Heterocyclic compounds for inducing G12V mutant KRAS proteolysis

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and / or lung cancer. The inventors have studied a compound 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 activity of inducing G12V mutant KRAS proteolysis and an excellent G12V mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer and / or lung cancer, thereby completing the present invention. The heterocyclic compound or a salt thereof according to the present invention can be used as a therapeutic agent for pancreatic cancer and / or lung cancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition and a heterocyclic compound that is excellent in the effect of inducing the degradation of G12V mutant KRAS protein and is useful as a G12V mutant KRAS inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and / or lung cancer, for example. Background Art

[0002] Pancreatic cancer, mainly pancreatic ductal adenocarcinoma, is a cancer with a very poor prognosis, with a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, p.7-30). It is reported that there are about 460,000 new cases worldwide each year (CA Cancer J. Clin., 2018, 68, p.394-424). The most effective treatment for pancreatic cancer is surgery, but since it is difficult to detect it early, most cases have already metastasized, and surgical treatment cannot be expected to have a therapeutic effect. If surgery is not performed, chemotherapy and radiotherapy are used, but the survival rate is not ideal. Currently, FOLFIRINOX therapy (multi-drug combination therapy with leucovorin in addition to the three chemotherapy drugs 5-FU, irinotecan, and oxaliplatin) is used as the standard treatment for pancreatic cancer, but due to its strong toxicity, it is only prescribed to patients with an ECOG performance status of 1 or less, and careful patient selection is required (J. Clin. Oncol., 2018, 36, p.2545-2556). Although the combination therapy of epidermal growth factor receptor (EGFR) inhibitor erlotinib and gemcitabine has been approved as a molecular targeted therapy, the overall survival is only extended by about 2 weeks compared with gemcitabine alone, and satisfactory treatment effects are not achieved, and highly effective therapeutic drugs are still needed (J. Clin. Oncol., 2007, 25, p.1960-1966).

[0003] In addition, lung cancer is reported to cause the most deaths, with approximately 2.1 million new deaths worldwide each year (World Cancer Report 2020). In particular, non-small cell lung cancer (NSCLC), which accounts for 80-85% of lung cancer (American Cancer Society, Cancer Facts and Figures, 2022), can be treated with surgery before a certain stage, but after that stage, surgery is not suitable, and chemotherapy and radiotherapy become the mainstay of treatment. Based on cell morphology, adenocarcinoma and squamous cell carcinoma are classified as the most common types of NSCLC. The clinical course of these tumors is the same, but adenocarcinoma is characterized by localization in the periphery of the lungs.

[0004] RAS protein is a low molecular weight guanosine triphosphate (GTP) binding protein of about 21kDa composed of 188-189 amino acids. There are four main proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) produced by three genes, namely KRAS gene, NRAS gene, and HRAS gene. RAS protein exists in the GTP-binding type as an active type and the GDP-binding type as an inactive type. RAS protein is activated by exchanging guanosine diphosphate (GDP) with GTP due to ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to up to 20 effector proteins such as RAF, PI3K, and RALGDS to activate downstream signal cascades. On the other hand, active RAS converts GTP to GDP through endogenous GTP hydrolysis (GTPase) activity, thus becoming inactive. This GTPase activity can be enhanced by GTPase activating protein (GAP). Therefore, RAS plays an important role as a "molecular switch" in intracellular signal transduction pathways such as EGFR, and plays an important role in cell growth, proliferation, angiogenesis, etc. (Nature Rev. Cancer, 2011, 11, p.761-774, Nature Rev. Drug Discov., 2014, 13, p.828-851, Nature Rev. Drug Discov., 2016, 15, p.771-785).

[0005] When amino acid substitution occurs due to mutation of RAS gene, the function of RAS as GTPase decreases and the response to GAP decreases, resulting in a persistent activation state, which continuously transmits signals to the downstream. This excessive signal leads to carcinogenesis and hyperplasia of tumors. Pancreatic ductal adenocarcinoma is said to occur when pancreatic intraepithelial neoplasia (PanIN) undergoes a weak stage of dysplasia to a strong stage, and KRAS gene mutations can be seen in PanIN at the early stage. After that, the tumor suppressor genes INK4A, p53, and SMAD4 become abnormal and become malignant (Nature Rev. Cancer, 2010, 10, p.683-695). Furthermore, mutations can be seen in KRAS gene in more than 90% of pancreatic ductal adenocarcinomas, among which point mutations located in codon 12 of KRAS exon 2 account for the majority (Cancer Cell 2017, 32, p.185-203). In addition, in lung cancer, RAS gene mutations were observed in 32% of lung adenocarcinomas. The mutation frequencies were 96% for KRAS gene, 3% for NRAS gene, and 1% for HRAS gene. It was reported that there were more point mutations in KRAS exon 2 (codon 12, codon 13) (Nature Rev. Drug Discov., 2014, 13, p.828-851). Therefore, KRAS plays an important role in the carcinogenesis and progression of pancreatic cancer and lung adenocarcinoma.

