Heterocyclic compound for inducing degradation of g12v mutant KRAS protein

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and / or lung cancer.　The present inventors examined compounds useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and / or lung cancer and found that a heterocyclic compound represented by formula (I) has an excellent action for inducing the degradation of G12V mutant KRAS protein and an inhibitory activity on G12V mutant KRAS and can be used as a therapeutic agent for pancreatic cancer and / or lung cancer. The present invention has been completed on the basis of this finding. The heterocyclic compound of the present invention or a salt thereof can be used as a therapeutic agent for pancreatic cancer and / or lung cancer.

Description

Heterocyclic compounds for inducing degradation of G12V mutant KRAS protein

[0001] The present invention relates to pharmaceutical compositions and heterocyclic compounds that have excellent activity in inducing the degradation of G12V mutant KRAS protein, are useful as G12V mutant KRAS inhibitors, and are expected to be useful, for example, as active ingredients in pharmaceutical compositions for treating pancreatic cancer and / or lung cancer.

[0002] Pancreatic cancer, primarily pancreatic ductal adenocarcinoma, has a 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 survival rates are poor. Currently, FOLFIRINOX 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, it is prescribed only to patients with an ECOG performance status of 1 or less, and careful patient selection is required (J. Clin. Oncol., 2018, 36, pp. 2545-2556). Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, has been approved for use in combination with gemcitabine. However, the overall survival benefit is only about two weeks compared to gemcitabine alone, and the therapeutic effect is not satisfactory. Therefore, more effective treatments are still needed (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] Lung cancer is also responsible for the highest number of deaths, with approximately 2.1 million new cases reported annually worldwide (World Cancer Report 2020). Non-small cell lung cancer (NSCLC), in particular, accounts for 80-85% of lung cancer cases (American Cancer Society, Cancer Facts and Figures, 2022). While surgical treatment is considered for some stages, chemotherapy and radiation therapy are rarely indicated for later stages, and chemotherapy and radiation therapy become the mainstay of treatment. Based on cytomorphology, adenocarcinoma and squamous cell carcinoma are classified as the most common types of NSCLC. While the clinical course of these tumors is similar, adenocarcinoma is characterized by its peripheral location in the lung.

[0004] 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 active, GTP-bound forms and inactive, GDP-bound forms. 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).

[0005] 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). Furthermore, in lung cancer, mutations in the RAS gene have been observed in 32% of lung adenocarcinomas. The breakdown of mutation frequencies is 96% in the KRAS gene, 3% in the NRAS gene, and 1% in the HRAS gene, with point mutations in KRAS exon 2 (codons 12 and 13) being common (Nature Rev. Drug Discov., 2014, 13, pp. 828-851). This suggests that KRAS plays an important role in the carcinogenesis and development of pancreatic cancer and lung adenocarcinoma.

[0006] Known KRAS gene mutations include the KRAS G12V mutation, in which glycine at codon 12 is replaced by valine, the KRAS G12D mutation, in which glycine is replaced by aspartic acid, and the KRAS G12C mutation, in which glycine is replaced by cysteine. In recent years, several G12C mutation-selective inhibitors have been developed, and one of them, sotorasib, has been approved by the FDA for the treatment of non-small cell lung cancer (Drugs, 2021, 81, pp. 1573-1579).

[0007] Patent Documents 1, 2, and 3 disclose RAS inhibitors, and the compounds represented by the following formula (A) and formula (B) are disclosed in Patent Documents 2 and 3, respectively (see the publications for the meanings of the symbols in the formulas). Patent Documents 1, 2, and 3 describe that these compounds are useful for cancers with mutations in codon 12 of KRAS, one of which is the G12V mutation, but do not describe their effect on G12V-mutated KRAS.

[0008] Furthermore, Patent Document 9 discloses a pan-KRAS inhibitor.

[0009] 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 become 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 within 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.

[0010] There are over 600 types of E3 ligases in vivo, broadly classified 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.

[0011] A bifunctional compound is a compound in which a ligand for a target protein and a ligand for an E3 ligase are linked by a linker, and bifunctional compounds that degrade KRAS protein have been reported (Non-Patent Document 1, Non-Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Documents 10 to 22).

[0012] International Publication No. 2016 / 049565, International Publication No. 2016 / 049568, International Publication No. 2017 / 172979, International Publication No. 2013 / 106643, International Publication No. 2015 / 160845, U.S. Patent Application Publication No. 2018 / 0015087, International Publication No. 2019 / 195609, International Publication No. 2020 / 018788, International Publication No. 2022 / 132200, International Publication No. 2021 / 051034, International Publication No. 2022 / 087335 International Publication No. 2021 / 207172 International Publication No. 2022 / 111521 International Publication No. 2022 / 061348 International Publication No. 2022 / 148422 International Publication No. 2022 / 173032 International Publication No. 2022 / 228576 International Publication No. 2023 / 059609 International Publication No. 2023 / 077441 International Publication No. 2023 / 280026 Chinese Patent Application Publication No. 113956233 Chinese Patent Application Publication No. 115785199

[0013] Cell. Chem. Biol., 2020, 27, p19-31ACS Cent. Sci., 2020, 6, p1367-1375

[0014] Provided is a heterocyclic compound that is expected to be useful as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions that have an excellent effect of inducing the degradation of G12V mutant KRAS protein and are useful as G12V mutant KRAS inhibitors, for treating pancreatic cancer and / or lung cancer, particularly G12V mutant KRAS-positive pancreatic cancer and / or G12V mutant KRAS-positive lung cancer.

[0015]

[0003] The present inventors have conducted extensive research into compounds useful as active ingredients in pharmaceutical compositions for treating pancreatic and / or lung cancer, and have found that heterocyclic compounds of formula (I), particularly bifunctional compounds of formula (I) characterized by linking a substituent at position 8 of a heterocyclic compound selected from the group consisting of quinazoline and quinoline to a ligand for E3 ligase, or by linking a substituent at position 8 of a heterocyclic compound selected from the group consisting of quinazoline and quinoline to a ligand for E3 ligase via a linker, have excellent activity of inducing degradation of G12V mutant KRAS protein and inhibitory activity against G12V mutant KRAS.

[0004] The present invention relates to a compound of formula (I) or a salt thereof, and to a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. (Wherein, A is CR A , or N and R A is H or C 1-3 is alkyl, and X 1 is -CH2-, -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 alkyl, or X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, 1 is naphthyl optionally substituted with OH, or is represented by the following formula (II) or formula (III): R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1cis F, Cl, methyl or ethyl, R 2 H, halogen, C 1-3 alkyl, cyclopropyl, or vinyl, 1-3 The alkyl may be substituted with a group selected from the group consisting of OH and OCH3, and R 3 is a group selected from the group consisting of the following formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XXVI), R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3b is H or C 1-3 alkyl, and R 3c and R 3d is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3e is H, F or C 1-3 alkyl, and R 3f is H or C 1-3 alkyl, and R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3h is H, F or C 1-3 alkyl, and R 3i are the same or different and represent H, OH, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, -NH- optionally substituted C 1-3 Alkyl, -N-(optionally substituted C 1-3 alkyl) ２ , halogen, —CN, and oxo, or two R present on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be 1-3 Alkyl, -O-(C 1-3alkyl), OH, halogen, and oxo, or R present on two adjacent carbon atoms. 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocycle, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo, or R present on two non-adjacent carbon atoms. 3i may be combined with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 R is optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, and X 3 is O or S, and X 4 is -CH2-, -CH2-CH2- or -O-CH2-, n is 1 or 2, p is 1 or 2, q is 1 to 8, R 4 is C 1-6 Alkyl, R 4a piperidinyl or tetrahydropyranyl optionally substituted by 1-6 Alkyl is F, OH, OCH 3、 R 4a, cyclopropyl, N(R 4a )2, R 4a pyrrolidinyl, optionally substituted with R, and tetrahydrofuranyl; 4a may be substituted C 1-3 alkyl, Y is phenylene optionally substituted with F or Cl, or pyridinediyl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L 1 , L 2 , L 3 , L 4 , L 5 are the same or different and represent a bond, -O-, -NR L1 -, a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, an optionally substituted C 1-3 is a group selected from the group consisting of alkylene and C═O, L1 is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX), Ring B is a benzene ring or a 6-membered heterocycle containing 1 or 2 nitrogen atoms, and R Z1 is H, C 1-3 Alkyl, -O-(C 1-3 alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 alkyl, and R Z3 is H or C 1-3 alkyl, and R Z4 are the same or different and are H or C 1-3 alkyl, and R Z5 is C 1-3L is bonded to ring B of the above formula (XIII) or formula (XVIII) or to the benzene ring of formula (XIX) and formula (XX), m is 1 or 2, G is CH or N, provided that when G is N, Z is the above formula (XVII), formula (XVIII) or formula (XIX).

[0016] 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.

[0017] 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 G12V 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 G12V mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced G12V mutant KRAS-positive pancreatic cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory G12V mutant KRAS-positive pancreatic cancer, and in one embodiment, a pharmaceutical composition for treating G12V mutant KRAS-positive pancreatic cancer in treatment-naive and / or previously treated patients. The pharmaceutical composition for treating pancreatic cancer, which contains 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, G12V mutant KRAS-positive pancreatic cancer, which contains the compound of formula (I) or a salt thereof.

[0018] The present invention also relates to pancreatic cancer, in one embodiment, G12V 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 patients who have not been treated and / or who have been treated in the past, in one embodiment, metastatic G12V mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced G12V mutant KRAS-positive pancreatic cancer, in one embodiment, recurrent or refractory G12V mutant KRAS-positive pancreatic cancer, in one embodiment, untreated and / or treated in the past. The present invention relates to: use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating G12V mutant KRAS-positive pancreatic cancer in patients with a history of treatment; use of a compound of formula (I) or a salt thereof for the treatment of G12V mutant KRAS-positive pancreatic cancer in patients with a history of treatment; pancreatic cancer; in one embodiment, a compound of formula (I) or a salt thereof for use in the treatment of G12V mutant KRAS-positive pancreatic cancer; and a method for treating pancreatic cancer; in one embodiment, a method for treating G12V mutant KRAS-positive pancreatic cancer, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[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 lung cancer, in one embodiment, a pharmaceutical composition for treating G12V mutant KRAS-positive lung cancer, in one embodiment, a pharmaceutical composition for treating metastatic lung cancer, in one embodiment, a pharmaceutical composition for treating locally advanced lung cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory lung cancer, in one embodiment, a pharmaceutical composition for treating lung cancer in treatment-naïve and / or previously treated patients, in one embodiment, a pharmaceutical composition for treating metastatic G12V mutant KRAS-positive lung cancer, in one embodiment, a pharmaceutical composition for treating locally advanced G12V mutant KRAS-positive lung cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory G12V mutant KRAS-positive lung cancer, and in one embodiment, a pharmaceutical composition for treating G12V mutant KRAS-positive lung cancer in treatment-naïve and / or previously treated patients. In addition, the pharmaceutical composition for treating lung cancer containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients also includes a therapeutic agent for lung cancer, in one embodiment, G12V mutant KRAS-positive lung cancer, containing the compound of formula (I) or a salt thereof.

[0020] The present invention also relates to lung cancer, in one embodiment, G12V mutant KRAS-positive lung cancer, in one embodiment, metastatic lung cancer, in one embodiment, locally advanced lung cancer, in one embodiment, recurrent or refractory lung cancer, in one embodiment, lung cancer in patients who have not been treated and / or who have been treated in the past, in one embodiment, metastatic G12V mutant KRAS-positive lung cancer, in one embodiment, locally advanced G12V mutant KRAS-positive lung cancer, in one embodiment, recurrent or refractory G12V mutant KRAS-positive lung cancer, in one embodiment, untreated and / or treated The present invention relates to use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating G12V mutant KRAS-positive lung cancer in patients with a history of lung cancer, in one embodiment, use of a compound of formula (I) or a salt thereof for the treatment of G12V mutant KRAS-positive lung cancer, lung cancer, in one embodiment, a compound of formula (I) or a salt thereof for use in the treatment of G12V mutant KRAS-positive lung cancer, and a method for treating lung cancer, in one embodiment, G12V mutant KRAS-positive lung cancer, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0021] The present invention also relates to a compound of formula (I) or a salt thereof which is a G12V mutant KRAS proteolysis inducer and / or a G12V mutant KRAS inhibitor, a compound of formula (I) or a salt thereof for use as a G12V mutant KRAS proteolysis inducer and / or a G12V mutant KRAS inhibitor, and a G12V mutant KRAS proteolysis inducer and / or a G12V mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof.

[0022] 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.

[0023] The compound of formula (I) or a salt thereof has an effect of inducing degradation of G12V mutant KRAS protein and an inhibitory activity against G12V mutant KRAS, and can be used as a therapeutic agent for pancreatic cancer and / or lung cancer, particularly G12V mutant KRAS-positive pancreatic cancer and / or G12V mutant KRAS-positive lung cancer.

[0024] The present invention will be described in detail below.

[0025] 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 multiple substituents are present, the substituents may be the same or different from each other.

[0026] "C 1-12 The 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 1-6The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms, and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl; in one embodiment, it is methyl, ethyl, n-propyl, isopropyl, or sec-butyl; in one embodiment, it is methyl, ethyl, isopropyl, or tert-butyl; and in one embodiment, it is methyl, ethyl, n-propyl, isopropyl, or n-butyl. Similarly, "C 1-3 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, or isopropyl, in one embodiment, methyl or ethyl, in one embodiment, n-propyl or isopropyl, in one embodiment, methyl or isopropyl, in one embodiment, ethyl or isopropyl, in one embodiment, methyl, in one embodiment, ethyl, in one embodiment, isopropyl, or in one embodiment, n-propyl.

[0027] "C 3-6 The term "cycloalkane" refers to a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0028] "C 3-6 The term "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.

[0029] "C 1-3 "Alkylene" means C 1-3 A divalent group formed by removing a hydrogen atom from an alkyl, and is a straight-chain or branched C 1-3Alkylene, for example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In one embodiment, a linear 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.

[0030] A "saturated heterocycle" is a saturated hydrocarbon ring containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. Furthermore, the sulfur atom as a ring-constituting atom of the saturated heterocycle may be oxidized. Accordingly, a "4- to 6-membered saturated heterocycle" is a 4- to 6-membered saturated hydrocarbon ring containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. One embodiment of a "4- to 6-membered saturated heterocycle" is a 4- to 6-membered saturated heterocycle containing, as a ring-constituting atom, one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, and one embodiment is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, or dioxothiomorpholine.

