanol, and n-propanol; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, or chloroform; acetonitrile; water; and mixtures thereof.

[1099] (Step 2)

[1100] This step is a step of obtaining compound (1)-1 by subjecting compound (3) and compound (4) to condensation reaction conditions.

[1101] In this reaction, compound (3) and compound (4) are used in equal or excess amounts, and a condensing agent and a base are added to the mixture. The mixture is stirred in a solvent inert to the reaction at room temperature for typically 1 hour to 1 day. Examples of the condensing agent used herein are not particularly limited, and include HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, COMU, and PyBOP. Examples of the base are not particularly limited, and include organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine; and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate. Examples of the solvent include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; alcohols such as methanol, ethanol, and n-propanol; N,N-dimethylformamide; and mixtures thereof.

[1102] (Raw Material Manufacturing Method 2)

[1103] This production method is a first method for producing compound (2)-1 contained in compound (2) which is a raw material in raw material production method 1.

[1104]

[1105] (where PG 3 Represents the protecting group of OH, LG 1 represents a leaving group, and BLG represents a boronic acid group or a trifluoroborate group protected by a boronic acid protecting group such as a boronic acid group or a boronic acid pinacol ester group (hereinafter sometimes referred to as a boronic acid group, etc.). Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies hereinafter).

[1106] (First step)

[1107] This step is a method for producing compound (7) by an in situ substitution reaction of compound (5)-1 with compound (6)-1.

[1108] In this reaction, compound (5)-1 and compound (6)-1 are used in equal or excess equivalents, and the mixture is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or under heating at reflux, preferably at 0°C to 120°C, for typically 0.1 hour to 5 days. Examples of the solvent 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, dehydrated THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN, and NMP; and mixtures thereof. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, NMM, DABCO, and t-BuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate may be advantageous in terms of smoothing the reaction.

[1109] Alternatively, compound (7) can be produced by subjecting the compound obtained by the Mizoroki-Heck reaction of compound (5)-1 and compound (6)-1 to catalytic hydrogenation.

[1110] [literature]

[1111] Chem.Rev.,2003,103,p.2945-2964

[1112] (Step 2)

[1113] This step is a method for producing compound (9) by an in situ substitution reaction between compound (7) and compound (8).

[1114] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1115] Alternatively, compound (9) can be produced by reacting a compound obtained by converting the hydrogen atom of compound (8) into a halogen with compound (7) through a Negishi coupling reaction.

[1116] [literature]

[1117] ACC.Chem.Res.,1982,15,p.340-348

[1118] (Step 3)

[1119] This step is to react compound (9) with PG 3 A method for producing compound (10)-1 by in-situ substitution reaction of -OH.

[1120] As the PG used here 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.

[1121] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1122] (Step 4)

[1123] This step is to prepare a compound (10) containing either compound (10)-1 obtained in the third step of this synthesis method or compound (10)-2 obtained in the third step of the raw material production method 9 described later, and a compound (10) containing R Q A method for producing compound (11) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a boronic acid group. Examples of the boronic acid group used herein are not particularly limited, and examples thereof include boronic acid groups, boronic acid ester groups, boronic acid pinacol ester groups, triol borate salt groups, and trifluoroborate salt groups.

[1124] In this reaction, the compound (10) and the compound containing R are used in the same amount or in an excess amount. QA mixture of these is stirred in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20°C to 140°C, for typically 0.1 hour to 5 days. Examples of solvents used herein are not particularly limited and include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and pentanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, and water; and mixtures thereof. Examples of bases include inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, and cesium carbonate. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and methylsulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II). Conducting the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, 1,1'-bis(diphenylphosphino)ferrocene, butyldi-1-adamantylphosphine, or di(adamantan-1-yl)(butyl)phosphine may be advantageous in terms of smoothing the reaction. Alternatively, a precatalyst of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) may be used as the palladium catalyst for this reaction. Furthermore, heating the mixture by microwave irradiation may be advantageous in terms of smoothing the reaction.

[1125] [literature]

[1126] J.Am.Chem.Soc.,2005,127,p.4685-4696

[1127] Org.Lett.2011,13,p.3948-3951

[1128] Org.Lett.2012,14,p.1278-1281

[1129] Compound (11) (wherein R Q is hydrogen).

[1130] [literature]

[1131] J.Org.Chem.,1977,42,p.3491-3494

[1132] Tetrahedron Letters 2013,54,5207-5210

[1133] (Step 5)

[1134] This step is a method for producing compound (13) by Suzuki-Miyaura coupling reaction of compound (11) and compound (12).

[1135] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1136] It should be noted that compound (13) sometimes has axial asymmetry and sometimes is obtained as a mixture of stereoisomers. 1 Compound (13) having a protecting group or a compound obtained by subjecting compound (13) to a deprotection reaction (e.g., compound (14)) is subjected to a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer.

[1137] (Step 6)

[1138] This step is a method for producing compound (14) by deprotecting compound (13) by catalytic hydrogenation.

[1139] This reaction can be carried out by stirring compound (13) in a solvent inert to the reaction such as MeOH, EtOH, ethyl acetate, etc. under a hydrogen atmosphere at normal pressure to increased pressure in the presence of a metal catalyst under cooling or heating, preferably at room temperature for 1 hour to 5 days. As the metal catalyst, palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plates and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, etc. can be used. Tetrahydro-2H-pyran-2-yl can be used as PG 1 When a protecting group is present in the reaction mixture, a base may be used to suppress its deprotection. Examples of the base used herein are not particularly limited, and include sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.

[1140] It should be noted that compound (14) may have axial asymmetry and be obtained as a mixture of stereoisomers. 1 Compound (14) having a protecting group or a compound obtained by subjecting compound (14) to a deprotection reaction is subjected to a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer.

[1141] As references for this reaction, for example, the following documents can be referred to.

[1142] "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 5th edition, Volume 13, Maruzen, 2004

[1143] (Step 7)

[1144] This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15).

[1145] In this reaction, the compound (14) and the compound (15) are used in equal or excess amounts, and the mixture is reacted in the presence of a base in a solvent inert to the reaction, preferably at 0°C to 80°C, under cooling or under reflux, for a period of typically 0.1 hour to 5 days. The solvent used herein is not particularly limited, and examples thereof 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 the base are not particularly limited, and examples thereof 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. It is sometimes advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.

[1146] As references for this reaction, for example, the following documents can be referred to.

[1147] "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 5th edition, Volume 14, Maruzen, 2005

[1148] It should be noted that compound (2)-1 sometimes has axial asymmetry and is obtained as a mixture of stereoisomers. 1 Compound (2)-1 having a protecting group or a compound obtained by subjecting compound (2)-1 to a deprotection reaction is subjected to a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer.

[1149] Furthermore, compound (15) can be combined with LG 1 LG can be produced by sulfonylation of a compound containing a considerable portion of hydroxyl groups in the presence of a base. 1is a compound having a sulfonyloxy group. Examples of the sulfonylating agent used herein are not particularly limited, and examples thereof include methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. Examples of the base are not particularly limited, and examples thereof include TEA, DIPEA, pyridine, and tetramethylethylenediamine.

[1150] As references for this reaction, for example, the following documents can be referred to.

[1151] Synthesis 1999,9,p.1633-1636

[1152] (Raw Material Manufacturing Method 3)

[1153] This production method is a second method for producing compound (2)-1 contained in compound (2) which is a raw material in the production method 1 for producing raw materials.

[1154]

[1155] (In the formula, q represents 1 or 2. The same applies to the following)

[1156] (First step)

[1157] This step is to react compound (7) with R LG A method for producing compound (16) by in-situ substitution reaction of -SH. LG Examples of -SH include C 1-12 Alkyl mercaptan, such as ethyl mercaptan and dodecanethiol.

[1158] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1159] (Step 2)

[1160] This step is to react compound (16) with PG 3 A method for producing compound (17)-1 by in-situ substitution reaction of -OH. 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.

[1161] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1162] (Step 3)

[1163] This step is to prepare a compound (17) containing either the compound (17)-1 obtained in the second step of this synthesis method or the compound (17)-2 obtained in the fourth step of the raw material production method 8 described later, and a compound (17) containing R Q A method for producing compound (18) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[1164] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1165] Compound (18) (wherein R Q is hydrogen).

[1166] [literature]

[1167] J.Org.Chem.,1977,42,p.3491-3494

[1168] Tetrahedron Letters 2013,54,5207-5210

[1169] (Step 4)

[1170] This step is a method for preparing compound (19) by Suzuki-Miyaura coupling reaction of compound (18) and compound (12).

[1171] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1172] It should be noted that compound (19) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (19) can be isolated by conventional resolution procedures, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, the stereoisomers of compound (19) can be isolated by deprotecting compound (19) and then isolating the stereoisomers, followed by reprotection with a protecting group.

[1173] Examples of the protecting group in the case of reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1174] (Step 5)

[1175] This step is a method for producing compound (20) by oxidation reaction of compound (19).

[1176] In this reaction, compound (19) is treated with an equivalent or excess equivalent of an oxidizing agent in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 80°C, for usually 0.1 hour to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is preferably used. Examples of solvents include aromatic hydrocarbons such as benzene and toluene; ethers such as THF; halogenated hydrocarbons such as chloroform and dichloromethane; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, potassium monopersulfate (Oxone), activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.

[1177] [literature]

[1178] "Experimental Chemistry Lectures" edited by the Chemical Society of Japan, 5th edition, Volume 17, Maruzen, 2004 (Step 6)

[1179] This step is a method for producing compound (13) by an in situ substitution reaction between compound (20) and compound (8).

[1180] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1181] When compound (13) has axial asymmetry, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[1182] (Step 7)

[1183] This step is a method for producing compound (14) by deprotecting compound (13) by catalytic hydrogenation.

[1184] The reaction conditions are the same as those in the sixth step of the raw material production method 2.

[1185] It should be noted that compound (14) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (14) can be isolated as individual stereoisomers by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[1186] (Step 8)

[1187] This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15).

[1188] The reaction conditions are the same as those in the seventh step of the raw material production method 2.

[1189] It should be noted that compound (2)-1 may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (2)-1 can be isolated by conventional resolution procedures, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (2)-1 may be deprotected to isolate the stereoisomers, and then protected again with a protecting group to isolate the stereoisomers.

[1190] Examples of the protecting group in the case of reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1191] (Raw Material Manufacturing Method 4)

[1192] This production method is a third method for producing compound (2)-1 contained in compound (2) which is a raw material in the raw material production method 1.

[1193]

[1194] (First step)

[1195] This step is a method for producing compound (21) by deprotecting compound (20) by catalytic hydrogenation.

[1196] The reaction conditions are the same as those in the sixth step of the raw material production method 2.

[1197] It should be noted that compound (21) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (21) can be isolated as individual stereoisomers by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[1198] (Step 2)

[1199] This step is a method for producing compound (22) by alkylation reaction of compound (21) and compound (15).

[1200] The reaction conditions are the same as those in the seventh step of the raw material production method 2.

[1201] It should be noted that compound (22) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (22) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (22) may be deprotected to isolate the stereoisomers, and then protected again with a protecting group to isolate the stereoisomers.

[1202] Examples of the protecting group in the case of reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1203] (Step 3)

[1204] This step is a method for preparing compound (2)-1 by an in situ substitution reaction between compound (22) and compound (8).

[1205] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1206] It should be noted that compound (2)-1 sometimes has axial asymmetry and is obtained as a mixture of stereoisomers. The individual stereoisomers can be isolated by subjecting compound (2)-1 or the compound obtained by subjecting compound (2)-1 to a deprotection reaction to conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[1207] The reaction conditions of the deprotection reaction used here are the same as those in the procedure described in Production Method 1.

[1208] (Raw Material Manufacturing Method 5)

[1209] This production method is a first method for producing compound (2)-2 contained in compound (2) which is a raw material in the raw material production method 1.

[1210]

[1211]

[1212] (where PG 22 represents tert-butyl. The same applies below)

[1213] (First step)

[1214] This step is a method for producing compound (23) by hydrolyzing compound (5)-1.

[1215] In this reaction, compound (5)-1 and a hydrolysis agent are used in equal or excess equivalents in a solvent inert to the reaction, and the mixture is stirred under cooling or heating under reflux for generally 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include alcohols such as methanol and ethanol; acetone, DMF, THF, etc. In addition, a mixed solvent of the above solvents and water may be suitable for the reaction. Examples of the hydrolysis agent are not particularly limited, and include aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.

[1216] As references for this reaction, for example, the following documents can be referred to.

[1217] "Experimental Chemistry Lectures (5th Edition)" 16 volumes (2005) edited by the Chemical Society of Japan (Maruzen)

[1218] Angew.Chem.Int.Ed.2005,44,p.1378-1382.

[1219] (Step 2)

[1220] This step is a method for producing compound (24) by protecting the hydroxyl group of compound (23) with a tert-butyl group.

[1221] In this reaction, the compound (23) and the tert-butyl protecting agent are used in equal or excess amounts in a solvent inert to the reaction, and the mixture is stirred under cooling or heating under reflux for generally 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and include ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; t-BuOH, DMF, etc. Examples of the tert-butyl protecting agent are not particularly limited, and include isobutylene, 2-tert-butyl-1,3-diisopropylisourea, etc.

[1222] Alternatively, compound (24) can be produced by a dehydration condensation reaction of compound (23) with tBuOH.

[1223] As references for this reaction, for example, the following documents can be referred to.

