Heterocyclic compound that acts on g12d mutant kras protein

Abstract

To provide a compound that is effective as an active ingredient in a therapeutic pharmaceutical composition for pancreatic cancer.SOLUTION: A heterocyclic compound represented by formula (I) or a salt thereof is used as a therapeutic agent for pancreatic cancer (where EUB is a group having the ability to bind to cerebron).SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Pancreatic cancer, which is primarily pancreatic ductal adenocarcinoma, has an extremely poor prognosis, with a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, pp. 7-30), and approximately 460,000 new cases are reported annually worldwide (CA Cancer J. Clin., 2018, 68, pp. 394-424). While surgery is the most effective treatment for pancreatic cancer, early detection is difficult, leading to frequent metastasis and often ineffective surgical treatment. If surgical treatment is not an option, chemotherapy and radiation therapy are used, but these have poor survival rates. Currently, FOLFRINOX therapy (a combination therapy of 5-FU, irinotecan, and oxaliplatin with the addition of levofolinate) is the standard treatment for pancreatic cancer. However, due to its high toxicity, careful patient selection is required, such as by limiting its prescribing to patients with an ECOG performance status of 1 or less (J. Clin. Oncol., 2018, 36, pp. 2545-2556). While the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved for use in combination with gemcitabine, its overall survival benefit is only about two weeks compared to gemcitabine alone, indicating that a satisfactory therapeutic effect has not been achieved. Therefore, there is still a need for more effective treatments (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] RAS proteins are small guanosine triphosphate (GTP)-binding proteins of approximately 21 kDa, consisting of 188–189 amino acids. There are four major RAS proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) produced by three genes: KRAS, NRAS, and HRAS. RAS proteins exist in an active GTP-bound form and an inactive GDP-bound form. RAS proteins are activated by the exchange of guanosine diphosphate (GDP) for GTP upon ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signaling cascades. On the other hand, active RAS becomes inactive by converting GTP to GDP through its intrinsic GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). This indicates that RAS functions as an important "molecular switch" in intracellular signaling pathways such as EGFR, and plays an important role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, pp. 761-774; Nature Rev. Drug Discov., 2014, 13, pp. 828-851; Nature Rev. Drug Discov., 2016, 15, pp. 771-785).

[0004] When RAS mutations result in amino acid substitutions, RAS becomes constitutively active due to impaired GTPase function and reduced response to GAPs, resulting in continuous downstream signaling. This excessive signaling leads to carcinogenesis and accelerated tumor proliferation. Pancreatic ductal adenocarcinoma (PDA) is thought to develop through a process of mild to severe dysplasia (PanIN), and KRAS mutations are already present in early-stage PanIN. Subsequently, abnormalities in the tumor suppressor genes INK4A, p53, and SMAD4 occur, leading to malignant progression (Nature Rev. Cancer, 2010, 10, pp. 683-695). Furthermore, KRAS mutations are found in over 90% of PDAs, with the majority of these mutations being point mutations at codon 12 in KRAS exon 2 (Cancer Cell, 2017, 32, pp. 185-203). This indicates that KRAS plays an important role in the oncogenesis and development of pancreatic cancer.

[0005] Known KRAS gene mutations include the KRAS G12C mutation and the KRAS G12D mutation. While the G12C mutation is common in non-small cell lung cancer, it is only present in a small percentage of pancreatic cancers (Cancer Cell 2014, 25, pp. 272-281). Therefore, therapeutic drugs for other KRAS mutations are desired. The G12D mutation is reported to be present in approximately 34% of pancreatic cancers, the highest proportion of all KRAS mutations (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0006] Patent Documents 1, 2, and 3 disclose RAS inhibitors, and compounds represented by the following formula (A) and formula (B) are respectively disclosed in Patent Documents 2 and 3. Patent Documents 1, 2, and 3 describe that they are useful for cancers with mutations in codon 12 of KRAS, one of which is the G12D mutation, but do not describe their effects on G12D-mutated KRAS-positive cancers. [ka]

[0007] Furthermore, Patent Documents 9, 10, 11, 12, 13, 14, 15 and 16 disclose KRAS G12D inhibitors.

[0008] In recent years, bifunctional compounds, collectively known as PROTACs (PROteolysis-TArgeting Chimeras) and SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers), have been discovered as a technology for inducing targeted protein degradation and are expected to be a novel drug discovery modality (Drug. Discov. Today Technol., 2019, 31, pp. 15-27). Bifunctional compounds promote the formation of a complex between the target protein and an E3 ligase in the cell, which then induces degradation of the target protein by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases recognize and ubiquitinate proteins to be degraded, which then leads to degradation in the proteasome.

[0009] There are over 600 types of E3 ligases in vivo, broadly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, only a limited number of E3 ligases are used in bifunctional degradation inducers, such as PROTACs and SNIPERs. Representative examples include von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). In particular, VHL has been reported in Patent Document 4, and CRBN in Patent Document 5.

[0010] A bifunctional compound is a compound in which a ligand for a target protein and a ligand for an E3 ligase are linked via a linker, and bifunctional compounds that degrade KRAS protein have been reported (Non-Patent Document 1, Non-Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 12, and 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 degradation of G12D mutant KRAS protein. However, other than Patent Documents 18 to 22, there are currently no reports suggesting that bifunctional compounds degrade G12D mutant KRAS protein. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2016 / 049565 [Patent Document 2] International Publication No. 2016 / 049568 [Patent Document 3] International Publication No. 2017 / 172979 [Patent Document 4] International Publication No. 2013 / 106643 [Patent Document 5] International Publication No. 2015 / 160845 [Patent Document 6] U.S. Patent Application Publication No. 2018 / 0015087 [Patent Document 7] International Publication No. 2019 / 195609 [Patent Document 8] International Publication No. 2020 / 018788 [Patent Document 9] International Publication No. 2021 / 041671 [Patent Document 10] International Publication No. 2021 / 106231 [Patent Document 11] International Publication No. 2021 / 107160 [Patent Document 12] International Publication No. 2022 / 002102 [Patent Document 13] International Publication No. 2022 / 015375 [Patent Document 14] International Publication No. 2022 / 098625 [Patent Document 15] International Publication No. 2022 / 105855 [Patent Document 16] International Publication No. 2022 / 031678 [Patent Document 17] International Publication No. 2021 / 207172 [Patent Document 18] International Publication No. 2022 / 148421 [Patent Document 19] International Publication No. 2022 / 148422 [Patent Document 20] International Publication No. 2022 / 173032 [Patent Document 21] International Publication No. 2022 / 228576 [Patent Document 22] International Publication No. 2023 / 280026 [Non-patent literature]

[0012] [Non-Patent Document 1] Cell. Chem. Biol., 2020, 27, p19-31 [Non-patent document 2] ACS Cent. Sci., 2020, 6, p1367-1375 Summary of the Invention [Problem to be solved by the invention]

[0013] Provided is a heterocyclic compound that is useful as an active ingredient in pharmaceutical compositions, for example, that has excellent activity in inducing degradation of G12D mutant KRAS protein and / or is useful as a G12D mutant KRAS inhibitor, and is expected to be useful as an active ingredient in pharmaceutical compositions for treating pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer. [Means for solving the problem]

[0014] The present inventors have conducted extensive research into compounds useful as active ingredients in pharmaceutical compositions for treating pancreatic cancer, and as a result have found that a heterocyclic compound of formula (I), for example, a bifunctional compound of formula (I), characterized in that a heterocyclic compound selected from the group consisting of quinazoline and quinoline has a substituent at the 8th position linked to a ligand of E3 ligase via a linker, has excellent activity of inducing degradation of G12D mutant KRAS protein and / or inhibitory activity against G12D mutant KRAS, thereby completing the present invention. That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1 may be substituted C 1-3 naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH and halogen, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV): [ka] R 1a , R 1b and R 1care the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 may be substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; Linker, Y 2 and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0015] Furthermore, examples of compounds having an effect of inducing degradation of G12D mutant KRAS protein and / or an inhibitory activity against G12D mutant KRAS include 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 E3 ligase via a linker. That is, the present invention also relates to a compound of formula (XXI) or a salt thereof, and a pharmaceutical composition containing a compound of formula (XXI) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1 may be substituted C 1-3 naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH and halogen, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV): [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 3P may be substituted C 1-6 alkylene, optionally substituted heterocycloalkylene, or optionally substituted heteroarylene; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2-*Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; R 5 But, 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), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered saturated heterocyclic ring, and the 4- to 8-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, Linker is R 3P and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0016] Furthermore, examples of compounds having an effect of inducing degradation of G12D mutant KRAS protein and / or an inhibitory activity against G12D mutant KRAS include bifunctional compounds of formula (XXII) in which a substituent at the 7th position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand for E3 ligase via a linker. That is, the present invention also relates to a compound of formula (XXII) or a salt thereof, and a pharmaceutical composition containing a compound of formula (XXII) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1P may be substituted C 1-3 naphthylene optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH, and halogen, or a group selected from the group consisting of the following formulae (II-22A), (II-22B), (II-22C), (III-22A), (III-22B), (III-22C), and (III-22D): [ka] [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 may be substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; R 5 But, 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), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered saturated heterocyclic ring, and the 4- to 8-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, Linker is R 1P and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.

[0017] Furthermore, compounds having an activity of inducing the degradation of G12D mutant KRAS protein and / or an activity of inhibiting G12D mutant KRAS may be, for example, bifunctional compounds of formula (XXIII) characterized by GDB - Linker - EUB. That is, the present invention also relates to a compound of formula (XXIII) or a salt thereof, and a pharmaceutical composition containing a compound of formula (XXIII) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - EUB is a group selected from the group consisting of the following formulae (LE-1) to (LE-40): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0018] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0019] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, in one embodiment, a pharmaceutical composition for treating pancreatic cancer, in one embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating metastatic pancreatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced pancreatic cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory pancreatic cancer, in one embodiment, a pharmaceutical composition for treating pancreatic cancer in treatment-naive and / or previously treated patients, in one embodiment, a pharmaceutical composition for treating metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, and in one embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer in treatment-naive and / or previously treated patients. Furthermore, the pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients encompasses a therapeutic agent for pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, containing the compound of formula (I) or a salt thereof. The present invention also relates to pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, recurrent or refractory pancreatic cancer, in one embodiment, pancreatic cancer in untreated and / or previously treated patients, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, in one embodiment, G12D mutant pancreatic cancer in untreated and / or previously treated patients. Use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating KRAS-positive pancreatic cancer; pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, relapsed or refractory pancreatic cancer, in one embodiment, pancreatic cancer in treatment-naive and / or previously treated patients, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, and in one embodiment, relapsed or refractory G12D mutant KRAS-positive pancreatic cancer. In one embodiment, use of a compound of formula (I) or a salt thereof for the treatment of G12D mutant KRAS-positive pancreatic cancer in treatment-naive and / or previously treated patients; pancreatic cancer; in one embodiment, G12D mutant KRAS-positive pancreatic cancer; in one embodiment, metastatic pancreatic cancer; in one embodiment, locally advanced pancreatic cancer; in one embodiment, recurrent or refractory pancreatic cancer; in one embodiment, pancreatic cancer in treatment-naive and / or previously treated patients; in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer; in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer; and a compound of formula (I) or a salt thereof for use in treating G12D mutant KRAS-positive pancreatic cancer in a patient who has not been treated and / or has been previously treated, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject. In one embodiment, the compound of formula (I) or a salt thereof is for use in treating G12D mutant KRAS-positive pancreatic cancer in a patient who has not been treated and / or has been previously treated, and a method for treating pancreatic cancer ...The present invention relates to a method for treating metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, relapsed or refractory G12D mutant KRAS-positive pancreatic cancer, and in one embodiment, G12D mutant KRAS-positive pancreatic cancer in untreated and / or previously treated patients. The present invention also relates to a compound of formula (I) or a salt thereof which is a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor, a compound of formula (I) or a salt thereof for use as a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor, and a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof.

[0020] The present invention also 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, and in one embodiment, the pharmaceutical composition is for treating pancreatic cancer, in one embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating metastatic pancreatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced pancreatic cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory pancreatic cancer, in one embodiment, a pharmaceutical composition for treating pancreatic cancer in treatment-naive and / or previously treated patients, in one embodiment, a pharmaceutical composition for treating metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, and in one embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer in treatment-naive and / or previously treated patients. Furthermore, the pharmaceutical composition containing the compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof, and one or more pharmaceutically acceptable excipients encompasses a therapeutic agent for pancreatic cancer containing the compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof, and in one embodiment, a therapeutic agent for G12D mutant KRAS-positive pancreatic cancer containing the compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof. The present invention also relates to the following: use of a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof for the manufacture of a pharmaceutical composition for treating pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, relapsed or refractory pancreatic cancer, in one embodiment, pancreatic cancer in untreated and / or previously treated patients, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, relapsed or refractory G12D mutant KRAS-positive pancreatic cancer, in one embodiment, untreated and / or previously treated patients; use of a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof for the treatment of pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, relapsed or refractory pancreatic cancer, in one embodiment, pancreatic cancer in untreated and / or previously treated patients, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, relapsed or refractory G12D mutant KRAS-positive pancreatic cancer, in one embodiment, untreated and / or previously treated patients; a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof for use in the treatment of pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, relapsed or refractory pancreatic cancer, in one embodiment, pancreatic cancer in untreated and / or previously treated patients, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, relapsed or refractory G12D mutant KRAS-positive pancreatic cancer, in one embodiment, untreated and / or previously treated patients; a method for treating pancreatic cancer, which comprises administering to a subject an effective amount of a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof, in one embodiment, G12D mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, recurrent or refractory pancreatic cancer, in one embodiment, pancreatic cancer in a patient who has not been treated and / or has been treated before, in one embodiment, metastatic G12D mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12D mutant KRAS-positive pancreatic cancer, in one embodiment, recurrent or refractory G12D mutant KRAS-positive pancreatic cancer, in one embodiment, G12D mutant KRAS-positive pancreatic cancer in a patient who has not been treated and / or has been treated before; a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof, which is a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor; A compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof for use as a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor, and A G12D mutant KRAS proteolysis inducer and / or G12D mutant KRAS inhibitor, comprising a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof. The "subject" refers to a human or other animal in need of treatment, and in one embodiment, a human in need of prevention or treatment. [Effects of the Invention]

[0021] The compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof has an effect of inducing degradation of G12D mutant KRAS protein and / or G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will be described in detail below.

[0023] In this specification, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In one embodiment, it means unsubstituted or having 1 to 3 substituents. When there are multiple substituents, the substituents may be the same or different from each other.

[0024] "C 1-12The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (Hereinafter, the number of carbon atoms will be expressed in the same manner). In one embodiment, it is ethyl or dodecyl. Similarly, "C 1-6 The term "alkyl" refers to a straight-chain or branched alkyl 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, methyl, ethyl, n-propyl, isopropyl, or sec-butyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, or tert-butyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, or n-butyl; in one embodiment, methyl, ethyl, or n-propyl; in one embodiment, methyl or n-propyl; in one embodiment, methyl, ethyl, or n-propyl; in one embodiment, methyl, ethyl, or n-propyl. Similarly, "C 1-3 "Alkyl" refers to a straight-chain or branched alkyl having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, or isopropyl, and 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, and in one embodiment, it is n-propyl.

[0025] "C 3-6"Cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, it is cyclobutyl, cyclopentyl, or cyclohexyl, in one embodiment, cyclobutyl or cyclopentyl, in one embodiment, cyclopentyl or cyclohexyl, in one embodiment, cyclopropyl or cyclobutyl, in one embodiment, cyclopropyl, in one embodiment, cyclobutyl, in one embodiment, cyclopentyl, and in one embodiment, cyclohexyl.

[0026] "C 1-3 The term "alkylene" refers to the above-mentioned "C 1-3 The carbon atom of the alkyl group has another bond. Examples include methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In one embodiment, a straight-chain or branched C 1-3 It is alkylene, and in one embodiment, it is methylene, ethylene, or trimethylene, in one embodiment, it is methylene or ethylene, in one embodiment, it is methylene, and in one embodiment, it is ethylene.

[0027] "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 a partially unsaturated bond. Furthermore, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized. One embodiment of "heterocycloalkyl" is "4- to 6-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms," another embodiment is "4- to 6-membered heterocycloalkyl containing 1 to 2 oxygen atoms as ring-constituting atoms," another embodiment is "4- to 6-membered heterocycloalkyl containing one oxygen atom as ring-constituting atom," another embodiment is "4- to 6-membered heterocycloalkyl containing 1 oxygen atom as ring-constituting atom," another embodiment is "4- to 6-membered heterocycloalkyl containing 1 to 2 nitrogen atoms as ring-constituting atoms," and another embodiment is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, It is piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, in some embodiments, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl, in some embodiments, tetrahydropyranyl or tetrahydrofuranyl, in some embodiments, tetrahydropyranyl, in some embodiments, tetrahydrofuranyl, in some embodiments, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, in some embodiments, piperidinyl or piperazinyl, in some embodiments, piperidinyl, and in some embodiments, piperazinyl.

[0028] "Heterocycloalkylene" is a divalent group among the above-mentioned "heterocycloalkyl" in which a nitrogen atom or carbon atom constituting the ring has another bond. One embodiment of "heterocycloalkylene" is "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 "4- to 6-membered heterocycloalkylene containing 1 to 2 oxygen atoms as ring-constituting atoms", another embodiment is "4- to 6-membered heterocycloalkylene containing one oxygen atom as ring-constituting atom", another embodiment is "4- to 6-membered heterocycloalkylene containing 1 to 2 nitrogen atoms as ring-constituting atoms", and another embodiment is oxetanediyl, tetrahydrofurandiyl, tetrahydropyrandiyl, azetidinediyl, pyrrolidinediyl, piperidinediyl, oxazolidinyl, benzo ... In one embodiment, the alkyl group is tetrahydropyrandiyl, imidazolidinediyl, piperazinediyl, morpholinediyl, thiomorpholinediyl, or dioxothiomorpholinediyl; in one embodiment, the alkyl group is oxetanediyl, tetrahydropyrandiyl, or tetrahydrofurandiyl; in one embodiment, the alkyl group is tetrahydropyrandiyl or tetrahydrofurandiyl; in one embodiment, the alkyl group is tetrahydropyrandiyl; in one embodiment, the alkyl group is tetrahydrofurandiyl; in one embodiment, the alkyl group is azetidinediyl, pyrrolidinediyl, piperidinediyl, or piperazinediyl; in one embodiment, piperidinediyl or piperazinediyl; in one embodiment, piperidinediyl; and in one embodiment, piperazinediyl.