[0031] A "saturated heterocyclic group" is a saturated hydrocarbon ring group containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. Furthermore, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized. Therefore, a "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. One embodiment of the "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing, as a ring-constituting atom, one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen.One embodiment of the 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms is a 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, another embodiment is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and another embodiment is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. In one embodiment, it is a 4-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and in one embodiment, it is a 5-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and in one embodiment, it is a 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and in one embodiment, it is an oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazine, and in some embodiments, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl. In some embodiments, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholinyl. In one embodiment, it is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, in one embodiment, pyrrolidinyl or piperidinyl, in one embodiment, oxetanyl, in one embodiment, tetrahydrofuranyl, in one embodiment, tetrahydropyranyl, in one embodiment, pyrrolidinyl, in one embodiment, piperidinyl, in one embodiment, morpholinyl, and in one embodiment, oxazolidinyl.

[0032] The "divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms" refers to a divalent 4- to 11-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms as ring-constituting atoms, and may be a divalent saturated heterocyclic group having a spiro ring or a fused ring. Certain embodiments of the "divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms" include azetidinediyl, pyrrolidinediyl, imidazolidinediyl, piperidinediyl, piperazinediyl, azepanediyl, diazepanediyl, azocanediyl, diazocanediyl, azonanediyl, and diazonanediyl, or divalent groups represented by the following formulae (XXI) to (XXV). An embodiment of the "divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms" is pyrrolidinediyl, piperazinediyl, or a divalent group represented by the following formula (XXI) or formula (XXII). An embodiment of the "divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms" is pyrrolidinediyl, piperazinediyl, or a divalent group represented by the following formula (XXI), formula (XXII), or formula (XXV).

[0033] The "divalent saturated heterocyclic group containing two nitrogen atoms" refers to a divalent 4- to 11-membered saturated heterocyclic group containing two nitrogen atoms as ring-constituting atoms, and may be a divalent saturated heterocyclic group having a spiro ring or a fused ring. Some embodiments of the "divalent saturated heterocyclic group containing two nitrogen atoms" include imidazolidinediyl, piperazinediyl, diazepanediyl, diazocanediyl, diazonanediyl, or divalent groups represented by the following formulae (XXI) to (XXV). An embodiment of the "divalent saturated heterocyclic group containing two nitrogen atoms" is piperazinediyl or a divalent group represented by the following formula (XXI) or formula (XXII). An embodiment of the "divalent saturated heterocyclic group containing two nitrogen atoms" is piperazinediyl or a divalent group represented by the following formula (XXI), formula (XXII), or formula (XXV).

[0034] A "heterocycle" is an aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. Thus, a "6-membered heterocycle containing 1 to 2 nitrogen atoms" is a 6-membered aromatic hydrocarbon ring containing 1 to 2 nitrogen atoms as ring-constituting atoms, and in one embodiment is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, or triazine ring, and in another embodiment is a pyridine ring.

[0035] "Heteroaryl" is a heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. Accordingly, a "5-membered heteroaryl" is a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. One embodiment of a "5-membered heteroaryl" is a 5-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and one embodiment is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, one embodiment is pyrazolyl, imidazolyl, triazolyl, oxazolyl, or thiazolyl, and one embodiment is pyrazolyl, imidazolyl, oxazolyl, or thiazolyl. In one embodiment, it is pyrazolyl, imidazolyl, triazolyl, or isoxazolyl, in one embodiment, pyrazolyl, oxazolyl, or thiazolyl, in one embodiment, pyrazolyl, triazolyl, or isoxazolyl, in one embodiment, pyrazolyl or thiazolyl, in one embodiment, pyrazolyl or triazolyl, in one embodiment, pyrazolyl, in one embodiment, imidazolyl, in one embodiment, oxazolyl, in one embodiment, thiazolyl, and in one embodiment, triazolyl.

[0036] The "6-membered heteroaryl" is a 6-membered heterocyclic group containing 1 to 3 nitrogen atoms as ring-constituting atoms. In one embodiment, the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, in another embodiment, pyridyl or pyridazinyl, in another embodiment, pyridyl or pyrimidinyl, in another embodiment, pyridyl, and in another embodiment, pyrimidinyl.

[0037] "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.

[0038] The term "spiro ring" refers to a polycyclic ring structure in which two ring structures are bonded by sharing a spiro atom, which is a quaternary carbon; the term "fused ring" refers to a polycyclic ring structure in which two or more ring structures are bonded by sharing two or more adjacent atoms that constitute one ring; and the term "bridged structure" refers to a divalent chain structure that links two non-adjacent atoms among the ring constituent atoms of one ring.

[0039] "Optionally substituted C 1-6 alkyl," "optionally substituted C 1-3 "Alkyl" and "Optionally substituted C 1-3 Some embodiments of the substituents allowed for "alkylene" include F, OH, OCH3, N(C optionally substituted with F), and the like. 1-3 alkyl)2, optionally substituted C 3-6 cycloalkyl, azabicyclo[3.3.0]octanyl, or an optionally substituted 4- to 6-membered saturated heterocyclic group. 3、 Cyclopropyl, N(C optionally substituted with F) 1-3 alkyl)2, (C optionally substituted with F 1-3and tetrahydrofuranyl, optionally substituted with alkyl), and tetrahydrofuranyl, and in some embodiments, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, and in some embodiments, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, or optionally substituted pyrrolid ... In some embodiments, the alkyl group is methyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl, or methylpyrrolidinyl; in some embodiments, the alkyl group is F, OH, OCH3, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, or methylpyrrolidinyl; in some embodiments, the alkyl group is F, OH, or cyclopropyl; in some embodiments, the alkyl group is F, OH, or OCH3; in some embodiments, the alkyl group is OH or OCH3; in some embodiments, the alkyl group is F or OCH3; in some embodiments, the alkyl group is OH; in some embodiments, the alkyl group is F; and in some embodiments, the alkyl group is OCH3.

[0040] In the "optionally substituted 5-membered heteroaryl" and the "optionally substituted 6-membered heteroaryl," one embodiment of the permissible substituents is a C-membered heteroaryl optionally substituted with a group selected from the group consisting of OH and OCH3. 1-3 Alkyl, -SO2CH3, halogen, OH, OCH3, or C 3-6 In one embodiment, a C alkyl group optionally substituted with a group selected from the group consisting of OH and OCH3 is used. 1-3 C is alkyl, and in one embodiment, optionally substituted with OH. 1-3 alkyl, and in one embodiment, C optionally substituted with OCH 1-3alkyl, and in one embodiment C 1-3 It is alkyl or halogen, and in one embodiment, it is methyl, ethyl, methoxymethyl or F, and in another embodiment, it is methyl, ethyl or F.

[0041] "Optionally substituted 4- to 6-membered saturated heterocyclic group", "optionally substituted pyrrolidinyl", "optionally substituted C 3-6 Some embodiments of the substituents permitted in the "cycloalkyl," "divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted," and "divalent saturated heterocyclic group containing two nitrogen atoms which may be substituted" include C, which may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3 In one embodiment, it is F, OH, or OCH3, in another embodiment, it is OH or methyl, and in another embodiment, it is C optionally substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 C is alkyl, F, oxo, or oxetanyl, and in one embodiment, may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3 C is alkyl or oxo, and in one embodiment, may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3 C is alkyl, and in one embodiment, optionally substituted with F. 1-3 C is alkyl, and in one embodiment, optionally substituted with OH. 1-3 alkyl, and in one embodiment, C optionally substituted with OCH 1-3 alkyl, and in one embodiment, optionally substituted with N(CH3)2. 1-3 alkyl, and in some embodiments, C 1-3 In one embodiment, C(CH3)2 optionally substituted with alkyl. 1-3 It is alkyl or oxo.

[0042] "C optionally substituted with OH 1-3In one embodiment, "alkyl" is methyl optionally substituted with one OH group or ethyl optionally substituted with one or two OH groups. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl. In one embodiment, it is methyl, ethyl, or hydroxymethyl, in another embodiment, it is methyl or hydroxymethyl, in another embodiment, it is hydroxymethyl or hydroxyethyl, in another embodiment, it is hydroxymethyl, and in another embodiment, it is hydroxyethyl.

[0043] "C optionally substituted with OCH3 1-6 C optionally substituted with alkyl and OCH 1-3 In one embodiment of "alkyl," it is methyl optionally substituted with one OCH3 or ethyl optionally substituted with one or two OCH3. For example, it is methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, or 1,2-dimethoxyethyl. In one embodiment, it is methoxymethyl or methoxyethyl, in another embodiment, methoxymethyl, and in another embodiment, methoxyethyl.

[0044] "N(C 1-3 C optionally substituted with alkyl)2 1-6 One embodiment of "alkyl" is "C optionally substituted with N(CH3)2." 1-3 alkyl" and in one embodiment, one N(C 1-3 methyl optionally substituted with one N(C alkyl); 1-3 ethyl optionally substituted with N(C alkyl)2 or 1-3 In one embodiment, one N(C alkyl) is n-propyl. 1-3 Methyl optionally substituted with N(C alkyl)2 or one N(C 1-3 ethyl optionally substituted with N(CH3)2; 1-3In one embodiment, "alkyl" is methyl optionally substituted with one N(CH3)2 or ethyl optionally substituted with one N(CH3)2. In another embodiment, it is methyl, ethyl, dimethylaminomethyl, or dimethylaminoethyl, in another embodiment, it is methyl or dimethylaminomethyl, in another embodiment, it is dimethylaminomethyl, and in another embodiment, it is dimethylaminoethyl.

[0045] One embodiment of "phenylene optionally substituted with F or Cl" is phenylene optionally substituted with 1 or 2 F or Cl. One embodiment is phenylene optionally substituted with one F, one embodiment is phenylene optionally substituted with one Cl, one embodiment is phenylene or fluorophenylene, one embodiment is phenylene, one embodiment is 2-fluoro-1,4-phenylene, and one embodiment is 3-fluoro-1,4-phenylene.

[0046] The term "G12V 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 valine.

[0047] "G12V mutated KRAS" refers to KRAS having the above-mentioned "G12V mutation."

[0048] "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.

[0049] "Lung cancer" refers to malignant tumors that occur in the lungs. Examples include small cell lung cancer and non-small cell lung cancer, and in some embodiments, small cell lung cancer and non-small cell lung cancer. Furthermore, in some embodiments, lung cancer is metastatic lung cancer, locally advanced lung cancer, recurrent or refractory lung cancer, and lung cancer in untreated and / or previously treated patients.

[0050] "G12V mutant KRAS-positive pancreatic cancer" refers to pancreatic cancer that is positive for G12V mutant KRAS. For example, it refers to pancreatic cancer in which KRAS G12V mutation has occurred, and pancreatic cancer with a high rate of positive for G12V mutant KRAS. In one embodiment, it is G12V mutant KRAS-positive pancreatic ductal carcinoma, and in another embodiment, it is G12V mutant KRAS-positive pancreatic ductal adenocarcinoma.

[0051] "G12V mutant KRAS-positive lung cancer" refers to lung cancer that is positive for G12V mutant KRAS. For example, it is lung cancer in which KRAS G12V mutation has occurred, and lung cancer with a high positive rate for G12V mutant KRAS. In one embodiment, it is G12V mutant KRAS-positive small cell lung cancer, and in another embodiment, it is G12V mutant KRAS-positive non-small cell lung cancer.

[0052] Certain embodiments of the compound of formula (I) or a salt thereof according to the present invention are shown below.

[0053] (1-1) A is CR A , or N and R A is H or C 1-3 (1-2) A is CR A , or N and R A is H. (1-3) A is CR A , or N and R A is C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl.

[0054] (2-1) X 1 is -CH2-, -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 alkyl, or X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may be taken together with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. 1 is -O- or -NR X1 - and RX1 is H or optionally substituted C 1-3 alkyl, or X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may be taken together with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. 1 is -O- or -NR X1 - and R X1 is H or C 1-3 The compound of formula (I) or a salt thereof, wherein X is alkyl. 1 is —O—, or a salt thereof.

[0055] (3-1) R 1 is naphthyl optionally substituted with OH, or is represented by the following formula (II) or formula (III): R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1c (3-2) A compound of formula (I) or a salt thereof, wherein R is F, Cl, methyl or ethyl. 1 is the following formula (II), R 1a is H, methyl, F or Cl, R 1c (3-3) R is F, Cl, methyl or ethyl, 1 is the following formula (II), R 1a is F and R 1c is methyl; or a salt thereof.

[0056] (4-1) R 2 H, halogen, C 1-3 alkyl, cyclopropyl, or vinyl, 1-3 The compound of formula (I) or a salt thereof, wherein the alkyl may be substituted with a group selected from the group consisting of OH and OCH3. (4-2) R 2(4-3) The compound of formula (I) or a salt thereof, wherein R is cyclopropyl or vinyl. 2 is cyclopropyl; or a salt thereof.

[0057] (5-1) R 3 is a group selected from the group consisting of the following formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XXVI), R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3b is H or C 1-3 alkyl, and R 3c and R 3d is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3e is H, F or C 1-3 alkyl, and R 3f is H or C 1-3 alkyl, and R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3h is H, F or C 1-3 alkyl, and R 3i are the same or different and represent H, OH, optionally substituted C 1-3 Alkyl, -O- (optionally substituted C 1-3 alkyl), -NH- (optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl) ２ , halogen, —CN, and oxo, or two R present on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be 1-3 Alkyl, -O-(C 1-3alkyl), OH, halogen, and oxo, or R present on two adjacent carbon atoms. 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocycle, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo, or R present on two non-adjacent carbon atoms. 3i may be combined with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 R is optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, and X 3 is O or S, and X 4 (5-2) A compound of formula (I) or a salt thereof, wherein R is -CH2-, -CH2-CH2-, or -O-CH2-, n is 1 or 2, p is 1 or 2, and q is 1 to 8. 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2)p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3b is H or C 1-3 alkyl, and R 3e is H, F or C 1-3 alkyl, and R 3f is H or C 1-3 alkyl, and R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3h is H, F or C 1-3 alkyl, and R N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, and X 3 (5-3) A compound of formula (I) or a salt thereof, wherein R is O or S, n is 1 or 2, and p is 1 or 2. 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H or C 1-3 alkyl, and R 3e is H and R 3g is an optionally substituted 6-membered heteroaryl, R 3h is H or F, R N1 and R N2 are the same or different C 1-3 alkyl, or R N1 and R N2 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O- or -NH-, and X 3 (5-4) R is O or S, n is 1, and p is 1, or a salt thereof. 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H or C 1-3 alkyl, and R 3e is H and R 3gis an optionally substituted 6-membered heteroaryl, R 3h is H or F, R N1 and R N2 are the same or different C 1-3 is alkyl, and X 2 is -O- or -NH-, and X 3 is O or S, n is 1, and p is 1. (5-5) R is a compound of formula (I) or a salt thereof. 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H and R 3e is H and R 3g is an optionally substituted 6-membered heteroaryl, R 3h is F and R N1 and R N2 are the same or different, C 1-3 is alkyl, and X 2 is -O- or -NH-, and X 3 is O, and n and p are both 1. 3 is a group selected from the group consisting of the following formulas (IV-1), (VII-1), (VIII-1), (IX), (X), (XI) and (XII-1), a compound of formula (I) or a salt thereof.