[0006] As KRAS gene mutations, in particular, the KRAS G12V mutation in which glycine at codon 12 is substituted with valine, the KRAS G12D mutation in which glycine is substituted with aspartic acid, and the KRAS G12C mutation in which glycine is substituted with cysteine ​​are known. In recent years, a number of G12C mutation-selective inhibitors have been developed, among which sotorasib has been approved by the FDA as a treatment for non-small cell lung cancer (Drugs, 2021, 81, p.1573-1579).

[0007] Patent documents 1, 2 and 3 disclose RAS inhibitors, and Patent documents 2 and 3 disclose compounds represented by the following formula (A) and formula (B), respectively (the meanings of the symbols in the formulas refer to the publications). Patent documents 1, 2 and 3 record that they are useful for cancers with mutations in KRAS codon 12, one of which includes the G12V mutation, but do not record the effect on the G12V mutant KRAS.

[0008]

[0009]

[0010] In addition, Patent Document 9 discloses a pan-KRAS inhibitor.

[0011] In recent years, bifunctional compounds collectively referred to as PROTAC (PROteolysis-TArgeting Chimera) and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser) have been discovered as technologies for inducing the degradation of target proteins, and are expected to be one of the new drug development models (Drug. Discov. Today Technol., 2019, 31, p15-27). Bifunctional compounds promote the formation of a complex between target proteins and E3 ligases in cells, and induce the degradation of target proteins by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms in cells. Proteins called E3 ligases recognize proteins to be degraded and ubiquitinate them, thereby promoting degradation in the proteasome.

[0012] There are more than 600 E3 ligases in the body, which can be roughly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. At present, there are limited E3 ligases used for bifunctional decomposition inducers such as PROTAC and SNIPER. Representative examples include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog 2 (mouse double minute 2 homolog, MDM2), etc. In particular, Patent Document 4 reports VHL, and Patent Document 5 reports CRBN.

[0013] Bifunctional compounds are compounds formed by connecting a ligand of a target protein and a ligand of an E3 ligase with a linker, and bifunctional compounds that degrade KRAS protein have been reported previously (Non-Patent Document 1, Non-Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 10 to Patent Document 22).

[0014] Prior art literature

[0015] Patent Literature

[0016] Patent Document 1: International Publication No. 2016 / 049565

[0017] Patent Document 2: International Publication No. 2016 / 049568

[0018] Patent Document 3: International Publication No. 2017 / 172979

[0019] Patent Document 4: International Publication No. 2013 / 106643

[0020] Patent Document 5: International Publication No. 2015 / 160845

[0021] Patent Document 6: U.S. Patent Application Publication No. 2018 / 0015087

[0022] Patent Document 7: International Publication No. 2019 / 195609

[0023] Patent Document 8: International Publication No. 2020 / 018788

[0024] Patent Document 9: International Publication No. 2022 / 132200

[0025] Patent Document 10: International Publication No. 2021 / 051034

[0026] Patent Document 11: International Publication No. 2022 / 087335

[0027] Patent Document 12: International Publication No. 2021 / 207172

[0028] Patent Document 13: International Publication No. 2022 / 111521

[0029] Patent Document 14: International Publication No. 2022 / 061348

[0030] Patent Document 15: International Publication No. 2022 / 148422

[0031] Patent Document 16: International Publication No. 2022 / 173032

[0032] Patent Document 17: International Publication No. 2022 / 228576

[0033] Patent Document 18: International Publication No. 2023 / 059609

[0034] Patent Document 19: International Publication No. 2023 / 077441

[0035] Patent Document 20: International Publication No. 2023 / 280026

[0036] Patent Document 21: Chinese Patent Application Publication No. 113956233

[0037] Patent Document 22: Chinese Patent Application Publication No. 115785199

[0038] Non-patent literature

[0039] Non-patent literature 1: Cell. Chem. Biol., 2020, 27, p19-31

[0040] Non-patent document 2: ACS Cent. Sci., 2020, 6, p1367-1375 Summary of the invention

[0041] Problems to be solved by the invention

[0042] Provided is a pharmaceutical composition, for example, a heterocyclic compound that has an excellent effect of inducing degradation of G12V mutant KRAS protein and is useful as a G12V mutant KRAS inhibitor and is expected to be useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and / or lung cancer, particularly G12V mutant KRAS-positive pancreatic cancer and / or G12V mutant KRAS-positive lung cancer.