[0029] A "bridged heterocycloalkyl" is a 7- to 9-membered bridged heterocyclic group containing one or two nitrogen atoms as ring-constituting atoms. In one embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing one or two nitrogen atoms as ring-constituting atoms, in another embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkyl containing two nitrogen atoms as ring-constituting atoms, and in another embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkyl containing two nitrogen atoms as ring-constituting atoms, one of the two nitrogen atoms being bonded to a hydrogen atom. Examples include diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, and diazabicyclo[3.3.1]nonanyl. In one embodiment, the diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]oct-6-enyl, diazabicyclo[3.2.1]oct-2-enyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]hept-5-enyl, and in another embodiment, the diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1]heptanyl, or diazabicyclo[2.2.1]heptanyl. In one embodiment, it is diazabicyclo[2.2.1]heptanyl or diazabicyclo[3.2.1]octanyl, in one embodiment, it is diazabicyclo[2.2.1]heptanyl, in one embodiment, it is diazabicyclo[3.2.1]octanyl, in one embodiment, it is 2,5-diazabicyclo[2.2.1]heptanyl or 3,8-diazabicyclo[3.2.1]octanyl, in one embodiment, it is 2,5-diazabicyclo[2.2.1]heptanyl, and in one embodiment, it is 3,8-diazabicyclo[3.2.1]octanyl.

[0030] A "bridged heterocycloalkylene" is a divalent group among the above-mentioned "bridged heterocycloalkyls" in which a nitrogen atom or carbon atom constituting the ring has another bond. In one embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkylene containing two nitrogen atoms, and in another embodiment, it is a saturated 7- to 9-membered bridged heterocycloalkylene containing two nitrogen atoms, one of the two nitrogen atoms being 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, the diazabicyclo[2.2.2]octanediyl is 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, or diazabicyclo[2.2.1]hept-5-enediyl. In one embodiment, the diazabicyclo[2.2.2]octanediyl is diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl, or diazabicyclo[2.2.1]hept-5-enediyl. In one embodiment, it is diazabicyclo[2.2.1]heptanediyl or diazabicyclo[3.2.1]octanediyl, in one embodiment, diazabicyclo[2.2.1]heptanediyl, in one embodiment, diazabicyclo[3.2.1]octanediyl, in one embodiment, 2,5-diazabicyclo[2.2.1]heptanediyl or 3,8-diazabicyclo[3.2.1]octanediyl, in one embodiment, 2,5-diazabicyclo[2.2.1]heptanediyl, and in one embodiment, 3,8-diazabicyclo[3.2.1]octanediyl.

[0031] A "bridged piperazinyl" is a piperazinyl having a bridge structure between carbon atoms on the ring, and the bridge structure is composed of carbon atoms. For example, it is diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octanyl, or diazabicyclo[3.1.1]heptanyl. In one embodiment, it is diazabicyclo[2.2.1]heptanyl. In one embodiment, it is diazabicyclo[3.2.1]octanyl. In one embodiment, it is diazabicyclo[3.1.1]heptanyl, in one embodiment, 2,5-diazabicyclo[2.2.1]heptanyl, or 3,8-diazabicyclo[3.2.1]octanyl, in one embodiment, 2,5-diazabicyclo[2.2.1]heptanyl, or 3,8-diazabicyclo[3.2.1]octanyl.

[0032] A "bridged piperazinediyl" is a divalent group in which the nitrogen atom constituting the ring of the "bridged piperazinyl" 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, or in another embodiment, it is 3,8-diazabicyclo[3.2.1]octanediyl.

[0033] "Spiroheterocycloalkyl" refers to a saturated 7- to 9-membered heterocyclocyclic group containing one or two nitrogen atoms as ring-constituting atoms and a spiro atom. In one embodiment, it is a saturated 7- to 9-membered heterocyclocyclic group containing two nitrogen atoms as ring-constituting atoms and a spiro atom. Examples include diazaspiro[3.3]heptanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, and diazaspiro[4.4]nonanyl. In one embodiment, it is 2,6-diazaspiro[3.4]octanyl, and in another embodiment, it is 2,6-diazaspiro[3.3]heptanyl.

[0034] "Spiroheterocycloalkylene" refers to a divalent group among the "spiroheterocycloalkyls" described above, which has two nitrogen atoms as ring-constituting atoms, and each of the two nitrogen atoms has a bond. Examples include 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. In one embodiment, it is 2,6-diazaspiro[3.4]octanediyl, and in another embodiment, it is 2,6-diazaspiro[3.3]heptanediyl. Furthermore, "spiroheterocycloalkylene" may be a divalent group among the "spiroheterocycloalkyls" described above, where a nitrogen atom or carbon atom constituting the ring has an additional bond. That is, one embodiment of "spiroheterocycloalkylene" is a saturated 7- to 9-membered spiroheterocycloalkylene containing 1 or 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, and in another embodiment, it is 2,6-diazaspiro[3.3]heptanediyl.

[0035] A "heterocycle" is an aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms.

[0036] The "five-membered heterocycle" is a five-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. One embodiment of the "five-membered heterocycle" is a pyrazole ring, imidazole ring, triazole ring, tetrazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, oxadiazole ring, or thiadiazole ring, and another embodiment is a pyrazole ring, imidazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, oxadiazole ring, or thiadiazole ring.

[0037] The "6-membered heterocycle" is a 6-membered heterocycle containing 1 to 3 nitrogen atoms as ring-constituting atoms. One embodiment of the "6-membered heterocycle" is a 6-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.

[0038] The "5- or 6-membered heterocycle" is a 5-membered heterocycle or a 6-membered heterocycle. In one embodiment, the "5- or 6-membered heterocycle" is a 5-membered heterocycle, and in another embodiment, a 6-membered heterocycle.

[0039] "Heteroaryl" refers to a 5- or 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 containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, or a 6-membered heteroaryl containing 1 to 3 nitrogen atoms as ring-constituting atoms, in one embodiment, a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, in one embodiment, a 6-membered heteroaryl containing 1 to 3 nitrogen atoms as ring-constituting atoms, and in one embodiment, pyrazolyl, imidazolyl, and pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, and in one embodiment, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, and in another embodiment, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0040] "Heteroarylene" is a divalent group among the above-mentioned "heteroaryl" in which two different carbon and / or nitrogen atoms constituting the ring have bonds. One embodiment of "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, and another embodiment is pyrazolediyl, imidazolediyl, triazolediyl, tetrazolediyl, oxazolidinyl, or the like.

[0039] In one embodiment, the aryl group is pyrazolediyl, imidazolediyl, triazolediyl, tetrazolediyl, oxazolediyl, isoxazolediyl, thiazoldiyl, isothiazolediyl, oxadiazolediyl, thiazoldiyl, isothiazolediyl, oxadiazolediyl, thiazoldiyl, or thiadiazolediyl. In another embodiment, the aryl group is pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl, or triazinediyl.

[0041] The "4- to 8-membered saturated heterocycle" refers to a 4- to 8-membered saturated heterocycle containing 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and may contain a partially unsaturated bond, may have a bridge, or may form a spiro ring. Furthermore, the sulfur atom contained in the heterocycle may be oxidized. Some embodiments include 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. Some embodiments include oxetane, tetrahydrofuran, The compound is tetrahydropyran, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, azaspiro[3.3]heptane, or oxazaspiro[3.3]heptane; in one embodiment, the compound is azetidine, tetrahydropyran, morpholine, or oxazaspiro[3.3]heptane; in one embodiment, the compound is azetidine or tetrahydropyran; in one embodiment, the compound is morpholine or oxazaspiro[3.3]heptane; and in one embodiment, the compound is tetrahydropyran.

[0042] "Optionally substituted heterocycloalkyl", "optionally substituted heterocycloalkylene", "optionally substituted C 1-6 One embodiment of the permissible substituents for "alkylene" is C 1-3 Alkyl, -O(C 1-3 alkyl), C=O, halogen, OH, and in one embodiment, C 1-3 Alkyl, -O(C 1-3 alkyl), halogen, and in one embodiment, —O(C 1-3 alkyl), halogen, and in one embodiment, C 1-3It is alkyl, in one embodiment, OH, in one embodiment, F, in one embodiment, methyl, and in one embodiment, ethyl.

[0043] "Optionally substituted C 1-6 Alkyl, optionally substituted C 1-3 Alkyl, optionally substituted C 1-3 One embodiment of the permissible substituents for "alkylene" is C 1-3 Alkyl, -O(C 1-3 alkyl), C=O, halogen, OH, and in one embodiment, C 1-3 Alkyl, -O(C 1-3 alkyl), halogen, and in one embodiment, —O(C 1-3 alkyl), halogen, and in one embodiment, C 1-3 It is alkyl, in one embodiment, OH, in one embodiment, F, in one embodiment, methyl, and in one embodiment, ethyl.

[0044] Some embodiments of the permissible substituents for "optionally substituted heteroarylene", "optionally substituted phenylene", and "optionally substituted heteroaryl" include C 1-3 Alkyl, -O(C 1-3 alkyl), halogen, OH, and in some embodiments, C 1-3 Alkyl, -O(C 1-3 alkyl), halogen, and in one embodiment, C 1-3 In one embodiment, it is alkyl, in one embodiment, it is methyl, in one embodiment, it is ethyl, in one embodiment, it is halogen, and in one embodiment, it is F.

[0045] Some embodiments of the substituents permitted in the "optionally substituted oxazolyl" include C 1-3 It is alkyl, and in one embodiment, it is methyl or isopropyl, and in one embodiment, it is methyl, and in one embodiment, it is isopropyl.

[0046] "Halogen" means F, Cl, Br, and I. In one embodiment, it is F, Cl, or Br, in another embodiment, it is F or Cl, in another embodiment, it is F or Br, in another embodiment, it is F, in another embodiment, it is Cl, and in another embodiment, it is Br.

[0047] "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 cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. In one embodiment, it is a group capable of binding to cereblon, IAP, or MDM2. In another embodiment, it is a group capable of binding to cereblon. Those skilled in the art can understand this by referring to the following documents, but the present invention is not limited to these. [Literature] Current Research in Chemical Biology., 2022, 2, 100020 Front. Chem., 2021, 9, 707317 J. Am. Chem. Soc., 2021, 143, 5141 Signal Transduct. Target. Ther., 2020, 5, 129 Nat. Cham. Biol., 2019, 15(7), 737 Communications Biology., 2020, 3, 140 Sci. Rep., 2020, 10(1), 15543 ACS Cham. Biol., 2019, 14, 2430 Cell Chem. Biol., 2021, 28(4), 559 J. Am. Chem. Soc., 2022, 144, 701 ACS Cham. Biol., 2019, 14, 2822

[0048] "GDB" is a group capable of binding to G12D mutant KRAS protein, and is limited to the example compounds described in the following documents. [Literature] International Publication No. 2021 / 041671 International Publication No. 2021 / 106231 International Publication No. 2021 / 107160 International Publication No. 2022 / 002102 International Publication No. 2022 / 105855 International Publication No. 2022 / 161443 International Publication No. 2022 / 171013 International Publication No. 2022 / 171147 International Publication No. 2022 / 184178 International Publication No. 2022 / 187528 International Publication No. 2022 / 194066 International Publication No. 2022 / 199586 International Publication No. 2022 / 246092 International Publication No. 2022 / 266069

[0049] The term "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid.

[0050] "G12D mutant KRAS" refers to KRAS having the above-mentioned "G12D mutation."

[0051] "Pancreatic cancer" refers to malignant tumors that occur in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, and in some embodiments, pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. Furthermore, in some embodiments, the cancer is metastatic pancreatic cancer, locally advanced pancreatic cancer, recurrent or refractory pancreatic cancer, and pancreatic cancer in untreated and / or previously treated patients.

[0052] "G12D mutant KRAS-positive pancreatic cancer" refers to pancreatic cancer that is positive for G12D mutant KRAS. For example, it refers to pancreatic cancer in which KRAS G12D mutation has occurred, and pancreatic cancer with a high rate of positive for G12D mutant KRAS. In one embodiment, it is G12D mutant KRAS-positive pancreatic ductal carcinoma, and in another embodiment, it is G12D mutant KRAS-positive pancreatic ductal adenocarcinoma.

[0053] "Z N1 " is the following formula (Z N1 -1) to (Z N1 -15) ( *LGZ is LG Z or indicates the bond with the Linker, R Z1’ are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n' is an integer from 0 to 2, and R Z2’ , R Z3’ and R Z4‘ are the same or different and represent H or optionally substituted C 1-6 alkyl, and ring B1′ is a benzene ring or a 6-membered heterocycle, wherein R Z1’ and- *LGN forms a bond with the carbon atom constituting ring B1'.) [ka] [ka] [ka]

[0054] "Z N2 " is the following formula (Z N2 -1) to (Z N2-15) ( *LGZ is LG Z or indicates the bond with the Linker, R Z1’ are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n' is an integer from 0 to 2, and R Z2’ and R Z3’ are the same or different and represent H or optionally substituted C 1-6 alkyl, and ring B1′ is a benzene ring or a 6-membered heterocycle, wherein R Z1’ and- *LGN forms a bond with the carbon atom constituting ring B1'.) [ka] [ka] [ka]

[0055] "Z C " is the following formula (Z C -16)~(Z C -27) ( *LGZ is LG Z or indicates the bond with the Linker, R Z1’ are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6alkyl)2, n' is an integer from 0 to 2, and R Z2’ , R Z4’ and R Z5’ are the same or different and represent H or optionally substituted C 1-6 alkyl, and M' is a bond, -O-, -S-, -N(R M’ )- or optionally substituted C 1-3 alkylene, and R M’ is H or optionally substituted C 1-3 alkyl, and ring B2' is a benzene ring or a 5- or 6-membered heterocycle, wherein R Z1’ and- *LGC forms a bond with the carbon atom constituting ring B1', and M', R Z1’ and- *LGC forms a bond with the carbon atom that constitutes ring B2'. [ka] [ka] [ka]

[0056] Certain embodiments of the compound of formula (I) or a salt thereof according to the present invention are shown below. (1-1) A is CR A or N, R A H, optionally substituted C 1-3 A compound or a salt thereof which is alkyl or cyano. (1-2) A compound or a salt thereof, wherein A is CH or N. (1-3) A compound or a salt thereof, wherein A is CH. (1-4) A compound or a salt thereof, wherein A is N. (2-1) Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6cycloalkyl, or vinyl, or a salt thereof. (2-2) Q is CR Q and R Q But C 3-6 A compound or a salt thereof, wherein: (2-3) Q is CR Q and R Q is cyclopropyl, or a salt thereof. (3-1) A compound or a salt thereof, wherein E is CH or N. (3-2) A compound or a salt thereof, wherein E is CH.

[0057] (4-1)R 1 may be substituted C 1-3 naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH and halogen, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV): [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 The compound or salt thereof is alkyl, vinyl, or halogen. (4-2)R 1 is the following formula (II): [ka] R 1a and R 1c are the same or different, C 1-3 The compound or salt thereof, wherein the aryl group is alkyl or halogen. (4-3)R 1 is the following formula (II): [ka] R 1a is a halogen, and R 1cBut C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (4-4)R 1 is the following formula (II-2) or a salt thereof: [ka]

[0058] (5-1)R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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), A compound or a salt thereof, wherein m is an integer of 0 to 2. (5-2)R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 But C 3-6 C optionally substituted with one group selected from the group consisting of cycloalkyl, halogen, and —OH 1-3 is alkyl, V 2 is represented by the following formula (V-2) or (VI-2), [ka] A compound or a salt thereof, wherein 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): [ka] (5-3)R 2 But -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )- and R V1 But C 1-3 is alkyl, V 2 is the following formula (VI-2), [ka] A compound or a salt thereof, wherein W is the following formula (XII): [ka] (5-4)R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] A compound or a salt thereof, wherein W is the following formula (XII): [ka] (5-5)R 2 But -V 1 -V 2 or W, V 1 is -O-, V 2 is the following formula (VI-2), [ka] A compound or a salt thereof, wherein W is the following formula (XII): [ka] (5-6)R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 But C 3-6 C optionally substituted with one group selected from the group consisting of cycloalkyl, halogen, and —OH 1-3 is alkyl, V 2 is represented by the following formula (V-2) or (VI-2), [ka] A compound or a salt thereof, wherein W is a group selected from the group consisting of the following formulae (VII-4), (XI) and (XII): [ka] (5-6―2)R 2 But -V 1 -V 2 or W, V 1 is -O- or -N(R V1 )- and R V1 But C 1-3is alkyl, V 2 is represented by the following formula (V-2) or (VI-2), [ka] A compound or a salt thereof, wherein W is a group selected from the group consisting of the following formulae (VII-4), (XI) and (XII): [ka] (5-7)R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] A compound or a salt thereof, wherein W is the following formula (VII-4) or (XII): [ka]

[0059] (6-1)R 3 may be substituted C 1-6 A compound or a salt thereof, wherein the compound is alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. (6-2)R 3 But -O-(C 1-6 alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 C optionally substituted with 1 group selected from the group consisting of alkyl)2 and heterocycloalkyl 1-6 alkyl, or optionally substituted heterocycloalkyl, or a salt thereof. (6-3)R 3 But -O(C 1-6C optionally substituted with one group selected from the group consisting of alkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl 1-6 A compound or a salt thereof, which is alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. (6-4)R 3 C optionally substituted by -OCH3 or tetrahydrofuranyl 1-3 The compound or a salt thereof, wherein the compound is alkyl, tetrahydrofuranyl, or tetrahydropyranyl. (6-5)R 3 is n-propyl optionally substituted with -OCH3, or tetrahydropyranyl, or a salt thereof.

[0060] (7-1) X is a bond, —CH—, —O—, —S—, or —NR 4X - and R 4X is H or optionally substituted C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (7-2) X is -O- or -NR 4X - and R 4X But C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (7-3) A compound or a salt thereof, wherein X is —O—.

[0061] (8-1)Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2, -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (8-2)Y 1 But -O-(C 1-3 alkylene)- *Y2 Or -(C 1-3 alkylene)-O- *Y2 ( *Y2 is Y 2 ) a compound or a salt thereof. (8-3)Y 1 But -O-(C 1-3 alkylene)- *Y2 ( *Y2 is Y 2 ) a compound or a salt thereof. (8-4)Y 1 But -O-(methylene)- *Y2 ( *Y2 is Y 2 ) a compound or a salt thereof.

[0062] (9-1)Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene, or a salt thereof. (9-2)Y 2 is phenylene or pyridinediyl, or a salt thereof. (9-3)Y 2 is phenylene optionally substituted with fluorine, or a salt thereof. (9-4)Y 2 is phenylene, or a salt thereof. (9-5)Y 2 is optionally substituted phenylene or pyridinediyl, or a salt thereof.