[0058] (6-1) R 4 is C 1-6 Alkyl, R 4a piperidinyl or tetrahydropyranyl optionally substituted by 1-6 Alkyl is F, OH, OCH 3、 R 4a , cyclopropyl, N(R 4a )2, R 4apyrrolidinyl, optionally substituted with R, and tetrahydrofuranyl; 4a may be substituted C 1-3 (6-2) R is a compound of formula (I) or a salt thereof. 4 is OCH 3、 N(R 4a )2 and R 4a pyrrolidinyl optionally substituted with C 1-6 alkyl, and R 4a may be substituted C 1-3 (6-3) R is a compound of formula (I) or a salt thereof. 4 is OCH3 or N(C 1-3 C optionally substituted with alkyl)2 1-6 Alkyl, C 1-3 The compound of formula (I) or a salt thereof, wherein R is piperidinyl or tetrahydropyranyl optionally substituted by alkyl. 4 is OCH 3、 N(C 1-3 alkyl)2 and R 4a pyrrolidinyl optionally substituted with C 1-6 alkyl, or tetrahydropyranyl, R 4a may be substituted C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl.

[0059] (7-1) A compound of formula (I) or a salt thereof, wherein Y is phenylene optionally substituted with F or Cl, or pyridinediyl. (7-2) A compound of formula (I) or a salt thereof, wherein Y is phenylene optionally substituted with F or Cl. (7-3) A compound of formula (I) or a salt thereof, wherein Y is phenylene.

[0060] (8-1) L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L 1 , L 2 , L3 , L 4 , L 5 are the same or different and represent a bond, -O-, -NR L1 -, a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, an optionally substituted C 1-3 is a group selected from the group consisting of alkylene and C═O, L1 is H or C 1-3 (8-2) The compound of formula (I) or a salt thereof, wherein L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L 1 , L 2 , L 3 , L 4 , L 5 are the same or different and represent a bond, -NR L1 -, a bivalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, an optionally substituted C 1-3 is a group selected from the group consisting of alkylene and C═O, L1 is H or C 1-3 (8-3) The compound of formula (I) or a salt thereof, wherein L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L is included in L 1 binds to Y, and L 1 is C 1-3 alkylene or C═O, 2 is a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, and L 3 is C 1-3 is alkylene, and L 4 is a bond, -O- or -N(C 1-3 alkyl), and L 5 is a bond or C 1-3 (8-4) A compound of formula (I) or a salt thereof, wherein L is alkylene. A group selected from the group consisting of* The compound of formula (I) or a salt thereof, wherein the carbon atom marked with is bonded to Y.

[0061] (9-1) Z is a group selected from the group consisting of the following formulae (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX), Ring B is a benzene ring or a 6-membered heterocycle containing 1 or 2 nitrogen atoms, and R Z1 is H, C 1-3 Alkyl, -O-(C 1-3 alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 alkyl, and R Z3 is H or C 1-3 alkyl, and R Z4 are the same or different and are H or C 1-3 alkyl, and R Z5 is C 1-3 (9-2) A compound of formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of the following formulae (XIII), (XVII) and (XIX): Ring B is a benzene ring or a 6-membered heterocycle containing 1 or 2 nitrogen atoms, and R Z1 is H, C 1-3 Alkyl, -O-(C 1-3 alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 alkyl, and R Z4 are the same or different and are H or C 1-3 alkyl, and R Z5 is C 1-3A compound of formula (I) or a salt thereof, wherein Z is an alkyl group, L is bonded to ring B of formula (XIII) or (XVII), and m is 1 or 2. (9-3) Z is a group selected from the group consisting of formulas (XIII), (XVII), and (XIX): Ring B is a benzene ring, and R Z1 is H or C 1-3 alkyl, and R Z2 is H or C 1-3 A compound of formula (I) or a salt thereof, wherein Z is an alkyl group selected from the group consisting of the following formulae (XIII), (XVII) and (XIX): Ring B is a benzene ring, and R Z1 is H and R Z2 is C 1-3 (9-5) A compound of formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of the following formulae (XIII-1), (XVII-1) and (XIX-1): (9-6) A compound of formula (I) or a salt thereof, wherein L is bonded to the benzene ring of formula (XIII-1) or formula (XVII-1) above. (9-6) Z is formula (XIII) or formula (XVII) below: Ring B is a benzene ring, L is bonded to ring B in the above formulas (XIII) and (XVII), and R Z1 is H and R Z2 is C 1-3 A compound of formula (I) or a salt thereof, wherein:

[0062] (10-1) A compound of formula (I) or a salt thereof, wherein G is CH or N, provided that when G is N, Z is the above formula (XVII), formula (XVIII) or formula (XIX). (10-2) A compound of formula (I) or a salt thereof, wherein G is CH or N, provided that when G is N, Z is the above formula (XVII) or formula (XIX). (10-3) A compound of formula (I) or a salt thereof, wherein G is CH or N, provided that when G is N, Z is the above formula (XVII-1) or formula (XIX-1). (10-4) A compound of formula (I) or a salt thereof, wherein G is CH or N, provided that when G is N, Z is the above formula (XVII).

[0063] (11) A compound or a salt thereof which is a combination of any two or more of the above embodiments (1-1) to (10-4) that are not contradictory.

[0064] Specific examples of the combination described in (11) above include the following: (11-1-1) A compound of formula (I) or a salt thereof. (Wherein, A is CR A , or N and R A is H and X 1 is -O- and R 1 is the following formula (II), R 1a is F and R 1c is methyl and R 2 is cyclopropyl, and R 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H and R 3e is H and R 3g is an optionally substituted 6-membered heteroaryl, R 3h is F and R N1 and R N2 are the same or different, C1-3 is alkyl, and X 2 is -O- or -NH-, and X 3 is O, n and p are both 1, R 4 is OCH 3、 N(R 4a )2 and R 4a pyrrolidinyl optionally substituted with C 1-6 alkyl, and R 4a may be substituted C 1-3 alkyl, Y is phenylene, and L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L 1 , L 2 , L 3 , L 4 , L 5 are the same or different and represent a bond, -NR L1 -, a bivalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, an optionally substituted C 1-3 is a group selected from the group consisting of alkylene and C═O, L1 is H or C 1-3 is alkyl, Z is represented by the following formula (XIII) or formula (XVII): Ring B is a benzene ring, L is bonded to ring B in the above formulas (XIII) and (XVII), and R Z1 is H and R Z2 is C 1-3 alkyl, m is 1, G is CH or N, provided that when G is N, Z is the above formula (XVII).

[0065] (11-1-2) A compound of formula (I) or a salt thereof. (Wherein, A is CR A , or N and R A is H or C 1-3 is alkyl, and X 1 is -CH2-, -O- or -NR X1 - and R X1is H or optionally substituted C 1-3 alkyl, or X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, 1 is naphthyl optionally substituted with OH, or is represented by the following formula (II) or formula (III): R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, R 2 H, halogen, C 1-3 alkyl, cyclopropyl, or vinyl, 1-3 The alkyl may be substituted with a group selected from the group consisting of OH and OCH3, and R 3 is a group selected from the group consisting of the following formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XXVI), R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C 1-3 Alkylene-NR N1 R N2 , -OR 3f, and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3b is H or C 1-3 alkyl, and R 3c and R 3d is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3e is H, F or C 1-3 alkyl, and R 3f is H or C 1-3 alkyl, and R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3h is H, F or C 1-3 alkyl, and R 3i are the same or different and represent H, OH, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3Alkyl, -NH- optionally substituted C 1-3 Alkyl, -N-(optionally substituted C 1-3 alkyl) ２ , halogen, —CN, and oxo, or two R present on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo, or R present on two adjacent carbon atoms. 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocycle, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo, or R present on two non-adjacent carbon atoms. 3i may be combined with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 R is optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2is -O-, -NH-, or -N(C 1-3 alkyl)-, and X 3 is O or S, and X 4 is -CH2-, -CH2-CH2- or -O-CH2-, n is 1 or 2, p is 1 or 2, q is 1 to 8, R 4 is C 1-6 Alkyl, R 4a piperidinyl or tetrahydropyranyl optionally substituted by 1-6 Alkyl is F, OH, OCH 3、 R 4a , cyclopropyl, N(R 4a )2, R 4a pyrrolidinyl, optionally substituted with R, and tetrahydrofuranyl; 4a may be substituted C 1-3 alkyl, Y is phenylene optionally substituted with F or Cl, or pyridinediyl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L 1 , L 2 , L 3 , L 4 , L 5 are the same or different and represent a bond, -O-, -NR L1 -, a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, an optionally substituted C 1-3 is a group selected from the group consisting of alkylene and C═O, L1 is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX), Ring B is a benzene ring or a 6-membered heterocycle containing 1 or 2 nitrogen atoms, and R Z1 is H, C 1-3 Alkyl, -O-(C 1-3 alkyl), -NRZ4 2. -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 alkyl, and R Z3 is H or C 1-3 alkyl, and R Z4 are the same or different and each represents H or C 1-3 alkyl, and R Z5 is C 1-3 L is bonded to ring B of the above formula (XIII) or formula (XVIII) or to the benzene ring of formula (XIX) and formula (XX), m is 1 or 2, G is CH or N, provided that when G is N, Z is the above formula (XVII), formula (XVIII) or formula (XIX). (11-2) X 1 is -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 alkyl, or X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, 1 is the following formula (II), R 1a is H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, R 2 is cyclopropyl or vinyl, R 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, and R 3b is H or C 1-3 alkyl, and R 3e is H, F or C 1-3 alkyl, and R 3f is H or C 1-3 alkyl, and R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3h is H, F or C 1-3 alkyl, and R N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, and X 3represents O or S, n represents 1 or 2, p represents 1 or 2, Y represents phenylene which may be substituted with F or Cl, Z represents a group selected from the group consisting of the following formulae (XIII), (XVII) and (XIX), Ring B is a benzene ring or a 6-membered heterocycle containing 1 or 2 nitrogen atoms, and R Z1 is H, C 1-3 Alkyl, -O-(C 1-3 alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 alkyl, and R Z4 are the same or different and each represents H or C 1-3 alkyl, and R Z5 is C 1-3 The compound or salt thereof according to (11-1-2) above, wherein L is alkyl, L is bonded to ring B of formula (XIII) or (XVII) above, m is 1 or 2, G is CH or N, and when G is N, Z is formula (XVII) or formula (XIX) above.

[0066] (11-3) X 1 is -O- or -NR X1 - and R X1 is H or C 1-3 alkyl, and R 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H or C 1-3 alkyl, and R 3e is H and R 3g is an optionally substituted 6-membered heteroaryl, R 3h is H or F, R N1 and RN2 are the same or different C 1-3 alkyl, or R N1 and R N2 may form, together with the nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O- or -NH-, and X 3 is O or S, n is 1, p is 1, Z is a group selected from the group consisting of the following formulas (XIII), (XVII) and (XIX), Ring B is a benzene ring, and R Z1 is H or C 1-3 alkyl, and R Z2 is H or C 1-3 The compound or salt thereof according to (11-2) above, wherein L is alkyl, L is bonded to ring B of formula (XIII) or (XVII) above, or to a benzene ring of formula (XIX), m is 1 or 2, G is CH or N, and when G is N, Z is formula (XVII) or formula (XIX) above.

[0067] (11-4) A is CR A , or N and R A is H and X 1 is -O- and R 1 is the following formula (II), R 1a is F and R 1c is methyl and R 2 is cyclopropyl, and R 3 is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI) and (XII), R 3a is -(CH2) p CHR 3e -NR N1 R N2 and R 3b is H or C 1-3 alkyl, and R 3e is H and R 3gis an optionally substituted 6-membered heteroaryl, R 3h is H or F, R N1 and R N2 are the same or different C 1-3 is alkyl, and X 2 is -O- or -NH-, and X 3 is O or S, n is 1, p is 1, R 4 is OCH 3、 N(C 1-3 alkyl)2 and R 4a pyrrolidinyl optionally substituted with C 1-6 alkyl, or tetrahydropyranyl, R 4a may be substituted C 1-3 alkyl, Y is phenylene, and L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L is included in L 1 binds to Y, and L 1 is C 1-3 alkylene or C═O, 2 is a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, and L 3 is C 1-3 is alkylene, and L 4 is a bond, -O- or -N(C 1-3 alkyl), and L 5 is a bond or C 1-3 alkylene, Z is a group selected from the group consisting of the following formulas (XIII), (XVII) and (XIX): Ring B is a benzene ring, and R Z1 is H or C 1-3 alkyl, and R Z2 is H or C 1-3 (11-5) The compound or salt thereof according to (11-2) above, wherein R is alkyl, L is bonded to ring B of formula (XIII) or (XVII) above, or to the benzene ring of formula (XIX), and m is 1 or 2.3 is a group selected from the group consisting of the following formulas (IV-1), (VII-1), (VIII-1), (IX), (X), (XI) and (XII-1), L is a group represented by the following formula (XXVII) to formula (XXXIV): A group selected from the group consisting of * The carbon atom marked with is bonded to Y, and Z is a group selected from the group consisting of the following formulas (XIII-1), (XVII-1) and (XIX-1): wherein L is bonded to the benzene ring of the above formula (XIII-1) or formula (XVII-1), G is CH or N, and when G is N, Z is the above formula (XVII-1) or formula (XIX-1), the compound or salt thereof according to the above (11-4).

[0068] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds or salts thereof: 1-{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-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-3-carbonitrile; (2S)-1-{6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2-methylpiperazine-1-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-2-carboxamide.

[0069] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds or salts thereof: 1-{(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-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-3-carbonitrile; (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2-methylpiperazine-1-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-2-carboxamide.

[0070] Examples of specific compounds encompassed by the present invention include, in one embodiment, the following compounds or salts thereof: 1-{(7P)-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-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-3-carbonitrile; (2S)-1-{(7P)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2-methylpiperazine-1-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-2-carboxamide.

[0071] Compounds of formula (I) may exist as tautomers or geometric isomers depending on the type of substituents. Although compounds of formula (I) may be described herein in only one isomeric form, the present invention also encompasses other isomers, including separated isomers and mixtures thereof. Furthermore, compounds of formula (I) may have asymmetric carbon atoms or axial asymmetry, and diastereomers based on this may exist. The present invention also encompasses separated diastereomers of compounds of formula (I) and mixtures thereof.

[0072] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I). 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., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0073] The salt of the compound of formula (I) is 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 substituents. 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.