[0043] Methods used to solve problems

[0044] The present inventors have conducted intensive studies on compounds useful as active ingredients of pharmaceutical compositions for treating pancreatic cancer and / or lung cancer, and as a result, have found that heterocyclic compounds of formula (I), particularly bifunctional compounds of formula (I) characterized in that a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand of an E3 ligase, or a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline is linked to a ligand of an E3 ligase via a linker, have excellent effects of inducing the degradation of G12V mutant KRAS protein and G12V mutant KRAS inhibitory activity, thereby completing the present invention.

[0045] That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0046]

[0047] (Where,

[0048] A is CR A or N,

[0049] R A H or C 1-3 alkyl,

[0050] X 1 -CH2-, -O- or -NR X1 -,

[0051] R X1 H or a replaceable C 1-3 alkyl,

[0052] Or, in X 1 For-NR X1 -, the R X1 and R 4 Together with the adjacent nitrogen atom, it may form a 4- to 6-membered saturated heterocyclic group which may be substituted,

[0053] R 1 is a naphthyl group which may be substituted with OH or the following formula (II) or formula (III),

[0054]

[0055] R 1a , R 1b are the same or different from each other and are H, methyl, F or Cl,

[0056] R 1c is F, Cl, methyl or ethyl,

[0057] R 2 H, halogen, C 1-3 Alkyl, cyclopropyl or vinyl, the C 1-3 The alkyl group may be substituted with a group selected from the group consisting of OH and OCH3,

[0058] R 3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and formula (XXVI),

[0059]

[0060] R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , C1-3 Alkylene-NR N1 R N2 、-OR 3f and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0061] R 3b H or C 1-3 alkyl,

[0062] R 3c and R 3d -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The group consisting of C 3-6 Cycloalkyl,

[0063] R 3e H, F or C 1-3 alkyl,

[0064] R 3f H or C 1-3 alkyl,

[0065] R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted,

[0066] R 3h H, F or C 1-3 alkyl,

[0067] R 3i are the same or different from each other and are selected from H, OH, substituted C 1-3 Alkyl, -O-C 1-3 Alkyl, -NH- may be substituted C 1-3 Alkyl, -N-(which may be substituted C 1-3 alkyl)2, halogen, -CN and oxo, or

[0068] Two Rs on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The spiro ring of the ring in the group consisting of cycloalkane and 4- to 6-membered saturated heterocyclic ring can be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0069] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 A condensed ring of a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring, the condensed ring may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0070] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridged structure containing 1 to 2 carbon atoms may be formed. The ring having the bridged structure may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo,

[0071] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0072] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or

[0073] R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group.

[0074] X 2is -O-, -NH- or -N(C 1-3 alkyl)-,

[0075] X 3 is O or S,

[0076] X 4 is -CH2-, -CH2-CH2- or -O-CH2-,

[0077] n is 1 or 2,

[0078] p is 1 or 2,

[0079] q is 1 to 8,

[0080] R 4 C 1-6 Alkyl, can be R 4a substituted piperidinyl or tetrahydropyranyl, the C 1-6 The alkyl group may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a substituted with a group selected from the group consisting of substituted pyrrolidinyl and tetrahydrofuranyl,

[0081] R 4a C 1-3 alkyl,

[0082] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0083] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-,

[0084] L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O,

[0085] R L1 H or C 1-3 alkyl,

[0086] Z is a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX) and formula (XX),

[0087]

[0088] Ring B is a benzene ring or a 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms,

[0089] R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 ,

[0090] R Z2 H or C 1-3 alkyl,

[0091] R Z3 H or C 1-3 alkyl,

[0092] R Z4 The same or different, each is H or C 1-3 alkyl,

[0093] R Z5 C 1-3 alkyl,

[0094] Furthermore, L is bonded to the ring B of the above formula (XIII) to formula (XVIII) or the benzene ring of formula (XIX) and formula (XX),

[0095] m is 1 or 2,

[0096] G is CH or N,

[0097] Wherein, when G is N, Z is the above-mentioned formula (XVII), formula (XVIII) or formula (XIX).