[0063] (10-1) Linker, Y 2 and a compound or a salt thereof, which is a group that chemically bonds the EUB. (10-2) Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 , L 2 , L 3 and L 4 are the same or different and are a bond, C=O, -O-, -S-, -SO2-, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7- to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-6 alkylene; R L But H or C 1-6 A compound or a salt thereof, wherein the compound is alkyl. (10-3) Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O- or C1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-3―2) Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-4) Linker 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), Here, C═O in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) is Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene, or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-5) Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O- or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-5―2)Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-6) Linker 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 in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) represents Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene, or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 A compound or a salt thereof, wherein the compound is alkyl. (10-7) A compound or a salt thereof, wherein Linker is the following formula (L-5A) or (L-7A): [ka]

[0064] (11-1) A compound or a salt thereof, wherein EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. (11-2) A compound or a salt thereof, wherein EUB is a group capable of binding to cereblon. (11-3) EUB is represented by the following formula (XV): [ka] G is CR G or N, R G But H or C 1-6 is 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), [ka] [ka] [ka] [ka] R Z1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 and R Z4 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 is alkylene, R M is H or optionally substituted C 1-3 is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, where M, R Z1and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof. (11-3-2) EUB is a group capable of binding to cereblon, and the group capable of binding to cereblon is represented by the following formula (XV): [ka] G is CR G or N, R G But H or C 1-6 is 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), [ka] [ka] [ka] [ka] RZ1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 and R Z4 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 is alkylene, R M is H or optionally substituted C 1-3 is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof. (11-4) EUB is represented by the following formula (XV): [ka] 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-6 alkyl or halogen; n is an integer of 0 or 1, R Z2 and R Z4 are the same or different and are H or C 1-6 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof. (11-5) EUB is represented by the following formula (XV): [ka] 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker; provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-3 alkyl or halogen; n is an integer between 0 and 1, R Z2 But C 1-3 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof. (11-6) EUB is represented by the following formula (XV): [ka] 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), wherein the benzene ring or the 6-membered heterocycle in the 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) forms a bond with Linker, provided that 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), or a salt thereof. [ka] [ka] [ka] (11-7) EUB is represented by the following formula (XV): [ka] G is CH; 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), wherein the benzene ring or 6-membered heterocycle in the formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), and (Z-15A) forms a bond with Linker, or a salt thereof. [ka] [ka] (11-8) EUB is the following formula (XV): [ka] 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), wherein the benzene ring or the 6-membered heterocycle in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A), and (Z-22A) forms a bond with Linker, However, when G is N, Z is (Z-16A) or (Z-22A), or a salt thereof. [ka] (11-9) EUB is represented by the following formula (XV), [ka] G is CR G or N, R G But H or C 1-6 is alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-1 1), (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), wherein ring B1 and ring B2 in 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) form a bond with Linker; provided that 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); [ka] [ka] [ka] [ka] [ka] R Z1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 , R Z4 and R Z5 are the same or different and are H or optionally substituted C1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 is alkylene, R M is H or optionally substituted C 1-3 is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof. (11-10) EUB is represented by the following formula (XV): [ka] 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), [ka] [ka] [ka] [ka] wherein the benzene ring or 6-membered heterocycle in the 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) forms a bond with Linker, and the benzene ring in (Z-24A) forms a bond with Linker, provided that 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) or a salt thereof.

[0065] (12) Compounds or salts thereof that are a combination of two or more of the embodiments described in (1-1) to (11-10) above that are not contradictory to each other. Examples include, but are not limited to, the following combinations: (12-1) A compound of formula (I) or a salt thereof. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1 may be substituted C 1-3naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH and halogen, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV): [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 may be substituted C 1-6alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; Linker, Y 2 and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. (12-2) The compound or salt thereof according to (12-1), wherein EUB is a group capable of binding to cereblon. (12-3) EUB is represented by the following formula (XV): [ka] G is CR G or N, R G But H or C 1-6 is 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), and (Z-23), [ka] [ka] [ka] [ka] R Z1are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 and R Z4 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 is alkylene, R M is H or optionally substituted C 1-3 is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (12-2). (12-4) EUB is represented by the following formula (XV), [ka] 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-6 alkyl or halogen; n is an integer of 0 or 1, R Z2 and R Z4 are the same or different and are H or C 1-6 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (12-3). (12-5) A is CH or N; Q is CR Q and R Q But C 3-6 is cycloalkyl, E is CH; R 1 is the following formula (II): [ka] R 1a and R 1c are the same or different, C 1-3 alkyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 But C 3-6 C optionally substituted with one group selected from the group consisting of cycloalkyl, halogen, and —OH 1-3 is alkyl, V 2 is represented by the following formula (V-2) or (VI-2), [ka] 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), [ka] R 3 But -O-(C 1-6 alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 C optionally substituted with 1 group selected from the group consisting of alkyl)2 and heterocycloalkyl 1-6 alkyl, or optionally substituted heterocycloalkyl; X is -O- or -NR 4X - and R 4X But C 1-3 is alkyl, Y 1 But -O-(C 1-3 alkylene)- *Y2 Or -(C 1-3 alkylene)-O- *Y2 And ( *Y2 is Y 2) and the bond. Y 2 is phenylene or pyridinediyl, Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 , L 2 , L 3 and L 4 are the same or different and are a bond, C=O, -O-, -S-, -SO2-, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7- to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-6 alkylene; R L But H or C 1-6 The compound or salt thereof according to (12-4), wherein R is alkyl. (12-6) R 1 is the following formula (II): [ka] R 1a is a halogen, and R 1c But C 1-3 is alkyl, R 2 But -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )- and R V1 But C 1-3 is alkyl, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 But -O(C 1-6 C optionally substituted with one group selected from the group consisting of alkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; X is -O-, Y 1 But -O-(C 1-3 alkylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Y 2 is phenylene Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O- or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), [ka] 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker; provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-3 alkyl or halogen; n is an integer of 0 or 1, R Z2 But C 1-3 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (12-5). (12-6―2) R 1 is the following formula (II): [ka] R 1a is a halogen, and R 1c But C 1-3 is alkyl, R 2 But -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )- and R V1 But C 1-3 is alkyl, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 But -O(C 1-6 C optionally substituted with one group selected from the group consisting of alkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; X is -O-, Y 1 But -O-(C 1-3 alkylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Y 2 is phenylene Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), [ka] 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker; provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-3 alkyl or halogen; n is an integer of 0 or 1, R Z2 But C 1-3 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (12-5). (12-7) Q is CR Q and R Q is cyclopropyl, R 1 is the following formula (II-2), [ka] R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 C optionally substituted by -OCH3 or tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl; Y 1 -O-(methylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Linker 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 in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), and (L-7) represents Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), [ka] 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), wherein the benzene ring or the 6-membered heterocycle in the 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) forms a bond with Linker, The compound or salt thereof according to (12-6), 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). [ka] [ka] [ka] (12-8) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-3), (3-2), (4-4), (5-5), (6-5), (7-3), (8-4), (9-4), (10-7), or (11-8). (12-9) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-2), (6-3), (7-2), (8-2), (9-3), (10-5), or (11-4). (12-10) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-2), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), or (11-4). (12-11) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-1), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), or (11-4). (12-12) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-1), (5-6), (6-2), (7-2), (8-2), (9-2), (10-2), or (11-6). (12-13) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-4), (9-4), (10-5), or (11-5). (12-14) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), or (11-5). (12-15) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), or (11-6). (12-16) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-3), or (11-5). (12-17) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-2), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-4), or (11-6). (12-18) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-3), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), or (11-5). (12-19) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-4), (2-2), (3-2), (4-3), (5-3), (6-3), (7-3), (8-3), (9-4), (10-5), or (11-5). (12-20) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-3), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), or (11-6). (12-21) A compound of formula (I) or a salt thereof, which is a combination of the above embodiments (1-4), (2-3), (3-2), (4-4), (5-4), (6-4), (7-3), (8-4), (9-4), (10-6), or (11-6). (12-22) R 2 But -V 1 -V 2 or W, V 1 is -O-, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 is n-propyl optionally substituted with —OCH3, or tetrahydropyranyl, Linker is represented by the following formula (L-5A) or (L-7A), [ka] EUB is represented by the following formula (XV), [ka] 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), [ka] wherein the benzene ring or the 6-membered heterocycle in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A), and (Z-22A) forms a bond with Linker, The compound or salt thereof according to (12-7), wherein when G is N, Z is (Z-16A) or (Z-22A). (12-23) EUB is represented by the following formula (XV), [ka] G is CR G or N, R G But H or C 1-6 is alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-1 1), (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), wherein ring B1 and ring B2 in 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) form a bond with Linker; provided that 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); [ka] [ka] [ka] [ka] [ka] R Z1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl)2, n is an integer from 0 to 2, R Z2 , R Z3 , R Z4 and R Z5 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-3 is alkylene, R M is H or optionally substituted C 1-3 is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (12-2). (12-24) A is CH or N; Q is CR Q and R Q is cyclopropyl, R 1 is the following formula (II-2), [ka] R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (VII-4) or (XII), [ka] R 3 C optionally substituted by -OCH3 or tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl; X is -O-, Y 1 But -O-(methylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Y 2 is phenylene Linker 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 in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) represents Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), [ka] 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), [ka] [ka] [ka] [ka] wherein the benzene ring or 6-membered heterocycle in the 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) forms a bond with Linker, and the benzene ring in (Z-24A) forms a bond with Linker, However, 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) or a salt thereof.

[0066] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 5-[(8-{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-[(oxan-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-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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-[({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, 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, 1-(6-{[(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-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 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, 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-[(oxan-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-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinan-2,4-dione, or a salt thereof.

[0067] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 5-[(8-{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-[(oxan-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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-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]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, 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 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, 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-[(oxan-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 a compound selected from the group consisting of 1-(7-{[(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-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinan-2,4-dione, or a salt thereof.

[0068] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 5-[(8-{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-[(oxan-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-[({(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-[(oxan-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-[({(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, 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, 1-(6-{[(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-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione, 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, 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-[(oxan-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 a compound selected from the group consisting of 1-(7-{[(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-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinan-2,4-dione, or a salt thereof.

[0069] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 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-[(oxan-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 n-phosphate, 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.

[0070] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 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-[(oxan-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 n-phosphate, 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.

[0071] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds. 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-[(oxan-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 n-phosphate, 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.

[0072] Certain embodiments of the compound of formula (XXI) or a salt thereof according to the present invention are shown below. (21-1) A compound of formula (XXI) or a salt thereof. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1 may be substituted C 1-3 naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH and halogen, or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV): [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 3P may be substituted C 1-6 alkylene, optionally substituted heterocycloalkylene, or optionally substituted heteroarylene; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. RY is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; R 5 But, 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), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered saturated heterocyclic ring, and the 4- to 8-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, Linker is R 3P and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. (21-2) A is CH or N; Q is CR Q and R Q But C 3-6 is cycloalkyl, E is CH; R 1 is the following formula (II): [ka] R 1a is a halogen and R 1c C 1-3 is alkyl, R 2 But -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )- and R V1 But C 1-3 is alkyl, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3P But -O(C 1-6 C optionally substituted with one group selected from the group consisting of alkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl 1-6 alkylene, oxetanediyl, tetrahydrofurandiyl, or tetrahydropyrandiyl 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), [ka] R 5a and R5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; X is -O-, Y 1 But -O-(C 1-3 alkylene)- *Y2 And ( *Y2 is Y 2 ) Y 2 is phenylene, Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 is alkyl, EUB is a group capable of binding to cereblon, and the group capable of binding to cereblon is represented by the following formula (XV): [ka] 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker; provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-3 alkyl or halogen; n is an integer between 0 and 1, R Z2 But C 1-3 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (21-1). (21-3) A is CH or N; Q is CR Q and R Q is cyclopropyl, E is CH; R 1 is the following formula (II-2), [ka] R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3P But -O(C 1-3 C optionally substituted with alkyl 1-6 is alkylene, R 5 is H, X is -O-, Y 1 But -O-(methylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Y 2 is phenylene, Linker 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), Here, C═O in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) is Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene, or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is a group capable of binding to cereblon, and the group capable of binding to cereblon is represented by the following formula (XV): [ka] 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), wherein the benzene ring or the 6-membered heterocycle in the 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) forms a bond with Linker, The compound or salt thereof according to (21-2), 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). [ka] [ka]

[0073] Certain embodiments of the compound of formula (XXII) or a salt thereof according to the present invention are shown below. (22-1) A compound of formula (XXII) or a salt thereof. [ka] (In the formula, A is CR A or N, R A H, optionally substituted C 1-3 alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-3 Alkyl, C 3-6 cycloalkyl, or vinyl; E is CH or N; R 1P may be substituted C 1-3 naphthylene optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH, and halogen, or a group selected from the group consisting of the following formulae (II-22A), (II-22B), (II-22C), (III-22A), (III-22B), (III-22C), and (III-22D): [ka] [ka] R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen; R 2 But -V 1 -V 2 or W, V 1 is a bond, -CH2-, -O-, -S- or -N(RV1 )- and R V1 is H or optionally substituted C 1-3 is alkyl, V 2 is represented by the following formula (V) or formula (VI), [ka] W is a 7- to 9-membered bridged heterocycloalkyl group represented by the following formula (VII) or (VII-2) or containing 1 or 2 nitrogen atoms, [ka] R 2a are the same or different and are OH, OCH3, F or optionally substituted C 1-3 alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 may be substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is a bond, -CH2-, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-3 is alkyl, Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , -SO2-(optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2, -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 Alkylene)-S- *Y2 , -(optionally substituted C 1-3 Alkylene)-SO2- *Y2 or -(optionally substituted C 1-3 (Alkylene)-NR Y - *Y2 And ( *Y2 is Y 2 ) and the bond. R Y is H or optionally substituted C 1-3 is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; R 5 But, 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), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered saturated heterocyclic ring, and the 4- to 8-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, Linker is R 1P and EUB, EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR. (22-2) A is CH or N; Q is CR Q and R Q But C 3-6 is cycloalkyl, E is CH; R 1P may be substituted C 1-3 naphthylene optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH, and halogen, or a group selected from the group consisting of the following formulae (II-22A), (II-22B), and (II-22C): [ka] R 1a is a halogen and R 1c C 1-3 is alkyl, R 2 But -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )- and R V1 But C 1-3 is alkyl, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 may be substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; 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), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; X is -O-, Y 1 But -O-(C 1-3 alkylene)- *Y2 And ( *Y2 is Y 2 ) Y 2 is phenylene, Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 is alkyl, EUB is a group capable of binding to cereblon, and the group capable of binding to cereblon is represented by the following formula (XV): [ka] 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker; provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), [ka] [ka] R Z1 But C 1-3 alkyl or halogen; n is an integer between 0 and 1, R Z2 But C 1-3 is alkyl, M is a bond or C 1-3 is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1and Linker forms a bond with the carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, where M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to (22-1). (22-3) A is CH or N; Q is CR Q and R Q is cyclopropyl, E is CH; R 1P may be substituted C 1-3 naphthylene optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH, and halogen, or a group selected from the group consisting of the following formulae (II-22A), (II-22B), and (II-22C): [ka] R 1a is F and R 1c is methyl, R 2 But -V 1 -V 2 or W, V 1 is —O— or —N(CH3)—, V 2 is the following formula (VI-2), [ka] W is represented by the following formula (XII): [ka] R 3 C optionally substituted by -OCH3 or tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl; R 5 is H, X is -O-, Y 1 But -O-(methylene)- *Y2 And ( *Y2 is Y 2 ) and the bond. Y 2 is phenylene, Linker 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), Here, C═O in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) is Y 2 It forms a bond with [ka] L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH3)(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene, or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is a group capable of binding to cereblon, and the group capable of binding to cereblon is represented by the following formula (XV): [ka] 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), wherein the benzene ring or the 6-membered heterocycle in the 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) forms a bond with Linker, The compound or salt thereof according to (22-2), 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). [ka] [ka]

[0074] Certain embodiments of the compound of formula (XXIII) or a salt thereof of the present invention are shown below. (23-1) A compound of formula (XXIII) or a salt thereof. [ka] (In the formula, GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - EUB is a group selected from the group consisting of the following formulae (LE-1) to (LE-37): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (23-2) GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - 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 formula (LE-23), or a salt thereof. [ka] (23-3) GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - EUB is the compound or salt thereof according to (23-2), which is represented by the following formula (LE-10): [ka]

[0075] (23-4) A compound of formula (XXIII) or a salt thereof. [ka] (In the formula, GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - EUB is a group selected from the group consisting of the following formulae (LE-1) to (LE-40): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (23-5) GDB is a group that has the ability to bind to the G12D mutant KRAS protein, -Linker - 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), or a salt thereof. [ka]

[0076] The compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) may exist as tautomers or geometric isomers depending on the type of substituents. In this specification, the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) may be described in only one isomeric form, but the present invention also includes other isomers, and also includes isolated isomers or mixtures thereof. Furthermore, the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) may have asymmetric carbon atoms or axial asymmetry, and therefore may have diastereomers. The present invention also encompasses separated diastereomers of the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII), or mixtures thereof.

[0077] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I), formula (XXI), formula (XXII), or formula (XXIII). A pharmaceutically acceptable prodrug is a compound 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 groups that form prodrugs include those described in Prog. Med., 1985, 5, pp. 2157-2161 and "Drug Development," Vol. 7, Molecular Design, Hirokawa Shoten, 1990, pp. 163-198.

[0078] Furthermore, the salt of the compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII) refers to a pharmaceutically acceptable salt of the compound of formula (I), which may form an acid addition salt or a salt with a base depending on the type of substituent. Examples include salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific 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 acetylleucine, lysine, and ornithine; and ammonium salts.

[0079] Furthermore, the present invention also encompasses various hydrates and solvates, and crystalline polymorphic substances of the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) and salts thereof.

[0080] The present invention also encompasses all compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used for isotopic 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 Isotopes of sulphur (e.g., sulphur) are included. It can be used for research such as tissue distribution studies of the compounds, drugs and / or substrates of the present invention labeled with isotopes. For example, tritium ( 3 H), carbon-14 ( 14 Radioisotopes such as C may be used for this purpose because of their ease of labeling and convenience of detection. Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 2 H) substitution may be therapeutically advantageous due to increased metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, and reduced drug interactions). Positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 Substitutions to 2,4-diaminobenzyl- ... The isotopically labeled compounds of the present invention can generally be produced by conventional methods known to those skilled in the art, or by a process similar to that described in the Examples or Preparations, using an appropriate isotopically labeled reagent instead of an unlabeled reagent.

[0081] (manufacturing method) The compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) and salts thereof can be produced by various known synthetic methods, taking advantage of characteristics based on their basic structure or the type of substituents. In this case, depending on the type of functional group, it may be effective from a manufacturing technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 5th Edition, by P.G.M. Wuts and T.W. Greene, John Wiley & Sons Inc., 2014, and the like. These protecting groups may be appropriately selected and used depending on the reaction conditions. In such methods, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group, if necessary. Furthermore, prodrugs of the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting groups, or by further reacting the obtained compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Representative methods for producing the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) are described below. Each method can also be performed by referring to the references attached to the description. Note that the production methods of the present invention are not limited to the examples shown below.

[0082] In this specification, the following abbreviations may be used. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropyl alcohol, tBuOH: tert-butyl alcohol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphoric acid, iPr2O: diisopropyl ether, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 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-methylmethanaminium Hexafluorophosphate, NMM: N-methylmorpholine, CDI: 1,1'-carbodiimidazole, 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'-diisopropoxidephenyl, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0083] (First manufacturing method) This process is the first method for producing the compound of formula (I) or a salt thereof. [ka] (PG in the formula 1 -R 11 is R 1 The NH or OH contained in 1 is a group to which PG 2 -R 21 is R 2 The NH or OH contained in 2 is a group to which the following are bonded.