[0074] Furthermore, the present invention also encompasses various hydrates and solvates, and crystalline polymorphic substances of the compound of formula (I) and its salts.

[0075] The present invention also encompasses all compounds of formula (I) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used to isotopic label 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 ( 35Isotopes of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 3 H), carbon 14 ( 14 Radioactive isotopes such as C may be used for this purpose due to their ease of labeling and detection. Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 2 Substitution with positron-emitting isotopes (H) may be therapeutically advantageous due to increased metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, and fewer drug interactions). 11 C, 18 F, 15 O and 13 Substitution with an isotopically labeled N or the like can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described in the Examples or Preparations, using appropriate isotopically labeled reagents in place of unlabeled reagents.

[0076] (Production Method) The compound of formula (I) and its salts can be produced by various known synthetic methods, taking advantage of characteristics based on its 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 can be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary. A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Publishing, 1990), Vol. 7, Molecular Design, 163-198. Similarly to the above-mentioned protecting groups, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, or by further reacting the resulting compound of formula (I). The reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation, and dehydration. Representative methods for producing the compound of formula (I) are described below. Each method can also be carried out with reference to the references provided in the description. The production methods of the present invention are not limited to the examples shown below.

[0077] In the present 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-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CHCl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, PyAOP: (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphoric acid, SFC: supercritical fluid chromatography, NMM: N-methylmorpholine, CDI: 1,1'-carbonyldiimidazole, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2]octane, TFA: trifluoroacetic acid, DBU: 1,8-diazabicyclo[5.4.0]-7-undecene, TBAF: tetra-n-butylammonium fluoride.

[0078] (Manufacturing method 1) (In the formula, -L 35 - is -L-contained in -L 3 -L 4 -L 5 This production method is for the compound of formula (I) where A is N and -L is included in -L-. 1 - is CO, -L 2 -Ga-N(R L2 )- or a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, 3 -L 4 -L 5 -Ga-L 35 - and R L2 is H or C1-6 This is a method for producing a compound of formula (I-1), wherein the alkyl group is methyl. This reaction involves using equal amounts of compound (1) and compound (2), or an excess of either, and stirring a mixture of these 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 to obtain an amide compound. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include PyBOP, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), CDI, and diphenylphosphoryl azide (DPPA). The use of an additive (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, may be advantageous for smooth reaction progression. Alternatively, compound (1) may be converted to a reactive derivative followed by acylation. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and activated esters obtained by condensation with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with compound (2) can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling or heating, preferably at temperatures between -20°C and 120°C. [References] SR Sandler and W. Karo, "Organic Functional Group Preparations," 2nd Edition, Vol. 1, Academic Press Inc., 1991; and "Experimental Chemistry Lectures (5th Edition)," edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen).

[0079] (Manufacturing method 2) (PG 71 is R 1 represents the NH protecting group contained in R 11 is R 1 It represents a divalent group in which H is eliminated from NH contained in the above. The same applies below.)

[0080] This method is another method for producing a compound of formula (I). Compound (I) can also be obtained by deprotecting compound (3). Examples of protecting groups include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl. This deprotection reaction is typically carried out under cooling or reflux with stirring for 0.1 hours to 5 days. Examples of solvents used herein include, but are not limited to, alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, water, and mixtures thereof. Examples of deprotection reagents include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, and other acids. By selecting a protecting group, deprotection can also be performed by catalytic hydrogenation. Examples of protecting groups include a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, and the like. Deprotection can also be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include a tert-butyl(dimethyl)silyl group and a (trimethylsilyl)ethoxymethyl group. Furthermore, examples of protecting groups that can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, a benzoyl group, and the like. References include, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th Edition, John Wiley & Sons Inc., 2014; AR Katritzky and RJK Taylor, "Comprehensive Organic Functional Group Transformations II," Vol. 2, Elsevier Pergamon, 2005.

[0081] (Manufacturing method 3) This production method is a method for producing a compound of formula (I-2) in which A is N, among compounds of formula (I), by reacting compound (4) with compound (5). This reaction involves using equal amounts of compound (4) and compound (5), or an excess of either, 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, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include PyBOP, HATU, CDI, and PyAOP. Performing 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, may be advantageous for smooth reaction progression. Alternatively, the compound of formula (I-2) can be obtained by converting compound (4) to a reactive derivative in which the hydroxyl group at the 4-position of compound (4) is converted to a chloro group using a chlorinating reagent such as phosphorus oxychloride or thionyl chloride, and then adding compound (5) in the presence of an organic base such as TEA, DIPEA, or pyridine, or an inorganic base such as potassium carbonate, cesium carbonate, or potassium acetate. The reaction of these reactive derivatives with compound (5) can be carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling to heating, preferably at temperatures between -20°C and 120°C.

[0082] (Manufacturing method 4) In this production method, among the compounds of formula (I), -L included in -L- 1 - is CO, -L 2 -Ga-N(R L2 )- or a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, 3 -L 4 -L 5 -Ga-L 35 -wherein R L2 is H or C 1-6This is a method for producing a compound of formula (I-3), which is an alkyl group. In this reaction, compound (69) and compound (2) are subjected to the same reaction conditions as in Production Method 1 to obtain compound (I-3).

[0083] (Raw material synthesis 1) (In the formula, LG 2 , L.G. 4 , L.G. 6 , L.G. 7 , L.G. 8 and L.G. 81 are the same or different and each represents a leaving group. PG 4 is the protecting group for OH, PG 7 and PG 71 are R 1 The protecting group of NH contained in R 11 is R 1 A divalent group formed by removing H from NH contained in PG 8 denotes a protecting group that can be removed under catalytic hydrogenation conditions, PG 81 indicates a protecting group for COOH. 4 , P.G. 7 , P.G. 71 , P.G. 8 and PG 81 In the case of R, protecting groups that can be deprotected under different deprotection conditions can be selected and deprotection can be carried out stepwise. LG2 is C 1-12 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, I, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. (The same applies hereinafter.)

[0084] This production method is the first method for producing compound (1), which is a starting compound for Production Method 1.

[0085] (Step 1) This step is a method for producing compound (7) from compound (6). This reaction is carried out by stirring compound (6) under cooling or reflux, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols, acetone, DMF, THF, etc. Mixing the above solvents with water may also be suitable for the reaction. Examples of reagents used in this reaction include, but are not limited to, aqueous sodium hydroxide and aqueous potassium hydroxide. References for this reaction include, for example, the following: "Experimental Chemistry Lectures (5th Edition)," edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen); Angew. Chem. Int. Ed. 2005, 44, pp. 1378-1382.

[0086] (Step 2) This step involves protecting the hydroxyl group of compound (7) with a protecting group to produce compound (8). For example, when protecting with a tert-butyl group, this reaction is carried out by stirring compound (7) in the presence of a tert-butyl protecting reagent, typically under cooling or reflux, for 0.1 hours to 5 days. Examples of solvents used here 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. Compound (8) can also be produced by a dehydration condensation reaction between compound (7) and tBuOH. For references regarding this reaction, see, for example, the following: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014. Org. Lett., 2012, 14, 17, pp. 4678-4681

[0087] (Third Step) This step is a reaction of compound (8) with compound (9), R LG2This method is a method for producing compound (10) by ipso substitution reaction with —SH. LG2 An example of -SH is C 1-12 Examples of suitable alkylthiols include ethanethiol and dodecanethiol. This reaction involves using equal amounts of compound (8) and compound (9), or an excess of either, and stirring the mixture in a reaction-inert solvent, or without solvent, under cooling to reflux, preferably at temperatures between 0°C and 80°C, for typically 0.1 hours to 5 days. Examples of suitable solvents 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; DMF, DMAc, DMSO, ethyl acetate, MeCN, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), or tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction.

[0088] (Fourth Step) This step is a reaction of compound (10) with compound (11), i.e., PG. 8 This method produces compound (12) by ipso substitution reaction with —OH. 8 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol. The reaction conditions are the same as those in the third step of the present Raw Material Synthesis 1.

[0089] (Fifth Step) This step is a reaction of compound (12) with compound (13) R 2 This method involves the Suzuki-Miyaura coupling reaction of a boronic acid derivative containing a -boronic acid group or the like to produce compound (14). 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 triol borate base, a trifluoroborate base, etc. This reaction is carried out by reacting compound (12) with R 2A 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, for typically 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, and barium hydroxide. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf)·CHCl2, (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, and palladium(II) acetate. 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, or 1,1'-bis(diphenylphosphino)ferrocene in order to facilitate the reaction. Heating the mixture by microwave irradiation may also be advantageous in order to facilitate the reaction. [References] J. Am. Chem. Soc., 2005, 127, pp. 4685-4696; Org. Lett. 2011, 13, pp. 3948-3951; Org. Lett. 2012, 14, pp. 1278-1281. LG 6When R is a halogen, compound (12) can be dehalogenated using a Pd catalyst and a reducing agent to give compound (14) (where R 2 (Hydrogen can be produced.) [References] J. Org. Chem., 1977, 42, pp. 3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0090] (Step 6) This step is a method for producing compound (16) by Suzuki-Miyaura coupling reaction between compound (14) and compound (15). The reaction conditions are the same as in Step 5 of the present Raw Material Synthesis 1. When compound (16) has axial asymmetry, 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.

[0091] (Step 7) This step is a method for producing compound (17) by oxidation of compound (16). In this reaction, compound (16) is treated with an equal or excess amount 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, ethers, halogenated hydrocarbons such as 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. [References] "Experimental Chemistry Lectures," edited by the Chemical Society of Japan, 5th edition, Vol. 17, Maruzen, 2004. When compound (17) has axial asymmetry, it may be 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, or resolution by SFC using a chiral column.

[0092] (Step 8) This step is a method for producing compound (19) by ipso substitution reaction between compound (17) and compound (18). The reaction conditions are the same as those in Step 3 of the present Raw Material Synthesis 1.

[0093] (Step 9) This step is a method for producing compound (20) by deprotecting compound (19) through catalytic hydrogenation. This reaction can be carried out by stirring compound (19) under a hydrogen atmosphere at atmospheric to elevated pressure in a reaction-inert solvent such as MeOH, EtOH, or ethyl acetate, in the presence of a metal catalyst, with stirring under cooling to heating, preferably at room temperature, for 1 hour to 5 days. Examples of the metal catalyst that can be used 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.

[0094] (Step 10) This step is a method for producing compound (22) from compound (20) and compound (21). This reaction is carried out by using equal amounts of compound (20) and compound (21) or an excess of either compound, and reacting a mixture of these 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. The solvent used here is not particularly limited, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, 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. References for this reaction include, for example, the following: "Experimental Chemistry Lectures," edited by the Chemical Society of Japan, 5th edition, Vol. 14, Maruzen, 2005. Compound (21) can also be prepared by the reaction of LG81 By halogenating a compound in which the moiety corresponding to LG is a hydroxy group, 81 is a halogen. Examples of the halogenating agent used here include, but are not limited to, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, etc. References for this reaction include, for example, the following: "Experimental Chemistry Lectures," edited by the Chemical Society of Japan, 5th edition, Vol. 13, Maruzen, 2004. Furthermore, compound (21) can be produced by the reaction of LG 81 The compound having a hydroxy group in the corresponding position is sulfonylated in the presence of a base to give LG 81 is 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. References for this reaction include, for example, the following: Synthesis 1999, 9, pp. 1633-1636

[0095] (Eleventh Step) This step is to remove the protecting group PG of compound (22). 4 and PG 7 Deprotection of R 11 The deprotected NH group contained in 71 The reaction conditions are the same as those in the process of Production Method 2, and compound (22) and a deprotection reagent are added to the reaction mixture, and the NH group is protected with PG. 71 The reaction can be carried out by adding a protecting reagent for protecting with a group.

[0096] (Step 12) This step is a method for producing compound (24) by reacting compound (23) with compound (5). The reaction conditions are the same as in Production Method 3.

[0097] (Step 13) This step is a method for producing compound (1) by subjecting compound (24) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0098] (Raw material synthesis 2) (In the formula, PG 82 is C 1-3 (The same applies below.)

[0099] In this production method, in the compound (3) which is the raw material compound in Production Method 2, A is N, and in -L-, -L 1 - is CO, -L 2 -Ga-N(R L2 )- or a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, 3 -L 4 -L 5 -Ga-L 35 -wherein R L2 is H or C 1-6 This is the first method for producing the compound (3-1), which is an alkyl group.

[0100] (First Step) This step is a method for producing compound (26) by reacting compound (25) with compound (5). The reaction conditions are the same as in Production Method 3.

[0101] (Step 2) This step is a method for producing compound (27) by hydrolyzing compound (26) under basic conditions. This reaction is carried out by stirring compound (26) under cooling or reflux, typically for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols, acetone, DMF, THF, etc. Mixing the above solvents with water may also be suitable for the reaction. Examples of hydrolysis reagents include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, trimethyltin hydroxide, etc. References for this reaction include, for example, the following: "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen), Angew. Chem. Int. Ed. 2005, 44, pp. 1378-1382.

[0102] (Step 3) This step is a method for producing compound (3-1) by subjecting compound (27) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the step described in Production Method 1.

[0103] (Raw material synthesis 3)

[0104] In this production method, in the compound (3) which is the raw material compound in Production Method 2, A is N, and in -L-, -L 1 - is CO, -L 2 -Ga-N(R L2 )- or a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, 3 -L 4 -L 5 -Ga-L 35 -wherein R L2 is H or C 1-6 This is the second method for producing the compound (3-1), which is an alkyl group.

[0105] (First Step) This step is a method for producing compound (29) from compound (20) and compound (28). The reaction conditions are the same as those in the tenth step of Starting Material Synthesis 1.

[0106] (Second Step) This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction. The reaction conditions are the same as those in the second step of Starting Material Synthesis 2.

[0107] (Step 3) This step is a method for producing compound (31) by subjecting compound (30) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the step described in Production Method 1.

[0108] (Fourth Step) This step is carried out by removing the protecting group PG of compound (31). 4 and P.G. 7 Deprotection of R 11 The deprotected NH group contained in 71 The reaction conditions are the same as those in the step described in Production Method 2, and compound (31) and a deprotection reagent are added to the reaction product, and the NH group is protected with PG. 71The reaction can be carried out by adding a protecting reagent for protecting with a group.

[0109] (Fifth Step) This step is a method for producing a compound (3-1) by reacting a compound (32) with a compound (5). The reaction conditions are the same as in Production Method 3.

[0110] (Raw material synthesis 4) (In the formula, -L'- is -L included in -L-. 1 -L 2 -L 3 - indicates -R Z -CHO or -CH2-LG 81 indicates PG 83 represents a protecting group for NH bonded to L'. L ' is H or C 1-3 It may be alkyl, or may combine with the adjacent nitrogen atom and L' to form a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms.