[1224] PGM Wuts and TW Greene, “Greene’s Protective Groups in Organic Synthesis,” 5th edition, John Wiley & Sons Inc., 2014

[1225] Org.Lett.,2012,14,17,p.4678-4681

[1226] (Step 3)

[1227] This step is to react compound (24) with R LG A method for producing compound (25) by in-situ substitution reaction of -SH.

[1228] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1229] (Step 4)

[1230] This step is to react compound (25) with PG 3 A method for producing compound (26) by in-situ substitution reaction of -OH.

[1231] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1232] (Step 5)

[1233] This step is to react compound (26) with a Q A method for producing compound (27) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[1234] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1235] Compound (27) (wherein R Q is hydrogen).

[1236] [literature]

[1237] J.Org.Chem.,1977,42,p.3491-3494

[1238] Tetrahedron Letters 2013,54,5207-5210

[1239] (Step 6)

[1240] This step is a method for preparing compound (28) by Suzuki-Miyaura coupling reaction of compound (27) and compound (12).

[1241] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1242] It should be noted that compound (28) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (28) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (28) may be deprotected to isolate the stereoisomers, and then protected again with a protecting group to isolate the stereoisomers.

[1243] Examples of the protecting group in the case of reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1244] (Step 7)

[1245] This step is a method for producing compound (29) by oxidation reaction of compound (28).

[1246] The reaction conditions are the same as those in the fifth step of the raw material production method 3.

[1247] As references for this reaction, for example, the following documents can be referred to.

[1248] PGM Wuts and TW Greene, “Greene’s Protective Groups in Organic Synthesis,” 5th edition, John Wiley & Sons Inc., 2014

[1249] (Step 8)

[1250] This step is a method for producing compound (30) by an in situ substitution reaction between compound (29) and compound (8).

[1251] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1252] (Step 9)

[1253] This step is a method for producing compound (31) by deprotecting compound (30) by catalytic hydrogenation.

[1254] The reaction conditions are the same as those in the sixth step of the raw material production method 2.

[1255] It should be noted that compound (31) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (31) can be isolated as individual stereoisomers by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography.

[1256] (Step 10)

[1257] This step is a method for producing compound (32) by alkylation reaction of compound (31) and compound (15).

[1258] The reaction conditions are the same as those in the seventh step of the raw material production method 2.

[1259] It should be noted that compound (32) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (32) can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (32) may be deprotected to isolate the stereoisomers, and then protected again with a protecting group to isolate the stereoisomers.

[1260] (Step 11)

[1261] This step is a method for producing compound (33) by subjecting compound (32) to a deprotection reaction.

[1262] The reaction conditions are the same as those in the steps described in the first production method.

[1263] Furthermore, after deprotection, compound (33) may be protected again with a protecting group. Examples of the protecting group for reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1264] Alternatively, the above-mentioned series of deprotection and reprotection with a protecting group can be carried out as a single-step reaction.

[1265] (Step 12)

[1266] This step is a method for producing compound (2)-2 by reacting compound (33) with compound (6)-1.

[1267] In this reaction, compound (33) and compound (6)-1 are used in equal or excess equivalents, and a mixture of these is stirred in a solvent inert to the reaction in the presence of a condensing agent under cooling or heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days. Examples of solvents are not particularly limited, and include: aromatic hydrocarbons such as benzene and toluene; ethers such as THF and DOX; halogenated hydrocarbons such as chloroform and dichloromethane; alcohols such as methanol and ethanol; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of condensing agents include PyBOP, HATU, and CDI. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate is sometimes advantageous in terms of smoothing the reaction.

[1268] (Raw Material Manufacturing Method 6)

[1269] This production method is a method for producing compound (13)-1 contained in compound (13) which is an intermediate in raw material production method 2.

[1270]

[1271] (First step)

[1272] This step is a method for producing compound (34) by subjecting compound (30) to a deprotection reaction.

[1273] The reaction conditions are the same as those in the steps described in the first production method.

[1274] Furthermore, after deprotection, compound (34) may be protected again with a protecting group. Examples of the protecting group for reprotection include tetrahydro-2H-pyran-2-yl and the like.

[1275] Alternatively, the above-mentioned series of deprotection and reprotection with a protecting group can be carried out as a single-step reaction.

[1276] (Step 2)

[1277] This step is a method for preparing compound (13)-1 by reacting compound (34) with compound (6)-1.

[1278] The reaction conditions are the same as those in the twelfth step of the raw material production method 5.

[1279] (Raw Material Manufacturing Method 7)

[1280] This production method is a method for producing compound (30) which is a raw material in the raw material production method 6.

[1281]

[1282] (First step)

[1283] This step is a method for producing compound (37) by an in situ substitution reaction between compound (24) and compound (8).

[1284] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1285] (Step 2)

[1286] This step is to react compound (37) with PG 3 A method for producing compound (38) by in-situ substitution reaction of -OH.

[1287] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1288] (Step 3)

[1289] This step is to react compound (38) with a Q A method for producing compound (39) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[1290] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1291] Compound (39) (wherein R Q is hydrogen).

[1292] [literature]

[1293] J.Org.Chem.,1977,42,p.3491-3494

[1294] Tetrahedron Letters 2013,54,5207-5210

[1295] (Step 4)

[1296] This step is a method for preparing compound (30) by Suzuki-Miyaura coupling reaction of compound (39) and compound (15).

[1297] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1298] It should be noted that compound (30) may have axial asymmetry and may be obtained as a mixture of stereoisomers. Compound (30) can be isolated by conventional resolution procedures, such as resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (30) may be deprotected to isolate the stereoisomers, and then protected again with a protecting group to isolate the stereoisomers.

[1299] (Raw Material Manufacturing Method 8)

[1300] This production method is a method for producing compound (17)-2 contained in compound (17) which is an intermediate in raw material production method 3.

[1301]

[1302] (First step)

[1303] This step is a method for producing compound (5)-2 by chlorination reaction of compound (40).

[1304] In this reaction, the compound (40) and the chlorinating agent are used in equal or excess amounts, and the mixture is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or heating to reflux, preferably at 60°C to heating to reflux, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; DMF, DMAc, etc. Examples of the chlorinating agent include phosphorus oxychloride and thionyl chloride. It is sometimes advantageous to conduct the reaction in the presence of an organic base such as TEA, DIPEA, or NMM in order to facilitate the reaction.

[1305] (Step 2)

[1306] This step is to react compound (5)-2 with R LG A method for producing compound (41) by in-situ substitution reaction of -SH.

[1307] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1308] (Step 3)

[1309] This step is to react compound (41) with PG 3 A method for producing compound (42) by in-situ substitution reaction of -OH.

[1310] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1311] (Step 4)

[1312] This step is a method for preparing compound (17)-2 by an in situ substitution reaction between compound (42) and compound (6)-1.

[1313] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1314] (Raw Material Manufacturing Method 9)

[1315] This production method is a method for producing compound (10)-2.

[1316]

[1317] (First step)

[1318] This step is a method for preparing compound (43) by an in situ substitution reaction between compound (5)-2 and compound (8).

[1319] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1320] Alternatively, compound (43) can be produced by coupling a compound in which the hydrogen atom of compound (8) is converted to a halogen with the negishi of compound (5)-2.

[1321] (Step 2)

[1322] This step is to react compound (43) with PG 3 A method for producing compound (44) by in-situ substitution reaction of -OH.

[1323] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1324] (Step 3)

[1325] This step is a method for preparing compound (10)-2 by an in situ substitution reaction between compound (44) and compound (6)-1.

[1326] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1327] (Raw Material Manufacturing Method 10)

[1328] This production method is a method for producing compound (4)-1 contained in compound (4) which is an intermediate in raw material production method 1.

[1329]

[1330] (Where, L 2B Indicates that it can be C 1-3 Alkyl-substituted piperazinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, PG E3 and PG L2 Represents the protecting group of NH, LG Z represents a leaving group, and BLG represents a boronic acid group or a trifluoroborate group protected by a boronic acid protecting group such as a boronic acid group or a boronic acid pinacol ester group (hereinafter sometimes referred to as a boronic acid group, etc.). E3 Compounds partially containing H can also be used to produce compound (4)-1 by the same reaction. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies hereinafter)

[1331] (First step)

[1332] This step is a step of obtaining compound (47) by subjecting compound (45) and compound (46) to Suzuki-Miyaura coupling reaction conditions.

[1333] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1334] (Step 2-1A)

[1335] This step is a step of obtaining a 1,2-diol compound by subjecting the compound (47) to oxidation reaction conditions.

[1336] In this reaction, a compound of compound (47), an oxidizing agent, and an excess equivalent of a reoxidizing agent are used, and the reaction is carried out by stirring in a solvent inert to the reaction under ice cooling to room temperature for usually 1 hour to 2 days. Examples of the oxidizing agent used here are not particularly limited, and examples include osmium (VIII) tetroxide, PI osmium (VIII) oxide, or PEM polymer microcapsule osmium (VIII) oxide. Examples of the reoxidizing agent used here are not particularly limited, and examples include NMO, trimethylamine oxide, tBuOOH, K3Fe(CN)6, etc. The solvent used here is not particularly limited, and ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tBuOH, acetone, acetonitrile, toluene, water, and mixtures thereof are used.

[1337] (Step 2-1B)

[1338] This step is a step of obtaining compound (48) by subjecting the compound obtained in the above (Second Step-1A) to oxidative cleavage reaction conditions.

[1339] This reaction is carried out using the compound obtained in (Step 2-1A) and an equal amount or an excess amount of an oxidizing agent in a reaction-inert solvent, stirring under ice cooling to room temperature, typically for 1 hour to 2 days. Examples of the oxidizing agent used here are not particularly limited, and include sodium periodate or periodic acid. Examples of the solvent used here are not particularly limited, and include ethereal solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, halogenated hydrocarbons such as acetonitrile, water, dichloromethane, dichloroethane, and chloroform, and mixtures thereof.

[1340] Alternatively, the above-mentioned (Second Step-1A) and (Second Step-1B) can also be carried out as a one-step reaction.

[1341] [literature]

[1342] J.Org.Chem.1956,21,4,478-479

[1343] (Step 2-2)

[1344] This step is a step of subjecting compound (47) to oxidation reaction conditions to obtain compound (48). This step is a method for obtaining compound (48) by a method different from Step 2-1A and Step 2-1B.

[1345] In this reaction, the compound (47) is stirred in an ozone atmosphere in a solvent inert to the reaction under ice cooling to room temperature, usually for 1 hour to 1 day, and then treated with a reducing agent. Examples of the reducing agent used herein are not particularly limited, and examples include dimethyl sulfide, triphenylphosphine, and metallic zinc. The solvent used herein is not particularly limited, and alcoholic solvents such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ethyl acetate, and mixtures thereof, etc. can be used.

[1346] (Step 3)

[1347] This step is a step of obtaining compound (4)-1' by subjecting compound (48) and compound (49) to reductive amination reaction conditions.

[1348] In this reaction, the compound (48) and the compound (49) are used in equal or excess amounts of one of them, and the reaction is carried out by stirring in a solvent inert to the reaction under ice cooling to room temperature in the presence of a reducing agent and acetic acid, usually for 1 hour to 5 days. Examples of the reducing agent used here are not particularly limited, and include NaBH(OAc)3, 2-methylpyridine borane, NaBH3CN, etc. The solvent used here is not particularly limited, and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, alcohol solvents such as methanol and ethanol, and acetonitrile are used.

[1349] (Step 4)

[1350] This step is a step of obtaining compound (4)-1 by subjecting (4)-1' to deprotection conditions.

[1351] The reaction conditions are the same as those in the first production method.

[1352] (Raw Material Manufacturing Method 11)

[1353] This production method is for producing compound (45)-1' contained in compound (45) as a raw material of raw material production method 10 and PG of compound (45)-1' contained in compound (45). E3 Method for compound (45)-1 wherein the moiety is H.

[1354]

[1355] (where LG E3 represents a leaving group. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below)

[1356] (First step)

[1357] This step is a step of obtaining compound (45)-1' by subjecting compound (50) and compound (51) to alkylation reaction conditions.

[1358] In this reaction, compound (50) and compound (51) are used in equal amounts or in excess of one of them, and the reaction is carried out in the presence of a base in a solvent inert to the reaction, under ice cooling or heating under reflux, usually with stirring for 1 hour to 1 day. Examples of the base used here are not particularly limited, and include sodium hydride, tBuOK, LHMDS, NHMDS, potassium carbonate, cesium carbonate, etc. The solvent used here is not particularly limited, and ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, DMF, MeCN, etc. are used.

[1359] Here, when the compound obtained by the above reaction has a protecting group, the obtained compound can be subjected to deprotection reaction conditions after the above reaction to obtain compound (45)-1'.

[1360] The reaction conditions are the same as those in the first production method.

[1361] (Step 2)

[1362] This step is a step of obtaining compound (45)-1 by subjecting (45)-1' to deprotection conditions.

[1363] The reaction conditions are the same as those in the first production method.

[1364] (Raw Material Manufacturing Method 12)

[1365] This production method is for producing compound (45)-2' contained in compound (45) as a raw material of raw material production method 10 and PG of compound (45)-2' contained in compound (45). E3 Method for compound (45)-2 wherein the moiety is H.

[1366]

[1367] (First step)

[1368] This step is a step of obtaining compound (45)-2' by subjecting compound (52) and compound (53) to coupling reaction conditions using a copper catalyst.