[0098] It should be noted that, unless otherwise specified, when a symbol in a chemical formula in the present specification is used in another chemical formula, the same symbol has the same meaning.

[0099] In addition, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients; a pharmaceutical composition for treating pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12V mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating metastatic pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced pancreatic cancer as one embodiment; a pharmaceutical composition for treating recurrent or refractory pancreatic cancer as one embodiment; a pharmaceutical composition for treating pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment; a pharmaceutical composition for treating metastatic G12V mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced G12V mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating recurrent or refractory G12V mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12V mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment. It should be noted that the pharmaceutical composition for treating pancreatic cancer containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients includes a therapeutic agent for pancreatic cancer containing a compound of formula (I) or a salt thereof, and G12V mutant KRAS-positive pancreatic cancer as one embodiment.

[0100] In addition, the present invention relates to a compound of formula (I) or a salt thereof for use in the manufacture of pancreatic cancer, as an embodiment, G12V mutation KRAS-positive pancreatic cancer, as an embodiment, metastatic pancreatic cancer, as an embodiment, locally advanced pancreatic cancer, as an embodiment, recurrent or refractory pancreatic cancer, as an embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment, as an embodiment, metastatic G12V mutation KRAS-positive pancreatic cancer, as an embodiment, locally advanced G12V mutation KRAS-positive pancreatic cancer, as an embodiment, recurrent or refractory G12V mutation KRAS-positive pancreatic cancer. Use of a pharmaceutical composition for treating pancreatic cancer, or G12V mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as a method; use of a compound of formula (I) or a salt thereof in treating pancreatic cancer, or G12V mutation KRAS-positive pancreatic cancer as a method; a compound of formula (I) or a salt thereof for treating pancreatic cancer, or G12V mutation KRAS-positive pancreatic cancer as a method; and a method for treating pancreatic cancer, or G12V mutation KRAS-positive pancreatic cancer as a method, comprising the step of administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0101] In addition, 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, a pharmaceutical composition for treating lung cancer as an embodiment, a pharmaceutical composition for treating G12V mutation KRAS-positive lung cancer as an embodiment, a pharmaceutical composition for treating metastatic lung cancer as an embodiment, a pharmaceutical composition for treating locally advanced lung cancer as an embodiment, a pharmaceutical composition for treating recurrent or refractory lung cancer as an embodiment, a pharmaceutical composition for treating lung cancer in patients who have not been treated and / or have a history of treatment as an embodiment, a pharmaceutical composition for treating metastatic G12V mutation KRAS-positive lung cancer as an embodiment, a pharmaceutical composition for treating locally advanced G12V mutation KRAS-positive lung cancer as an embodiment, a pharmaceutical composition for treating recurrent or refractory G12V mutation KRAS-positive lung cancer as an embodiment, and a pharmaceutical composition for treating G12V mutation KRAS-positive lung cancer in patients who have not been treated and / or have a history of treatment as an embodiment. It should be noted that the pharmaceutical composition for treating lung cancer containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients also includes a therapeutic agent for lung cancer containing a compound of formula (I) or a salt thereof, as a mode of G12V mutation KRAS-positive lung cancer.

[0102] In addition, the present invention relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating lung cancer, G12V mutation KRAS-positive lung cancer as one embodiment, metastatic lung cancer as one embodiment, locally progressive lung cancer as one embodiment, recurrent or refractory lung cancer as one embodiment, lung cancer in patients who have not been treated and / or have a history of treatment as one embodiment, metastatic G12V mutation KRAS-positive lung cancer as one embodiment, locally progressive G12V mutation KRAS-positive lung cancer as one embodiment, recurrent or refractory G12V mutation KRAS-positive lung cancer as one embodiment, and G12V mutation KRAS-positive lung cancer in patients who have not been treated and / or have a history of treatment as one embodiment; the use of a compound of formula (I) or a salt thereof in the treatment of lung cancer, G12V mutation KRAS-positive lung cancer as one embodiment; a compound of formula (I) or a salt thereof for treating lung cancer, G12V mutation KRAS-positive lung cancer as one embodiment; and a method for treating lung cancer, G12V mutation KRAS-positive lung cancer as one embodiment, comprising the step of administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0103] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a G12V mutant KRAS protein decomposition inducer and / or a G12V mutant KRAS inhibitor; a compound of formula (I) or a salt thereof used as a G12V mutant KRAS protein decomposition inducer and / or a G12V mutant KRAS inhibitor; and a G12V mutant KRAS protein decomposition inducer and / or a G12V mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0104] It should be noted that the "subject" refers to a human or other animal in need of the treatment, and as a mode, refers to a person in need of the prevention or treatment.