[0111] This production method is a method for producing compound (4), which is a raw material compound of production method 3, by using -L- 4 -Ga-N(R L’ )- and -L 5 This is a method for producing a compound (4-1) in which - is -CH2-.

[0112] (First Step) This step is a method for producing compound (34) from compound (20) and compound (33). The reaction conditions are the same as those in the tenth step of Starting Material Synthesis 1.

[0113] (Step 2) This step is a method for producing compound (35) by subjecting compound (34) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0114] (Step 3) In this step, compound (35) and compound (36) are converted into -R Z When -CHO is used, it is converted by reductive amination, and when -R Z Ga-CH2-LG 81 In the case of -R, the compound (4-1) is obtained by alkylation. ZWhen -R is -CHO, the reaction is carried out by using equal equivalents of compound (35) and compound (36), or an excess equivalent of either, 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 the reducing agent used here include, but are not limited to, NaBH(OAc)3, 2-picoline borane, NaBH3CN, etc. The solvent used here is also not limited to, but includes halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc.; ether solvents such as THF, diethyl ether, DOX, etc.; alcoholic solvents such as MeOH, EtOH, etc.; and MeCN. Z Ga-CH2-LG 81 The reaction conditions in this case are the same as those in the tenth step of Raw Material Synthesis 1.

[0115] (Raw material synthesis 5) (In the formula, PG 41 represents a protecting group for NH, and R 31 is R 3a -N(R 3b )CO-, R 3c -OCO- or R 3d -CO-.)

[0116] In this production method, R 3 is represented by formula (IV), formula (V) or formula (VI), and X 3 is O.

[0117] (First Step) This step is a reaction of compound (6) with compound (9), R LG2 This method produces compound (37) by ipso substitution reaction with -SH. The reaction conditions are the same as those in the third step of Starting Material Synthesis 1.

[0118] (Step 2) This step is a method for producing compound (38) by ipso substitution reaction between compound (37) and compound (11). The reaction conditions are the same as those in Step 4 of Starting Material Synthesis 1.

[0119] (Step 3) This step is a reaction of compound (38) with a protecting group PG 41This method produces compound (40) by an ipso substitution reaction with compound (39) having an amino group protected by . This reaction involves using equal amounts of compound (38) and compound (39), or an excess of either, and stirring the mixture in a reaction-inert solvent under cooling or 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 toluene, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Performing 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, may be advantageous for smooth reaction progression.

[0120] (Fourth Step) This step is a reaction of compound (40) with compound (13), R 2 This is a method for producing compound (41) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group, etc. The reaction conditions are the same as those in the fifth step of Starting Material Synthesis 1.

[0121] (Step 5) This step is a method for producing compound (42) by Suzuki-Miyaura coupling reaction between compound (41) and compound (15). The reaction conditions are the same as those in Step 5 of Starting Material Synthesis 1. When compound (42) has axial asymmetry, 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.

[0122] (Step 6) This step is a method for producing compound (43) by oxidation of compound (42). The reaction conditions are the same as those in Step 7 of Starting Material Synthesis 1. When compound (43) has axial asymmetry, it may be 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, or resolution by SFC using a chiral column.

[0123] (Seventh Step) This step is a method for producing compound (44) by ipso substitution reaction between compound (43) and compound (18). The reaction conditions are the same as those in the third step of Starting Material Synthesis 1.

[0124] (Step 8) This step is a method for producing compound (45) by deprotecting compound (44) through catalytic hydrogenation. The reaction conditions are the same as those in Step 9 of Starting Material Synthesis 1.

[0125] (Step 9) This step is a method for producing compound (46) from compound (45) and compound (21). The reaction conditions are the same as those in Step 1 of Starting Material Synthesis.

[0126] (Step 10) This step is a method of producing compound (47) by subjecting compound (46) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0127] (Step 11) This step involves subjecting compound (47) to a urea reaction using compound (48), a carbamate reaction using compound (49), and an amidation reaction using compound (50) to obtain compound (51). In the urea reaction using compound (48) and the carbamate reaction using compound (49), an equivalent amount of compound (48) or compound (49) or an excess amount of either compound is used relative to compound (47), and the mixture is stirred in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at -20°C to 60°C, typically for 0.1 hours to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include CDI, triphosgene, bis(4-nitrophenyl) carbonate, and 4-nitrophenyl chloroformate. The use of an additive (e.g., 1-hydroxybenzotriazole or dimethylaminopyridine) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, may be advantageous for smooth reaction. The reaction conditions for the amidation reaction using compound (50) are the same as those described in Production Method 1.

[0128] (Step 12) This step is a method of producing compound (52) by subjecting compound (51) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0129] (Raw material synthesis 6)

[0130] This production method is a second method for producing compound (1), which is a starting compound in Production Method 1.

[0131] (Step 1) This step is a method for producing compound (53) by deprotecting compound (17) through catalytic hydrogenation. The reaction conditions are the same as those in Step 9 of Starting Material Synthesis 1.

[0132] (Second Step) This step is a method for producing compound (54) from compound (53) and compound (21). The reaction conditions are the same as those in the tenth step of Starting Material Synthesis 1.

[0133] (Step 3) This step is a method for producing compound (55) by ipso substitution reaction between compound (54) and compound (18). The reaction conditions are the same as those in Step 3 of Starting Material Synthesis 1.

[0134] (Step 4) This step is a method for producing compound (56) by subjecting compound (55) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0135] (Step 5) This step is a method for producing compound (57) by reacting compound (56) with compound (5). The reaction conditions are the same as in Production Method 3.

[0136] (Step 6) This step is a method for producing compound (1) by subjecting compound (57) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0137] (Raw material synthesis 7)

[0138] This production method is a method for producing a compound (3) which is a raw material compound of Production Method 2, in which A is N and -L is included in -L-. 1 - is CO, -L 2 -Ga-N(R L2 )- or a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms which may be substituted, 3 -L 4 -L 5 -Ga-L 35 - and R L2 is H or C 1-6 The present invention relates to a method for producing compound (61), which is an alkyl group.

[0139] (Step 1) This step is a method for producing compound (58) by subjecting compound (29) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0140] (Second Step) This step is a method for producing a compound (59) by reacting a compound (58) with a compound (5). The reaction conditions are the same as in Production Method 3.

[0141] (Step 3) This step is a method for producing compound (60) by subjecting compound (59) to a deprotection reaction. The reaction conditions are the same as those in Step 2 of Starting Material Synthesis 2.

[0142] (Step 4) This step is a method for producing compound (61) by subjecting compound (60) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the step described in Production Method 1.

[0143] (Raw material synthesis 8)

[0144] This production method is a method for producing compound (69), which is a starting compound for Production Method 4.

[0145] (First Step) This step is a method for producing compound (62) by ipso substitution reaction between compound (38) and compound (5). The reaction conditions are the same as those in the third step of Starting Material Synthesis 5.

[0146] (Second Step) In this step, compound (62) and compound (13) R 2 This is a method for producing compound (63) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group, etc. The reaction conditions are the same as those in the fifth step of Starting Material Synthesis 1.

[0147] (Step 3) This step is a method for producing compound (64) by Suzuki-Miyaura coupling reaction between compound (63) and compound (15). The reaction conditions are the same as those in Step 5 of Starting Material Synthesis 1. When compound (64) has axial asymmetry, 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.

[0148] (Step 4) This step is a method for producing compound (65) by oxidation of compound (64). The reaction conditions are the same as those in Step 7 of Starting Material Synthesis 1. When compound (65) has axial asymmetry, it may be obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, such as resolution using ODS column chromatography or silica gel column chromatography, or resolution by SFC using a chiral column.

[0149] (Step 5) This step is a method for producing compound (66) by ipso substitution reaction between compound (65) and compound (18). The reaction conditions are the same as those in Step 3 of Starting Material Synthesis 1.

[0150] (Step 6) This step is a method for producing compound (67) by deprotecting compound (66) through catalytic hydrogenation. The reaction conditions are the same as those in Step 9 of Starting Material Synthesis 1.

[0151] (Seventh Step) This step is a method for producing compound (68) from compound (67) and compound (21). The reaction conditions are the same as those in the tenth step of Starting Material Synthesis 1.

[0152] (Step 8) This step is a method of producing compound (69) by subjecting compound (68) to a deprotection reaction. The reaction conditions are the same as those in the step described in Production Method 2.

[0153] (Raw material synthesis 9) (In the formula, LG CB indicates a leaving group, and PG CB is L 2 The protecting group for NH contained therein is shown.)

[0154] This production method is carried out by using -L 2 - is a divalent saturated heterocyclic group containing two nitrogen atoms which may be substituted, and -L 35 The compound (2-1) is produced by the method of claim 1, wherein - is -CH2-.

[0155] (Step 1) This step is a method for producing compound (72) by Suzuki-Miyaura coupling reaction between compound (70) and compound (71). The reaction conditions are the same as those in the fifth step of Starting Material Synthesis 1.

[0156] (Step 2) This step is a method for producing an aldehyde compound (73) from compound (72). In this reaction, compound (72) is reacted with osmium tetroxide in a reaction-inert solvent in the presence of an organic base at room temperature or under cooling to obtain the corresponding 1,2-diol compound. Then, a periodic acid is added to the reaction mixture to oxidize the 1,2-diol to obtain the aldehyde compound (73). Examples of solvents used in this step include alcohols such as tBuOH, ethers such as THF, DOX, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetone, and mixtures of these with water. Examples of organic bases used in this step include pyridine and 2,6-lutidine. Examples of periodic acids used in this step include sodium periodate and periodic acid.

[0157] (Third Step) This step is a method for producing compound (75) by reductive amination using compound (73) and compound (74), which is an amine compound. The reaction conditions are the same as those of the third step of Raw Material Synthesis 4 -R Z is the same as in the case of -CHO.

[0158] (Step 4) This step is a reaction in which compound (75) is subjected to a deprotection reaction to obtain compound (2-1). The reaction conditions are the same as in Production Method 2.

[0159] The pharmacological activity of the compound of formula (I) was confirmed by the following tests.

[0160] Test Example 1: Evaluation of RAS G12V degradation activity in human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902 The RAS G12V degradation activity of the test compound was evaluated by measuring the RAS G12V expression level by cell ELISA. PA-TU-8902 cells (DSMZ, ACC 179) were cultured at 1.5 x 10 per well.4Cells were seeded in 36 μL aliquots into 384-well plates (Greiner Bio-One). Cell culture conditions were DMEM medium (Sigma-Aldrich) containing 10% fetal bovine serum (Cytiva) at 37°C in the presence of 5% CO2. The following day, test compounds (10 concentrations ranging from 3 μM to 0.1 nM), the compound of Example No. 7 (3 μM final concentration) as a positive control, and dimethyl sulfoxide (DMSO), the solvent for the test compounds, were diluted 100-fold with fresh medium and added in 4 μL aliquots to each well. The cells were then cultured for 24 hours. The following day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (FUJIFILM Wako) was added to each well. The cells were then fixed by leaving the wells at room temperature for 30 minutes. The supernatant was then removed, and 20 μL of phosphate-buffered saline (PBS) containing 0.1% Triton X-100 (Amersham Biosciences) was added to each well. After 10 minutes at room temperature, the supernatant was removed, and 25 μL of PBS was added to each well. Each well was washed twice by removing the supernatant. Subsequent washing procedures were performed in the same manner. Next, the supernatant was removed, and 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; ThermoFisher Scientific) was added to each well. After 10 minutes at room temperature, the plate was centrifuged to remove the supernatant. After washing with PBS, the supernatant was removed by centrifugation, and 20 μL of blocking solution (PVDF Blocking Reagent for Can Get Signal [TOYOBO]) was added to each well. After allowing the plate to stand at room temperature for 30 minutes, the supernatant was removed by centrifugation, and 15 μL of a solution containing anti-Ras (G12V Mutant Specific) antibody (Ras (G12V Mutant Specific) (D2H12) Rabbit mAb; Cell Signaling Technology; 1:500 dilution) and anti-β-Actin antibody (Anti-β Actin antibody; Abcam; 1:5,000 dilution) diluted with Can Get Signal Solution 2 (TOYOBO) was added to each well as primary antibodies and the plate was allowed to stand overnight at 4°C.The next day, the supernatant was removed by centrifugation and the plates were washed with PBS. The supernatant was then removed by centrifugation, and 15 μL of a solution of anti-rabbit IgG antibody (IRDye 800CW Goat anti-Rabbit IgG; LI-COR Biosciences) and anti-mouse IgG antibody (IRDye 680RD Donkey anti-Mouse IgG; LI-COR Biosciences) diluted 1:1,000 in Can Get Signal Solution 2 was added to each well. After incubating at room temperature for 1 hour, the supernatant was removed by centrifugation and the plates were washed with PBS. After removing the supernatant, the plates were air-dried at room temperature for at least 2 hours, and the fluorescence signals at 700 nm and 800 nm were measured using an Aerius (LI-COR Biosciences). The RAS G12V signal value corrected by the β-Actin signal value when DMSO was added was set to 0%, and the RAS G12V signal value when the compound of Example No. 7 was added at a final concentration of 3 μM was set to 100%, and the degradation rate of RAS G12V was calculated by taking the degradation rate at the compound concentration that showed the highest degradation effect as Dmax, and the 50% degradation value of RAS G12V (DC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) are shown in the table below.

[0161]

[0162] Test Example 2: Evaluation of ERK phosphorylation inhibitory effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902. The inhibitory effect of test compounds on ERK phosphorylation was evaluated by measuring the phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is downstream of the KRAS signal, using Cell ELISA. PA-TU-8902 cells were cultured at 5.0 x 10 per well. 3Cells were seeded into a 384-well plate at 36 μL per well. Cell culture was performed under the same conditions as in Test Example 1. The next day, the test compound (9 points with final concentrations ranging from 3 μM to 0.3 nM), trametinib (MEK inhibitor) at a final concentration of 300 nM as a positive control, and DMSO (the solvent for the test compound) as a negative control were diluted 100-fold with fresh medium and added at 4 μL per well. Culture was then continued for 24 hours. Immediately after culture, 30 μL of 30% glyoxal solution (40% glyoxal [Nacalai Tesque, Inc.] diluted with PBS) was added to each well and allowed to stand at room temperature for 1 hour and 30 minutes to fix the cells. The plate was then centrifuged (110 × g, 7 seconds; centrifugation was performed under the same conditions below unless otherwise noted) to remove the supernatant, and 20 μL of PBS containing 0.1% Triton X-100 was added to each well. After incubating at room temperature for 10 minutes, the supernatant was removed by centrifugation and the same procedure was repeated. Next, 20 μL of 0.5% SDS-containing PBS was added to each well, and the plate was incubated at room temperature for 30 minutes. The supernatant was then removed by centrifugation. 20 μL of blocking solution (Intercept Blocking Buffer) was then added to each well and the plate was incubated at room temperature for 1 hour. The supernatant was then removed by centrifugation, and 15 μL of a primary antibody, a phosphorylated ERK (Thr202 / Tyr204) antibody (Phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology) diluted 2,500-fold in blocking solution, was added to each well, and the plate was incubated overnight at 4°C. The next day, the plate was centrifuged to remove the supernatant, and 50 μL of PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 diluted 20 times with ion-exchanged water) was added to each well. The supernatant was then removed by centrifugation to wash each well. This was repeated three times. After washing, 15 μL of anti-rabbit antibody diluted 1:1,000 in blocking solution was added to each well as the secondary antibody, and the plate was left to stand at room temperature for 1 hour. The supernatant was then removed by centrifugation, 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 the third wash, centrifugation was performed at 171 x g for 17 seconds. 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 defined as 0% inhibition, and the signal value when 300 nM trametinib was added was defined as 100% inhibition, with the 50% inhibition value (IC). 50 ) is calculated using Sigmoid-Emax model nonlinear regression analysis.