[1369] In this reaction, compound (52) and compound (53) are used in equal or excess amounts of one of them, and a copper catalyst, a ligand, and a base are used, and the reaction is carried out in a solvent inert to the reaction, usually by stirring at room temperature or under heating and reflux for 1 hour to 5 days. Examples of the copper catalyst used herein are not particularly limited, and examples include copper (I) iodide, ketone (I) chloride, and copper (I) oxide. Examples of the ligand used herein are not particularly limited, and examples include DMEDA and trans-N,N'-dimethylcyclohexane-1,2'-diamine. Examples of the base used herein are not particularly limited, and examples include organic bases such as diisopropylethylamine and triethylamine; and inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, and potassium phosphate. Examples of the solvent used herein are not particularly limited, and examples include ether solvents such as tetrahydrofuran and 1,4-dioxane; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, N,N-dimethylformamide, and water. In addition, heating the mixture by irradiating microwaves may be advantageous in terms of smoothly proceeding the reaction.

[1370] (Step 2)

[1371] This step is a step of obtaining compound (45)-2 by subjecting (45)-2' to deprotection conditions.

[1372] The reaction conditions are the same as those in the first production method.

[1373] (Raw Material Manufacturing Method 13)

[1374] This production method is a method for producing compound (4)-2 contained in compound (4) which is an intermediate in raw material production method 1.

[1375]

[1376] (wherein, PG of compound (51) E3 Compounds partially containing H can also be prepared by the same reaction to form compound (4)-2' PG E3 Compounds partially H. The same applies below)

[1377] (First step)

[1378] This step is a step of obtaining compound (55) by subjecting compound (54) and compound (50) to Suzuki-Miyaura coupling reaction conditions.

[1379] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1380] (Step 2)

[1381] This step is a step of obtaining compound (4)-2' by subjecting compound (55) and compound (51) to alkylation reaction conditions.

[1382] The reaction conditions are the same as those in the first step of the raw material production method 11.

[1383] (Step 3)

[1384] This step is a step of obtaining compound (4)-2 by subjecting (4)-2' to deprotection conditions.

[1385] The reaction conditions are the same as those in the first production method.

[1386] (Raw Material Manufacturing Method 14)

[1387] This production method is a method for producing compound (4)-3 contained in compound (4) which is an intermediate in raw material production method 1.

[1388]

[1389] (where LG Zrepresents a leaving group. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below)

[1390] (First step)

[1391] This step is a step of obtaining compound (57) by subjecting compound (54) and compound (56) to Suzuki-Miyaura coupling reaction conditions.

[1392] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1393] (Step 2)

[1394] This step is a step of obtaining compound (4)-3' by subjecting compound (57) and compound (53) to coupling reaction conditions using a copper catalyst.

[1395] The reaction conditions are the same as those in the first step of the raw material production method 12.

[1396] (Step 3)

[1397] This step is a step of obtaining compound (4)-3 by subjecting (4)-3' to deprotection conditions.

[1398] The reaction conditions are the same as those in the first production method.

[1399] (Raw Material Manufacturing Method 15)

[1400] This production method is a method for producing compound (4)-1 contained in compound (4) which is an intermediate in raw material production method 1.

[1401]

[1402] (wherein, PG of compound (45) E3 Compounds partially containing H can also be used to produce compound (4)-1 by the same reaction. (The same applies hereinafter)

[1403] (First step)

[1404] This step is a step of obtaining compound (4)-1' by subjecting compound (54) and compound (45) to Suzuki-Miyaura coupling reaction conditions.

[1405] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1406] (Step 2)

[1407] This step is a step of obtaining compound (4)-1 by subjecting (4)-1' to deprotection conditions.

[1408] The reaction conditions are the same as those in the first production method.

[1409] (Raw Material Manufacturing Method 16)

[1410] This production method is a method for producing compound (4)-5 contained in compound (4) which is an intermediate in raw material production method 1.

[1411]

[1412] (where LG Z3 represents a leaving group. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc. (The same applies below)

[1413] (First step)

[1414] This step is a step of obtaining compound (60) by subjecting compound (58) and compound (59) to cyclization reaction conditions.

[1415] In this reaction, compound (58) and compound (59) are used in equal amounts or in excess of one of them, and the reaction is carried out in the presence of a base in a solvent inert to the reaction, under ice cooling or heating under reflux, usually with stirring for 1 hour to 5 days. Examples of the base used here are not particularly limited, and include organic bases such as triethylamine and N,N'-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate. Examples of the solvent used here are not particularly limited, and include ether solvents such as tetrahydrofuran and 1,4-dioxane, and N,N-dimethylformamide.

[1416] (Step 2)

[1417] This step is a step of obtaining compound (61) by subjecting compound (60) and compound (54) to Suzuki-Miyaura coupling reaction conditions.

[1418] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1419] (Step 3)

[1420] This step is a step of obtaining compound (4)-5' by subjecting compound (61) to cyclization reaction conditions.

[1421] The reaction conditions are the same as those in the third step of the raw material production method 17.

[1422] (Step 4)

[1423] This step is a step of obtaining compound (4)-5 by subjecting compound (4)-5' to deprotection conditions.

[1424] The reaction conditions are the same as those in the first production method.

[1425] (Raw Material Manufacturing Method 17)

[1426] This production method is a method for producing compound (4)-6. By using compound (4)-6 instead of compound (4) described in the raw material production method 1, some compounds included in the compound of formula (1) can be synthesized.

[1427]

[1428] (wherein the linking group is -(-L 2 -L 3 -L 4 )-,L 2 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl, L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene, R L3 H or C 1-3 Alkyl, R L4 H or C 1-3 Alkyl, PG L Represents a protecting group for NH or OH. LG Indicates C 1-12 Alkyl. Same below)

[1429] (First step)

[1430] This step is a step of obtaining compound (64) by subjecting compound (62) and compound (63) to Michael addition reaction.

[1431] In this reaction, compound (62) and compound (63) are used in equivalent amounts or in excess of one of them, and the reaction is carried out by stirring in the presence of a base and an excess of an acidic reagent at room temperature or under heating reflux for generally 1 to 5 days. Examples of the base used herein are not particularly limited, and organic bases such as 1,8-diazabicyclo[5.4.0]undec-7ene and N,N'-diisopropylethylamine are used. Examples of the acidic reagent used herein are not particularly limited, and lactic acid, trifluoroacetic acid, or acetic acid are used.

[1432] (Step 2)

[1433] This step is a step of obtaining compound (65) by subjecting compound (64) to urea reaction conditions.

[1434] The reaction is carried out by stirring in the presence of compound (64), a ureidating agent, and an acid in a solvent inert to the reaction or without a solvent at room temperature or under heating under reflux for generally 1 to 5 days. Examples of the ureidating agent used herein are not particularly limited, and sodium cyanate or potassium cyanate are used. Examples of the acid used herein are not particularly limited, and acetic acid, hydrochloric acid, or trifluoroacetic acid are used. Examples of the solvent used herein are not particularly limited, and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as tetrahydrofuran and 1,4-dioxane, acetic acid, toluene, water, and mixtures thereof are used.

[1435] (Step 3)

[1436] This step is a step of obtaining compound (4)-6' by subjecting compound (65) to cyclization reaction conditions.

[1437] The reaction is carried out by stirring compound (65) in a solvent inert to the reaction in the presence of a base under ice cooling or heating under reflux, usually for 1 hour to 5 days. Examples of the base used herein are not particularly limited, and examples include Triton B, potassium trimethylsiliconate, and sodium ethoxide. Examples of the solvent used herein are not particularly limited, and examples include ether solvents such as tetrahydrofuran and 1,4-dioxane; N,N-dimethylformamide; and acetonitrile.

[1438] (Step 4)

[1439] This step is a step of obtaining compound (4)-6 by subjecting compound (4)-6' to deprotection conditions.

[1440] The reaction conditions are the same as those in the first production method.

[1441] (Raw Material Manufacturing Method 18)

[1442] This production method is a method for producing compound (67). By using compound (67) instead of compound (4) described in the raw material production method 1, some compounds included in the compound of formula (1) can be synthesized.

[1443]

[1444] (Where, L 1 To be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3Alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L 2 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl, L 3 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene, R L3 H or C 1-3 Alkyl, R L4 H or C 1-3 Alkyl, X L Indicates oxygen or nitrogen atoms, PG L1 Represents a protecting group for NH or OH, PG E3 represents a protecting group of NH or H. The same applies hereinafter)

[1445] (First step)

[1446] This step is a step of obtaining compound (67') by subjecting compound (66) and compound (65) to in situ reaction conditions.

[1447] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1448] Alternatively, compound (67') can be produced by subjecting the compound to coupling reaction conditions using a copper catalyst.

[1449] The reaction conditions are the same as those in the first step of the raw material production method 12.

[1450] Alternatively, compound (67') can be produced by providing carbon-nitrogen bond-forming reaction conditions.

[1451] In this reaction, compound (66) and compound (65) are used in equal amounts or in excess of one of them. A metal catalyst, a ligand, and a base are added to the mixture, and the mixture is stirred in a solvent inert to the reaction at 80°C to reflux for usually 1 hour to 5 days.

[1452] Examples of metal reagent catalysts used herein are not particularly limited, and examples thereof include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct. Examples of ligands are not particularly limited, and examples thereof include Xantphos, Ruphos, Xphos, and BINAP. Examples of bases are not particularly limited, and examples thereof include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide; and organic bases such as triethylamine and N,N-diisopropylethylamine. Examples of solvents are not particularly limited, and examples thereof include 1,4-dioxane, toluene, N,N-dimethylformamide, and mixtures thereof. In addition, this reaction can be carried out under microwave irradiation.

[1453] Alternatively, compound (67') can be produced by subjecting the compound to alkylation reaction conditions.

[1454] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1455] (Step 2)

[1456] This step is a step of obtaining compound (67) by subjecting compound (67') to deprotection conditions.

[1457] The reaction conditions are the same as those in the first production method.

[1458] (Raw Material Manufacturing Method 19)

[1459] The present production method is a method for producing compound (1)-2 contained in compound (1) which is a raw material of the first production method.

[1460]

[1461] (Where, L 1A and L 4A represents a substituted heterocycloalkylene group, a substituted heteroarylene group, a saturated 7-membered to 9-membered spiroheterocycloalkylene group containing 1 to 2 nitrogen atoms, a saturated 7-membered to 9-membered bridged heterocycloalkylene group containing 2 nitrogen atoms, and a substituted C 1-6 A group in the group consisting of alkylene, L 3A Indicates that it can be C 1-3 Alkyl-substituted piperidine diyl, which can be C 1-3 Alkyl-substituted piperazine diyl, which can be C 1-3 Alkyl-substituted pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl. The same applies to the following)

[1462] (First step)

[1463] This step is a method for producing compound (69) by alkylation reaction of compound (14) and compound (68).

[1464] The reaction conditions are the same as those in the seventh step of the raw material production method 2.

[1465] (Step 2)

[1466] This step is a step of obtaining compound (70) by subjecting compound (69) to hydrolysis conditions.

[1467] The reaction conditions are the same as those in the first step of the raw material production method 1.

[1468] (Step 3)

[1469] This step is a step of obtaining compound (1)-2 by subjecting compound (70) and compound (71) to condensation reaction conditions.

[1470] The reaction conditions are the same as those in the second step of the raw material production method 1.

[1471] (Raw Material Manufacturing Method 20)

[1472] This production method is a method for producing compound (74). By using compound (74) instead of compound (4) described in the raw material production method 1, some compounds included in the compound of formula (1) can be synthesized.

[1473]

[1474] (wherein, PG of compound (51) E3 Compounds partially containing H can also be prepared by the same reaction to form compound (74).

[1475] (First step)

[1476] This step is a step of obtaining compound (73) by subjecting compound (72) and compound (51) to nucleophilic substitution reaction conditions.

[1477] The reaction conditions are the same as those in the first step of the raw material production method 11.

[1478] (Step 2)

[1479] This step is a step of obtaining compound (74) by subjecting compound (73) to deprotection conditions.

[1480] The reaction conditions are the same as those in the first production method.

[1481] (Raw Material Manufacturing Method 21)

[1482]

[1483] This production method is a method for producing compound (2)-3 contained in (2) which is a raw material of production method 1.

[1484] (First step)

[1485] This step is a method for producing compound (77) by reacting compound (75) and compound (76).

[1486] In this reaction, compound (75) is converted to the corresponding enoate under acidic conditions using an orthoester such as trimethyl orthoformate, and then an equivalent amount or an excess amount of compound (76) is added. The mixture is stirred in a solvent inert to the reaction under heating and reflux, preferably at 60°C, for a period of usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include aromatic hydrocarbons such as toluene; ethers such as THF and DOX; DMF, DMAc, and the like.

[1487] (Step 2)

[1488] This step is a method for producing compound (78) from compound (77).

[1489] This reaction is carried out by stirring compound (77) in a reaction-inert solvent under heating and reflux, preferably at 150°C for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include NMP and the like.

[1490] (Step 3)

[1491] This step is a method for producing compound (79) from compound (78).

[1492] In this reaction, compound (78) and a brominating agent are used in equal amounts or in excess of one of them, and the mixture is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or under heating under reflux, preferably at room temperature, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; and DMF. Examples of the brominating agent include N-bromosuccinimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, and dibromoisocyanuric acid.

[1493] (Step 4)

[1494] This step is a method for producing compound (80) from compound (79).

[1495] The reaction conditions are the same as those in the first step of the raw material production method 8.

[1496] (Step 5)

[1497] This step is a method for producing compound (81) by an in situ substitution reaction between compound (80) and compound (6)-1.

[1498] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1499] (Step 6)

[1500] This step is a method for producing compound (82) by an in situ substitution reaction between compound (81) and compound (8)-1.

[1501] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1502] (Step 7)

[1503] This step is to react compound (82) with PG 3 A method for producing compound (82) by in-situ substitution reaction of -OH.