[0084] The compound of formula (I) can be obtained by subjecting compound (1) to deprotection reaction conditions under acidic conditions. Examples of protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl. This reaction is carried out by using an equivalent or excess amount of a deprotecting reagent to compound (1) in a reaction-inert solvent, stirring under cooling to reflux for usually 0.1 hours to 5 days. Examples of the deprotecting reagent used here include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, Examples of the solvent used herein include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, and chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN, TfOH, water, and mixtures thereof. Furthermore, by selecting the protecting group, deprotection can also be carried out by catalytic hydrogenation or under basic conditions. Examples of protecting groups that can be deprotected by catalytic hydrogenation include benzyl, p-methoxybenzyl, and benzyloxycarbonyl groups. Deprotection can also be carried out using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl groups. Examples of protecting groups that can be deprotected under basic conditions include acetyl, trifluoroacetyl, and benzoyl groups. Furthermore, deprotection can be carried out stepwise by selecting protecting groups that can be deprotected under different deprotection conditions as PG1 and PG2. As references for this reaction, for example, the following can be referred to. P.G. M. Uts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis" (5th ed., 2014). When the starting compound (1) has axial chirality, the compound (1) may be separated and the resulting stereoisomer may be used to carry out this reaction.

[0085] (Second manufacturing method) This process is the second method for preparing salts of compounds of formula (I). [ka]

[0086] The compound of formula (I) or a salt thereof can be obtained by subjecting compound (1) to deprotection reaction conditions under acidic conditions, isolating the free form by treatment under basic conditions, and then subjecting the compound to salt-forming reaction conditions. Examples of protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl. In this reaction, an equivalent or excess amount of a deprotecting reagent to compound (1) is used in a reaction-inert solvent, and the mixture is stirred under cooling to reflux, usually for 0.1 to 5 days, and then treated with a basic aqueous solution to isolate the free form. The reaction is then carried out by adding an equivalent or excess amount of an acidic reagent to compound (1) in a reaction-inert solvent, and stirring under cooling to reflux, usually for 0.1 to 5 days. Examples of deprotecting reagents that can be used include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, Examples of the solvent used herein include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, and chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN, TfOH, water, and mixtures thereof. Examples of the acidic reagent used herein include acids such as hydrogen chloride (DOX solution), phosphoric acid, and p-toluenesulfonic acid. Examples of the basic aqueous solution used herein include, but are not limited to, aqueous sodium bicarbonate solution. Furthermore, by selecting the protecting group, deprotection can also be carried out by catalytic hydrogenation or under basic conditions. Examples of protecting groups that can be deprotected by catalytic hydrogenation include benzyl, p-methoxybenzyl, and benzyloxycarbonyl groups. Deprotection can also be carried out using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl groups. Examples of protecting groups that can be deprotected under basic conditions include acetyl, trifluoroacetyl, and benzoyl groups. Furthermore, deprotection can be carried out stepwise by selecting protecting groups that can be deprotected under different deprotection conditions as PG1 and PG2. As references for this reaction, for example, the following can be referred to. P.G. M. Uts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis" (5th ed., 2014). When the starting compound (1) has axial chirality, the compound (1) may be separated and the resulting stereoisomer may be used to carry out this reaction.

[0087] (Raw material manufacturing method 1) This production method is a method for producing compound (1)-1, which is included in compound (1), which is the raw material for production methods 1 and 2. [ka] (L in the formula 2A is C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 R represents pyrrolidinediyl, bridged piperazinediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted with alkyl; LG is C 1-12 (This indicates an alkyl group. The same applies below.)

[0088] (first step) This step is a step of subjecting compound (2) to hydrolysis conditions to obtain compound (3). This reaction is carried out by using an equivalent or excess amount of a hydrolysis reagent to compound (2) in a reaction-inert solvent, stirring under cooling to reflux, usually for 1 hour to 5 days. Examples of the hydrolysis reagent used here include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, trimethyltin hydroxide, etc. Examples of the solvent include, but are not limited to, alcohols such as methanol, ethanol, and n-propanol; ethers such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; acetonitrile; water; and mixtures thereof.

[0089] (Second process) In this step, compound (3) and compound (4) are subjected to condensation reaction conditions to obtain compound (1)-1. This reaction is carried out by adding a condensing agent and a base to a mixture of equal or an excess of compound (3) and compound (4) in an inert solvent at room temperature, usually for one hour to one day. Examples of the condensing agent include, but are not limited to, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, COMU, and PyBOP. Examples of the base include, but are not limited to, 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 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.

[0090] (Raw material manufacturing method 2) This production method is the first method for producing compound (2)-1, which is included in compound (2), which is the raw material in Raw Material Production Method 1. [ka] [ka] (In the formula, PG 3 is the protecting group for OH, LG 1represents a leaving group, and BLG represents a boronic acid group, a boronic acid group protected by a boronic acid protecting group such as a boronic acid pinacol ester group, or a trifluoroborate group (hereinafter, sometimes referred to as a boronic acid group, etc.). Examples of leaving groups shown here include Cl, Br, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. (The same applies below).

[0091] (first step) This step is a method for producing compound (7) by ipso substitution reaction between compound (5)-1 and compound (6)-1. This reaction involves using equimolar amounts of compound (5)-1 and compound (6)-1, or an excess of either compound. The resulting mixture is stirred in a reaction-inert solvent, or without solvent, under cooling to reflux, preferably at 0°C to 120°C, typically for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, 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, NMP, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, NMM, DABCO, or tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction progress. Furthermore, the compound (7) can be produced by catalytic hydrogenation of the compound obtained by the Mizoroki-Heck reaction of the compound (5)-1 with the compound (6)-1. [Literature] Chem. Rev., 2003, 103, p.2945-2964

[0092] (Second process) This step is a method for producing compound (9) by ipso substitution reaction between compound (7) and compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2. Furthermore, compound (9) can be produced by Negishi coupling of compound (8) in which the hydrogen atom is converted to a halogen atom with compound (7). [Literature] ACC. Chem. Res., 1982, 15, p.340-348

[0093] (Third step) This process involves the reaction of compound (9) with PG 3 This method involves the production of compound (10)-1 by an ipso substitution reaction with —OH. The PG used here 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0094] (Fourth step) This step is a step of synthesizing a compound (10) containing both the compound (10)-1 obtained in the third step of this synthesis method and the compound (10)-2 obtained in the third step of the raw material production method 9 described later, and R Q This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative containing a -boronic acid group or the like to produce compound (11). Examples of the boronic acid group or the like used here include, but are not limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triolborate base, and a trifluoroborate base. This reaction is carried out by reacting compound (10) with R QA mixture of these compounds is stirred in the presence of a base and a palladium catalyst in a reaction-inert solvent at room temperature to reflux, preferably at 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, and cesium carbonate. Palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II). In some cases, it may be advantageous to carry out 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 in order to ensure smooth progress of the reaction.Alternatively, the precatalyst (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) can be used as a palladium catalyst for this reaction. Microwave heating of the mixture may be beneficial for smooth reaction progression. [Literature] J. Am. Chem. Soc., 2005, 127, p.4685-4696 Org. Lett. 2011, 13, p.3948-3951 Org. Lett. 2012, 14, p.1278-1281 Compound (10) is deiodinated using a Pd catalyst and a reducing agent to give compound (11) (where R Q can produce hydrogen). [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0095] (Fifth step) This step is a method for producing compound (13) by Suzuki-Miyaura coupling reaction of compound (11) and compound (12). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Compound (13) may have axial chirality and may be obtained as a mixture of stereoisomers. 1 Compound (13) in which is a protecting group or a compound obtained by deprotecting compound (13) (e.g., compound (14)) can be subjected to a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer.

[0096] (Sixth step) This step is a method for producing compound (14) by deprotecting compound (13) through catalytic hydrogenation. This reaction can be carried out by stirring compound (13) under a hydrogen atmosphere in a reaction-inert solvent such as MeOH, EtOH, or ethyl acetate under normal to elevated pressure in the presence of a metal catalyst, with stirring for 1 hour to 5 days, preferably at room temperature. Examples of suitable metal catalysts include palladium catalysts such as Pd / C or palladium black, platinum catalysts such as platinum plate or platinum oxide, and nickel catalysts such as reduced nickel or Raney nickel. PG 1 When a tetrahydro-2H-pyran-2-yl group or the like is used as a protecting group of (I), a base may be used to suppress deprotection. Examples of the base used here include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc. Compound (14) may have axial chirality and may be obtained as a mixture of stereoisomers. 1 Compound (14) in which is a protecting group or a compound obtained by deprotecting compound (14) can be subjected to a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 13, Maruzen, 2004

[0097] (Seventh step) This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15). This reaction is carried out by reacting a mixture of equal amounts of compound (14) and compound (15), or an excess of either, in the presence of a base in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents used include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases include, but are not limited to, 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 may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 14, Maruzen, 2005 Compound (2)-1 may have axial chirality and may be obtained as a mixture of stereoisomers. 1 The compound (2)-1 in which is a protecting group or the compound obtained by subjecting the compound (2)-1 to a deprotection reaction can be subjected to a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer. Furthermore, compound (15) can be prepared by the reaction of LG 1 The compound having a hydroxy group in the corresponding position is sulfonylated in the presence of a base to give LG 1is a sulfonyloxy group. Examples of the sulfonylation reagent used here include, but are not limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, etc. Examples of the base include, but are not limited to, TEA, DIPEA, pyridine, tetramethylethylenediamine, etc. As references for this reaction, for example, the following can be referred to. Synthesis 1999, 9, p.1633-1636

[0098] (Raw material manufacturing method 3) This production method is a second method for producing compound (2)-1, which is included in compound (2), which is the raw material in Raw Material Production Method 1. [ka] [ka] [ka] (wherein q represents 1 or 2, the same applies hereinafter)

[0099] (first step) This step involves the reaction of compound (7) with R LG This method produces compound (16) by ipso substitution with —SH. LG An example of -SH is C 1-12 Alkyl thiols such as ethanethiol and dodecanethiol are included. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0100] (Second process) This process involves the reaction of compound (16) with PG 3 This method produces compound (17)-1 by ipso substitution reaction with —OH. 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0101] (Third step) This step is carried out by reacting compound (17) with R Q This is a method for producing compound (18) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like. The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Compound (17) is deiodinated using a Pd catalyst and a reducing agent to give compound (18) (where R Q can produce hydrogen). [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0102] (Fourth step) This step is a method for producing compound (19) by Suzuki-Miyaura coupling reaction of compound (18) and compound (12). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Although compound (19) may have axial chirality and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (19) can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (19) can be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (19). Examples of the protecting group for reprotection include a tetrahydro-2H-pyran-2-yl group.

[0103] (Fifth step) This step is a method for producing compound (20) by oxidation of compound (19). In this reaction, compound (19) is treated with an equivalent or excess equivalent of an oxidizing agent in a reaction-inert solvent under cooling to heating, preferably at -20°C to 80°C, typically for 0.1 hours to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used. Examples of solvents include aromatic hydrocarbons 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, oxone, activated manganese dioxide, chromic acid, potassium permanganate, and sodium periodate. [Literature] Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 17, Maruzen, 2004

[0104] (Sixth step) This step is a method for producing compound (13) by ipso substitution reaction between compound (20) and compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2. When compound (13) has axial chirality, it is obtained as a mixture of stereoisomers, but each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0105] (Seventh step) This step is a method for producing compound (14) by deprotecting compound (13) through catalytic hydrogenation. The reaction conditions are the same as those in the sixth step of Raw Material Production Method 2. Compound (14) may have axial chirality and may be obtained as a mixture of stereoisomers. However, compound (14) can be resolved into individual stereoisomers by a conventional resolution procedure, for example, by ODS column chromatography or silica gel column chromatography.

[0106] (Eighth process) This step is a method for producing compound (2)-1 by reacting compound (14) with compound (15). The reaction conditions are the same as those in the seventh step of Raw Material Production Method 2. Although compound (2)-1 may have axial asymmetry and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (2)-1 can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (2)-1 may be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (2)-1. Examples of the protecting group for reprotection include a tetrahydro-2H-pyran-2-yl group.

[0107] (Raw material manufacturing method 4) This production method is the third method for producing compound (2)-1, which is included in compound (2), which is the raw material in Raw Material Production Method 1. [ka]

[0108] (first step) This step is a method for producing compound (21) by deprotecting compound (20) through catalytic hydrogenation. The reaction conditions are the same as those in the sixth step of Raw Material Production Method 2. Compound (21) may have axial chirality and may be obtained as a mixture of stereoisomers. However, compound (21) can be resolved into individual stereoisomers by a conventional resolution procedure, for example, by ODS column chromatography or silica gel column chromatography.

[0109] (Second process) This step is a method for producing compound (22) by alkylation reaction of compound (21) with compound (15). The reaction conditions are the same as those in the seventh step of Raw Material Production Method 2. Although compound (22) may have axial chirality and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (22) can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (22) can be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (22). Examples of the protecting group for reprotection include a tetrahydro-2H-pyran-2-yl group.

[0110] (Third step) This step is a method for producing compound (2)-1 by the ipso substitution reaction of compound (22) with compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2. Compound (2)-1 may have axial asymmetry and is obtained as a mixture of stereoisomers. However, compound (2)-1 or a compound obtained by subjecting compound (2)-1 to a deprotection reaction can be resolved by a conventional resolution procedure, for example, using ODS column chromatography or silica gel column chromatography, to isolate the individual stereoisomers. The reaction conditions for the deprotection reaction used here are the same as those in the step described in Production Method 1.

[0111] (Raw material manufacturing method 5) This production method is the first method for producing compound (2)-2, which is included in compound (2), which is the raw material in Raw Material Production Method 1. [ka] [ka] [ka] (PG in the formula 22 indicates a tert-butyl group. The same applies below.)

[0112] (first step) This step is a method for producing compound (23) by hydrolyzing compound (5)-1. This reaction is carried out by using equal amounts of compound (5)-1 and a hydrolysis reagent, or an excess of one, in a reaction-inert solvent, stirring under cooling to reflux for typically 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, alcohols such as methanol and ethanol, acetone, DMF, and THF. Mixing the above solvents with water may also be suitable for the reaction. Examples of the hydrolysis reagent include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0113] (Second process) This step is a method for producing compound (24) by protecting the hydroxyl group of compound (23) with a tert-butyl group. This reaction is carried out by using equal equivalents of compound (23) and a tert-butyl protecting reagent, or an excess equivalent of either, in a reaction-inert solvent, stirring under cooling to reflux for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, tBuOH, and DMF. Examples of tert-butyl protecting reagents include, but are not limited to, isobutene and 2-tert-butyl-1,3-diisopropylisourea. Additionally, compound (24) can be produced by a dehydration condensation reaction between compound (23) and tBuOH. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014 Org. Lett., 2012, 14, 17, p.4678-4681

[0114] (Third step) This step involves the reaction of compound (24) with R LG This is a method for producing compound (25) by ipso substitution reaction with —SH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0115] (Fourth step) This step involves the reaction of compound (25) with PG 3 This method involves the production of compound (26) by ipso substitution reaction with —OH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0116] (Fifth step) This step involves the reaction of compound (26) with R Q This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like to produce compound (27). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Compound (26) is deiodinated using a Pd catalyst and a reducing agent to give compound (27) (where R Q can produce hydrogen). [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0117] (Sixth step) This step is a method for producing compound (28) by Suzuki-Miyaura coupling reaction between compound (27) and compound (12). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Although compound (28) may have axial chirality and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (28) can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (28) can be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (28). Examples of the protecting group for reprotection include a tetrahydro-2H-pyran-2-yl group.

[0118] (Seventh step) This step is a method for producing compound (29) by oxidation of compound (28). The reaction conditions are the same as those in the fifth step of Raw Material Production Method 3. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014

[0119] (Eighth process) This step is a method for producing compound (30) by ipso substitution reaction of compound (29) with compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0120] (Ninth step) This step is a method for producing compound (31) by deprotecting compound (30) through catalytic hydrogenation. The reaction conditions are the same as those in the sixth step of Raw Material Production Method 2. Compound (31) may have axial asymmetry and may be obtained as a mixture of stereoisomers. However, compound (31) can be resolved into individual stereoisomers by a conventional resolution procedure, for example, by ODS column chromatography or silica gel column chromatography.

[0121] (10th step) This step is a method for producing compound (32) by alkylation of compound (31) and compound (15). The reaction conditions are the same as those in the seventh step of Raw Material Production Method 2. Although compound (32) may have axial chirality and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (32) can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (32) can be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (32).

[0122] (Eleventh step) This step is a method for producing compound (33) by subjecting compound (32) to a deprotection reaction. The reaction conditions are the same as those described in the first production process. After deprotection, compound (33) can be reprotected with a protecting group, such as a tetrahydro-2H-pyran-2-yl group. Alternatively, the above series of deprotection and reprotection with a protecting group may be carried out as a one-step reaction.

[0123] (12th step) This step is a method for producing compound (2)-2 by reacting compound (33) with compound (6)-1. This reaction involves using equimolar amounts of compound (33) and compound (6)-1, or an excess of either compound, and stirring the mixture in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, for typically 0.1 hours to 5 days. Examples of solvents include, but are not limited to, 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. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction.

[0124] (Raw material manufacturing method 6) This method is a method for producing compound (13)-1, which is included in compound (13), an intermediate of raw material method 2. [ka]

[0125] (first step) This step is a method for producing compound (34) by subjecting compound (30) to a deprotection reaction. The reaction conditions are the same as those described in the first production process. After deprotection, compound (34) can be reprotected with a protecting group, such as a tetrahydro-2H-pyran-2-yl group. Alternatively, the above series of deprotection and reprotection with a protecting group may be carried out as a one-step reaction.

[0126] (Second process) This step is a method for producing compound (13)-1 by reacting compound (34) with compound (6)-1. The reaction conditions are the same as those in the twelfth step of Raw Material Production Method 5.

[0127] (Raw material manufacturing method 7) This production method is a method for producing compound (30), which is the raw material in Raw Material Production Method 6. [ka]

[0128] (first step) This step is a method for producing compound (37) by ipso substitution reaction between compound (24) and compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0129] (Second process) This step involves the reaction of compound (37) with PG 3 This method involves the production of compound (38) by ipso substitution reaction with —OH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0130] (Third step) This step involves the reaction of compound (38) with R Q This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like to produce compound (39). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Compound (38) is dehalogenated using a Pd catalyst and a reducing agent to give compound (39) (where R Q can produce hydrogen). [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0131] (Fourth step) This step is a method for producing compound (30) by Suzuki-Miyaura coupling reaction between compound (39) and compound (15). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. Although compound (30) may have axial asymmetry and may be obtained as a mixture of stereoisomers, each stereoisomer of compound (30) can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. Alternatively, compound (30) can be deprotected to isolate the stereoisomers, and then reprotected with a protecting group to isolate the stereoisomers of compound (30).