[0163] Test Example 3: Evaluation of the Anchorage-Independent Cell Growth Inhibitory Effect on Human KRAS G12V Mutation-Positive Pancreatic Cancer Line PA-TU-8902 The anchorage-independent cell growth inhibitory effect of the test compound was evaluated using 3D spheroid culture. PA-TU-8902 cells were cultured at 5x10 per well. 2 Cells were seeded into a low-cell-adsorption U-bottom 384-well plate (Prime Surface, Sumitomo Bakelite Co., Ltd.) at 36 μL / well. Cell culture was performed under the same conditions as in Test Example 1. The next day, test compounds (8 to 10 concentrations ranging from 3 μM to 0.1 nM in final concentrations) and DMSO, the solvent for the test compounds, were diluted 100-fold with fresh medium and added at 4 μL per well. After culturing for 6 days at 37°C in the presence of 5% CO2, 20 μL of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring for 1 hour at room temperature using a plate mixer (FINEPCR), luminescence signals were measured using an ARVO X3 (PerkinElmer). Signal values ​​in DMSO treatment were defined as 0% inhibition, and signal values ​​in medium alone without cells were defined as 100% inhibition, with 50% inhibition (IC 50 ) was calculated using Sigmoid-Emax model nonlinear regression analysis. The results for several test compounds of formula (I) are shown in the table below. For Example No. 17, the inhibition rate at 30 nM was calculated. Note that 50% inhibition @ 30 nM indicates that the test compound has 50% inhibitory activity at a concentration of 30 nM.

[0164]

[0165] Test Example 4: Evaluation of anchorage-independent cell growth inhibitory effect on human KRAS G12V mutation-positive lung adenocarcinoma line LCLC-97TM1. The anchorage-independent cell growth inhibitory effect of the test compound was evaluated using 3D spheroid culture. LCLC-97TM1 cells (DSMZ, ACC 388) were cultured at 7.5 x 10 per well. ２ Cells were seeded at 36 μL per well into a low-cell-binding U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite Co., Ltd.). Cell culture conditions were RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS) at 37°C in the presence of 5% CO2. The following day, test compounds (9 concentrations ranging from 10 μM to 0.1 nM) and DMSO (the solvent for the test compounds) were diluted 100-fold with fresh medium and added at 4 μL per well. After incubation at 37°C in the presence of 5% CO2 for 6 days, 20 μL of CellTiter-Glo 2.0 (Promega) was added to each well. After mixing 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 defined as 100% viability, and the signal value in the absence of cells and medium alone was defined as 0% viability, and the 50% viability value (IC50) was calculated using Sigmoid-Emax model nonlinear regression analysis.

[0166] Test Example 5: Evaluation of antitumor activity in mice bearing the human KRAS G12V mutation-positive pancreatic cancer strain PA-TU-8902. PA-TU-8902 cells were cultured under the same conditions as in Test Example 1. PA-TU-8902 cells were harvested and suspended in PBS, and two equivalent volumes of VitroGel Hydrogel Matrix (TheWell Bioscience) were added to form 1.0-3.0x10 cells. 7A cell suspension prepared at 100 μL / mL was implanted subcutaneously into 4-6 week-old male nude mice (BALB / c-nu (nu / nu), Charles River Japan). Approximately two weeks after implantation, the mice were divided into groups so that tumor volume and body weight were approximately equal, and test compound administration began the following day. The test was conducted with five mice in each of the vehicle and test compound groups. The compounds were dissolved in a solvent containing ethanol (FUJIFILM Wako), 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 dissolved test compound or the solvent was administered intravenously into the tail vein. The administration is once or twice a week for a maximum of 3 weeks. The tumor diameter and body weight are measured twice a week. The tumor volume is calculated using the following formula: [tumor volume (mm 3 )] = [Tumor long diameter (mm)] x [Tumor short diameter (mm)] 2 The tumor growth inhibition rate (%) by the test compound is 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 on the final measurement day as 0% inhibition. In addition, if 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 is set as 0% regression, and a tumor volume of 0 is set as 100% regression, and the tumor regression rate (%) of the test compound is calculated.

[0167] Test Example 6: Evaluation of antitumor activity in mice bearing the human G12V mutant KRAS-positive lung adenocarcinoma line LCLC-97TM1 Cell culture was performed under the same conditions as in Test Example 4. LCLC-97TM1 cells were collected and suspended in PBS, and a 2-fold volume of VitroGel Hydrogel Matrix (The Well Bioscience) was added. ６Cell suspensions prepared at 100 μL per cell were implanted subcutaneously into 4-6 week-old male nude mice (BALB / c-nu (nu / nu), Charles River Japan). Approximately 2-3 weeks after implantation, the mice were divided into groups so that tumor volumes were approximately equal between groups, and administration of the test compound began. The test was conducted with 5 mice in each of the vehicle group and test compound administration group. The vehicle was administered intravenously to the vehicle group, and the test compound dissolved in the vehicle was administered intravenously to the test compound administration group. The same vehicle as in Test Example 5 was used. Administration was once a week, for a total of two times. Tumor diameter and body weight were measured twice a week. The following formula was used to calculate tumor volume. [Tumor volume (mm3)] = [tumor long diameter (mm)] x [tumor short diameter (mm)]2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated by setting the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition and the tumor volume of the vehicle group on the final measurement day as 0% inhibition. In addition, when the tumor volume of the test compound administration group was 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.

[0168] As a result of the above test, some compounds of formula (I) were confirmed to have the effect of inducing the degradation of G12V mutant KRAS. In addition, some compounds of formula (I) were confirmed to have a cell growth inhibitory effect on human G12V mutant KRAS-positive pancreatic cancer and / or lung cancer lines. In addition, some compounds of formula (I) were confirmed to have an antitumor effect in tumor-bearing mice with human G12V mutant KRAS-positive lung cancer lines. Therefore, the compounds of formula (I) can be used for the treatment of pancreatic cancer and / or lung cancer, particularly KRAS G12V mutation-positive pancreatic cancer and / or lung cancer.

[0169] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as an active ingredient can be prepared by a commonly used method 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 intraarticular, intravenous, or intramuscular injections, transmucosal agents, inhalants, etc.

[0170] Solid compositions for oral administration include tablets, powders, granules, and the like. 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, as needed. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contain commonly used inert diluents, such as purified water or EtOH. In addition to the inert diluent, the liquid compositions may contain auxiliary agents such as solubilizers, wetting agents, and suspending agents, as well as sweeteners, flavors, fragrances, and preservatives.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] The compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is 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.

[0176] The production method of the compound of formula (I) will be explained in more detail below based on examples. Note that the present invention is not limited to the compounds described in the following examples. In addition, the production methods of the starting compounds are shown in the respective production examples. In addition, the production method of the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can also be produced by a combination of these production methods or by methods obvious to those skilled in the art.

[0177] In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0178] 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.

[0179] Preparation Example 1: 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (30.9 g) was suspended in THF (310 mL), and sodium hydroxide (1 M aqueous solution, 147 mL) was added dropwise under ice cooling so that the internal temperature was below 12°C, followed by stirring for 2 hours under ice cooling. The reaction solution was poured into an Erlenmeyer flask containing hydrogen chloride (1 M aqueous solution, 147 mL) and water (700 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was collected by filtration while washing with water, and dried under reduced pressure at 40°C overnight to obtain 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (24.6 g) as a solid.

[0180] Preparation 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 atmosphere, 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes and stirred at the same temperature for 2.5 hours. The mixture was allowed to cool to room temperature, and the insoluble material was filtered off while washing with THF (500 mL). The filtrate was concentrated, and the resulting solid was added to MeOH (210 mL), stirred at room temperature for 1 hour, and suspended and washed. The insoluble material was collected by filtration using MeOH (100 mL), yielding 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[0181] Preparation Example 3: To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (29 g) in dichloromethane (300 mL), ethanethiol (5 mL) and DABCO (11 g) were added at room temperature, and the mixture was stirred overnight at room temperature under an argon atmosphere. Water was added under ice cooling to quench the reaction. Chloroform was added, and the organic and aqueous layers were separated by liquid separation. The aqueous layer was extracted three times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (32 g) as a solid.

[0182] Preparation Example 4: To a solution of 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (32 g) and (1S)-1-phenylethan-1-ol (11 mL) in THF (400 mL), tBuOK (10 g) was added under ice-cooling, and the mixture was stirred under an argon atmosphere for 1 hour under ice-cooling. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution under ice-cooling. Water and ethyl acetate were added, and the organic and aqueous layers were separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g) as an oil.

[0183] Preparation Example 5: 7-Bromo-4-tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g), cyclopropylboronic acid (7.5 g), PdCl(dppf)-CHCl (7.6 g), potassium phosphate tripotassium (53 g), MeCN (440 mL), and water (80 mL) were mixed at room temperature and stirred at 90°C for 4 hours under an argon atmosphere. The reaction mixture was returned to room temperature and then diluted with ethyl acetate and water. The organic and aqueous layers were separated, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (22.9 g) as an oil.

[0184] Production Example 6 To 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (14.21 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (19.3 g), palladium(II) acetate (0.67 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (2.67 g), anhydrous barium hydroxide (14.6 g), DOX (500 mL), and water (100 mL) were added. The mixture was degassed and purged with argon gas several times, and then heated and stirred overnight at 50°C under an argon atmosphere. The cooled reaction suspension was filtered through Celite® while washing with ethyl acetate, and gray insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to approximately ¼, water 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. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (a diastereomeric mixture of approximately 3.3:1 due to axial asymmetry, 16.44 g) as a solid.

[0185] Preparation Example 7: 4-tert-Butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (a diastereomeric mixture of approximately 3.7:1 due to axial chirality, 22.6 g) was dissolved in dichloromethane (300 mL), and m-chloroperbenzoic acid (approximately 30% water, 15 g) was added under ice-cooling (internal temperature: 5-10 °C). The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. To the reaction mixture, an aqueous solution (300 mL) of sodium thiosulfate pentahydrate (14 g) and saturated aqueous sodium bicarbonate (300 mL) were poured under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The mixture was then extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. To the resulting residue, iPrOH (600 mL) was added and stirred overnight at room temperature. The resulting insoluble matter was collected by filtration, washed with iPrOH, and dried under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (a diastereomeric mixture of approximately 1:1 due to axial chirality, 9.5 g, Preparation 7-2) as a solid. The filtrate was concentrated to give 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (a single diastereomer of undetermined axial configuration, 15.5 g, Preparation 7-1) as a foamy solid.

[0186] Preparation Example 8: To a solution of 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (1386 mg) and (2S)-2-methoxypropan-1-ol (189 μL) in THF (20 mL), tBuOK (254 mg) was added in an ice-MeOH bath and stirred at the same temperature for 30 minutes under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction mixture under ice cooling, and the mixture was extracted twice with ethyl acetate. The combined 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 (hexane / ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinazoline (1.25 g) as an oil.

[0187] Preparation Example 9: To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL), and dichloromethane (1880 mL), 1,1',1''-(chloromethanetriyl)tribenzene (335 g) was added and stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1.5 L), the organic and aqueous layers were separated, and the aqueous layer was extracted three times with dichloromethane (400 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was powdered with petroleum ether (550 mL) (0°C, 2 hours), filtered, and dried under reduced pressure to give 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

[0188] Preparation Example 10: To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL) was added lithium diisopropylamide (2M THF solution, 214.28 mL) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 hours. Methyl iodide (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layer was dried over anhydrous sodium sulfate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate (50 mL) / petroleum ether (50 mL), filtered, and dried under reduced pressure to give 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) as a solid.

[0189] Preparation Example 11: To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL) was added palladium(II) acetate (4.52 g) at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and refilled with nitrogen three times, then stirred at 100°C for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layer was dried over anhydrous sodium sulfate, and insoluble material was removed by filtration. Activated carbon (50 g) was added to the resulting solution, which was stirred at 20°C for 1 hour and then filtered while washing with ethyl acetate (50 mL) three times. The filtrate was concentrated under reduced pressure, and the resulting residue was powdered with MeOH (200 mL), filtered, and dried under reduced pressure to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0190] Preparation Example 12: To a solution of 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinazoline (1.25 g) in MeOH (15 mL) and THF (15 mL) was added sodium bicarbonate (1.62 g) and 10% Pd / C (approximately 50% water content, 609 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 3 hours. 10% Pd / C (approximately 50% water content, 304 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 3 hours. The mixture was filtered through Celite® using chloroform / iPrOH (4 / 1) and EtOH / water (10 / 1), and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-ol (923 mg) as a solid.

[0191] Preparation Example 13: To a solution of 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-ol (1115 mg) in DMF (10 mL), DIPEA (1036 μL), tert-butyl 4-(chloromethyl)benzoate (515 mg), and cesium carbonate (2220 mg) were added in this order at room temperature, and the mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 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 (1347 mg) as a solid.

[0192] Preparation Example 14: To a solution of tert-butyl 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 (1347 mg) in THF (20 mL) were added 4-methylbenzene-1-sulfonic acid monohydrate (216 mg) and 3,4-dihydro-2H-pyran (1.08 mL) at room temperature, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 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 (966 mg) as a solid.

[0193] Preparation Example 17: To a solution of methyl 4-[({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 (100 mg) in THF (1 mL) and MeCN (1 mL) was added sodium hydroxide (1 M aqueous solution, 1000 μL) at room temperature, and the mixture was stirred at 50° C. for 5 hours. Hydrogen chloride (1M aqueous solution, 1000 μL) and water were added, and the mixture was extracted with chloroform / iPrOH (4 / 1). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-[({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]benzoic acid (111 mg) as an oil.