[1504] As the PG used here 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.

[1505] The reaction conditions are the same as those in the first step of the raw material production method 2.

[1506] (Step 8)

[1507] This step is a method for producing compound (84) by Suzuki-Miyaura coupling reaction of compound (83) with compound (12), a boronic acid derivative.

[1508] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1509] When compound (84) has axial asymmetry, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[1510] In addition, in order to be able to react with the protective group PG introduced later 2 Deprotection under different conditions, sometimes compound (84) is subjected to deprotection reaction and then PG 1 Convert to other protecting groups.

[1511] The reaction conditions of the deprotection reaction used here are the same as those in the procedure described in Production Method 1.

[1512] As the next converted PG 1Examples of the protecting group include tetrahydro-2H-pyran-2-yl and the like.

[1513] As references for this reaction, for example, the following documents can be referred to.

[1514] PGM Wuts and TW Greene, “Greene’s Protective Groups in Organic Synthesis,” 5th edition, John Wiley & Sons Inc., 2014

[1515] (Step 9)

[1516] This step is a method for producing compound (85) by deprotecting compound (84) by catalytic hydrogenation.

[1517] The reaction conditions are the same as those in the sixth step of the raw material production method 2.

[1518] (Step 10)

[1519] This step is a method for producing compound (2)-3 by reacting compound (85) with compound (15).

[1520] The reaction conditions are the same as those in the seventh step of the raw material production method 2.

[1521] (Raw Material Manufacturing Method 22)

[1522]

[1523] This production method is a method for producing compound (4)-7 contained in compound (4) which is an intermediate in raw material production method 1.

[1524] (First step)

[1525] This step is a method for preparing compound (87) from compound (86).

[1526] The reaction conditions are the same as those in the first step of the raw material production method 17.

[1527] (Step 2)

[1528] This step is a method for preparing compound (88) from compound (87).

[1529] The reaction is carried out by adding an ammonia reagent to a solvent inert to the reaction in the presence of compound (87), triphosgene, and a base at room temperature and stirring for generally 1 to 5 days. Examples of the ammonia reagent used herein are not particularly limited, and ammonia methanol solution and the like are used. Examples of the base used herein are not particularly limited, and organic bases such as pyridine, triethylamine, or N,N-diisopropylethylamine are used. Examples of the solvent used herein are not particularly limited, and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform are used.

[1530] (Step 3)

[1531] This step is a method for producing compound (89) from compound (88).

[1532] The reaction conditions are the same as those in the third step of the raw material production method 17.

[1533] (Step 4)

[1534] This step is a step of obtaining compound (90) by subjecting compound (89) and compound (54) to Suzuki-Miyaura coupling reaction conditions.

[1535] The reaction conditions are the same as those in the fourth step of the raw material production method 2.

[1536] (Step 5)

[1537] This step is a step of obtaining compound (4)-7 by subjecting compound (90) to deprotection conditions.

[1538] The reaction conditions are the same as those in the first production method.

[1539] (Raw Material Manufacturing Method 23)

[1540] This production method is a method for producing compound (45)-3 contained in compound (45) which is a raw material in raw material production method 10.

[1541]

[1542] This step is a step of obtaining compound (45)-3 by subjecting compound (92) and compound (53) to coupling reaction conditions using a copper catalyst.

[1543] The reaction conditions are the same as those in the first step of the raw material production method 12.

[1544] The compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) is isolated and purified as a free compound, a salt, a hydrate, a solvate, a polymorph or an amorphous solid. Salts of the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) can also be produced by a salt-forming reaction using conventional methods.

[1545] Isolation and purification can be carried out using common chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography.

[1546] Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., fractional crystallization with diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can be produced from appropriate optically active starting compounds.

[1547] In addition, compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or their intermediates sometimes have axial asymmetry and are obtained as mixtures of stereoisomers. Individual stereoisomers can be isolated by performing conventional resolution operations, such as resolution using octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

[1548] The pharmacological activities of the compounds of formula (I) were confirmed by the following tests.

[1549] Experimental Example 1 Evaluation of KRAS-degrading Effects on Human G12D Mutant KRAS-Positive Pancreatic Cancer Line AsPC-1 (CRL-1682; ATCC)

[1550] The KRAS G12D expression level was measured by cell ELISA to evaluate the KRAS degradation effect of the test compound.

[1551] AsPC-1 cells were plated at 2.0×10 4 20 μL of each cell was seeded into a 384-well plate (Greiner Bio-One) at 37°C in the presence of 5% CO 2 using RPMI1640 (Sigma-Aldrich) medium containing 10% fetal bovine serum (Cytiva).

[1552] The next day, the test compound (final concentration range 10 μM to 0.3 nM, 10 points) and the solvent of the test compound as a negative control, DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.), were diluted 500-fold with fresh culture medium, 20 μL each was added to each well, and cultured overnight.

[1553] The next day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde in phosphate buffer (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to each well. The cells were allowed to stand at room temperature for 30 minutes to fix the cells. The supernatant was then removed, and 20 μL of phosphate-buffered saline (PBS; Fujifilm Wako Pure Chemical Industries, Ltd.) containing 0.1% Triton X-100 (Amersham Biosciences) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed, and 25 μL of PBS was added to each well, and the supernatant was removed to wash the wells. This was washed twice in total. The supernatant was then removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator. The supernatant was removed in the same manner thereafter). 25 μL of PBS was added to each well, and the supernatant was removed to wash the wells. This was washed twice in total. The supernatant was removed, and 20 μL of blocking solution (Intercept Blocking Buffer; Li-COR Biosciences) was added to each well. After standing at room temperature for 30 minutes, the supernatant was removed, and 15 μL of a solution of anti-β-actin antibody (Anti-beta Actin antibody [mAbcam 8226] - Loading Control; abcam) diluted 1000-fold with blocking solution was added to the positive control wells. In the other wells, 15 μL of a solution of anti-Ras (G12D Mutant Specific) antibody (Ras (G12DMutant Specific) (D8H7) Rabbit mAb #14429; Cell Signaling Technology) and anti-β-actin antibody (abcam) diluted 1000-fold was added. The plates were then allowed to stand at 4°C overnight.

[1554] The next day, the supernatant was removed, 25 μL of PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. The supernatant was removed, and 15 μL of a solution prepared by diluting donkey anti-mouse IgG H&L (IRDye680RD) (Li-COR Biosciences) and goat anti-rabbit IgG H&L (IRDye 800CW) (Li-CORBiosciences) 1000 times with a blocking solution was added to each well as a secondary antibody. To the wells serving as the positive control, a solution prepared by diluting donkey anti-mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) 1000 times with a blocking solution was added as a secondary antibody. After standing at room temperature for 1 hour, the supernatant was removed, 25 μL of PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. After removing the supernatant, the plate was air-dried at room temperature for more than 2 hours, and the fluorescence signals at 700 nm and 800 nm were measured using Aerius (Li-COR Biosciences).

[1555] The signal value of RAS measured at a fluorescence wavelength of 800 nm was corrected by the signal value of β-actin measured at a fluorescence wavelength of 700 nm. The signal value when DMSO was added was set to 0%, and the signal value when stained with anti-β-actin antibody alone was set to 100%. The degradation rate at the compound concentration that showed the highest degradation effect was set to Dmax. Based on the degradation rate up to the compound concentration that showed Dmax, the 50% degradation value (DC) of the KRAS amount was calculated by Sigmoid-Emax model nonlinear regression analysis. 50 The results for several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% decomposition values ​​were outside the evaluation range, the decomposition rates at the highest evaluation concentration (10 μM) are shown.

[1556] In the following table, Ex represents the example number. 50 , calculated as 4 hydrochloride salt, about DC of Ex 14 50 , the molecular weight was calculated based on the 3-hydrochloride salt form.

[1557] [Table 1]

[1558] Ex <![CDATA[DC 50 (nM)]]> Dmax(%) Ex <![CDATA[DC 50 (nM)]]> Dmax(%) 1 1946 59 23 2807 61 2 4899 59 24 297 78 3 53 83 25 856 70 4 40% 10 μM 40 26 5216 67 5 308 84 27 25% 10 μM 25 6 2731 49 28 5534 54 7 35 80 29 22 86 8 13 86 30 1482 71 9 55 65 31 115 71 10 8 86 32 46 78 11 58 84 33 79 88 12 18 82 34 202 85 13 408 66 35 3674 48 14 2180 51 36 79 80 15 406 60 37 30 87 16 71 86 38 22 86 17 4274 52 39 22 83 18 85 77 40 23 88 19 278 93 41 52 78 20 488 78 42 294 89 21 4961 52 43 9 90 22 114 84 44 41 74

[1559] Experimental Example 2 Evaluation of the Inhibitory Effect on ERK Phosphorylation in Human G12D Mutant KRAS-Positive Pancreatic Cancer Line AsPC-1

[1560] Phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is located downstream of KRAS signaling, was measured by cell ELISA to evaluate the inhibitory effect of the test compound on ERK phosphorylation.

[1561] AsPC-1 cells were plated at 2.0×10 4 Cells were seeded in 384-well plates at 20 μL / well. Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO 2 .

[1562] The next day, the test compound (final concentration range: 10 μM to 0.3 nM, 10 points), trametinib (MEK inhibitor) at a final concentration of 1 μM as a positive control, and DMSO, the solvent for the test compound as a negative control, were diluted 500-fold with fresh culture medium. 20 μL of each solution was added to each well and incubated overnight. Following incubation, 30 μL of a 30% glyoxal solution (40% glyoxal [Nacalai Tesque] diluted with PBS) was quickly added to each well and the cells were fixed by incubation at room temperature for 120 minutes. The plate was then centrifuged and the supernatant removed (using a centrifugal dehydrator. The supernatant was removed using the same method 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 and the same procedure was repeated. Next, 20 μL of PBS containing 0.5% SDS was added to each well and incubated at room temperature for 30 minutes before the supernatant was removed. Next, 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well and incubated at room temperature for 1 hour. The supernatant was removed, and 15 μL of a primary antibody (phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology) diluted 2500-fold with blocking buffer was added to each well and incubated at 4°C overnight.

[1563] The next day, the supernatant was removed, and 50 μL of PBS containing 0.05% Tween-20 (Thermo Fisher Scientific) was added to each well, and the supernatant was removed to wash each well. Washing was performed a total of 3 times. After washing, 15 μL of goat anti-rabbit IgG H&L (IRDye 800CW) diluted 1000-fold with blocking solution was added to each well and allowed to stand at room temperature for 1 hour. The supernatant was removed, and the wells were washed 3 times in the same manner after reacting with the primary antibody in PBS containing 0.05% Tween-20. After removing the supernatant, the plate was air-dried at room temperature for more than 3 hours, and the fluorescence signal at 800 nm was measured using Aerius.

[1564] 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 (IC 50 The results for several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% inhibition rate exceeded the evaluation range, the inhibition rate at the highest evaluation concentration (10 μM) is shown.

[1565] In the following table, Ex represents the example number. 50 , calculated molecular weight in the form of 4 hydrochloride, about IC of Ex 14 50 , the molecular weight was calculated based on the 3-hydrochloride salt form.

[1566] [Table 2]

[1567] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 3358 23 1563 2 4771 24 231 3 94 25 668 4 33% at 10 μM 26 2020 5 329 27 2768 6 3937 28 2189 7 60 29 24 8 21 30 1280 9 69 31 158 10 9 32 69 11 59 33 102 12 16 34 200 13 608 35 1507 14 1514 36 78 15 503 37 41 16 158 38 31 17 1345 39 30 18 250 40 30 19 555 41 90 20 1068 42 365 21 2283 43 13 22 283 44 69

[1568] Experimental Example 3 Evaluation of the Anchorage-Independent Cell Proliferation Inhibitory Effect on Human G12D Mutant KRAS-Positive Pancreatic Cancer Line AsPC-1

[1569] The anchorage-independent cell proliferation inhibitory effect of the test compound was evaluated by 3D spheroid culture.

[1570] AsPC-1 cells were plated at 5×10 2 Cells were seeded in a low-adhesion U-bottom 384-well plate (PrimeSurface, Sumitomo Bakelite Co., Ltd.) at 20 μL (or 36 μL) per well. Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[1571] The next day, the test compound (final concentration range: 10 μM to 0.3 nM, 10 or 6 points) and the test compound solvent DMSO as a negative control were diluted 500-fold (or 100-fold) with fresh culture medium, and 20 μL (or 4 μL) were 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 an ARVO X3 (PerkinElmer).

[1572] The signal value in the case of DMSO treatment was set as 100%, and the signal value in the case of medium alone in the absence of cells was set as 0%. The 50% inhibition value (IC 50 The results for several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% inhibition rate was outside the evaluation range, the inhibition rate at the highest evaluation concentration (10 μM) is shown.

[1573] In the following table, Ex represents the example number. 50 , calculated molecular weight in the form of 4 hydrochloride, about IC of Ex 14 50 , the molecular weight was calculated based on the 3-hydrochloride salt form.