[0132] (Raw material manufacturing method 8) This production method is a method for producing compound (17)-2, which is included in compound (17), which is an intermediate in Raw Material Production Method 3. [ka]

[0133] (first step) This step is a method for producing compound (5)-2 by chlorination of compound (40). This reaction is carried out by stirring a mixture of compound (40) and a chlorinating agent in equimolar amounts or in an excess of one in an inert solvent, either in the presence of a solvent or without a solvent, under cooling to reflux, preferably at 60°C to reflux, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, DMF, and DMAc. Examples of chlorinating agents include phosphorus oxychloride and thionyl chloride. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM may be advantageous for smooth reaction progression.

[0134] (Second process) In this process, compound (5)-2 and R LG This is a method for producing compound (41) by ipso substitution reaction with —SH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0135] (Third step) This step involves the reaction of compound (41) with PG 3 This method involves the production of compound (42) by ipso substitution reaction with —OH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0136] (Fourth step) This step is a method for producing compound (17)-2 by the ipso substitution reaction of compound (42) with compound (6)-1. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0137] (Raw material manufacturing method 9) This method is a method for producing compound (10)-2. [ka]

[0138] (first step) This step is a method for producing compound (43) by ipso substitution reaction between compound (5)-2 and compound (8). The reaction conditions were the same as those in the first step of Raw Material Production Method 2. Furthermore, compound (43) can be produced by Negishi coupling of compound (8) in which the hydrogen atom is converted to a halogen atom with compound (5)-2.

[0139] (Second process) This step involves the reaction of compound (43) with PG 3 This method involves the production of compound (44) by ipso substitution reaction with —OH. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0140] (Third step) This step is a method for producing compound (10)-2 by ipso substitution reaction between compound (44) and compound (6)-1. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0141] (Raw material manufacturing method 10) This production method is a method for producing compound (4)-1, which is included in compound (4), which is an intermediate in Raw Material Production Method 1. [ka] (In the formula, L 2B is C 1-3 Piperazinediyl optionally substituted with alkyl, bridged piperazinediyl, or 2,6-diazaspiro[3.4]octanediyl; PG E3 and P.G. L2 is the protecting group for NH, LG Z represents a leaving group, and BLG represents a boronic acid group, a boronic acid group protected by a boronic acid protecting group such as a boronic acid pinacol ester group, or a trifluoroborate group (hereinafter, sometimes referred to as a boronic acid group, etc.). E3 Compound (4)-1 can be produced by a similar reaction for compounds in which the moiety is H. Examples of leaving groups shown here include Cl, Br, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. (The same applies below).

[0142] (first step) In this step, compound (45) and compound (46) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (47). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0143] (Second process-1A) This step is a step of subjecting compound (47) to oxidation reaction conditions to obtain a 1,2-diol compound. This reaction is carried out by stirring compound (47), an oxidizing agent, and an excess equivalent of a reoxidizing agent in a reaction-inert solvent at ice-cooling to room temperature for typically 1 hour to 2 days. Examples of oxidizing agents include, but are not limited to, osmium(VIII) tetroxide, PI osmium(VIII) oxide, and PEM polymer-microencapsulated osmium(VIII) oxide. Examples of reoxidizing agents include, but are not limited to, NMO, trimethylamine oxide, tBuOOH, and KFe(CN). Examples of solvents include, but are not limited to, ethers such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; tBuOH; acetone; acetonitrile; toluene; water; and mixtures thereof.

[0144] (Second process-1B) This step is a step of subjecting the compound obtained in the above (Second Step-1A) to oxidative cleavage reaction conditions to obtain compound (48). This reaction is carried out by using an oxidizing agent in an equivalent or excess amount to the compound obtained in (Second Step-1A) in a reaction-inert solvent, stirring at ice-cooling to room temperature for usually 1 hour to 2 days. Examples of the oxidizing agent used here include, but are not limited to, sodium periodate or periodic acid. Examples of the solvent used here include, but are not limited to, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, acetonitrile, water, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and mixtures thereof. The above (Second Step-1A) and (Second Step-1B) can also be carried out as a one-step reaction. [Literature] J. Org. Chem. 1956, 21, 4, 478-479

[0145] (Second process-2) This step is a step of obtaining compound (48) by subjecting compound (47) to oxidation reaction conditions. This step is a method of obtaining compound (48) by a method different from that of Second Step-1A and Second Step-1B. This reaction is carried out by stirring compound (47) in an ozone atmosphere in a reaction-inert solvent at ice-cooling to room temperature for typically 1 hour to 1 day, followed by treatment with a reducing agent. Examples of the reducing agent used here include, but are not limited to, dimethyl sulfide, triphenylphosphine, and metallic zinc. Examples of the solvent used here include, but are not limited to, alcoholic solvents such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ethyl acetate, and mixtures thereof.

[0146] (Third step) This step is a step of subjecting compound (48) and compound (49) to reductive amination reaction conditions to obtain compound (4)-1′. This reaction is carried out by using equal amounts of compound (48) and compound (49), or an excess of one, in the presence of a reducing agent and acetic acid, in a reaction-inert solvent, stirring at ice-cooling to room temperature for typically 1 hour to 5 days. Examples of reducing agents that can be used include, but are not limited to, NaBH(OAc)3, 2-picoline borane, and NaBH3CN. The solvent that can be used includes, but is not limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane; alcoholic solvents such as methanol and ethanol; and acetonitrile.

[0147] (Fourth step) In this step, compound (4)-1 is obtained by subjecting (4)-1' to deprotection conditions. The reaction conditions are the same as in the first production method.

[0148] (Raw material manufacturing method 11) This method is for the synthesis of compound (45)-1' contained in compound (45), which is the raw material of raw material synthesis method 10, and PG of compound (45)-1' contained in compound (45). E3 The compound (45)-1, in which the moiety is H, is prepared by the method of the present invention. [ka] (In the formula, LG E3 represents a leaving group. Examples of the leaving group include Cl, Br, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. (The same applies below.)

[0149] (first step) In this step, compound (50) and compound (51) are subjected to alkylation reaction conditions to obtain compound (45)-1'. This reaction is carried out by using equal equivalents of compound (50) and compound (51), or an excess equivalent of either, in a reaction-inert solvent in the presence of a base, and stirring the mixture under ice-cooling to reflux for typically 1 hour to 1 day. Examples of the base used here include, but are not limited to, sodium hydride, tBuOK, LHMDS, NHMDS, potassium carbonate, and cesium carbonate. Examples of the solvent used here include, but are not limited to, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, as well as DMF and MeCN. Here, when the compound obtained by the above reaction has a protecting group, the compound obtained can be subjected to deprotection reaction conditions following the reaction to obtain compound (45)-1′. The reaction conditions are the same as in the first production method.

[0150] (Second process) In this step, compound (45)-1 is obtained by subjecting (45)-1' to deprotection conditions. The reaction conditions are the same as in the first production method.

[0151] (Raw material manufacturing method 12) This method is a method for producing compound (45)-2', which is a raw material in the raw material production method 10, and compound (45)-2', which is a PG of compound (45)-2', which is a raw material in the raw material production method 10. E3 The compound (45)-2 is prepared by the method of claim 1, wherein the moiety is H. [ka]

[0152] (first step) In this step, compound (52) and compound (53) are subjected to coupling reaction conditions using a copper catalyst to obtain compound (45)-2'. This reaction is carried out by using equimolar amounts of compound (52) and compound (53), or an excess of one, in a reaction-inert solvent, a copper catalyst, a ligand, and a base, and stirring at room temperature or under reflux for typically 1 hour to 5 days. Examples of copper catalysts that can be used include, but are not limited to, copper(I) iodide, copper(I) chloride, and copper(I) oxide. Examples of ligands that can be used include, but are not limited to, DMEDA and trans-N,N'-dimethylcyclohexane-1,2'-diamine. Examples of bases that can be used include, but are not limited to, organic bases such as diisopropylethylamine and triethylamine, and inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, and tripotassium phosphate. Examples of solvents that can be used include, but are not limited to, ether solvents such as tetrahydrofuran and 1,4-dioxane, alcohol solvents such as methanol and ethanol, dimethyl sulfoxide, N,N-dimethylformamide, water, and the like. In addition, it may be advantageous to heat the mixture by microwave irradiation in order to ensure smooth progress of the reaction.

[0153] (Second process) In this step, compound (45)-2' is subjected to deprotection conditions to obtain compound (45)-2. The reaction conditions are the same as in the first production method.

[0154] (Raw material manufacturing method 13) This production method is a method for producing compound (4)-2, which is included in compound (4), which is an intermediate in Raw Material Production Method 1. [ka] (Wherein, PG of compound (51) E3 For compounds in which the moiety is H, the same reaction is carried out to obtain compound (4)-2' PG E3 It is possible to prepare a compound in which the moiety is H. (The same applies below.)

[0155] (first step) In this step, compound (54) and compound (50) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (55). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0156] (Second process) This step is a step of subjecting compound (55) and compound (51) to alkylation reaction conditions to obtain compound (4)-2'. The reaction conditions are the same as those in the first step of Raw Material Production Method 11.

[0157] (Third step) In this step, compound (4)-2' is subjected to deprotection conditions to obtain compound (4)-2. The reaction conditions are the same as in the first production method.

[0158] (Raw material manufacturing method 14) This production method is a method for producing compound (4)-3, which is included in compound (4), which is an intermediate in Raw Material Production Method 1. [ka] (In the formula, LG Z represents a leaving group. Examples of the leaving group include Cl, Br, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. (The same applies below.)

[0159] (first step) In this step, compound (54) and compound (56) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (57). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0160] (Second process) In this step, compound (57) and compound (53) are subjected to coupling reaction conditions using a copper catalyst to obtain compound (4)-3'. The reaction conditions are the same as those in the first step of Raw Material Production Method 12.

[0161] (Third step) In this step, compound (4)-3' is subjected to deprotection conditions to obtain compound (4)-3. The reaction conditions are the same as in the first production method.

[0162] (Raw material manufacturing method 15) This production method is a method for producing compound (4)-1, which is included in compound (4), which is an intermediate in Raw Material Production Method 1. [ka] (Wherein, PG of compound (45) E3 Compound (4)-1 can be produced by the same reaction as for a compound in which the moiety is H. (The same applies below.)

[0163] (first step) In this step, compound (54) and compound (45) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (4)-1'. The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0164] (Second process) In this step, compound (4)-1 is obtained by subjecting (4)-1' to deprotection conditions. The reaction conditions are the same as in the first production method.

[0165] (Raw material manufacturing method 16) This production method is a method for producing compound (4)-5, which is included in compound (4), which is an intermediate in raw material production method 1. [ka] (In the formula, LG Z3 represents a leaving group. Examples of the leaving group include Cl, Br, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. (The same applies below.)

[0166] (first step) This step is a step of subjecting compound (58) and compound (59) to cyclization reaction conditions to obtain compound (60). This reaction is carried out by using equal equivalents of compound (58) and compound (59), or an excess equivalent of either, in a reaction-inert solvent in the presence of a base, stirring under ice-cooling to reflux, typically for 1 hour to 5 days. Examples of the base used here include, but are not limited to, 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 include, but are not limited to, ethereal solvents such as tetrahydrofuran and 1,4-dioxane, and N,N-dimethylformamide.

[0167] (Second process) In this step, compound (60) and compound (54) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (61). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0168] (Third step) In this step, compound (61) is subjected to cyclization reaction conditions to obtain compound (4)-5'. The reaction conditions were the same as those in the third step of Raw Material Production Method 17.

[0169] (Fourth step) In this step, compound (4)-5' is subjected to deprotection conditions to obtain compound (4)-5. The reaction conditions are the same as in the first production method.

[0170] (Raw material manufacturing method 17) This method is a method for producing compound (4)-6. By using compound (4)-6 instead of compound (4) described in Raw Material Production Method 1, some compounds included in the compound of formula (1) can be synthesized. [ka] (Wherein, Linker is -(-L 2 -L 3 -L 4 )- and L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, and L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 alkylene, and R L3 But H or C 1-3 alkyl, and R L4 But H or C 1-3 alkyl, PG L represents a protecting group for NH or OH. LG is C 1-12 (This indicates an alkyl group. The same applies below.)

[0171] (first step) This step is a step of obtaining compound (64) by subjecting compound (62) and compound (63) to Michael addition reaction conditions. This reaction is carried out by using equivalent amounts of compound (62) and compound (63), or an excess of either, in the presence of a base or an excess amount of an acid reagent, stirring at room temperature or under reflux for typically 1 to 5 days. Examples of the base used here include, but are not limited to, organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N'-diisopropylethylamine. Examples of the acid reagent used here include, but are not limited to, lactic acid, trifluoroacetic acid, or acetic acid.

[0172] (Second process) In this step, compound (64) is subjected to urea reaction conditions to obtain compound (65). This reaction is carried out by stirring compound (64), a urea-forming reagent, and an acid in a reaction-inert solvent or without a solvent at room temperature or under reflux, typically for 1 to 5 days. Examples of the urea-forming reagent used here include, but are not limited to, sodium cyanate or potassium cyanate. Examples of the acid used here include, but are not limited to, acetic acid, hydrochloric acid, trifluoroacetic acid, and the like. Examples of the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; ether solvents such as tetrahydrofuran and 1,4-dioxane; acetic acid; toluene; water; and mixtures thereof.

[0173] (Third step) In this step, compound (65) is subjected to cyclization reaction conditions to obtain compound (4)-6'. This reaction is carried out by stirring compound (65) in a reaction-inert solvent in the presence of a base under ice-cooling to reflux, usually for 1 hour to 5 days. Examples of the base used here include, but are not limited to, Triton B, potassium trimethylsilanolate, sodium ethoxide, etc. Examples of the solvent used here include, but are not limited to, ether solvents such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, acetonitrile, etc.

[0174] (Fourth step) In this step, compound (4)-6' is subjected to deprotection conditions to obtain compound (4)-6. The reaction conditions are the same as in the first production method.

[0175] (Raw material manufacturing method 18) This production method is a method for producing compound (67). Compound (67) can be used in place of compound (4) described in Raw Material Production Method 1 to synthesize some of the compounds included in the compound of formula (1). [ka] (In the formula, L 1 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 2 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, and L 3 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 alkylene, and R L3 But H or C 1-3 alkyl, and R L4 But H or C 1-3 is alkyl, and X L represents an oxygen atom or a nitrogen atom, and PG L1 represents a protecting group for NH or OH, and PG E3 represents a protecting group for NH or H. The same applies below.)

[0176] (first step) This step is a step of obtaining compound (67') by subjecting compound (66) and compound (65) to Ipso reaction conditions. The reaction conditions were the same as those in the first step of Raw Material Production Method 2. Alternatively, compound (67') can be prepared by subjecting the compound to coupling reaction conditions using a copper catalyst. The reaction conditions are the same as those in the first step of Raw Material Production Method 12. Alternatively, compound (67') can be prepared by subjecting the compound to carbon-nitrogen bond forming reaction conditions. In this reaction, compound (66) and compound (65) are used in equivalent amounts or in excess of one equivalent, and a metal catalyst, a ligand, and a base are added to a mixture thereof, followed by stirring in a reaction-inert solvent at 80°C or higher under reflux, usually for 1 hour to 5 days. Examples of metal reagent catalysts used herein include, but are not limited to, 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 include, but are not limited to, Xantphos, Ruphos, Xphos, and BINAP. Examples of bases include, but are not limited to, 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 include, but are not limited to, 1,4-dioxane, toluene, N,N-dimethylformamide, and mixtures thereof. This reaction may also be performed under microwave irradiation. Alternatively, compound (67') can be prepared by subjecting the compound to alkylation reaction conditions. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0177] (Second process) In this step, compound (67) is obtained by subjecting compound (67') to deprotection conditions. The reaction conditions are the same as in the first production method.

[0178] (Raw material manufacturing method 19) This production method is a method for producing compound (1)-2, which is included in compound (1), which is the raw material for the first production method. [ka] (L in the formula 1A and L 4A is an optionally substituted heterocycloalkylene, an optionally substituted heteroarylene, a saturated 7- to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, a saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and an optionally substituted C 1-6 alkylene; L 3A is C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 It refers to pyrrolidinediyl, bridged piperazinediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted with alkyl. The same applies below.

[0179] (first step) This step is a method for producing compound (69) by alkylation reaction of compound (14) with compound (68). The reaction conditions are the same as those in the seventh step of Raw Material Production Method 2.

[0180] (Second process) In this step, compound (69) is subjected to hydrolysis conditions to obtain compound (70). The reaction conditions were the same as those in the first step of Raw Material Production Method 1.

[0181] (Third step) This step is a step of subjecting compound (70) and compound (71) to condensation reaction conditions to obtain compound (1)-2. The reaction conditions are the same as those in the second step of Raw Material Production Method 1.

[0182] (Raw material manufacturing method 20) This production method is a method for producing compound (74). Compound (74) can be used in place of compound (4) described in Raw Material Production Method 1 to synthesize some of the compounds included in the compound of formula (1). [ka] (Wherein, PG of compound (51) E3 Compound (74) can be produced by a similar reaction for a compound in which the moiety is H.

[0183] (first step) This step is a step of obtaining compound (73) by subjecting compound (72) and compound (51) to nucleophilic substitution reaction conditions. The reaction conditions are the same as those in the first step of Raw Material Production Method 11.

[0184] (Second process) In this step, compound (73) is subjected to deprotection conditions to obtain compound (74). The reaction conditions are the same as in the first production method.

[0185] (Raw material manufacturing method 21) [ka]

[0186] This production method is a method for producing compound (2)-3 contained in (2), which is the raw material of Production Method 1.

[0187] (first step) This step is a method for producing compound (77) by reacting compound (75) with compound (76). This reaction is carried out by converting compound (75) to the corresponding enolate under acidic conditions using an orthoester such as trimethyl orthoformate, adding an equivalent amount of compound (76) or an excess amount of either compound, and stirring the mixture in a reaction-inert solvent under reflux, preferably at 60° C. or under reflux, for usually 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, DMF, DMAc, etc.

[0188] (Second process) This step is a method for producing compound (78) from compound (77). This reaction is carried out by stirring compound (77) in a reaction-inert solvent under reflux, preferably at 150° C. or higher, for a period of usually 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, NMP.

[0189] (Third step) This step is a method for producing compound (79) from compound (78). This reaction is carried out by stirring a mixture of compound (78) and a brominating agent in equal amounts, or in excess of one, in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at room temperature, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, and DMF. Examples of brominating agents include N-bromosuccinimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, and dibromoisocyanuric acid.

[0190] (Fourth step) This step is a method for producing compound (80) from compound (79). The reaction conditions are the same as those for the first step of Raw Material Production Method 8.

[0191] (Fifth step) This step is a method for producing compound (81) by ipso substitution reaction between compound (80) and compound (6)-1. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0192] (Sixth step) This step is a method for producing compound (82) by ipso substitution reaction between compound (81) and compound (8)-1. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0193] (Seventh step) In this step, compound (82) and PG 3 This method involves the production of compound (82) by ipso substitution reaction with —OH. The PG used here 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol. The reaction conditions were the same as those in the first step of Raw Material Production Method 2.