[0194] Preparation Example 20: To a solution of N,N-dimethylethylenediamine (6 mL) in THF (50 mL), CDI (8.9 g) was added under ice-cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and iPrOH (50 mL) and azetidin-3-ol hydrochloride (5 g) were added to the residue at room temperature, and the mixture was stirred at 80°C under an argon atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH / 28% aqueous ammonia) to give N-[2-(dimethylamino)ethyl]-3-hydroxyazetidine-1-carboxamide (9.67 g) as an oil.

[0195] Preparation Example 21: To a solution of tert-butyl 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 (2 mL), PyBOP (180 mg) and cesium carbonate (120 mg) were added at room temperature, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. A solution of azetidine-3-carbonitrile mono(trifluoroacetate) salt (150 mg) in THF (2 mL), DIPEA (0.5 mL), and cesium carbonate (140 mg) were added at room temperature, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Ethyl acetate was added to the reaction mixture, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 4-[({(7M)-4-(3-cyanoazetidin-1-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]benzoate (73.1 mg) as a solid.

[0196] Preparation Example 22: To a mixture of tert-butyl 4-[({(7M)-4-(3-cyanoazetidin-1-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]benzoate (72 mg) and dichloromethane (2 mL), TFA (0.4 mL) was added at room temperature and stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and chloroform and saturated aqueous sodium bicarbonate were added to the residue. The mixture was extracted with chloroform / iPrOH (4 / 1). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-[({(7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (67.1 mg) as a solid.

[0197] Preparation Example 29: To a solution of tert-butyl 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 (50 mg) in THF (5 mL) were added PyBOP (80 mg) and cesium carbonate (50 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (S)-Azetidine-2-carboxamide (45 mg) and cesium carbonate (68 mg) were added at room temperature, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH) to give tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-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]benzoate (80 mg) as an oil.

[0198] Preparation Example 30: To a solution of tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-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]benzoate (80 mg) in dichloromethane (5 mL) was added TFA (1 mL) at room temperature, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to give 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (45 mg) as a solid.

[0199] Preparation Example 38: Tert-butyl 4-[({4-tert-butoxy-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (320 mg) was dissolved in THF (6.2 mL), and 4-methylbenzene-1-sulfonic acid monohydrate (66 mg) was added at room temperature, followed by stirring overnight at room temperature under an argon atmosphere. At room temperature, saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[({6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-hydroxyquinazolin-8-yl}oxy)methyl]benzoate (222 mg) as an oil.

[0200] Preparation Example 40: To a mixture of tert-butyl 4-[({4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl}oxy)methyl]benzoate (245 mg) and dichloromethane (5 mL), TFA (1.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and saturated aqueous sodium bicarbonate was added to the fraction containing the less polar peak. The mixture was extracted twice with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)benzoic acid (single diastereomer, 36 mg) as a solid.

[0201] Preparation Example 43: tert-Butyl 4-({[6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-hydroxy-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl]oxy}methyl)benzoate (147 mg) was dissolved in THF (6 mL), and cesium carbonate (130 mg) and PyBOP (210 mg) were added at room temperature, followed by stirring at room temperature for 1 hour under a nitrogen atmosphere. (S)-Azetidine-2-carboxamide (67 mg) and cesium carbonate (220 mg) were added, followed by stirring at room temperature for 1 hour under a nitrogen atmosphere. Water and chloroform were added to the reaction mixture, which was then extracted three times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and the fractions containing the less polar peak were collected and concentrated. The residue was dissolved in MeCN / water, saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with chloroform / iPrOH (9 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}quinazolin-8-yl]oxy}methyl)benzoate (single diastereomer, 66 mg) as a solid.

[0202] Preparation Example 51: Acetic acid (60 μL) was added to a mixture of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbaldehyde (286 mg), (S)-1-(tert-butoxycarbonyl)-2-methylpiperazine (405 mg), dichloromethane (2.5 mL), and N-methyl-2-pyrrolidone (5 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (424 mg) was added, and the mixture was stirred at room temperature for 16 hours. Water and saturated aqueous sodium bicarbonate were added, and the mixture was stirred for a while. The mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / 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 (470 mg) as a foamy solid.

[0203] Preparation Example 52: Hydrogen chloride (4 M DOX solution, 8 mL) was added 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 (490 mg) and dichloromethane (10 mL), and the mixture was stirred overnight at room temperature under an argon atmosphere. Isopropyl ether was added to the mixture, and the insoluble matter was collected by filtration 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 hydrochloride (450 mg) as a solid.

[0204] Preparation Example 53: 1-(6-Bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (4143 mg), potassium vinyltrifluoroborate (6869 mg), PdCl(dppf)·CHCl (1047 mg), and cesium carbonate (8355 mg) were suspended in DOX (90 mL) and water (21 mL) and stirred at 80°C for 3 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and water was added. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH) to give 1-(6-ethenyl-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (3565 mg) as a solid.

[0205] Preparation Example 54: 1-(6-ethenyl-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (1590 mg) was dissolved in DOX (200 mL) and water (30 mL), and osmium(VIII) tetroxide (2.5 wt% tBuOH solution, 18.3 g) and 2,6-lutidine (1369 μL) were added. Sodium periodate (5023 mg) was gradually added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous solution of sodium thiosulfate pentahydrate (30 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water and saturated aqueous ammonium chloride were added, and the mixture was extracted five times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH). The obtained solid was filtered using hexane / ethyl acetate (2 / 1) to give 3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbaldehyde (1344 mg) as a solid.

[0206] Preparation Example 62: To a mixture of tert-butyl 6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (68 mg) and dichloromethane (1 mL), TFA (1 mL) was added in an ice bath and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH) to give 1-{6-[(2,6-diazaspiro[3.3]heptan-2-yl)methyl]-1-methyl-1H-indazol-3-yl}-1,3-diazinan-2,4-dione (68 mg) as a foamy solid.

[0207] Preparation Example 65: To a suspension of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30 g) in N-methyl-2-pyrrolidone (60 mL) at room temperature, trimethyl orthoacetate (32 mL) was added and stirred overnight at 110°C under an argon atmosphere. The reaction mixture was returned to room temperature, and MeOH was added to form a suspension. Insoluble matter was collected by filtration and dried overnight under reduced pressure at 50°C to obtain methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) as a solid.

[0208] Preparation Example 66: Under an argon atmosphere and ice cooling, lithium bis(trimethylsilyl)amide (1M THF solution, 160 mL) was added to a suspension of methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) in THF (250 mL) using a dropping funnel over 20 minutes. The mixture was then stirred at 40°C for 1 hour under an argon atmosphere. Under ice cooling, water was added to terminate the reaction, and the mixture was diluted with ethyl acetate and water. The organic and aqueous layers were separated by liquid separation, and the organic layer was extracted twice with water. Hydrogen chloride (1M aqueous solution, 200 mL) was slowly added to the combined aqueous layer under ice cooling, resulting in the precipitation of a solid. The insoluble matter was collected by filtration, washed with water and MeOH, and dried overnight under reduced pressure at 50°C to obtain 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (17.7 g) as a solid.

[0209] Preparation Example 67: Under a nitrogen atmosphere, DIPEA (30 mL) was added dropwise over 5 minutes to a suspension of 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (21.24 g) in phosphoryl chloride (95.2 mL) under ice cooling, and the mixture was stirred at 110°C for 2 hours. The reaction mixture was allowed to cool to room temperature, and MeCN (100 mL) was added and the mixture was stirred for 30 minutes under ice cooling. The insoluble matter was collected by filtration using MeCN (100 mL). The resulting solid was suspended in MeCN (50 mL) and ice water (200 mL) and stirred for 30 minutes. The insoluble matter was collected by filtration using water / MeCN (5 / 1, 250 mL) to give 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (18.95 g) as a solid.

[0210] Production Example 68: Under an argon atmosphere, DABCO (1.3 g) was added to a suspension of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (4.4 g) in N-methyl-2-pyrrolidone (45 mL), and the mixture was stirred at 40°C for 2 hours. Ethanethiol (850 μL) was added and the mixture was stirred at 60°C for 4 hours. After cooling to room temperature, water (200 mL) was added and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was collected by filtration and dried under reduced pressure to obtain 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (4.33 g) as a solid.

[0211] Preparation Example 70: 1-(tert-Butoxycarbonyl)-3-hydroxyazetidine (1 g) was dissolved in DMAc (10 mL), tBuOK (600 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 10 minutes to prepare an alkoxide. 7-Bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (2.12 g) was dissolved in DMAc (10 mL), and the prepared alkoxide solution was added dropwise in an ice-salt bath under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Insoluble matter was filtered off, and the resulting solid was purified by silica gel column chromatography (hexane / chloroform / MeOH) to give tert-butyl 3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (2.48 g) as a foamy solid.

[0212] Preparation Example 73: MeOH (120 mL) was added to tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (a diastereomeric mixture of approximately 3.5:1 due to axial chirality, 5.98 g), and the mixture was stirred at 50° C. for 1 hour and then at room temperature overnight. The insoluble matter, 3- ({6-cyclopropyl-2- (ethylsulfanyl) -7- [6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl] -8- [(1S) -1-phenylethoxy] quinolin-4-yl} oxy) azetidine-1-carboxylic acid tert- butyl (approximately 1: 1 diastereomeric mixture due to axial asymmetry, 1.82 g) was filtered off while washing with MeOH, and the filtrate was concentrated under reduced pressure to obtain the desired 3- ({(7M) -6-cyclopropyl-2- (ethylsulfanyl) -7- [6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl] -8- [(1S) -1-phenylethoxy] quinolin-4-yl} oxy) azetidine-1-carboxylic acid tert- butyl (single diastereomer, 3.43 g) as a foamy solid.

[0213] Preparation Example 74: tert-Butyl 3-({(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (950 mg) was dissolved in dichloromethane (25 mL), and m-chloroperbenzoic acid (about 30% water content, 600 mg) was added under ice-cooling, followed by stirring at the same temperature for 2 hours. Aqueous sodium thiosulfate solution was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted twice with chloroform, and the combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (chloroform / MeOH) to give tert-butyl 3-({(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (752 mg) as a foamy solid.

[0214] Preparation Example 79: To a solution of N,N-dimethylethylenediamine (90 μL) in THF (3 mL) was added CDI (130 mg) under ice cooling, and the mixture was stirred under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure, and a solution of methyl 4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoate (100 mg) in iPrOH (3 mL) was added, and the mixture was stirred under a nitrogen atmosphere at 90° C. for 30 minutes. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH) to give methyl 4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoate (89 mg) as a foamy solid.

[0215] Preparation Example 88: To a solution of tert-butyl (3S)-4-{[4-(hydroxymethyl)phenyl]methyl}-3-methylpiperazine-1-carboxylate (1730 mg) in dichloromethane (20 mL), DIPEA (2 mL) and methanesulfonyl chloride (650 μL) were added under ice-cooling. The mixture was stirred under a nitrogen atmosphere for 1 hour under ice-cooling and then overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-4-{[4-(chloromethyl)phenyl]methyl}-3-methylpiperazine-1-carboxylate (1550 mg) as a solid.

[0216] Preparation Example 89: To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (5 g) in DMF (25 mL) and THF (25 mL), 4-hydroxytetrahydropyran (1.45 mL), DABCO (120 mg), and cesium carbonate (7 g) were added at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere at room temperature. The reaction mixture was diluted with ethyl acetate, and insoluble matter was filtered off through Celite®. A saturated aqueous solution of ammonium chloride was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to give 7-bromo-4-tert-butoxy-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazoline (3.9 g) as a solid.

[0217] Preparation Example 97: To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (330 mg) in dichloromethane (10 mL), TFA (2 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was then concentrated under reduced pressure to prepare the amine. In a separate flask, TEA (120 μL) and PyAOP (440 mg) were added to a solution of tert-butyl 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoate (300 mg) in MeCN (10 mL) at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting amine and TEA (1.1 mL) in MeCN (5 mL) were added at room temperature, and the mixture was stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl 4-[({(7M)-4-(3-cyanoazetidin-1-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]benzoate (222 mg) as a solid.

[0218] Preparation Example 99: To a solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (5 g) and tert-butyl(3-iodophenoxy)di(methyl)silane (7.85 g) in 1,4-dioxane (200 mL), copper(I) iodide (4.07 g), N,N'-dimethylethylenediamine (4.59 mL), and tripotassium phosphate (13.59 g) were added under a nitrogen atmosphere, and the mixture was stirred at 120°C for 16 hours. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give 1-(3-{[tert-butyldi(methyl)silyl]oxy}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (8 g) as an oil.

[0219] Preparation Example 100: To a solution of 1-(3-{[tert-butyldi(methyl)silyl]oxy}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (8.9 g) in THF (90 mL) was added TBAF (1 M THF solution, 30.3 mL). The mixture was purged with nitrogen gas three times and stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed four times with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was suspended and stirred in ethyl acetate (30 mL). Insoluble matter was collected by filtration and dried under reduced pressure. The resulting solid was suspended in MeCN / water (2 / 1, 200 mL) and lyophilized to give 1-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (6.2 g) as a solid.

[0220] Preparation Example 101: To a solution of 1-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (1 g) in DMF (10 mL) was added potassium iodide (560 mg) and potassium carbonate (635 mg) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 115°C, and 2-bromo-1,1-dimethoxyethane (468 μL) was added. The mixture was stirred at the same temperature for 18 hours. The reaction mixture was filtered using MeCN, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (MeCN / 0.05% TFA aqueous solution) to give 1-[3-(2,2-dimethoxyethoxy)phenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (940 mg) as a solid.

[0221] Preparation Example 102: To a solution of 1-[3-(2,2-dimethoxyethoxy)phenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (920 mg) in acetone (9.2 mL) was added hydrogen chloride (2 M aqueous solution, 5.55 mL), and the mixture was stirred for 5 hours at 50° C. The reaction mixture was concentrated under reduced pressure and lyophilized to give (3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}phenoxy)acetaldehyde (889 mg) as a solid.

[0222] Preparation Example 104 A mixture of tert-butyl 9-[2-(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}phenoxy)ethyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (180 mg) and trifluoromethanesulfonic acid (180 μL) was purged with nitrogen gas three times and stirred under a nitrogen atmosphere at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was combined with the crude product of a similar reaction (using 270 mg of starting material), dissolved in MeCN (5 mL), and purified by reverse-phase chromatography (MeCN / 0.05% TFA aqueous solution) to give 1-{3-[2-(3,9-diazaspiro[5.5]undecan-3-yl)ethoxy]phenyl}-1,3-diazinan-2,4-dione n-(trifluoromethanesulfonic acid) salt (350 mg) as a solid.

[0223] The compounds shown in the table below were produced in the same manner as in the production examples shown above. The production method, structure and physicochemical data of each compound in the production examples are also shown in the table below.