[1574] [Table 3-1]

[1575] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 37% at 10 μM 23 1086 2 55% at 10 μM 24 223 3 120 25 460 4 22% at 10 μM 26 1349 5 490 27 1888 6 50% 10 μM 28 2017 7 73 29 33 8 27 30 1443 9 90 31 147 10 15 32 60 11 142 33 142 12 41 34 476 13 1224 35 1112 14 1119 36 159 15 211 37 64 16 73 38 51 17 684 39 52 18 217 40 46 19 242 41 155 20 884 42 399 21 852 43 33 22 128 44 123

[1576] [Table 3-2]

[1577] Ex <![CDATA[IC 50 (nM)]]> 45 162 46 1277 47 448 48 161

[1578] Experimental Example 4: Evaluation of the Antitumor Effect in Mice Bearing the Human G12D Mutant KRAS-Positive Pancreatic Cancer Line PK-59

[1579] PK-59 cells (RIKEN BioResearch Center, RCB1901) were cultured in RPMI1640 medium containing 10% fetal bovine serum in the presence of 5% CO2 at 37°C. PK-59 cells were recovered, suspended in PBS, and an equal amount of Matrigel (Becton, Dickinson and Company) was added to prepare a 1.0-2.0×10 7The resulting cell suspension was implanted subcutaneously in 100 μL of volume into 4- to 5-week-old male nude mice (BALB / c-nu (nu / nu), Charles River Laboratories, Japan). Approximately two weeks after implantation, the mice were divided into groups with approximately equal tumor volume and body weight, and test compound administration began the following day. The experiment was conducted with five mice in each of the solvent group and the test compound administration group. The compound was dissolved in a solvent containing ethanol (Fujifilm Wako Pure Chemical Industries, Ltd.), 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) at a volume ratio of 4:84.4:1.1:1:9:0.5. The test compound or solvent dissolved in each solvent was administered into the tail vein. Administration was performed twice, with one dose per week. Tumor diameter and body weight were measured twice a week. Tumor volume was calculated using the following formula.

[1580] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5

[1581] The tumor growth inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound-administered group on the day before dosing as 100% inhibition and the tumor volume of the vehicle-administered group two weeks after the first dose as 0% inhibition. If the tumor volume of the test compound-administered group was lower than the tumor volume on the day before dosing, the tumor volume on the day before dosing was set as 0% reduction, and a tumor volume of 0 was set as 100% reduction, and the tumor reduction rate (%) of the test compound was calculated. The results for several test compounds of formula (I) are shown in the table below.

[1582] [Table 4]

[1583] Ex Dosage (mg / kg) Antitumor effect 2 weeks after the first administration 8 3 28% retreat 10 3 28% retreat 12 3 35% retreat 29 3 5% back off

[1584] Experimental Example 5 Evaluation of the inhibitory effect on KRAS G12D / SOS / c-Raf complex formation

[1585] The inhibitory effects of the tested compounds on the complex formation of these proteins were studied using the time-resolved fluorescence resonance energy transfer (TR-FRET) method using human recombinant KRAS G12D, SOS, and c-Raf proteins.

[1586] To a 384-well plate (Corning), 2.5 μL of biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 μL; 400 nM) dissolved in assay buffer (50 mM HEPES [Jena], 150 mM NaCl [Nacalai Tesque], 5 mM MgCl2 [ThermoFisher Scientific], 0.05% Tween 20 [Sigma-Aldrich], pH 7.0) and the test compound were added in a volume of 2.5 μL. To this, c-Raf (amino acid region 51-131) GST (2.5 μL; 130 nM) containing Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μL; 1.3 μM) and GTP (Sigma-Aldrich; 2 μM) were added and incubated at room temperature for 1 hour. Then, 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 fluorescence intensity at 620 nm and 665 nm was measured using an EnVision 2104 (PerkinElmer) with excitation at 337 nm. The values ​​were normalized with the fluorescence intensity at a reference wavelength of 620 nm, and the signal value in the case of solvent treatment was set as 0% inhibition, and the signal value in the case of no GTP addition was set as 100% inhibition. The 50% inhibitory concentration (IC) was calculated by Sigmoid-Emax model nonlinear regression analysis. 50 ).

[1587] As a result of the above test, the G12D mutant KRAS decomposition effect was confirmed for several compounds of formula (I) (Test Example 1). In addition, the complex formation inhibitory effect (G12D mutant KRAS inhibitory effect) (Test Example 5) was confirmed. Furthermore, the phosphorylation inhibitory effect of ERK located downstream of the KRAS signal was confirmed for several compounds of formula (I) (Test Example 2). In addition, the cell proliferation inhibitory effect on human G12D mutant KRAS positive pancreatic cancer strains (Test Example 3) and the anti-tumor effect in tumor-bearing mice of human G12D mutant KRAS positive pancreatic cancer strains (Test Example 4) were confirmed for several compounds of formula (I). Therefore, the compound of formula (I) can be used for the treatment of pancreatic cancer, especially G12D mutant KRAS positive pancreatic cancer.

[1588] Pharmaceutical compositions containing one or more of the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or their salts as active ingredients can be prepared using excipients commonly used in the art, i.e., pharmaceutical excipients or pharmaceutical carriers, by commonly used methods.

[1589] Administration may be any of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intraarticular, intravenous, and intramuscular, transmucosal, and inhalant.

[1590] As solid compositions for oral administration, tablets, powders, granules, etc. can be used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition may contain inert additives such as lubricants, disintegrants, stabilizers, and dissolution aids according to conventional methods. Tablets or pills may be coated with a sugar coating or a film of a gastric-soluble or enteric-soluble substance as needed.

[1591] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain adjuvants such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavoring agents, aromatics, and preservatives.

[1592] Injections for parenteral administration include 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 isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubility aids. These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. Alternatively, these compositions may be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection prior to use.

[1593] Inhalants or transmucosal agents such as nasal agents can use solid, liquid or semi-solid substances and can be manufactured according to conventional methods. For example, known excipients, pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. Apparatus for appropriate inhalation or blowing can be used for administration. For example, known apparatuses or sprayers such as metered-dose inhalation apparatuses can be used to administer the compound alone or in the form of a powder to form a mixture of the formulation, or in combination with a pharmaceutically acceptable carrier and in the form of a solution or suspension. Dry powder inhalers, etc. can be inhalers for single or multiple administration, and dry powder or powder-containing capsules can be used. Alternatively, pressurized aerosol sprays using appropriate propellants, such as chlorofluoroalkanes or carbon dioxide, can be used.

[1594] In the case of oral administration, the daily dosage is about 0.001 to 100 mg / kg per unit body weight, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg, which is appropriate, and is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dosage is about 0.0001 to 10 mg / kg per unit body weight, which is appropriate, and is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per unit body weight is administered once a day or divided into multiple times. The dosage can be appropriately determined according to the symptoms, age, sex, etc.

[1595] Although it varies depending on the route of administration, dosage form, administration site, and the types of excipients or additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[1596] The compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) is believed to show effectiveness. The combination can be administered simultaneously, or administered separately, continuously or at intervals of desired time. The preparation for simultaneous administration can be a compounding agent, or can be formulated separately.

[1597] Example

[1598] Below based on embodiment, the manufacture method of the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) is described in further detail.It should be noted that, the present invention is not limited to the compound described in the following examples.In addition, the manufacture method of raw material compound is respectively shown in manufacture example.In addition, the compound described in the following examples is the specific compound included in formula (I), but the manufacture method of the compound of formula (I) is not limited to the manufacture method of the specific embodiment shown below, and the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) can also be manufactured by the combination of these manufacture methods or the method obvious to those skilled in the art.

[1599] In addition, in this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[1600] For convenience, the concentration mol / L is expressed as M. For example, a 1M sodium hydroxide aqueous solution means a 1 mol / L sodium hydroxide aqueous solution.

[1601] The “amorphous solid form” described in this specification includes both forms showing no peaks in a powder X-ray diffraction (XRD) pattern and forms having low crystallinity.

[1602] XRD was performed using Empyrean with a Cu bulb, 40 mA current, 45 kV voltage, 0.013° step size, and a wavelength of The diffraction angle range (2θ) is measured under conditions of 2.5 to 40°. It should be noted that, in terms of the nature of the data, the lattice spacing and overall pattern of the powder X-ray diffraction pattern are important in determining the identity of the crystal. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is generally ±0.2°. However, the diffraction angle and diffraction intensity may vary slightly depending on the crystal growth direction, grain size, and measurement conditions, and therefore should not be interpreted strictly.

[1603] Production Example 1

[1604] 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (40 g) was suspended in THF (400 mL). A 1 M sodium hydroxide aqueous solution (190 mL) was added dropwise under ice cooling, maintaining the internal temperature below 10°C, and stirred for 2 hours. The reaction mixture was poured all at once into a conical flask containing hydrochloric acid (1 M, 190 mL) and ice water (approximately 900 g) and stirred at room temperature for approximately 30 minutes (until the ice melted). The insoluble matter was filtered while being washed with water and dried under reduced pressure to obtain 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (33.56 g) as a solid.

[1605] Production Example 2

[1606] Under a nitrogen stream, 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise to a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (24.6 g) and THF (260 mL) heated to 60°C over 15 minutes. Stir at this temperature for 2.5 hours. Cool naturally to room temperature, and filter while washing the colorless solid with THF (approximately 500 mL). MeOH (210 mL) was added to the solid obtained by concentrating the filtrate, and the mixture was stirred at room temperature for 1 hour to suspend and wash. The solid was filtered using MeOH (100 mL) to obtain 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[1607] Production Example 3

[1608] To a mixture of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (38.4 g) and CH2Cl2 (500 mL) was added ethanethiol (5.3 mL) and DABCO (10.6 g) while stirring at room temperature. The mixture was stirred at room temperature for 17 hours under an argon atmosphere. Ethanethiol (1 mL) was added, and the mixture was further stirred at room temperature for 6 hours. DABCO (1.5 g) was then added, and the mixture was stirred at room temperature for 3 days. Cesium carbonate (2.1 g) was added, and the mixture was stirred at room temperature for 22 hours. Ice water was poured into the reaction mixture, and the mixture was extracted twice with CHCl3. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl (1S,4S)-5-[7-bromo-2-(ethylthio)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (43.2 g) as a foamy solid.

[1609] Production Example 4

[1610] To a mixture of tert-butyl (1S,4S)-5-[7-bromo-2-(ethylthio)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40.2 g), dehydrated THF (400 mL), and (1S)-1-phenylethan-1-ol (10 mL), which was thoroughly cooled and stirred in an ice / MeOH bath, tBuOK (15.3 g) was added. The mixture was stirred under cooling under an argon atmosphere for 30 minutes and then at room temperature for 30 minutes. Ice and saturated aqueous ammonium chloride were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain (1S,4S)-5-{7-bromo-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (45.94 g) as a foamy solid.

[1611] Production Example 5

[1612] Under an argon atmosphere, a mixture of (1S,4S)-5-{7-bromo-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.02 g), cyclopropylboronic acid (178 mg), potassium phosphate (1.06 g), PdCl2(dppf)·CH2Cl2 (113 mg), MeCN (15 mL) and water (3 mL) was stirred at 90°C for 6 hours. After cooling naturally to room temperature, ethyl acetate and water were added, and the two layers were separated by filtration through Celite (registered trademark). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated sodium chloride aqueous 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 column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (652 mg) as a foamy solid.

[1613] Production Example 6

[1614] Under an argon atmosphere, a mixture of tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.75 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (900 mg), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (138 mg), palladium(II) acetate (31 mg), anhydrous barium hydroxide (0.61 g), DOX (30 mL) and water (6 mL) was stirred at 50° C. for 30 min. 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (600 mg) was added at the same temperature, and the mixture was further stirred at 50°C for 1 hour. After cooling to room temperature, ethyl acetate and water were added, and the insoluble matter was removed by filtration through Celite (registered trademark). The filtrate was separated into two layers. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the insoluble matter, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (derived from an axially asymmetric diastereoisomer mixture in a ratio of approximately 4:1, 866 mg) as a solid. MeOH (5 mL) was added to the resulting solid (866 mg), heated to 60°C for dissolution, and stirred at room temperature under an argon atmosphere for 3 days. The precipitated solid was filtered while washing with a small amount of MeOH to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (a nearly single diastereomer with an axially asymmetric configuration and unclear structure, 200 mg) as a solid.

[1615] Production Example 7

[1616] Under ice cooling, (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.14 g) and CH2Cl2 (170 mL) was added m-chloroperbenzoic acid (about 30% water content, 7.9 g), and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. Ice, a saturated aqueous sodium thiosulfate solution, and a saturated aqueous sodium bicarbonate solution were added, and after stirring at room temperature for about 20 minutes, the reaction solution was diluted with CH2Cl2 and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-(

[00145] tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (9.02 g).

[1617] Production Example 8

[1618] Under cooling in an ice / MeOH bath, to (1S,4S)-5-[(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl ester (300 mg), (2S)-2-methoxypropane-1-ol (40 mg) and THF (4 mL) was added tBuOK (85 mg), and the mixture was stirred at the same temperature for 30 minutes under an argon atmosphere. Ice water and aqueous ammonium chloride solution were added to the reaction mixture to stop the reaction. It was extracted twice with ethyl acetate, and the combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. It was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(

[00145] tert-butyl 8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (255 mg).

[1619] Production Example 9

[1620] Under a nitrogen atmosphere, to a solution of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (180 mg) in MeOH (5 mL) and THF (5 mL) were added 10% Pd / C (50% aqueous solution, 40 mg) and sodium bicarbonate (80 mg). The mixture was then replaced with a normal pressure hydrogen atmosphere and stirred at room temperature for 4 hours. The reaction mixture was then replaced with a nitrogen atmosphere, filtered through Celite (registered trademark) using MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (160 mg) as a foamy solid.

[1621] Production Example 10

[1622] To a mixture of (1S, 4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg), methyl 4-(chloromethyl)benzoate (32 mg) and DMF (2 mL) was added cesium carbonate (172 mg) and stirred at room temperature for 6 hours. Ethyl acetate and water were added and the two layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (90 mg) as a foamy solid.