[0194] (Eighth process) This step is a method for producing compound (84) by Suzuki-Miyaura coupling reaction between compound (83) and compound (12), which is a boronic acid derivative. The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2. When compound (84) has axial chirality, it is obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography. In addition, the protecting group PG 2 After the deprotection reaction, compound (84) was deprotected under different conditions from PG 1 may be converted to another protecting group. The reaction conditions for the deprotection reaction used here are the same as those in the step described in Production Method 1. PG to be subsequently converted 1Examples of the protecting group include a tetrahydro-2H-pyran-2-yl group. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014

[0195] (Ninth step) This step is a method for producing compound (85) by deprotecting compound (84) through catalytic hydrogenation. The reaction conditions are the same as those in the sixth step of Raw Material Production Method 2.

[0196] (10th step) This step is a method for producing compound (2)-3 by reacting compound (85) with compound (15). The reaction conditions are the same as those in the seventh step of Raw Material Production Method 2.

[0197] (Raw material manufacturing method 22) [ka] This production method is a method for producing compound (4)-7, which is included in compound (4), which is an intermediate in raw material production method 1.

[0198] (first step) This step is a method for producing compound (87) from compound (86). The reaction conditions were the same as those in the first step of Raw Material Production Method 17.

[0199] (Second process) This step is a method for producing compound (88) from compound (87). This reaction is carried out in the presence of compound (87), triphosgene, and a base in a reaction-inert solvent at room temperature by adding an ammonia reagent and stirring for typically 1 to 5 days. Examples of the ammonia reagent used here include, but are not limited to, ammonia methanol solution. Examples of the base used here include, but are not limited to, organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine. Examples of the solvent used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform.

[0200] (Third step) This step is a method for producing compound (89) from compound (88). The reaction conditions were the same as those in the third step of Raw Material Production Method 17.

[0201] (Fourth step) In this step, compound (89) and compound (54) are subjected to Suzuki-Miyaura coupling reaction conditions to obtain compound (90). The reaction conditions are the same as those in the fourth step of Raw Material Production Method 2.

[0202] (Fifth step) In this step, compound (90) is subjected to deprotection conditions to obtain compound (4)-7. The reaction conditions are the same as in the first production method.

[0203] (Raw material manufacturing method 23) This production method is a method for producing compound (45)-3, which is included in compound (45), which is the raw material in Raw Material Production Method 10. [ka]

[0204] In this step, compound (92) and compound (53) are subjected to coupling reaction conditions using a copper catalyst to obtain compound (45)-3. The reaction conditions are the same as those in the first step of Raw Material Production Method 12.

[0205] The compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII) is isolated and purified as a free compound, a salt thereof, a hydrate, a solvate, or a crystalline polymorph, or an amorphous solid substance. A salt of the compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII) can also be prepared by subjecting the compound to a conventional salt-forming reaction. Isolation and purification are carried out by applying conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by taking advantage of the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by a general optical resolution method for a racemate (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, or chromatography using chiral columns, etc.), or can also be produced from appropriate optically active starting compounds. Furthermore, the compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII) or an intermediate thereof may have axial asymmetry and may be obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

[0206] The pharmacological activity of the compound of formula (I) was confirmed by the following tests.

[0207] Test Example 1 Evaluation of KRAS degradation activity against human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 (CRL-1682; ATCC) The KRAS G12D expression level was measured by Cell ELISA to evaluate the KRAS degradation activity of the test compounds. 2.0x10 AsPC-1 cells per well 420 μL of each aliquot was seeded onto a 384-well plate (Greiner Bio-One) to form cells. Cell culture was performed at 37°C in the presence of 5% CO2 using RPMI1640 (Sigma-Aldrich) medium containing 10% fetal bovine serum (Cytiva). The next day, the test compounds (10 points with final concentrations ranging from 10 μM to 0.3 nM) and DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.), the solvent for the test compounds as a negative control, were diluted 500-fold with fresh medium, and 20 μL each was added to each well and the cells were cultured overnight. The next day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to each well. The cells were fixed by incubating at room temperature for 30 minutes. 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 incubating at room temperature for 10 minutes, the supernatant was removed, and 25 μL of PBS was added to each well. Each well was washed by removing the supernatant. This washing was performed twice. Next, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) was added to each well. After allowing the plate to stand at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator; the same method was used hereafter), and 25 μL of PBS was added to each well. The supernatant was then removed, and each well was washed twice. The supernatant was then removed, and 20 μL of blocking solution (Intercept Blocking Buffer; Li-COR Biosciences) was added to each well. After allowing the plate to stand at room temperature for 30 minutes, the supernatant was removed. To the positive control wells, 15 μL of a solution of anti-β-Actin antibody (Anti-β Actin antibody [mAbcam 8226] - Loading Control; Abcam) diluted 1:1000 in blocking solution was added as the primary antibody. To the other wells, 15 μL of a solution of anti-Ras (G12D Mutant Specific) antibody (Ras (G12D Mutant Specific) (D8H7) Rabbit mAb #14429; Cell Signaling Technology) and anti-β-Actin antibody (Abcam) diluted 1:1000 was added. The plate was then left to stand overnight at 4°C. The next day, the supernatant was removed, and 25 μL of PBS was added to each well. Each well was washed by removing the supernatant. Washing was performed twice. The supernatant was removed, and 15 μL of a solution of Donkey anti-Mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) and Goat anti-Rabbit IgG H&L (IRDye 800CW) (Li-COR Biosciences) diluted 1:1,000 in blocking solution was added to each well as a secondary antibody. A solution of Donkey anti-Mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) diluted 1:1,000 in blocking solution was added to the positive control wells as a secondary antibody. After incubation at room temperature for 1 hour, the supernatant was removed, and 25 μL of PBS was added to each well. Each well was washed by removing the supernatant. Washing was performed twice. After removing the supernatant, the plate was air-dried at room temperature for 2 hours or more, and the fluorescent signals at 700 nm and 800 nm were measured using Aerius (Li-COR Biosciences). The RAS signal value measured at a fluorescence wavelength of 800 nm was corrected by the β-actin signal value 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 only with anti-β-actin antibody was set to 100%. The degradation rate at the compound concentration that showed the highest degradation effect was defined as Dmax. Based on the degradation rate up to the compound concentration that showed Dmax, the 50% degradation value of the KRAS amount (DC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% degradation value exceeded the concentration range evaluated, the degradation rate at the highest concentration evaluated (10 μM) is shown.

[0208] In the table below, Ex represents the example number. 50 The molecular weight is calculated as 4 hydrochloride salt, and the DC of Ex 14 50 The molecular weight was calculated as the trihydrochloride salt.

[0209] [Table 1]

[0210] Test Example 2: Evaluation of ERK phosphorylation inhibitory effect on human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 The inhibitory effect of test compounds on ERK phosphorylation was evaluated by measuring phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is downstream of KRAS signaling, by cell ELISA. 2.0x10 AsPC-1 cells per well 4 The cells were seeded in a 384-well plate at 20 μL / well. The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. The next day, 20 μL of the test compound (10 concentrations ranging from 10 μM to 0.3 nM), 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 medium and added to each well. The plates were then incubated overnight. Immediately after incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque] diluted with PBS) was added to each well and allowed to stand at room temperature for 120 minutes to fix the cells. The plate was then centrifuged to remove the supernatant (using a centrifugal dehydrator; the same method was used below). 20 μL of 0.1% Triton X-100-containing PBS 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 0.5% SDS-containing PBS was added to each well. After incubation at room temperature for 30 minutes, 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 2,500-fold in blocking solution was added to each well and incubated overnight at 4°C. 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. The supernatant was then removed and each well was washed. This was repeated three times. After washing, 15 μL of Goat anti-Rabbit IgG H&L (IRDye 800CW) diluted 1:1,000 in blocking solution was added to each well as the secondary antibody and incubated at room temperature for 1 hour. The supernatant was removed, and each well was washed three times with PBS containing 0.05% Tween-20 in the same manner as after the primary antibody reaction. After removing the supernatant, the plate was air-dried at room temperature for at least 3 hours, and the fluorescence signal at 800 nm was measured using an Aerius microscope. 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%, and the 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results of several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% inhibition rate exceeded the concentration range of evaluation, the inhibition rate at the highest concentration evaluated (10 μM) is shown.

[0211] In the table below, Ex represents the example number. 50 is calculated as the molecular weight of 4 hydrochloride, and the IC of Ex 14 50 The molecular weight was calculated as the trihydrochloride salt.

[0212] [Table 2]

[0213] Test Example 3 Evaluation of anchorage-independent cell growth inhibition against human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 The inhibitory effect of test compounds on anchorage-independent cell growth was evaluated using three-dimensional spheroid culture. 5x10 AsPC-1 cells per well 2 The cells were seeded in a 384-well plate (PrimeSurface, Sumitomo Bakelite Co., Ltd.) with a low cell-binding U-bottom at 20 μL (or 36 μL) per well. The cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. The next day, test compounds (10 or 6 points, with final concentrations ranging from 10 μM to 0.3 nM) and DMSO, the solvent for the test compounds, were diluted 500-fold (or 100-fold) with fresh medium and added in 20 μL (or 4 μL) to each well. After incubation at 37°C in the presence of 5% CO 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), luminescence signals were measured using an ARVO X3 (PerkinElmer). The signal value in DMSO treatment was set to 100%, and the signal value in the absence of cells and medium alone was set to 0%, and the 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results of several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% inhibition rate exceeded the concentration range of evaluation, the inhibition rate at the highest concentration evaluated (10 μM) is shown.

[0214] In the table below, Ex represents the example number. 50 is calculated as the molecular weight of 4 hydrochloride, and the IC of Ex 14 50 The molecular weight was calculated as the trihydrochloride salt.

[0215] [Table 3-1] [Table 3-2]

[0216] Test Example 4: Evaluation of antitumor activity in mice bearing the human G12D mutant KRAS-positive pancreatic cancer line PK-59 PK-59 cells (RIKEN BioResearch Center, RCB1901) were cultured in RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. PK-59 cells were harvested and suspended in PBS. An equal volume of Matrigel (Becton Dickinson) was added to the suspension, and the cells were grown at a density of 1.0–2.0 × 10 cells. 7A cell suspension prepared at 100 μL per cell was inoculated subcutaneously into 4-5 week-old male nude mice (BALB / c-nu (nu / nu), Charles River Japan). Approximately two weeks after inoculation, the mice were divided into groups so that tumor volume and body weight were approximately equal. The following day, administration of the test compound began. The test consisted of five mice in each of the vehicle and test compound groups. The compounds were dissolved in a solvent containing ethanol (Fujifilm Wako Pure Chemicals), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Chemical), 50% (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) aqueous solution (ROQUETTE), HCO-40 (Nikko Chemicals), and 1M sodium hydroxide aqueous solution (Kanto Chemical) in a volume ratio of 4:8, 4.4: 1.1: 1: 9: 0.5. The test compound dissolved in each solvent or the solvent was administered intravenously into the tail vein. The administration was performed twice a week. Tumor diameter and body weight were measured twice a week. The tumor volume was calculated using the following formula: [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] x [Tumor short diameter (mm)] 2 x 0.5 The tumor growth inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition, and the tumor volume of the vehicle group 2 weeks after the first administration as 0% inhibition.In addition, when the tumor volume of the test compound administration group is lower than the tumor volume on the day before the start of administration, the tumor volume on the day before the start of administration was set as 0% regression, and a tumor volume of 0 was set as 100% regression, and the tumor regression rate (%) of the test compound was calculated.The results of several test compounds of formula (I) are shown in the following table.

[0217] [Table 4]

[0218] Test Example 5 Evaluation of inhibitory effect on KRAS G12D / SOS / c-Raf complex formation Using recombinant human KRAS G12D, SOS, and c-Raf proteins, the inhibitory effect of test compounds on the complex formation of these proteins was examined by time-resolved fluorescence resonance energy transfer (TR-FRET) method. 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 [Thermo Fisher Scientific], 0.05% Tween 20 [Sigma-Aldrich], pH 7.0) and test compounds (2.5 μL each) ranging in concentration from 40,000 nM to 40 nM were added to a 384-well plate (Corning). Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μL; 1.3 μM) and c-Raf (amino acid region 51-131) GST (2.5 μL; 130 nM) containing GTP (Sigma-Aldrich; 2 μM) were added to the mixture and incubated for 1 hour at room temperature. A mixture of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled streptoavidin (PerkinElmer; 100 ng / mL) (10 μL) was then added, and the fluorescence intensity was measured at 620 nm and 665 nm using an EnVision 2104 (PerkinElmer) with an excitation wavelength of 337 nm. After normalizing the values ​​with the fluorescence intensity at a reference wavelength of 620 nm, the signal value with solvent treatment was defined as 0% inhibition, and the signal value without GTP was defined as 100% inhibition, and the 50% inhibitory concentration (IC 50 ) was calculated using Sigmoid-Emax model nonlinear regression analysis.

[0219] As a result of the above tests, the G12D mutant KRAS decomposition activity was confirmed for some compounds of formula (I) (Test Example 1). Furthermore, the complex formation inhibitory activity (G12D mutant KRAS inhibitory activity) was confirmed (Test Example 5). Furthermore, the phosphorylation inhibitory activity of ERK, which is downstream of KRAS signaling, was confirmed for some compounds of formula (I) (Test Example 2). Furthermore, the cell proliferation inhibitory activity against human G12D mutant KRAS-positive pancreatic cancer strains was confirmed for some compounds of formula (I) (Test Example 3), and the antitumor activity in mice bearing human G12D mutant KRAS-positive pancreatic cancer strains was confirmed (Test Example 4). Therefore, the compounds of formula (I) can be used for the treatment of pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.

[0220] Pharmaceutical compositions containing one or more compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients, pharmaceutical carriers, etc. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intra-articular, intravenous, or intramuscular injections, transmucosal agents, or inhalants.

[0221] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a film of a gastric or enteric substance, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents, such as purified water or ethanol. In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizing agents, wetting agents, and suspending agents, as well as sweeteners, flavors, aromatics, and preservatives.

[0222] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as EtOH. Such compositions may further contain an isotonic agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizer, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0223] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid, or semisolid form and may be prepared according to conventional methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., may be added as appropriate. Administration can be performed using a suitable inhalation or insufflation device. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be for single or multiple doses and may utilize a dry powder or powder-containing capsule. Alternatively, the compound may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0224] In general, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered once or in two to four divided doses. For intravenous administration, the daily dosage is approximately 0.0001 to 10 mg / kg of body weight, administered once or in multiple divided doses. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered once or in multiple divided doses. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.

[0225] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and 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.

[0226] The compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) can be used in combination with various therapeutic or preventive agents for diseases for which the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) are considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately. [Example]

[0227] Hereinafter, the methods for producing compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) will be described in more detail based on examples. Note that the present invention is not limited to the compounds described in the following examples. In addition, methods for producing starting compounds are shown in the respective production examples. In addition, the compounds described in the following examples are specific compounds included in formula (I), but the method for producing compounds of formula (I) is not limited to the production methods of the specific examples shown below. Compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) can also be produced by a combination of these production methods or by methods that are obvious to those skilled in the art.

[0228] In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0229] For convenience, the concentration in mol / L is expressed as M. For example, a 1M aqueous solution of sodium hydroxide means a 1 mol / L aqueous solution of sodium hydroxide.

[0230] As used herein, "amorphous solid form" encompasses both forms that exhibit no peaks in a powder X-ray diffraction (XRD) pattern and forms that have a low degree of crystallinity. XRD is performed using an Empyrean tube under the following conditions: tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step width: 0.013°, wavelength: 1.5418 Å, and diffraction angle range (2θ): 2.5 to 40°. Due to the nature of powder X-ray diffraction pattern data, the crystal lattice spacing and overall pattern are important in determining the identity of a crystal. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is typically ±0.2°, but the diffraction angle and diffraction intensity can vary slightly depending on the crystal growth direction, particle size, and measurement conditions, so this should not be interpreted strictly.

[0231] Manufacturing Example 1 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (40 g) was suspended in THF (400 mL) and aqueous sodium hydroxide (1 M, 190 mL) was added dropwise under ice cooling to maintain the internal temperature below 10°C. The mixture was stirred for 2 hours. The reaction mixture was poured into an Erlenmeyer 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, washed with water, and dried under reduced pressure to give 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (33.56 g) as a solid.

[0232] Manufacturing Example 2 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 under a nitrogen stream, 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes. The mixture was stirred at that temperature for 2.5 hours. The mixture was allowed to cool to room temperature, and the colorless solid was filtered off, washing with THF (approximately 500 mL). The filtrate was concentrated, and MeOH (210 mL) was added to the resulting solid, which was then stirred at room temperature for 1 hour for suspension washing. The solid was collected by filtration using MeOH (100 mL) to give 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[0233] Manufacturing Example 3 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 CHCl (500 mL), ethanethiol (5.3 mL) and DABCO (10.6 g) were added with 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 stirred at room temperature for an additional 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 added to the reaction mixture and the mixture was extracted twice with CHCl. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[7-bromo-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (43.2 g) as a foamy solid.

[0234] Production Example 4 To a mixture of tert-butyl (1S,4S)-5-[7-bromo-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40.2 g), anhydrous THF (400 mL), and (1S)-1-phenylethan-1-ol (10 mL) was added tBuOK (15.3 g), and the mixture was stirred under argon atmosphere for 30 minutes under cooling and at room temperature for 30 minutes. Ice and saturated aqueous ammonium chloride solution were poured into the reaction mixture, which was then 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 to give tert-butyl (1S,4S)-5-{7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (45.94 g) as a foamy solid.

[0235] Production Example 5 Under an argon atmosphere, a mixture of 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), cyclopropylboronic acid (178 mg), tripotassium phosphate (1.06 g), PdCl(dppf)·CHCl(113 mg), MeCN (15 mL), and water (3 mL) was stirred at 90°C for 6 hours. After cooling to room temperature, ethyl acetate and water were added, and the mixture was filtered through Celite® to separate the two layers. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0236] Manufacturing Example 6 Under an argon atmosphere, 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 A mixture of 1 mL of 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 stirred at 50°C for an additional 1 hour. The mixture was cooled to room temperature, and ethyl acetate and water were added. Insoluble matter was removed by filtration through Celite (registered trademark), and the two layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the insoluble material, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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 (a 4:1 diastereomeric mixture due to axial chirality, 866 mg) as a solid. The resulting solid (866 mg) was dissolved in MeOH (5 mL) and heated to 60 °C. The mixture was stirred at room temperature under an argon atmosphere for 3 days.The precipitated solid was collected by filtration while washing with a small amount of MeOH, and (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 tert-butyl ester (axially asymmetric, almost single diastereomer of unknown configuration, 200 mg) was obtained as a solid.