[0224] Example 2: HATU (38 mg) was added to a mixture of 4-[({(7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (57 mg), 3-(3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione hydrochloride (40 mg), DIPEA (100 μL), and DMF (2 mL), and the mixture was stirred overnight at room temperature. Ethyl acetate, water, and saturated aqueous sodium chloride were added, followed by extraction with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). A saturated aqueous solution of sodium bicarbonate was added to the target fraction, and the mixture was extracted twice with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to obtain 1-{(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-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-3-carbonitrile (44 mg) as a solid.

[0225] Example 3 TFA (0.4 mL) was added to a mixture of tert-butyl [(3S,4R)-1-{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}-3-fluoropiperidin-4-yl]carbamate (58 mg) and dichloromethane (1.2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). A saturated aqueous solution of sodium bicarbonate was added to the target fraction, and the mixture was extracted twice with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with hexane and dried under reduced pressure to give 3-(5-{[(3S)-4-{4-[({4-[(3S,4R)-4-amino-3-fluoropiperidin-1-yl]-6-cyclopropyl-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 (29.1 mg) as a solid.

[0226] Example 5: HATU (39 mg) was added to a mixture of 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (45 mg), 1-(1-methyl-6-{[(3S)-3-methylpiperazin-1-yl]methyl}-1H-indazol-3-yl)-1,3-diazinan-2,4-dione hydrochloride (34 mg), DIPEA (82 μL), and DMF (3 mL), and the mixture was stirred overnight at room temperature. Ethyl acetate, water, and saturated aqueous sodium chloride solution were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). A saturated aqueous solution of sodium bicarbonate was added to the target fraction, and the mixture was extracted three times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in MeCN / water and lyophilized to give (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2-methylpiperazine-1-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-2-carboxamide (20 mg) as a solid.

[0227] Example 20: To a solution of 1-(6-{[4-({4-[({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-3-oxopiperazin-1-yl]methyl}-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (45 mg) in THF (5 mL), PyBOP (63 mg) and cesium carbonate (40 mg) were added at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. (S)-Azetidine-2-carboxamide (25 mg) and DIPEA (90 μL) were added at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / MeOH) to give (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(4-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]methyl}-2-oxopiperazin-1-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}azetidine-2-carboxamide (31 mg) as a solid.

[0228] The example compounds shown in the table below were produced in the same manner as in the above-mentioned examples. The production method and physicochemical data of each example compound are also shown in the table below.

[0229] Furthermore, the following abbreviations may be used in the tables below: PEx: Production Example number, Ex: Example number, PSyn: Production Example number produced by a similar method, Syn: Example number produced by a similar method (for example, Syn 1 indicates that the compound was produced by a similar method to Example 1), Str: Chemical structural formula (a compound with "#" in its chemical structural formula indicates that the compound is a diastereomeric mixture with axial chirality of 3:1 to 5:1. A compound with "##" in its chemical structural formula indicates that the compound has single axial chirality but the stereochemistry is undetermined. A compound with "###" in its chemical structural formula indicates that the compound is a diastereomeric mixture with axial chirality of 3:1 to 5:1 but the stereochemistry is undetermined). n HCl: n hydrochloride (compounds with manufacturing example numbers are monohydrochloride to trihydrochloride), n TfOH: n trifluoromethanesulfonic acid (compounds with manufacturing example numbers are monotrifluoromethanesulfonate to tritrifluoromethanesulfonate), DAT: physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, [M−H] unless otherwise specified) - ), NMR: DMSO-d6 at 27 °C 1 δ value (ppm) of peak in H-NMR (500 MHz), NMR (90 °C): in DMSO-d6 at 90 °C 1 Peak δ values ​​(ppm) in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), ddd: double double doublet (spectrum), t: triplet (spectrum), dt: double triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad line (spectrum).

[0230]

[0231]

[0232]

[0233]

[0234] The compound of the present invention or a salt thereof has an excellent effect of inducing degradation of G12V mutant KRAS protein and is useful as a G12V mutant KRAS inhibitor, and can be used as an active ingredient in pharmaceutical compositions, for example, pharmaceutical compositions for treating pancreatic cancer and / or lung cancer.

Claims

1. Compound of formula (I) or salt thereof 【Chemistry 1】 (In the formula, A is CR A , or N, R A is H or C 1-3 It is alkyl, X 1 is, -CH 2 -, -O-, or -NR X1 -and, R X1 is H or C which may be substituted. 1-3 It is alkyl, or X 1 is -NR X1 - in the case where R X1 and R 4 adjacent to the nitrogen atom are combined with the nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, R 1 is naphthyl which may be substituted with OH, or the following formula (II) or formula (III), 【Chemistry 2】 R 1a , R 1b These are H, methyl, F, or Cl, which are the same or different from each other. R 1c is F, Cl, methyl, or ethyl. R 2 H, halogen, C 1-3 The C is alkyl, cyclopropyl, or vinyl. 1-3 Alkyl groups are OH and OCH 3 The group may be substituted with a group selected from the group consisting of the following: R 3 This is a group selected from the following formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), and (XXVI): 【Transformation 3】 R 3a is, -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , -C 1-3 Alkilen-NR N1 R N2 , and -NR N1 R N2 A 4- to 6-membered saturated heterocyclic group which may be substituted with a group selected from the group consisting of; or C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , C 1-3 Alkilen-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C may be substituted with a group selected from the group consisting of the above. 3-6 It is a cycloalkyl, R 3b is H or C 1-3 It is alkyl, R 3c and R 3d is, -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , -C 1-3 Alkilen-NR N1 R N2 , and -NR N1 R N2 A 4- to 6-membered saturated heterocyclic group which may be substituted with a group selected from the group consisting of; or C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , -C 1-3 Alkilen-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C may be substituted with a group selected from the group consisting of the above. 3-6 It is a cycloalkyl, R 3e is H, F, or C 1-3 It is alkyl, R 3f is H or C 1-3 It is alkyl, R 3g C may be substituted. 3-6 A cycloalkyl group, an optionally substituted five-membered heteroaryl group, an optionally substituted six-membered heteroaryl group, or an optionally substituted four- to six-membered saturated heterocyclic group. R 3h is H, F, or C 1-3 It is alkyl, R 3i is, independently of one another, H, OH, optionally substituted C 1-3 alkyl, -O-optionally substituted C 1-3 alkyl, -NH-optionally substituted C 1-3 alkyl, -N-(optionally substituted C 1-3 alkyl), ２ a group selected from the group consisting of halogen, -CN, and oxo, or Two Rs present on the same carbon atom 3i may form, together with the adjacent carbon atom, a spiro ring having a ring selected from the group consisting of cycloalkane and 4- to 6-membered saturated heterocycles, and the spiro ring 3-6 may be substituted with one or two groups selected from the group consisting of alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or 1-3 ​ R present on two adjacent carbon atoms 3i However, when combined with those two carbon atoms, C 3-6 A condensed ring may be formed having a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterorings, and the condensed ring is C 1-3 Alkyl, -O-(C 1-3 It may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen, and oxo, or R located on two non-adjacent carbon atoms 3i However, the two carbon atoms may be integrated to form a cross-linked structure consisting of 1 to 2 carbon atoms, and the ring having the cross-linked structure is C 1-3 Alkyl, -O-(C 1-3 It may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen, and oxo. R N1 and R N2 are the same or different from each other, H or C 1-3 It is alkyl, or, R N1 and R N2 These may, together with the nitrogen atom to which they are bonded, form a substituted 4- to 6-membered saturated heterocyclic group, or, R 3e and R N1 These may, together with the carbon and nitrogen atoms to which they are bonded, form a substituted 4- to 6-membered saturated heterocyclic group. X 2 -O-, -NH-, or -N(C 1-3 Alkyl)-, X 3 is either O or S, X 4 is, -CH 2 -, -CH 2 -CH 2 - or -O-CH 2 -and, n is either 1 or 2. p is either 1 or 2. q is between 1 and 8. R 4 C 1-6 Alkyl, R 4a piperidinyl or tetrahydropyranyl which may be substituted with C 1-6 Alkyl groups are F, OH, OCH 3、 R 4a Cyclopropyl, N(R 4a ) 2 , R 4a It may be substituted with a group selected from the group consisting of pyrrolidinyl, which may be substituted with, and tetrahydrofuranyl, R 4a C may be substituted. 1-3 It is alkyl, Y is phenylene or pyridinediyl, which may be substituted with F or Cl. L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and, L 1 , L 2 , L 3 , L 4 , L 5 These are identical or different from each other, combined, -O-, -NR L1 - A divalent group of a saturated heterocycle containing one or two optionally substituted nitrogen atoms, optionally substituted C 1-3 A group selected from the group consisting of alkylenes and C=O, R L1 is H or C 1-3 It is alkyl, Z is a group selected from the following equations (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), and (XX): 【Chemistry 4】 Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms. R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2 ,-CONR Z4 2 , or -NR Z4 COR Z5 And, R Z2 is H or C 1-3 It is alkyl, R Z3 is H or C 1-3 It is alkyl, R Z4 These are either the same or different from each other, and are H or C respectively. 1-3 It is alkyl, R Z5 C 1-3 It is alkyl, Furthermore, L is bonded to ring B of formulas (XIII) to (XVIII) above, or to the benzene ring of formulas (XIX) and (XX). m is either 1 or 2. G is either CH or N. However, if G is N, then Z is given by equation (XVII), equation (XVIII), or equation (XIX) above.

2. X 1 -O- or -NR X1 -and, R X1 is H or C which may be substituted. 1-3 It is alkyl, Or, X 1 ga-NR X1 - In this case, R present on the same nitrogen atom X1 and R 4 It may form a substituted 4- to 6-membered saturated heterocyclic group together with the adjacent nitrogen atom. R 1 This is given by the following equation (II): 【Transformation 5】 R 1a is H, methyl, F, or Cl, R 1c is F, Cl, methyl, or ethyl. R 2 It is cyclopropyl or vinyl, R 3 This is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI), and (XII): 【Transformation 6】 R 3a is, -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , -C 1-3 Alkilen-NR N1 R N2 , and -NR N1 R N2 A 4- to 6-membered saturated heterocyclic group which may be substituted with a group selected from the group consisting of; or C 1-3 Alkyl, -C 1-3 Alkilen-OR 3f , C 1-3 Alkilen-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C may be substituted with a group selected from the group consisting of the above. 3-6 It is a cycloalkyl, R 3b is H or C 1-3 It is alkyl, R 3e is H, F, or C 1-3 It is alkyl, R 3f is H or C 1-3 It is alkyl, R 3g C may be substituted. 3-6 A cycloalkyl group, an optionally substituted five-membered heteroaryl group, an optionally substituted six-membered heteroaryl group, or an optionally substituted four- to six-membered saturated heterocyclic group. R 3h is H, F, or C 1-3 It is alkyl, R N1 and R N2 are the same or different from each other, H or C 1-3 It is alkyl, or, R N1 and R N2 These may, together with the nitrogen atom to which they are bonded, form a substituted 4- to 6-membered saturated heterocyclic group, or, R 3e and R N1 These may, together with the carbon and nitrogen atoms to which they are bonded, form a substituted 4- to 6-membered saturated heterocyclic group. X 2 -O-, -NH-, or -N(C 1-3 Alkyl)-, X 3 is either O or S, n is either 1 or 2. p is either 1 or 2. Y is phenylene which may be substituted with F or Cl. Z is a group selected from the group consisting of the following equations (XIII), (XVII), and (XIX): 【Transformation 7】 Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms. R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2 ,-CONR Z4 2 , or -NR Z4 COR Z5 And, R Z2 is H or C 1-3 It is alkyl, R Z4 These are either the same or different from each other, and are H or C respectively. 1-3 It is alkyl, R Z5 C 1-3 It is alkyl, Furthermore, L is bonded to ring B in the above formula (XIII) or (XVII), m is either 1 or 2. G is either CH or N. The compound or salt thereof according to claim 1, wherein if G is N, then Z is formula (XVII) or formula (XIX).

3. A is CR A , or N, R A H is, X 1 It is -O-, R 1 This is given by the following equation (II): 【Transformation 8】 R 1a F is, R 1c It is methyl, R 2 It is cyclopropyl, R 3 This is a group selected from the group consisting of the following formulas (IV), (VII), (VIII), (IX), (X), (XI), and (XII): 【Chemistry 9】 R 3a is, -(CH 2 ) p CHR 3e -NR N1 R N2 And, R 3b is H or C 1-3 It is alkyl, R 3e H is, R 3g is a substituted six-membered heteroaryl, R 3h is either H or F, R N1 and R N2 C is either the same or different from each other. 1-3 It is alkyl, X 2 is -O- or -NH-, X 3 is either O or S, n is 1, p is 1, R 4 OCH 3、 N(C 1-3 Alkyl) 2 and R 4a C may be substituted with a group selected from the group consisting of pyrrolidinyl which may be substituted with 1-6 Alkyl or tetrahydropyranyl, R 4a C may be substituted. 1-3 It is alkyl, Y is phenylene, L is -(L 1 -L 2 -L 3 -L 4 -L 5 )- and L is included in L 1 It is joined to Y, L 1 C 1-3 It is an alkylene or C=O. L 2 This is a divalent group of a saturated heterocycle containing one or two nitrogen atoms, which may be substituted. L 3 C 1-3 It is alkylene, L 4 is a bond, -O- or -N(C 1-3 Alkyl)-, L 5 is a combination or C 1-3 It is alkylene, Z is a group selected from the group consisting of the following equations (XIII), (XVII), and (XIX): 【Chemistry 10】 Ring B is a benzene ring, R Z1 is H or C 1-3 It is alkyl, R Z2 is H or C 1-3 It is alkyl, Furthermore, L is bonded to ring B of formula (XIII) or (XVII) above, or to the benzene ring of formula (XIX). m is either 1 or 2. The compound or salt thereof according to claim 2.

4. R 3 This is a group selected from the group consisting of the following formulas (IV-1), (VII-1), (VIII-1), (IX), (X), (XI), and (XII-1), 【Chemistry 11】 L is given by the following equations (XXVII) through (XXXIV) 【Chemistry 12】 A base selected from the group consisting of, * The carbon atom with the mark attached is bonded to Y, Z is a group selected from the group consisting of the following formulas (XIII-1), (XVII-1), and (XIX-1): 【Chemistry 13】 Furthermore, L is bonded to the benzene rings of formulas (XIII-1) and (XVII-1) above. G is either CH or N. The compound or salt thereof according to claim 3, wherein if G is N, then Z is the above formula (XVII-1) or formula (XIX-1).

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

6. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for the treatment of pancreatic cancer and / or lung cancer.

7. Use of the compound or salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer and / or lung cancer.

8. The compound or salt thereof according to claim 1 for use in the treatment of pancreatic cancer and / or lung cancer.

Images