[1623] Production Example 11

[1624] To a mixture of methyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (2.51 g) and THF (30 mL) were added 3,4-dihydro-2H-pyran (2.7 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (270 mg) at room temperature, and the mixture was stirred at 60°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(

[00145] methyl [(2S)-2-methoxypropoxy]quinazolin-8-yl]oxy]methyl]benzoate (1.79 g).

[1625] Production Example 12

[1626] To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylthio)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.1 g) and THF (150 mL) was added 3,4-dihydro-2H-pyran (10 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.7 g) while stirring at room temperature. The mixture was stirred at room temperature for 14 hours under an argon atmosphere. 3,4-dihydro-2H-pyran (5 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.3 g) were further added, and the mixture was stirred at room temperature for another 5 hours. The reaction was terminated by adding TEA (2 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-(

[00145] tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.15 g).

[1627] Production Example 13

[1628] Under nitrogen atmosphere, 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a THF (3 mL) solution of methyl]benzoate (100 mg) was added cesium carbonate (80 mg) and PyBOP (120 mg), and the mixture was stirred at the same temperature for 1 hour. At room temperature, tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (60 mg) and cesium carbonate (160 mg) were added, and the mixture was stirred at 60°C for 3 hours. After naturally cooling to room temperature, ethyl acetate was added and Celite (registered trademark) was filtered. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(

[00145] tert-butyl 8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}oxy)pyrrolidine-1-carboxylate (86 mg).

[1629] Production Example 14

[1630] Under ice cooling, (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl [(2-((2S)-2-methoxypropoxy)quinazolin-4-yl)-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (252 mg), MeOH (3.4 mL), and THF (1.7 mL) was added aqueous sodium hydroxide solution (1 M, 1.7 mL), and stirred at room temperature for 6 hours. Hydrochloric acid (1 M, 1.77 mL) and ice water were added, and the mixture was extracted twice with CHCl3 / MeOH (10 / 1). The combined organic layers were dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-[({(7M)-4-[(1S,4S)-5-(tert-butyloxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl]oxy)methyl]benzoic acid (250 mg).

[1631] Production Example 15

[1632] To (3S)-3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl [(4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}oxy]pyrrolidine-1-carboxylate (84 mg) and 1,2-dichloroethane (4 mL) was added trimethyltin (IV) hydroxide (100 mg), and the mixture was stirred at 80°C for 24 hours. After cooling to room temperature, trimethyltin (IV) hydroxide (100 mg) was added, and the mixture was stirred at 80°C for 48 hours. After cooling to room temperature, hydrochloric acid (1 M) was added, and the mixture was extracted twice with CHCl3 / iPrOH (4 / 1). The combined organic layers were washed with hydrochloric acid (1 M) and dried over anhydrous sodium sulfate. The insoluble matter was filtered off and the mixture was concentrated under reduced pressure to obtain 4-[({(7M)-4-{[(3S)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl]oxy}-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (86 mg).

[1633] Production Example 16

[1634] Under cooling in an ice / MeOH bath, 4-[({(7M)-4-[(1S,4S)-5-(tert-butyloxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a mixture of [(2-((2S)-2-methoxypropoxy)quinazolin-8-yl)methyl]benzoic acid (247 mg), 3-(3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione dihydrochloride (160 mg), DIPEA (0.3 mL), and DMF (4 mL) was added HATU (230 mg), and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Ice and saturated aqueous ammonium chloride were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (CHCl3 / iPrOH) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-({4-[(2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carbonyl]phenyl}methoxy)-7-[6-fluoro-5-methyl-1-(

[00145] tert-butyl 2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-1H-indazol-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (273 mg).

[1635] Production Example 17

[1636] After cooling a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) with ice, DIPEA (240 mL) and tert-butyl (1S, 4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) were added and stirred at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a total volume of about 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the resulting solution and stirred at room temperature. The precipitated solid was collected by filtration to obtain tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (123 g) as a solid.

[1637] Production Example 18

[1638] To a mixture of tert-butyl (1S,4S)-5-{6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (20.63 g, a mixture of isomers with an axial asymmetry of approximately 4.5:1) and EtOH (250 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (4.8 g) while stirring at room temperature. The mixture was stirred at room temperature for 1 hour under an argon atmosphere. Ice and saturated aqueous sodium bicarbonate were poured into the reaction mixture, and the resulting white insoluble matter was dissolved in ethyl acetate and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylthio)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (involving an axially asymmetric single isocyanate) as a low polarity fraction in the form of a foamy solid. The product was purified by HPLC-MS / ...

[1639] Production Example 19

[1640] To a mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (10 g) and N-methyl-2-pyrrolidone (20 mL) was added trimethyl orthoacetate (10.5 mL), and the mixture was stirred at 110° C. for 12 hours. After cooling to room temperature, MeOH (20 mL) was added, and the resulting solid was filtered while being washed with cooled methanol (about 60 mL), and then dried under reduced pressure to obtain methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (6.67 g) as a solid.

[1641] Production Example 20

[1642] Under an argon atmosphere, 2-acetamide-4-bromo-3-fluoro-5-iodobenzoic acid methyl ester (18 g) was added to a mixture of lithium bis(trimethylsilyl)amide (1.3 M THF solution, 100 mL) and THF (150 mL) in small amounts each time while cooling in a water bath. After stirring at 40°C for 1 hour, the mixture was cooled to room temperature, water was added, and the mixture was washed twice with ethyl acetate. Hydrochloric acid (1 M, 140 ml) and ice water were added to the aqueous layer under ice cooling to make it acidic, and the mixture was stirred for a while. The precipitated solid was filtered and dried under reduced pressure. The obtained solid was filtered while washing with methanol and dried under reduced pressure to obtain 7-bromo-8-fluoro-4-hydroxy-6-iodoquinoline-2(1H)-one (13.6 g) as a solid.

[1643] Production Example 21

[1644] Under an argon atmosphere, sulfonyl chloride (24 mL) was added to 7-bromo-8-fluoro-4-hydroxy-6-iodoquinolin-2(1H)-one (5 g). DIPEA (7 mL) was slowly added under ice cooling, and the mixture was stirred at 110°C for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Ice water was added to the residue and stirred for 30 minutes. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (5.03 g).

[1645] Production Example 22

[1646] Under an argon atmosphere, DABCO (1.8 g) was added to a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (6.4 g) and DMAc (70 mL), and the mixture was stirred at 40°C for 2 hours. Ethanethiol (1.4 mL) was added, and the mixture was stirred at 60°C for 1 hour. After cooling to room temperature, water was added and stirred for 5 minutes. The resulting solid was filtered and dried under reduced pressure. The resulting solid was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-chloro-2-(ethylthio)-8-fluoro-6-iodoquinoline (5.76 g) as a solid.

[1647] Production Example 23

[1648] Under an argon atmosphere, tBuOK (3.06 g) was added to a THF (50 mL) solution of 7-bromo-4-chloro-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinoline (6.47 g) and (1S)-1-phenylethane-1-ol (3.34 mL) in a cooling bath (approximately -10°C), followed by stirring at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-chloro-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinoline (4.67 g) as an oil.

[1649] Production Example 24

[1650] Under an argon atmosphere, tBuOK (1.59 g) was added to a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.7 g) in DMAc (20 mL), and the mixture was stirred at room temperature for 10 minutes. The prepared mixture was added dropwise to a mixture of 7-bromo-4-chloro-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (6.46 g) and DMAc (40 mL) under ice cooling, and stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution, ice, and ethyl acetate were added, stirred, and the layers separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate) gave tert-butyl (3S)-3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (4.6 g) as a solid.

[1651] Production Example 25

[1652] Under an argon atmosphere, (2S)-2-methoxypropan-1-ol (3 mL) was added to a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (10 g), DABCO (3.3 g), cesium carbonate (23.3 g), and DMAc (100 mL). The mixture was stirred at room temperature for 1.5 hours and then at 60°C for 12 hours. After cooling naturally to room temperature, water and ethyl acetate were added and stirred for a while. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off and the mixture was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-chloro-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinoline (5.97 g) as a solid.

[1653] Production Example 26

[1654] To a solution of 7-bromo-4-chloro-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinoline (1.6 g) in DMAc (5 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (832 mg) and potassium carbonate (768 mg) at room temperature, and the mixture was stirred at 120°C overnight. Tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (278 mg) and potassium carbonate (384 mg) were additionally added at 120°C, and the mixture was stirred at the same temperature overnight. The mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{7-bromo-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.02 g) as a foamy solid.

[1655] Production Example 27

[1656] Under an argon atmosphere, trifluoromethanesulfonic anhydride (809 μL) and pyridine (520 μL) were added to a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (800 mg) in CH2Cl2 (10 mL) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.1 g) as an oil.

[1657] Production Example 28

[1658] Under an argon atmosphere and cooling in an ice / sodium chloride bath, tBuOK (260 mg) was added to a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (350 mg) in THF (20 mL), and the mixture was stirred at the same temperature for 30 minutes. A solution of 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (700 mg) in THF (7 mL) was added dropwise over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was filtered and washed with ethyl acetate, and dried under reduced pressure to obtain 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (524 mg) as a solid.

[1659] Production Example 29

[1660] Under an argon atmosphere, to a mixture of tert-butyl 4-[(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)methyl]piperazine-1-carboxylate (285 mg) and THF (3 mL) was slowly added dropwise with ice cooling. Lithium bis(trimethylsilyl)amide (1M THF solution, 2.4 mL) was then added, followed by the addition of 3-bromopiperidine-2,6-dione (268 mg), and the mixture was stirred at 75 ° C for 16 hours. After cooling naturally to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was 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 obtained residue was purified by silica gel column chromatography (CHCl3 / iPrOH) to obtain tert-butyl 4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]methyl}piperazine-1-carboxylate (106 mg) as an oily substance.

[1661] Production Example 30

[1662] To 7-bromo-1,3-benzo To a mixture of oxazol-2(3H)-one (8.5 g), 3-bromopiperidine-2,6-dione (9.9 g) and MeCN (80 mL) was added potassium carbonate (8.2 g) and stirred at 70 ° C for 12 hours. Water (600 mL) was injected into the reaction mixture, and the insoluble matter produced was washed with water while filtering. Toluene was added to the obtained solid, concentrated under reduced pressure, and azeotroped with water. Petroleum ether / ethyl acetate (4 / 1) was added to the obtained crude product and powdered, filtered, and 3-(7-bromo-2-oxo-1,3-benzo[ ... oxazol-3(2H)-yl)piperidine-2,6-dione (11 g).

[1663] Production Example 32

[1664] To 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (500 mg) were added trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (5 mL), and the mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure until the volume was approximately half, ethyl acetate was added, and the mixture was poured into an ice-cold saturated aqueous sodium bicarbonate solution and stirred for a while. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (300 mg) as a solid.

[1665] Production Example 33

[1666] Under an argon atmosphere, a mixture of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (4.32 g), potassium vinyl trifluoroborate (7.5 g), PdCl2(dppf)·CH2Cl2 (1.16 g), cesium carbonate (9.2 g), DOX (50 mL), and water (5 mL) was stirred at 80°C for 3 hours. Ethyl acetate and water were added, and Celite (registered trademark) was filtered. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purified by silica gel column chromatography (hexane / ethyl acetate). The obtained solid was filtered while washing with iPr2O and dried under reduced pressure to obtain 3-(5-vinyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (559 mg) as a solid.

[1667] Production Example 34

[1668] To a mixture of 3-(5-vinyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (373 mg), DOX (10 mL), and water (1 mL) were added sodium periodate (570 mg), osmium tetroxide (2.5 wt% tBuOH solution, 13.3 g), and 4-methylmorpholine N-oxide (88 mg) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (280 mg) as a solid.

[1669] Production Example 35

[1670] 1-(6-vinyl-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (1.44 g) was dissolved in a mixed solvent of MeOH (30 mL) and CH2Cl2 (30 mL) at room temperature. The mixture was stirred for 1.5 hours while bubbling ozone gas under cooling with dry ice-acetone. Dimethyl sulfide (1.2 mL) was added at the same temperature, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with a mixed solvent of ethyl acetate and MeOH to obtain 3-(2,4-dioxo-1,3-diazinane-1-yl)-1-methyl-1H-indazole-6-carbaldehyde (527 mg) as a solid.

[1671] Production Example 36

[1672] To a mixture of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (148 mg), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (210 mg), CH2Cl2 (2 mL), and N-methyl-2-pyrrolidone (2 mL) was added acetic acid (31 μL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (220 mg) was added at room temperature, and the mixture was stirred overnight at room temperature. Water and a saturated aqueous sodium bicarbonate solution were added, and after stirring for a while, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3 / iPrOH) to obtain (2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (224 mg) as a foamy solid.

[1673] Production Example 37

[1674] To a mixture of (2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (200 mg) and CH2Cl2 (2 mL) was added hydrogen chloride (4M DOX solution, 3 mL), and the mixture was stirred at room temperature overnight. iPr2O was added to the reaction mixture, and the resulting solid was filtered, washed with iPr2O, and dried under reduced pressure to obtain 3-(3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione dihydrochloride (178 mg) as a solid.

[1675] Production Example 38

[1676] 5-Chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg), potassium {[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}tri(fluoro)borate (333 mg), palladium(II) acetate (12 mg), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (45 mg), cesium carbonate (532 mg), DOX (2 mL), and water (0.4 mL) were mixed under an argon atmosphere and reacted at 130°C for 1 hour under microwave irradiation. After cooling to room temperature, water and ethyl acetate were added, and the insoluble matter was filtered off using Celite (registered trademark). The two layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain tert-butyl 4-[(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)methyl]piperazine-1-carboxylate (120 mg) as an oily substance.