[0237] Manufacturing Example 7 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.14 g) and CHCl (170 mL), m-chloroperbenzoic acid (approximately 30% aqueous, 7.9 g) was added under ice cooling and stirred at room temperature for 1.5 hours under an argon atmosphere. Ice, saturated aqueous sodium thiosulfate, and saturated aqueous sodium bicarbonate were added, and the mixture was stirred at room temperature for approximately 20 minutes. The reaction mixture was then diluted with CHCl and 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 give (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (9.02 g) as a foamy solid.

[0238] Manufacturing Example 8 To a mixture of tert-butyl (1S,4S)-5-[(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (300 mg), (2S)-2-methoxypropan-1-ol (40 mg), and THF (4 mL) was added tBuOK (85 mg) under cooling in an ice / MeOH bath and stirred at the same temperature for 30 minutes under an argon atmosphere. The reaction mixture was quenched by adding ice water and aqueous ammonium chloride. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (255 mg) as a foamy solid.

[0239] Manufacturing Example 9 Under a nitrogen atmosphere, (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 tert-butyl (180 mg) in MeOH (5 mL), THF (5 mL) was added with 10% Pd / C (50% aqueous, 40 mg) and sodium bicarbonate (80 mg), then the mixture was purged with hydrogen at atmospheric pressure and stirred at room temperature for 4 hours. After the reaction mixture was purged with nitrogen, it was filtered through Celite® using MeOH, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0240] Manufacturing Example 10 Cesium carbonate (172 mg) was added to a mixture of 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 (100 mg), methyl 4-(chloromethyl)benzoate (32 mg), and DMF (2 mL) at room temperature. The mixture was stirred 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 saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0241] Manufacturing Example 11 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), 3,4-dihydro-2H-pyran (2.7 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (270 mg) were added at room temperature and stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give methyl 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (1.79 g) as a foamy solid.

[0242] Manufacturing Example 12 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-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), 3,4-dihydro-2H-pyran (10 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.7 g) were added with stirring at room temperature under an argon atmosphere for 14 hours. 3,4-dihydro-2H-pyran (5 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.3 g) were added, and the mixture was stirred at room temperature for an additional 5 hours. The reaction was quenched with TEA (2 mL) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (11.15 g) was obtained as a foamy solid.

[0243] Manufacturing Example 13 Under a nitrogen atmosphere, cesium carbonate (80 mg) and PyBOP (120 mg) were added to a solution of methyl 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (100 mg) in THF (3 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. (3S)-3-Hydroxypyrrolidine-1-carboxylate tert-butyl (60 mg) and cesium carbonate (160 mg) were added at room temperature, and the mixture was stirred at 60°C for 3 hours. After cooling to room temperature, ethyl acetate was added and the mixture was filtered through Celite (registered trademark). The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}oxy)pyrrolidine-1-carboxylate (86 mg) as an oil.

[0244] Manufacturing Example 14 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-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 (1 M, 1.7 mL) under ice cooling 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 layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-[({(7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (250 mg) as a foamy solid.

[0245] Manufacturing Example 15 To a mixture of tert-butyl (3S)-3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}oxy)pyrrolidine-1-carboxylate (84 mg) and 1,2-dichloroethane (4 mL), trimethyltin(IV) hydroxide (100 mg) was added at room temperature and stirred at 80°C for 24 hours. After cooling to room temperature, trimethyltin(IV) hydroxide (100 mg) was added and 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 layer was washed with hydrochloric acid (1 M) and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the mixture was concentrated under reduced pressure to give 4-[({(7M)-4-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (86 mg) as an oil.

[0246] Manufacturing Example 16 4-[({(7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)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 To a mixture of 1 mL of HCl (230 mg) was added HATU while cooling in an ice / MeOH bath, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Ice and saturated aqueous ammonium chloride solution were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl3 / iPrOH) to give tert-butyl (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-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (273 mg) as a solid.

[0247] Manufacturing Example 17 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was cooled on ice, followed by the addition of DIPEA (240 mL) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) and stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a total volume of approximately 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the resulting solution, which was then 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.

[0248] Manufacturing Example 18 To a mixture of tert-butyl (1S,4S)-5-{6-cyclopropyl-2-(ethylsulfanyl)-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 (approximately 4.5:1 isomer mixture with respect to axial chirality, 20.63 g) and EtOH (250 mL), 4-methylbenzene-1-sulfonic acid monohydrate (4.8 g) was added with 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 layer was 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), and the less polar fraction was purified as tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-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 (a single isomer with respect to axial chirality, 11.17 g) as a foamy solid, and the more polar fraction was (1S,4S)-5-{(7P)-6-cyclopropyl-2-(ethylsulfanyl)-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 (single isomer with respect to axial chirality, 1.92 g) as a foamy solid.

[0249] Manufacturing Example 19 To a mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (10 g) and N-methyl-2-pyrrolidone (20 mL), trimethyl orthoacetate (10.5 mL) was added and stirred for 12 hours at 110° C. After cooling to room temperature, MeOH (20 mL) was added, and the resulting solid was collected by filtration while washing with cooled methanol (approximately 60 mL), and dried under reduced pressure to obtain methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (6.67 g) as a solid.

[0250] Manufacturing Example 20 Under an argon atmosphere, methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (18 g) was added portionwise to a mixture of lithium bis(trimethylsilyl)amide (1.3 M in THF, 100 mL) and THF (150 mL) 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. The aqueous layer was acidified with hydrochloric acid (1 M, 140 ml) and ice water under ice cooling, and stirred for a while. The precipitated solid was collected by filtration and dried under reduced pressure. The resulting solid was collected by filtration, washed with methanol, and dried under reduced pressure to give 7-bromo-8-fluoro-4-hydroxy-6-iodoquinolin-2(1H)-one (13.6 g) as a solid.

[0251] Manufacturing Example 21 Under an argon atmosphere, phosphoryl chloride (24 mL) was added to 7-bromo-8-fluoro-4-hydroxy-6-iodoquinolin-2(1H)-one (5 g), and DIPEA (7 mL) was slowly added under ice cooling, followed by stirring at 110°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ice water was added to the residue, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (5.03 g).

[0252] Manufacturing Example 22 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 stirred at 40°C for 2 hours. Ethanethiol (1.4 mL) was added and stirred at 60°C for 1 hour. The mixture was cooled to room temperature, water was added, and the mixture was stirred for 5 minutes. The resulting solid was collected by filtration and dried under reduced pressure. The resulting solid was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (5.76 g) as a solid.

[0253] Manufacturing Example 23 Under an argon atmosphere, tBuOK (3.06 g) was added to a solution of 7-bromo-4-chloro-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinoline (6.47 g) and (1S)-1-phenylethan-1-ol (3.34 mL) in THF (50 mL) under a cooling bath (approximately -10 °C) and stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-chloro-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinoline (4.67 g) as an oil.

[0254] Manufacturing Example 24 Under an argon atmosphere, a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.7 g) in DMAc (20 mL) was added with tBuOK (1.59 g) and stirred at room temperature for 10 minutes. This mixture was added dropwise to a mixture of 7-bromo-4-chloro-2-(ethylsulfanyl)-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, ice, and ethyl acetate were added, stirred, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was 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 give 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.

[0255] Manufacturing Example 25 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 to room temperature, water and ethyl acetate were added and the mixture was stirred for a while. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration and the mixture was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-chloro-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinoline (5.97 g) as a solid.

[0256] Manufacturing Example 26 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, followed by stirring 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 added at 120 °C, followed by stirring at the same temperature overnight. After cooling to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0257] Manufacturing Example 27 To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (800 mg) in CHCl (10 mL) was added trifluoromethanesulfonic anhydride (809 μL) and pyridine (520 μL) under ice-cooling under an argon atmosphere, 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 give 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.1 g) as an oil.

[0258] Manufacturing Example 28 Under an argon atmosphere, 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) while cooling in an ice / sodium chloride bath, 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 aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 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.

[0259] Manufacturing Example 29 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), lithium bis(trimethylsilyl)amide (1 M THF solution, 2.4 mL) was slowly added dropwise under argon atmosphere and ice-cooling, 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 to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / iPrOH) to give 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 oil.

[0260] Manufacturing Example 30 To a mixture of 7-bromo-1,3-benzoxazol-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 poured into the reaction mixture, and the resulting insoluble material was collected by filtration while washing with water. Toluene was added to the resulting solid, and the mixture was concentrated under reduced pressure to azeotrope water. The resulting crude product was triturated with petroleum ether / ethyl acetate (4 / 1) and collected by filtration to give 3-(7-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)piperidine-2,6-dione (11 g) as a solid.

[0261] Manufacturing Example 32 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), trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (5 mL) were added and stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure until the liquid volume was reduced to approximately half, and ethyl acetate was added. The mixture was poured into saturated aqueous sodium bicarbonate solution under ice cooling 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 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 give 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (300 mg) as a solid.

[0262] Manufacturing Example 33 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 vinyltrifluoroborate (7.5 g), PdCl(dppf)·CHCl (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 the mixture was filtered through Celite®. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was 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). The resulting solid was collected by filtration, washing with iPr2O, and dried under reduced pressure to give 3-(5-ethenyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (559 mg) as a solid.

[0263] Manufacturing Example 34 To a mixture of 3-(5-ethenyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (373 mg), DOX (10 mL), and water (1 mL), sodium periodate (570 mg), osmium tetroxide (2.5 wt% solution in tBuOH, 13.3 g), and 4-methylmorpholine N-oxide (88 mg) were added at room temperature and stirred for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (280 mg) as a solid.

[0264] Manufacturing Example 35 1-(6-Ethenyl-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (1.44 g) was dissolved in a mixture of MeOH (30 mL) and CHCl (30 mL) at room temperature. The mixture was stirred for 1.5 hours while bubbling ozone gas under dry ice-acetone cooling. Dimethyl sulfide (1.2 mL) was added at the same temperature, and the mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with a mixture of ethyl acetate and MeOH to give 3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbaldehyde (527 mg) as a solid.

[0265] Manufacturing Example 36 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), CHCl (2 mL), and N-methyl-2-pyrrolidone (2 mL), acetic acid (31 μL) was added at room temperature and stirred for 30 minutes. Sodium triacetoxyborohydride (220 mg) was added at room temperature and stirred overnight. Water and saturated aqueous sodium bicarbonate were added, and the mixture was stirred for a while, followed by extraction twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and insoluble materials were removed by filtration. The mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / iPrOH) to give tert-butyl (2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carboxylate (224 mg) as a foamy solid.

[0266] Manufacturing Example 37 To a mixture of tert-butyl (2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carboxylate (200 mg) and CHCl (2 mL), hydrogen chloride (4 M DOX solution, 3 mL) was added and stirred at room temperature overnight. iPrO was added to the reaction mixture, and the resulting solid was collected by filtration, washed with iPrO, and dried under reduced pressure to give 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.

[0267] Manufacturing Example 38 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)boranide (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 insoluble matter was filtered off through Celite®. The two layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 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 oil.

[0268] Manufacturing Example 39 Palladium(II) acetate (13 mg) and di(adamantan-1-yl)(butyl)phosphine (42 mg) were added to a mixture of methyl 5-amino-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate (209.5 mg), potassium {[(3S)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl]methyl}tri(fluoro)boranide (380 mg), cesium carbonate (577 mg), water (1 mL), and DOX (5 mL) under an argon atmosphere, and the mixture was stirred at 100°C for 5 hours. After cooling, ethyl acetate and water were added, and the insoluble matter was filtered through Celite®. The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 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.

[0269] Manufacturing Example 40 To a mixture of 1-[(4-bromo-3-fluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (100 mg), potassium {[(3S)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl]methyl}tri(fluoro)boranide (150 mg), cesium carbonate (240 mg), water (0.4 mL), and DOX (degassed with argon bubbling, 2 mL), mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15 mg) was added at room temperature and 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® to obtain the filtrate. The aqueous layer was separated, and the organic layer was washed with saturated aqueous sodium chloride, 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 give 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 oil.

[0270] Manufacturing Example 41 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, the mixture was diluted with water and ethyl acetate and 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 afford 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.

[0271] Manufacturing Example 42 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, and the mixture was diluted with water and ethyl acetate and separated. The aqueous layer was extracted three times with ethyl acetate. 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 give methyl 5-amino-4-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate (209.5 mg) as a solid.

[0272] Manufacturing Example 43 Under an argon atmosphere, potassium trimethylsilanolate (40 mg) was added to a mixture of 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 (144 mg) and THF (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was diluted with water and ethyl acetate and 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 resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl (2S)-4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyl}-2-methylpiperazine-1-carboxylate (129 mg) as a solid.

[0273] Manufacturing Example 44 To a suspension of 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) in MeCN (20 mL), benzyltrimethylammonium hydroxide (40 wt% solution in MeOH, 480 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 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.

[0274] Manufacturing Example 45 To a solution of N-iodosuccinimide (13.9 g) in DMF (35 mL), (2-methyl-2H-indazol-6-yl)methanol (2.5 g) was added at room temperature, and the mixture was stirred at the same temperature overnight, followed by stirring at 60°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and 5% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added, followed by extraction twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the mixture was concentrated. The residue was washed with ethyl acetate to give (3-iodo-2-methyl-2H-indazol-6-yl)methanol (2.19 g) as a solid.

[0275] Manufacturing Example 46 3-[(4-Methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (1.05 g), (3-iodo-2-methyl-2H-indazol-6-yl)methanol (1.09 g), copper(I) iodide (420 mg), tripotassium 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, and ethyl acetate and water were added. The mixture was then filtered through Celite®. The organic layer was 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 (CHCl3 / MeOH) to give 1-[6-(hydroxymethyl)-2-methyl-2H-indazol-3-yl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (293 mg) as a foamy solid.

[0276] Manufacturing Example 47 To a solution of 7-bromo-3-iodoimidazo[1,2-a]pyridine (1.7 g) and 3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (1.5 g) in DOX (17 mL), DIPEA (4.58 mL), copper(I) iodide (1.0 g), and N,N'-dimethylethylenediamine (1.13 mL) were added sequentially and stirred at 130 °C for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, which was 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 silica gel column chromatography (petroleum ether / ethyl acetate) to give 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (750 mg) as a solid.

[0277] Manufacturing Example 48 To a solution of 1-[6-(hydroxymethyl)-2-methyl-2H-indazol-3-yl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (320 mg) in CHCl (10 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (470 mg) at room temperature and stirred for 1 hour. 5% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture, and after stirring for a while, it was extracted with CHCl. ​​The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-2-methyl-2H-indazole-6-carbaldehyde (208 mg) as a foamy solid.

[0278] Manufacturing Example 49 To tert-butyl (2S)-4-[(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-2-methyl-2H-indazol-6-yl)methyl]-2-methylpiperazine-1-carboxylate (153 mg), triisopropylsilane (165 μL), trifluoroacetic acid (1 mL), and trifluoromethanesulfonic acid (1 mL) were added at room temperature, followed by stirring 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-diazinan-2,4-dione (50 mg) as a solid.

[0279] Manufacturing Example 50 To a solution of tert-butyl (2S)-4-[(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}imidazo[1,2-a]pyridin-7-yl)methyl]-2-methylpiperazine-1-carboxylate (500 mg) in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (5 mL) was added and 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 layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (MeCN / 0.1% formic acid aqueous solution) to give 1-(7-{[(3S)-3-methylpiperazin-1-yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinan-2,4-dione n trifluoromethanesulfonate (185.9 mg) as a solid.

[0280] Manufacturing Example 51 Under an argon atmosphere, tBuOK (295 mg) was added in two portions to a mixture of (methoxymethyl)triphenylphosphonium chloride (900 mg) and THF (7 mL) under ice-cooling. The reaction mixture was stirred for 10 minutes under ice-cooling, and then a mixture of 3-iodo-1-methyl-1H-indazole-5-carbaldehyde (500 mg) and THF (7 mL) was added dropwise under ice-cooling and stirred at room temperature for 45 minutes. The resulting reaction mixture was again ice-cooled, and a suspension obtained by adding tBuOK (295 mg) to a mixture of (methoxymethyl)triphenylphosphonium chloride (900 mg) and THF (7 mL) under ice-cooling and stirring for 10 minutes was added to the mixture, followed by stirring at room temperature for 30 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture under ice-cooling, and the mixture was 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-methoxyethenyl)-1-methyl-1H-indazole (351 mg) as an oil.

[0281] Manufacturing Example 52 3-Iodo-5-(2-methoxyethenyl)-1-methyl-1H-indazole (250 mg) was added to water (2 mL) and formic acid (2 mL) and stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to CHCl (2 mL), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (200 mg), acetic acid (50 μL), and sodium triacetoxyborohydride (200 mg) and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with CHCl. ​​The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give tert-butyl (2S)-4-[2-(3-iodo-1-methyl-1H-indazol-5-yl)ethyl]-2-methylpiperazine-1-carboxylate (154 mg) as a foamy solid.

[0282] Manufacturing Example 53 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), methylhydrazine (10 mL) was added at room temperature and stirred at 100°C for 6 hours. The reaction mixture 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 give tert-butyl (2S)-4-[(3-amino-1-methyl-1H-indazol-5-yl)methyl]-2-methylpiperazine-1-carboxylate (4.56 g) as a solid.

[0283] Manufacturing Example 54 To a solution of 3-bromo-2-fluorobenzonitrile (9.00 g) in EtOH (100 mL) were added methylhydrazine sulfate (32.4 g) and TEA (75.2 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 volatiles. The resulting solid was collected by filtration and dried under reduced pressure. The resulting solid was triturated with ethyl acetate (50 mL) and stirred at 25°C for 10 minutes to give 7-bromo-1-methyl-1H-indazol-3-amine (8 g) as a solid.

[0284] Manufacturing Example 55 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) under ice cooling, and the mixture was left to stand at room temperature for 0.5 hours. After this, ethyl acrylate (3 mL) was added and the mixture was stirred at 90°C overnight. The reaction mixture was then allowed to cool to room temperature, and ethyl acetate and water were added, followed by stirring for a while. The aqueous and organic layers were 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. The residue was purified by silica gel chromatography (CHCl3 / MeOH) to give 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 oil.

[0285] Manufacturing Example 56 Acetic acid (24 mL), water (8 mL), and sodium cyanate (830 mg) were added 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) at room temperature, in that order, and the mixture was stirred at the same temperature for 3 days. The reaction mixture was concentrated, and water and saturated aqueous sodium bicarbonate were added to the residue, followed by extraction twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give 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.

[0286] Manufacturing Example 57 To a solution of 6-chloro-2-methyl-3-nitropyridine (1 g) in DMF (10 mL), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.4 g), DABCO (720 mg), and cesium carbonate (4.72 g) were added and stirred at room temperature for 2 hours. Ethyl acetate and water were added, and the organic layer was extracted. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]piperidine-1-carboxylate (447 mg) as a solid.

[0287] Manufacturing Example 58 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 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 give tert-butyl 4-[(4-iodo-3-methylpyridin-2-yl)oxy]piperidine-1-carboxylate (2.85 g) as an oil.