[1677] Production Example 39

[1678] Under an argon atmosphere, to a mixture of 5-amino-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid methyl ester (209.5 mg), {[(3S)-4-(tert-butoxycarbonyl)-3-methylpiperazine-1-yl]methyl}tri(fluoro)borate potassium (380 mg), cesium carbonate (577 mg), water (1 mL) and DOX (5 mL), palladium acetate (II) (13 mg) and di(adamantane-1-yl) (butyl) phosphine (42 mg) were added and stirred at 100 ° C for 5 hours. After natural cooling, ethyl acetate and water were added, and the insoluble matter was filtered out using Celite (registered trademark). The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. After filtering out the insoluble matter, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain tert-butyl (2S)-4-{[2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-2-methylpiperazine-1-carboxylate (148 mg) as a foamy solid.

[1679] Production Example 40

[1680] Methanesulfonyl[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15 mg) was added to a mixture of 1-[(4-bromo-3-fluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (100 mg), potassium {[(3S)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl]methyl}tri(fluoro)borate (150 mg), cesium carbonate (240 mg), water (0.4 mL), and DOX (degassed by argon bubbling, 2 mL) at room temperature. The mixture was stirred at 100°C for 1 hour. After cooling to room temperature, ethyl acetate and water were added, and the mixture was filtered through Celite (registered trademark) to obtain a filtrate. The aqueous layer was separated, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain tert-butyl (2S)-4-{[2-fluoro-4-({3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}methyl)phenyl]methyl}-2-methylpiperazine-1-carboxylate (59 mg) as an oily substance.

[1681] Production Example 41

[1682] Under an argon atmosphere, a mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1H-isoindole-1,3(2H)-dione (220 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (204 mg), DIPEA (0.3 mL), and N-methyl-2-pyrrolidone (4 mL) was stirred at 80°C for 3 hours. After cooling naturally, the mixture was diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 4-({[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}methyl)piperidine-1-carboxylate (86 mg) as a foamy solid.

[1683] Production Example 42

[1684] Under an argon atmosphere, a mixture of methyl 4-bromo-2-(bromomethyl)benzoate (300 mg), methyl 4,5-diamino-5-oxopentanoate monohydrochloride (231 mg), DIPEA (0.35 mL), and DMF (6 mL) was stirred at room temperature for 24 hours. Saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, diluted with water and ethyl acetate, and the layers separated. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain methyl 5-amino-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate (209.5 mg) as a solid.

[1685] Production Example 43

[1686] Under an argon atmosphere, to a mixture of (2S)-4-{[2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (144 mg) and THF (6 mL) was added potassium trimethylsilanol (40 mg) under ice cooling and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, diluted with water and ethyl acetate, and the liquids were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (2S)-4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (129 mg) as a solid.

[1687] Production Example 44

[1688] To a suspension of (2S)-tert-butyl 4-({3-[carbamoyl(3-ethoxy-3-oxopropyl)amino]-1-methyl-1H-indazol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (1.92 g) in MeCN (20 mL) was added benzyltrimethylammonium hydroxide (480 mg, 40% by weight solution in MeOH), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (CHCl / MeOH) to obtain tert-butyl (2S)-4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-5-yl]methyl}-2-methylpiperazine-1-carboxylate (1.09 g) as a solid.

[1689] Production Example 45

[1690] To a solution of N-iodosuccinimide (13.9 g) in DMF (35 mL) was added (2-methyl-2H-indazol-6-yl)methanol (2.5 g) at room temperature. The mixture was stirred at the same temperature overnight and then at 60°C for 2 hours. The reaction mixture was cooled to room temperature, and a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added, followed by extraction 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, the mixture was concentrated, and the residue was washed with ethyl acetate to obtain (3-iodo-2-methyl-2H-indazol-6-yl)methanol (2.19 g) as a solid.

[1691] Production Example 46

[1692] 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.05 g), (3-iodo-2-methyl-2H-indazol-6-yl)methanol (1.09 g), copper (I) iodide (420 mg), potassium phosphate (1.7 g), and racemic-(1R,2R)-cyclohexane-1,2-diamine (280 μL) were suspended in DOX (20 mL) and stirred at 120°C for 3 hours under microwave irradiation. The mixture was cooled to room temperature, ethyl acetate and water were added, and then filtered through Celite (registered trademark). The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 / MeOH) to obtain 1-[6-(hydroxymethyl)-2-methyl-2H-indazol-3-yl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (293 mg) as a foamy solid.

[1693] Production Example 47

[1694] To a solution of 7-bromo-3-iodoimidazo[1,2-a]pyridine (1.7 g) and 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.5 g) in DOX (17 mL) were added DIPEA (4.58 mL), copper(I) iodide (1.0 g), and N,N'-dimethylethylenediamine (1.13 mL) in sequence. The mixture was stirred at 130°C for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (750 mg) as a solid.

[1695] Production Example 48

[1696] To a solution of 1-[6-(hydroxymethyl)-2-methyl-2H-indazol-3-yl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (320 mg) in CH2Cl2 (10 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoyl-3-(1H)-one (470 mg) at room temperature, and the mixture was stirred for 1 hour. A 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, which was stirred for a while and then extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain 3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinane-1-yl}-2-methyl-2H-indazole-6-carbaldehyde (208 mg) as a foamy solid.

[1697] Production Example 49

[1698] To tert-butyl (2S)-4-[(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinane-1-yl}-2-methyl-2H-indazol-6-yl)methyl]-2-methylpiperazine-1-carboxylate (153 mg) was added triisopropylsilane (165 μL), trifluoroacetic acid (1 mL), and trifluoromethanesulfonic acid (1 mL) in that order at room temperature. The mixture was stirred overnight at room temperature and then at 70°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (0.1% formic acid in MeCN / 0.1% formic acid in water). Saturated aqueous sodium bicarbonate was added to the fraction containing the target product, and the mixture was extracted four times with CHCl3 / iPrOH (4 / 1). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-(2-methyl-6-{[(3S)-3-methylpiperazin-1-yl]methyl}-2H-indazol-3-yl)-1,3-diazinane-2,4-dione (50 mg) as a solid.

[1699] Production Example 50

[1700] To a solution of tert-butyl (2S)-4-[(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinane-1-yl}imidazo[1,2-a]pyridin-7-yl)methyl]-2-methylpiperazine-1-carboxylate (500 mg) in trifluoroacetic acid (5 mL) was added trifluoromethanesulfonic acid (5 mL), and the mixture was stirred at 60°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was poured into ice water (100 mL), stirred for 5 minutes, and then extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (MeCN / 0.1% aqueous formic acid solution) to obtain 1-(7-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione trifluoromethanesulfonate (185.9 mg) as a solid.

[1701] Production Example 51

[1702] Under an argon atmosphere, (methoxymethyl)triphenylphosphine chloride was added under ice cooling. To a mixture of (900 mg) and THF (7 mL) was added tBuOK (295 mg) in two portions. The reaction mixture was stirred under ice cooling for 10 minutes, and then a mixture of 3-iodo-1-methyl-1H-indazole-5-carboxaldehyde (500 mg) and THF (7 mL) was added dropwise under ice cooling and stirred at room temperature for 45 minutes. The obtained reaction mixture was ice-cooled again and a mixture of (methoxymethyl)triphenylphosphine chloride was added under ice cooling. In the mixture of (900mg) and THF (7mL), tBuOK (295mg) was added and stirred for 10 minutes to obtain a suspension, which was then stirred at room temperature for 30 minutes. Under ice cooling, saturated aqueous ammonium chloride solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-iodo-5-(2-methoxyvinyl)-1-methyl-1H-indazole (351mg) as an oily substance.

[1703] Production Example 52

[1704] Water (2 mL) and formic acid (2 mL) were added to 3-iodo-5-(2-methoxyvinyl)-1-methyl-1H-indazole (250 mg), and the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 (2 mL), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (200 mg), acetic acid (50 μL), and sodium triacetoxyborohydride (200 mg) were added to the residue, followed by stirring at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain tert-butyl (2S)-4-[2-(3-iodo-1-methyl-1H-indazol-5-yl)ethyl]-2-methylpiperazine-1-carboxylate (154 mg) as a foamy solid.

[1705] Production Example 53

[1706] Methylhydrazine (10 mL) was added to a mixture of tert-butyl (2S)-4-[(3-cyano-4-fluorophenyl)methyl]-2-methylpiperazine-1-carboxylate (4.46 g) and propan-1-ol (40 mL) at room temperature, and the mixture was stirred at 100°C for 6 hours. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain tert-butyl (2S)-4-[(3-amino-1-methyl-1H-indazol-5-yl)methyl]-2-methylpiperazine-1-carboxylate (4.56 g) as a solid.

[1707] Production Example 54

[1708] Methylhydrazine sulfate (32.4 g) and TEA (75.2 mL) were added to a solution of 3-bromo-2-fluorobenzonitrile (9.00 g) in EtOH (100 mL) at 25°C and stirred at 110°C for 48 hours. The reaction mixture was poured into water (300 mL) and concentrated under reduced pressure to remove volatile substances. The resulting solid was filtered and dried under reduced pressure. Ethyl acetate (50 mL) was added to the resulting solid, stirred at 25°C for 10 minutes, and crushed to obtain 7-bromo-1-methyl-1H-indazol-3-amine (8 g) as a solid.

[1709] Production Example 55

[1710] Under ice cooling, 1,8-diazabicyclo[5.4.0]-7-undecene (1.66 mL) and lactic acid (1 g) were added to tert-butyl (2S)-4-[(3-amino-1-methyl-1H-indazol-5-yl)methyl]-2-methylpiperazine-1-carboxylate (3 g). After standing at room temperature for 0.5 hours, ethyl acrylate (3 mL) was added and stirred at 90°C overnight. The reaction solution was allowed to cool to room temperature, ethyl acetate and water were added, and stirred for a while. The aqueous layer and the organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (CHCl 3 / MeOH) to obtain tert-butyl (2S)-4-({3-[(3-ethoxy-3-oxopropyl)amino]-1-methyl-1H-indazol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (1.95 g) as an oily substance.

[1711] Production Example 56

[1712] To tert-butyl (2S)-4-({3-[(3-ethoxy-3-oxopropyl)amino]-1-methyl-1H-indazol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (1.95 g) were added acetic acid (24 mL), water (8 mL), and sodium cyanate (830 mg) in that order, and the mixture was stirred at the same temperature for 3 days. The reaction solution was concentrated, and water and a saturated aqueous sodium bicarbonate solution were added to the residue, followed by extraction twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain tert-butyl (2S)-4-({3-[carbamoyl(3-ethoxy-3-oxopropyl)amino]-1-methyl-1H-indazol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (1.92 g) as a foamy solid.

[1713] Production Example 57

[1714] 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.4g), DABCO (720mg) and cesium carbonate (4.72g) are added to a DMF (10mL) solution of 6-chloro-2-methyl-3-nitropyridine (1g) and stirred at room temperature for 2 hours. Ethyl acetate and water are added and the organic layer is extracted. The organic layer is washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-[(6-methyl-5-nitropyridine-2-yl) oxy] piperidine-1-carboxylic acid tert-butyl ester (447mg) as a solid.

[1715] Production Example 58

[1716] To a mixture of sodium hydride (60% dispersion in mineral oil, 500 mg) and DMAc (25 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (2.10 g) at 20° C., and the mixture was stirred at 20° C. for 30 minutes. 2-Fluoro-4-iodo-3-methylpyridine (2.47 g) was added to the reaction mixture, and the mixture was stirred at 100° C. for 1 hour. Water (5 mL) was added to the reaction mixture, and the resulting solution was purified by reverse phase HPLC (0.05% aqueous ammonia / MeOH) to obtain tert-butyl 4-[(4-iodo-3-methylpyridin-2-yl)oxy]piperidine-1-carboxylate (2.85 g) as an oil.

[1717] Production Example 59

[1718] Zinc powder (830 mg) and ammonium chloride (680 mg) were added to a mixture of tert-butyl 4-[(6-methyl-5-nitropyridine-2-yl)oxy]piperidine-1-carboxylate (532 mg), DOX (10 mL) and water (2 mL) under ice cooling and stirred at room temperature for 2 hours. It was diluted with ethyl acetate, Celite (registered trademark) was added and stirred for a while. Insoluble matter was removed by filtration through Celite (registered trademark). The filtrate was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtering out the insoluble matter, it was concentrated under reduced pressure to obtain tert-butyl 4-[(5-amino-6-methylpyridine-2-yl)oxy]piperidine-1-carboxylate (480 mg) as an oil.

[1719] Production Example 60

[1720] Under a nitrogen atmosphere, diisopropyl azodicarboxylate (500 μL) was added to a mixture of 3-iodophenol (500 mg), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (525 mg), triphenylphosphine (650 mg), and THF (5 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl 4-[2-(3-iodophenoxy)ethyl]piperazine-1-carboxylate (742 mg) as an oily substance.

[1721] Production Example 61

[1722] Under a nitrogen atmosphere, sodium hydride (55% mineral oil dispersion, 70 mg) was added to a solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (300 mg) in DMF (6 mL) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. 1-Bromo-4-(bromomethyl)-2-fluorobenzene (430 mg) was added at the same temperature, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1-[(4-bromo-3-fluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (473 mg) as an oil.

[1723] Production Example 62

[1724] Under an argon atmosphere, potassium phosphate (1.52 g) was added to a mixture of (3S)-3-({7-bromo-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.38 g), cyclopropylboronic acid (255 mg), PdCl2(dppf)·CH2Cl2 (162 mg), MeCN (15 mL) and water (3 mL), and the mixture was stirred at 90°C for 6 hours. The mixture was naturally cooled to room temperature, ethyl acetate and water were added, and the two layers were separated. 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 magnesium sulfate. The insoluble matter was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (3S)-3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (589 mg) as a foamy solid.

[1725] Production Example 63

[1726] A mixture of tert-butyl (1S,4S)-5-{7-bromo-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (45.93 g), cyclopropylboronic acid (9.8 g), potassium phosphate (55 g), PdCl2(dppf)·CH2Cl2 (5.4 g), MeCN (360 mL), DOX (240 mL), and water (120 mL) was degassed, replaced with argon, and stirred at 90°C for 5 hours under an argon atmosphere. The reaction mixture, after cooling naturally, was concentrated to approximately half its volume under reduced pressure, and a saturated aqueous sodium bicarbonate solution (100 mL) and water (300 mL) were poured into the residue, followed by extraction twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, and then thiol-modified silica gel (approximately 10 g) and basic silica gel (approximately 10 g) were added and stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration while washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (27.74 g) as a foamy solid.

[1727] Production Example 64

[1728] Under an argon atmosphere, tert-butyl (3S)-3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.71 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (3.44 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (531 mg), palladium(II) acetate (106 mg), and anhydrous barium hydroxide (2.29 g) were suspended in DOX (110 mL) and water (22 mL), and the mixture was stirred at 50° C. for 15 minutes. 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.6 g) was added, and the mixture was further stirred at 50°C for 15 minutes. After cooling to room temperature, ethyl acetate and water were added, and insoluble matter was removed by filtration through Celite (registered trademark). The filtrate was separated into two layers. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering out the desiccant, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate as an oily substance (from an axially asymmetric diastereoisomer mixture of approximately 5:1, 3.88 g).

[1729] MeOH (2 mL) was added to tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a mixture of diastereomers with an axial asymmetry of approximately 5:1, 100 mg) and the mixture was heated to 70°C for dissolution. The mixture was stirred at room temperature overnight and then for another 3 days. Solid precipitation was confirmed (pale yellow suspension). The solid was collected by filtration and washed with a small amount of MeOH to obtain tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate as a powder (derived from an axially asymmetric diastereoisomer mixture of approximately 1:1, 21 mg). The filtrate was concentrated to obtain the target tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate as a solid (a single diastereoisomer with unclear axially asymmetric configuration, 70 mg).

[1730] Similarly, EtOH (6 mL) was added to tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a diastereoisomer mixture of approximately 5:1 due to axial asymmetry, 2.95 g), and the mixture was heated to 70°C for dissolution. A small amount of the powder of the axial asymmetric mixture (obtained above) was added at room temperature, and the mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration and washed with a small amount of EtOH to obtain (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (from an axially asymmetric diastereoisomer mixture of approximately 1:1, 699 mg) as a colorless powder. The filtrate was concentrated to obtain the target product, tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a single diastereomer with an axially asymmetric configuration of unknown structure, 2.33 g) as a foamy solid.

[1731] Production Example 65

[1732] A mixture of tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicycl...

Claims

1. A compound of formula (I) or a salt thereof, In formula (I), A is CR A or N, R A H, replaceable C 1-3 Alkyl or cyano, Q is CR Q or N, R Q H, halogen, substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or vinyl, E is CH or N, R 1 is a C which can be selected from a substitutable 1-3 a naphthyl group substituted with one or two groups selected from the group consisting of an alkyl group, a cyano group, an OH group and a halogen group, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV), R 1a , R 1b and R 1c The same or different, H, C which may be substituted 1-3 Alkyl, vinyl or halogen, R 2 -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-, R V1 H or a replaceable C 1-3 alkyl, V 2 is the following formula (V) or formula (VI), W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocycloalkyl group containing 1 to 2 nitrogen atoms, R 2a The same or different, OH, OCH3, F or substituted C 1-3 Alkyl, the R 2a is bonded only to carbon atoms that are constituent atoms of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI), a piperidine ring represented by formula (VII), and a piperazine ring represented by formula (VII-2), m is an integer from 0 to 2, R 3 C 1-6 alkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl, X is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X H or a replaceable C 1-3 alkyl, Y 1 -O-(C 1-3 Alkylene)- *Y2 、-S-(C 1-3 Alkylene)- *Y2 、-SO2-(C 1-3 Alkylene)- *Y2 、-NR Y -(C 1-3 Alkylene)- *Y2 、-(C 1-3 Alkylene)-O- *Y2 、-(C 1-3 Alkylene)-S- *Y2 、-(C 1-3 Alkylene)-SO2- *Y2 or -(C 1-3 Alkylene)-NR Y - *Y2 , *Y2 Indicates that Y 2 The bonding part, R Y H or a replaceable C 1-3 alkyl, Y 2 is a bond, a phenylene group which may be substituted, or a heteroarylene group which may be substituted, The connecting group is Y 2 A group chemically bonded to EUB, EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of hydroxycerebroside, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

2. The compound or salt thereof according to claim 1, wherein EUB is a group capable of binding to parahydroxycerebroside.

3. The compound or salt thereof according to claim 2, wherein EUB is the following formula (XV), G is CR G or N, R G H or C 1-6 alkyl, Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23), Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23), Ring B1 and Ring B2 form a bond with a linking group, Wherein, when G is N, Z is a group selected from the group consisting of formula (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23), R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 and R Z4 The same or different, H or C which may be substituted 1-6 alkyl, M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene, R M H or a replaceable C 1-3 alkyl, Ring B1 is a benzene ring or a 6-membered heterocyclic ring, Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring, Here, M, R Z1 The linking group forms a bond with the carbon atom constituting ring B2.

4. The compound or salt thereof according to claim 3, wherein EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulae (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), Here, the ring B1 and the ring B2 in the formula (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23) form a bond with the linking group, Wherein, when G is N, Z is a group selected from the group consisting of formula (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), R Z1 C 1-6 Alkyl or halogen, n is an integer of 0 or 1, R Z2 and R Z4 Same or different, H or C 1-6 alkyl, M is a bond or C 1-3 Alkylene, Ring B1 is a benzene ring or a pyridine ring, Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, Here, M, R Z1 The linking group forms a bond with the carbon atom constituting ring B2.

5. The compound or salt thereof according to claim 4, wherein A is CH or N, Q is CR Q , R Q C 3-6 Cycloalkyl, E is CH, R 1 is the following formula (II), R 1a and R 1c Same or different from each other, C 1-3 Alkyl or halogen, R 2 -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )-, R V1 Can be selected from C 3-6 C substituted with one of the following groups: cycloalkyl, halogen and -OH 1-3 alkyl, V 2 is the following formula (V-2) or (VI-2), W is a group selected from the group consisting of the following formulae (VII-3), (VII-4), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), R 3 Can be selected from -O-(C 1-6 Alkyl), -S-(C 1-6 Alkyl), -N-(C 1-6 C substituted by one of the groups consisting of alkyl)2 and heterocycloalkyl 1-6 an alkyl group or an optionally substituted heterocycloalkyl group, X is -O- or -NR 4X -, R 4X C 1-3 alkyl, Y 1 -O-(C 1-3 Alkylene)- *Y2 or -(C 1-3 Alkylene)-O- *Y2 , *Y2 Indicates that Y 2 The bonding part, Y 2 is phenylene or pyridinediyl, The linking group is -(L 1 -L 2 -L 3 -L 4 )-, L 1 , L 2 , L 3 and L 4 are the same or different from each other and are selected from free bonds, C=O, -O-, -S-, -SO2-, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7-membered to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7-membered to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-6 A group in the group consisting of alkylene, R L H or C 1-6 alkyl.

6. The compound or salt thereof according to claim 5, wherein R 1 is the following formula (II), R 1a is halogen, R 1c C 1-3 alkyl, R 2 -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )-, R V1 C 1-3 alkyl, V 2 It is the following formula (VI-2), W is the following formula (XII), R 3 Can be selected from -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl substituted with one of the following groups: 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, X is -O-, Y 1 -O-(C 1-3 Alkylene)- *Y2 , *Y2 Indicates that Y 2 The bonding part, Y 2 is phenylene, The linking group is -(L 1 -L 2 -L 3 -L 4 )-, L 1 For C=O, L 2 To be C 1-3 Alkyl-substituted piperidine diyl, C 1-3 Alkyl-substituted piperazine diyl, C 1-3 alkyl-substituted pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L 3 For the bond, -N(R L3 )-、C 1-3 Alkylene or piperazine diyl, L 4 For the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 Alkylene, R L3 H or C 1-3 alkyl, R L4 H or C 1-3 alkyl, EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23), Here, the ring B1 and the ring B2 in the formula (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with the linking group, Wherein, when G is N, Z is a group selected from the group consisting of formula (Z-16), (Z-20), (Z-22) and (Z-23), R Z1 C 1-3 Alkyl or halogen, n is an integer of 0 or 1, R Z2 C 1-3 alkyl, M is a bond or C 1-3 Alkylene, Ring B1 is a benzene ring or a pyridine ring, Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, Here, M, R Z1 The linking group forms a bond with the carbon atom constituting ring B2.

7. The compound or salt thereof according to claim 6, wherein Q is CR Q , R Q is cyclopropyl, R 1 It is the following formula (II-2), R 2 -V 1 -V 2 or W, V 1 is -O- or -N(CH3)-, V 2 It is the following formula (VI-2), W is the following formula (XII), R 3 C may be substituted by -OCH3 or tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl, Y 1 -O-(methylene)- *Y2 , *Y2 Indicates that Y 2 The bonding part, The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7), Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) are 2 Forming a bond, L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 Alkylene)-piperazinediyl, L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-, R L2 H or C 1-3 alkyl, EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F), Here, the benzene ring or 6-membered heterocyclic ring in the formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group, Wherein, when G is N, Z is a group selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F), 8. The compound or salt thereof according to claim 7, wherein R 2 -V 1 -V 2 or W, V 1 For -O-, V 2 It is the following formula (VI-2), W is the following formula (XII), R 3 is a n-propyl or tetrahydropyranyl group which may be substituted with -OCH3, and the linking group is the following formula (L-5A) or (L-7A), EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A), Here, the benzene ring or 6-membered heterocyclic ring in the formula (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with the linking group, When G is N, Z is (Z-16A) or (Z-22A).

9. The compound or salt thereof according to claim 2, wherein EUB is the following formula (XV), G is CR G or N, R G H or C 1-6 alkyl, Z is a group selected from the group consisting of the following formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27), Here, in the formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27), Ring B1 and Ring B2 form a bond with a linking group, Wherein, when G is N, Z is a group selected from the group consisting of formula (Z-1), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27), R Z1 The same or different from each other, C 1-6 Alkyl, halogen, cyano, -OH, -O- (C 1-6 Alkyl), -S-(which may be substituted C 1-6 Alkyl), -NH-(which may be substituted C 1-6 Alkyl) or -N-(which may be substituted C 1-6 Alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 , R Z4 and R Z5 The same or different, H or C which may be substituted 1-6 alkyl, M is a bond, -O-, -S-, -N(R M )- or C which may be substituted 1-3 Alkylene, R M H or a replaceable C 1-3 alkyl, Ring B1 is a benzene ring or a 6-membered heterocyclic ring, Here, R Z1 and the linking group forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- to 6-membered heterocyclic ring, Here, M, R Z1 The linking group forms a bond with the carbon atom constituting ring B2.

10. The compound or salt thereof according to claim 9, wherein A is CH or N, Q is CR Q , R Q is cyclopropyl, R 1 It is the following formula (II-2), R 2 -V 1 -V 2 or W, V 1 is -O- or -N(CH3)-, V 2 It is the following formula (VI-2), W is the following formula (VII-4) or (XII), R 3 C may be substituted by -OCH3 or tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl, X is -O-, Y 1 -O-(methylene)- *Y2 , *Y2 Indicates that Y 2 The bonding part, Y 2 is phenylene, The linking group is a group selected from the group consisting of the following formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7), Here, C═O and Y in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) are 2 Forming a bond, L' is -O-, -(C 1-3 Alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 Alkylene)-piperazinediyl, L" is a key, C 1-3 Alkylene or -(C 1-3 Alkylene)-O-, R L2 H or C 1-3 alkyl, EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A), Here, the benzene ring or 6-membered heterocyclic ring in the formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) forms a bond with a linking group, and the benzene ring in (Z-24A) forms a bond with a linking group, Wherein, when G is N, Z is a group selected from the group consisting of (Z-1A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A).

11. The compound or salt thereof according to claim 1, wherein The compound of formula (I) is selected from the group consisting of: 5-[(8-{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]benzoyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione, 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-[5-({(3S)-4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-4-{[(3S)-pyrrolidin-3-yl]oxy}quinolin-8-yl]oxy}methyl)benzoyl]-3-methylpiperazin-1-yl}methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione, 1-(6-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione, 3-(5-{[(3S)-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]quinolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-(5-{[(3S)-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]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, and 1-(7-{[(3S)-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-[( [0063] The compound of the invention is 1,3-diazinane-2,4-dione and 1,3-dioxadiazine-2,4-dione.

12. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for treating pancreatic cancer.

14. Use of the compound or salt thereof according to claim 1 in the manufacture of a pharmaceutical composition for treating pancreatic cancer.

15. The compound or salt thereof according to claim 1, for use in treating pancreatic cancer.

16. Use of the compound or salt thereof according to claim 1 in treating pancreatic cancer.

17. A method for treating pancreatic cancer, comprising the step of administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

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