[0288] Manufacturing Example 59 To a mixture of tert-butyl 4-[(6-methyl-5-nitropyridin-2-yl)oxy]piperidine-1-carboxylate (532 mg), DOX (10 mL), and water (2 mL) was added zinc powder (830 mg) and ammonium chloride (680 mg) under ice-cooling and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, and Celite® was added and stirred for a while. Insoluble matter was removed by filtration through Celite®. The filtrate was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off and then concentrated under reduced pressure to give tert-butyl 4-[(5-amino-6-methylpyridin-2-yl)oxy]piperidine-1-carboxylate (480 mg) as an oil.

[0289] Manufacturing Example 60 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 a nitrogen atmosphere, diisopropyl azodicarboxylate (500 μL) was added under ice-cooling and 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 give tert-butyl 4-[2-(3-iodophenoxy)ethyl]piperazine-1-carboxylate (742 mg) as an oil.

[0290] Manufacturing Example 61 Under a nitrogen atmosphere, sodium hydride (55% mineral oil dispersion, 70 mg) was added to a solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (300 mg) in DMF (6 mL) under ice cooling and stirred at the same temperature for 10 minutes. 1-Bromo-4-(bromomethyl)-2-fluorobenzene (430 mg) was added at the same temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, 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 give 1-[(4-bromo-3-fluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (473 mg) as an oil.

[0291] Manufacturing Example 62 Under an argon atmosphere, a mixture of tert-butyl (3S)-3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.38 g), cyclopropylboronic acid (255 mg), PdCl(dppf) CHCl (162 mg), MeCN (15 mL), and water (3 mL) was added with potassium phosphate trihydrate (1.52 g) and stirred at 90 °C for 6 hours. After cooling 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 layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0292] Manufacturing Example 63 A mixture of tert-butyl (1S,4S)-5-{7-bromo-2-(ethylsulfanyl)-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), tripotassium phosphate (55 g), PdCl(dppf)·CHCl(5.4 g), MeCN (360 mL), DOX (240 mL), and water (120 mL) was degassed and then purged with argon gas. The mixture was stirred at 90°C for 5 h under an argon atmosphere. The cooled reaction mixture was concentrated under reduced pressure to approximately half its volume. The residue was poured into saturated aqueous sodium bicarbonate (100 mL) and water (300 mL) and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, followed by the addition of thiol-modified silica gel (approximately 10 g) and basic silica gel (approximately 10 g) and stirring at room temperature for 30 minutes. The insoluble material 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 give tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (27.74 g) as a foamy solid.

[0293] Manufacturing Example 64 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 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 stirred at 50 ° C for an additional 15 minutes. After cooling to room temperature, ethyl acetate and water were added, and insoluble matter was removed by filtration through Celite (registered trademark), and the two layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a diastereomeric mixture of approximately 5:1 due to axial chirality, 3.88 g) as an oil. MeOH (2 mL) was added to tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a diastereomeric mixture of approximately 5:1 due to axial chirality, 100 mg), and the mixture was heated to 70°C to dissolve. The mixture was stirred at room temperature overnight and then for 3 days. A solid precipitate (light yellow suspension) was confirmed. The solid was collected by filtration and washed with a small amount of MeOH to give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a 1:1 mixture of diastereomers resulting from axial chirality, 21 mg) as a powder. The filtrate was concentrated to give the desired tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (axially chiral single diastereomer of unknown configuration, 70 mg) as a solid. Similarly, EtOH (6 mL) was added to tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a diastereomeric mixture of approximately 5:1 due to axial chirality, 2.95 g), and the mixture was dissolved by heating to 70°C. A trace amount of the powder of the axially 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 give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (a 1:1 mixture of diastereomers resulting from axial chirality, 699 mg) as a colorless powder. The filtrate was concentrated to give the desired tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (axially chiral single diastereomer of unknown configuration, 2.33 g) as a foamy solid.

[0294] Manufacturing Example 65 tert-Butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (17.7 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (19.6 g), palladium(II) acetate (0.7 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (2.7 g), barium hydroxide (14.6 g), DOX (500 mL), water (50 A mixture of 1 mL of ethanol was degassed, then purged with argon gas and stirred at 50°C under an argon atmosphere for 6 hours. The reaction suspension was allowed to cool and then filtered through Celite (registered trademark) while washing with ethyl acetate. The filtrate was concentrated under reduced pressure to about one-quarter of its original volume, and then water was poured into it, followed by extraction twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified twice by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-2-(ethylsulfanyl)-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 tert-butyl ester (a mixture of approximately 4.5:1 isomers with respect to axial chirality, 20.64 g) as a foamy solid.

[0295] Manufacturing Example 66 Under an argon atmosphere, m-chloroperbenzoic acid (approximately 30% water content, 1.6 g) was added to a solution of tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.70 g) in CHCl (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. An aqueous solution (10 mL) containing sodium thiosulfate pentahydrate (1.7 g) and saturated aqueous sodium bicarbonate (40 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then extracted with CHCl. ​​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 give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.68 g) as a foamy solid.

[0296] Manufacturing Example 67 To a mixture of tert-butyl (1S,4S)-5-[(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg), tetrahydro-2H-pyran-4-ol (32 mg), and THF (4 mL) was added tBuOK (56 mg) under cooling in an ice / MeOH bath and stirred at the same temperature for 30 minutes under an argon atmosphere. The reaction mixture was poured into ice water and saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (144 mg) as a foamy solid.

[0297] Manufacturing Example 68 To a solution of tert-butyl (3S)-3-{[6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinolin-4-yl]oxy}pyrrolidine-1-carboxylate (835 mg) and (2S)-2-methoxypropan-1-ol (97 μL) in THF (10 mL), tBuOK (114 mg) was added under ice cooling and stirred at the same temperature for 2 hours. The reaction solution was quenched by adding ice water and aqueous ammonium chloride solution. The mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-3-({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}oxy)pyrrolidine-1-carboxylate (374 mg) as a foamy solid.

[0298] Manufacturing Example 69 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (4.5 g) and MeOH (100 mL), 10% Pd / C (52% aqueous, 1 g) was added and stirred overnight at room temperature under a hydrogen atmosphere at atmospheric pressure. Celite® was added and the mixture was filtered, washing with ethyl acetate and CHCl3. Toluene (approximately 20 mL) was added to the filtrate and concentrated under reduced pressure. The resulting solid was added with MeOH (80 mL) and 10% Pd / C (52% aqueous, 1.4 g) and stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 3 hours. The mixture was filtered through Celite®, washed with ethyl acetate and CHCl. ​​The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxyquinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.42 g) as a foamy solid.

[0299] Manufacturing Example 70 Under a nitrogen atmosphere, 10% Pd / C (50% aqueous, 300 mg) and sodium bicarbonate (600 mg) were added to a solution of tert-butyl (3S)-3-({6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.3 g) in MeOH (15 mL) and THF (15 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was then quenched with nitrogen and filtered through Celite® using MeOH. The filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tert-butyl (3S)-3-({6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxyquinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.16 g) as a foamy solid.

[0300] Manufacturing Example 71 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxyquinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.01 g), DMF (30 mL), and methyl 4-(chloromethyl)benzoate (1 g) was added cesium carbonate (4 g) with stirring at room temperature. The mixture was stirred overnight under an argon atmosphere. Ice water and saturated aqueous ammonium chloride were poured into the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-[(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl ester (3.32 g) as a foamy solid.

[0301] Manufacturing Example 72 Cesium carbonate (2 g) was added to a mixture of tert-butyl (3S)-3-({6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxyquinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.16 g), methyl 4-(chloromethyl)benzoate (375 mg), and DMF (12 mL) at room temperature, followed by stirring at room temperature for 6 hours. Ethyl acetate and water were added to the reaction mixture, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-3-{[6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinolin-4-yl]oxy}pyrrolidine-1-carboxylate (1.22 g) as a foamy solid.

[0302] Manufacturing Example 73 To a mixture of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (142 mg), MeOH (1 mL), and THF (1 mL) was added aqueous sodium hydroxide (1 M, 1 mL) under ice-cooling and stirred at room temperature for 6 hours. Hydrochloric acid (1 M, 1 mL) was added under ice-cooling, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 4-[({(7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoic acid (132 mg) as a solid.

[0303] Manufacturing Example 74 To a solution of tert-butyl (3S)-3-({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}oxy)pyrrolidine-1-carboxylate (250 mg) in MeOH (2 mL) and THF (2 mL) was added aqueous sodium hydroxide (1 M, 1.2 mL) at room temperature and stirred at room temperature for 6 hours. Ethyl acetate and saturated aqueous ammonium chloride were added under ice-cooling, and the organic layer was extracted. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and iPrO was added to the resulting residue. The precipitated solid was collected by filtration and washed with iPrO to give 4-{[(4-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl)oxy]methyl}benzoic acid (216 mg) as a solid.

[0304] Manufacturing Example 75 To a mixture of 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), MeOH (1 mL), and THF (1 mL) was added aqueous sodium hydroxide (1 M, 430 μL) at room temperature. The mixture was stirred overnight at room temperature. Ethyl acetate and saturated aqueous ammonium chloride were added under ice-cooling, and the organic layer was extracted, washed with saturated aqueous ...

Claims

1. A compound of formula (I) or a salt thereof. 【Chemistry 1】 (In the formula, A is CR A or N, R A H, optionally substituted C 1-３ alkyl or cyano; Q is CR Q or N, R Q is H, halogen, optionally substituted C 1-３ Alkyl, C 3-６ cycloalkyl, or vinyl; E is CH or N; R 1 may be substituted C 1-３ naphthyl optionally substituted with one or two groups selected from the group consisting of alkyl, cyano, OH, and halogen, or a group selected from the group consisting of the following formula (II), formula (III), and formula (IV): 【Chemistry 2】 R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-３ alkyl, vinyl or halogen; R 2 But -V １ -V 2 or W, V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )- and R V1 is H or optionally substituted C 1-３ is alkyl, V 2 is represented by the following formula (V) or formula (VI), 【Transformation 3】 W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocycloalkyl containing 1 or 2 nitrogen atoms, 【Chemistry 4】 R 2a may be the same or different and may be OH, OCH 3 , F or optionally substituted C 1-３ alkyl, and the R 2a is bonded only to a carbon atom that is a constituent atom 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 may be substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; X is a bond, -CH 2 -, -O-, -S-, or -NR 4X - and R 4X is H or optionally substituted C 1-３ is alkyl, Y 1 is -O-(optionally substituted C 1-３ alkylene)- ＊Y2 , -S-(optionally substituted C 1-３ alkylene)- ＊Y2 , -SO 2 -(optionally substituted C 1-３ alkylene)- ＊Y2 , -NR Y -(optionally substituted C 1-３ alkylene)- ＊Y2 , -(optionally substituted C 1-３ alkylene)-O- ＊Y2 , -(optionally substituted C 1-３ Alkylene)-S- ＊Y2 , -(optionally substituted C 1-３ (Alkylene)-SO 2 - ＊Y2 or -(optionally substituted C 1-３ (Alkylene)-NR Y - ＊Y2 And ( ＊Y2 is Y 2 ) R Y is H or optionally substituted C 1-３ is alkyl, Y 2 is a bond, optionally substituted phenylene or optionally substituted heteroarylene; Linker, Y 2 and EUB, EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, 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 cereblon.

3. EUB is represented by the following formula (XV), 【Transformation 5】 G is CR G or N, R G But H or C 1-６ is 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23), 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 R Z1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl) 2 and n is an integer from 0 to 2, R Z2 , R Z3 and R Z4 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-３ is alkylene, R M is H or optionally substituted C 1-３ is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with a carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, Here, M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to claim 2 .

4. EUB is represented by the following formula (XV), 【Transformation 7】 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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), 【Chemistry 8-1】 【Chemistry 8-2】 R Z1 But C 1-６ alkyl or halogen; n is an integer of 0 or 1, R Z2 and R Z4 are the same or different and are H or C 1-６ is alkyl, M is a bond or C 1-３ is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with a carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, Here, M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to claim 3 .

5. A is CH or N; Q is CR Q and R Q But C 3-６ is cycloalkyl, E is CH; R 1 is the following formula (II): 【Chemistry 9】 R 1a and R 1c are the same or different, C 1-３ alkyl or halogen; R 2 But -V １ -V 2 or W, V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )- and R V１ But C 3-６ C optionally substituted with one group selected from the group consisting of cycloalkyl, halogen, and —OH 1-３ is alkyl, V 2 is represented by the following formula (V-2) or (VI-2), 【Chemistry 10】 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), 【Chemistry 11】 R 3 But -O-(C 1-6 alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 alkyl) 2 and C optionally substituted with one group selected from the group consisting of heterocycloalkyl 1-6 alkyl, or optionally substituted heterocycloalkyl; X is -O- or -NR 4X - and R 4X But C 1-３ is alkyl, Y 1 But -O-(C 1-３ alkylene)- ＊Y2 Or -(C 1-３ alkylene)-O- ＊Y2 And ( ＊Y2 is Y 2 ) Y 2 is phenylene or pyridinediyl, Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 , L 2 , L 3 and L 4 are the same or different and are a bond, C=O, -O-, -S-, -SO 2 -, -NR L -, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7- to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and optionally substituted C 1-６ is a group selected from the group consisting of alkylene; R L But H or C 1-６ The compound or salt thereof according to claim 4, wherein the aryl group is alkyl.

6. R 1 is the following formula (II): 【Chemistry 12】 R 1a is a halogen, and R 1c But C 1-3 is alkyl, R 2 But -V １ -V 2 or W, V 1 is a bond, -O- or -N(R V１ )- and R V１ But C 1-3 is alkyl, V 2 is the following formula (VI-2), 【Chemistry 13】 W is represented by the following formula (XII): 【Chemistry 14】 R 3 But -O(C 1-6 C optionally substituted with one group selected from the group consisting of alkyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl; X is -O-, Y 1 But -O-(C 1-３ alkylene)- ＊Y2 And ( ＊Y2 is Y 2 ) Y 2 is phenylene Linker is -(L 1 -L 2 -L 3 -L 4 )- and L 1 is C=O, L 2 But C 1-3 Piperidinediyl optionally substituted with alkyl, C 1-3 Piperazinediyl optionally substituted with alkyl, C 1-3 pyrrolidinediyl, 3,8-diazabicyclo[3.2.1]octanediyl, or 2,6-diazaspiro[3.4]octanediyl, which may be substituted by alkyl; L 3 is the bond, -N(R L3 )-, C 1-3 alkylene or piperazinediyl, L 4 is the bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 is alkylene, R L3 But H or C 1-3 is alkyl, R L4 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), 【Chemistry 15】 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), wherein ring B1 and ring B2 in formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22), and (Z-23) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulae (Z-16), (Z-20), (Z-22) and (Z-23), 【Chemistry 16-1】 【Chemistry 16-2】 R Z1 But C 1-3 alkyl or halogen; n is an integer of 0 or 1, R Z2 But C 1-３ is alkyl, M is a bond or C 1-３ is alkylene, Ring B1 is a benzene ring or a pyridine ring, where R Z1 and Linker forms a bond with a carbon atom constituting ring B1, Ring B2 is a benzene ring or a pyridine ring, Here, M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to claim 5 .

7. Q is CR Q and R Q is cyclopropyl, R 1 is the following formula (II-2), 【Chemistry 17】 R 2 But -V 1 -V 2 or W, V 1 is -O- or -N(CH 3 )- and V 2 is the following formula (VI-2), [Chemistry 18] W is represented by the following formula (XII): 【Chemistry 19】 R 3 But, -OCH ３ or C optionally substituted with tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl; Y 1 But -O-(methylene)- ＊Y2 And ( ＊Y2 is Y 2 ) Linker 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 in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) represents Y 2 It forms a bond with 【Chemistry 20】 L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), 【Chemistry 21】 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), wherein the benzene ring or the 6-membered heterocycle in the 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) forms a bond with the Linker, 7. The compound or salt thereof according to claim 6, 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). 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】

8. R 2 But -V 1 -V 2 or W, V 1 is -O-, V 2 is the following formula (VI-2), 【Chemistry 23】 W is represented by the following formula (XII): 【Chemistry 24】 R 3 But, -OCH ３ n-propyl, or tetrahydropyranyl, optionally substituted by Linker is represented by the following formula (L-5A) or (L-7A), 【Chemistry 25】 EUB is represented by the following formula (XV), 【Chemistry 26】 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), 【Chemistry 27】 wherein the benzene ring or the 6-membered heterocycle in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A), and (Z-22A) forms a bond with the Linker, 8. The compound or salt thereof according to claim 7, wherein when G is N, Z is (Z-16A) or (Z-22A).

9. EUB is represented by the following formula (XV), 【Chemistry 28】 G is CR G or N, R G But H or C 1-６ is alkyl, Z is the following formula (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), 1 group selected from the group consisting of (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), wherein ring B1 and ring B2 in 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) form a bond with Linker, provided that when G is N, Z is a group selected from the group consisting of formulas (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); 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 R Z1 are the same or different and may be substituted C 1-6 Alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-(optionally substituted C 1-6 alkyl), -NH-(optionally substituted C 1-6 alkyl) or -N-(optionally substituted C 1-6 alkyl) 2 and n is an integer from 0 to 2, R Z2 , R Z3 , R Z4 and R Z5 are the same or different and are H or optionally substituted C 1-6 is alkyl, M is a bond, -O-, -S-, -N(R M )- or optionally substituted C 1-３ is alkylene, R M is H or optionally substituted C 1-３ is alkyl, Ring B1 is a benzene ring or a 6-membered heterocycle, where R Z1 and Linker forms a bond with a carbon atom constituting ring B1, Ring B2 is a benzene ring or a 5- or 6-membered heterocycle, Here, M, R Z1 and Linker forms a bond with the carbon atom constituting ring B2, or a salt thereof, according to claim 2 .

10. A is CH or N; Q is CR Q and R Q is cyclopropyl, R 1 is the following formula (II-2), 【Transformation 30】 R 2 But -V 1 -V 2 or W, V 1 is -O- or -N(CH 3 )- and V 2 is the following formula (VI-2), 【Chemistry 31】 W is the following formula (VII-4) or (XII), 【Chemistry 32】 R 3 But, -OCH ３ or C optionally substituted with tetrahydrofuranyl 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl; X is -O-, Y 1 But -O-(methylene)- ＊Y2 And ( ＊Y2 is Y 2 ) Y 2 is phenylene Linker 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 in the formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) represents Y 2 It forms a bond with 【Transformation 33】 L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl, L'' is a bond, C 1-3 Alkylene or -(C 1-3 alkylene)-O-; R L2 But H or C 1-3 is alkyl, EUB is represented by the following formula (XV), 【Transformation 34】 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), 【Chemistry 35-1】 【Chemistry 35-2】 【Chemistry 35-3】 【Chemistry 35-4】 wherein the benzene ring or 6-membered heterocycle in the 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) forms a bond with Linker, and the benzene ring in (Z-24A) forms a bond with Linker, 10. The compound or salt thereof according to claim 9, 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. Use of the compound or salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for treating pancreatic cancer.

12. 10. The compound or salt thereof according to claim 1 for use in treating pancreatic cancer.

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