[0105] Effects of the Invention

[0106] The compound of formula (I) or a salt thereof has the effect of inducing the degradation of G12V mutant KRAS protein and the G12V mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer and / or lung cancer, especially G12V mutant KRAS positive pancreatic cancer and / or G12V mutant KRAS positive lung cancer. DETAILED DESCRIPTION

[0107] Hereinafter, the present invention will be described in detail.

[0108] In this specification, "may be substituted" means unsubstituted or having 1 to 5 substituents. As one embodiment, it means unsubstituted or having 1 to 3 substituents. It should be noted that when there are two or more substituents, these substituents may be the same or different from each other.

[0109] “C 1-12 "Alkyl" refers to a linear or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (hereinafter, the same expression is used with respect to the carbon number). As one embodiment, it is ethyl or dodecyl.

[0110] Likewise, “C 1-6 The term "alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl or sec-butyl. In one embodiment, it is methyl, ethyl, isopropyl or tert-butyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl or n-butyl.

[0111] Likewise, “C 1-3The term “alkyl” refers to a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group or an isopropyl group. In one embodiment, the alkyl group is a methyl group or an ethyl group. In one embodiment, the alkyl group is a n-propyl group or an isopropyl group. In one embodiment, the alkyl group is a methyl group or an isopropyl group. In one embodiment, the alkyl group is a methyl group. In one embodiment, the alkyl group is an isopropyl group. In one embodiment, the alkyl group is a methyl group. In one embodiment, the alkyl group is an isopropyl group. In one embodiment, the alkyl group is a n-propyl group.

[0112] “C 3-6 The term "cycloalkane" refers to a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0113] “C 3-6 The "cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, it is cyclobutyl, cyclopentyl, or cyclohexyl, in one embodiment, it is cyclobutyl or cyclopentyl, in one embodiment, it is cyclopentyl or cyclohexyl, in one embodiment, it is cyclopropyl or cyclobutyl, in one embodiment, it is cyclopropyl, in one embodiment, it is cyclobutyl, in one embodiment, it is cyclopentyl, in one embodiment, it is cyclohexyl.

[0114] “C 1-3 "Alkylene" refers to 1-3 A divalent group formed by removing a hydrogen atom from an alkyl group. It is a straight-chain or branched C 1-3 The alkylene group includes, for example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. In one embodiment, a linear or branched C 1-3 As one embodiment, the alkylene group is methylene, ethylene or trimethylene. As one embodiment, it is methylene or ethylene. As one embodiment, it is methylene. As one embodiment, it is ethylene.

[0115] "Saturated heterocycle" refers to a saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. In addition, the sulfur atom as a ring-constituting atom of the saturated heterocycle may be oxidized. Therefore, a "4- to 6-membered saturated heterocycle" refers to a 4- to 6-membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment of the "4- to 6-membered saturated heterocycle", it is a 4- to 6-membered saturated heterocycle containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms. As one embodiment, it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine or dioxothiomorpholine.

[0116] The "saturated heterocyclic group" refers to a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. In addition, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized.

[0117] Therefore, a "4- to 6-membered saturated heterocyclic group" refers to a 4- to 6-membered saturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. One embodiment of a "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. As one embodiment of the 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, it is a 4- to 6-membered saturated heterocyclic group containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment, it is a 5- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment, it is a 4-membered saturated heterocyclic group containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment, it is a 5-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment, it is a 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. As one embodiment, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxothiomorpholinyl, as an embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxothiomorpholinyl, as an embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or morpholinyl, as an embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, as an embodiment, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, as an embodiment, pyrrolidinyl or piperidinyl, as an embodiment, oxetanyl, as an embodiment, tetrahydrofuranyl, as an embodiment, tetrahydropyranyl, as an embodiment, pyrrolidinyl, as an embodiment, piperidinyl, as an embodiment, morpholinyl, as an embodiment, Oxazolidinyl.

[0118] "A divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms" refers to a divalent group of a 4- to 11-membered saturated heterocyclic group containing 1 to 2 nitrogen atoms as ring constituent atoms, and may be a divalent group of a saturated heterocyclic ring having a spiro ring or a condensed ring. One embodiment of the "divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms" is azetidinediyl, pyrrolidinediyl, imidazolidinediyl, piperidinediyl, piperazinediyl, azepandiyl, diazepandiyl, azoctanediyl, diazacyclooctanediyl, azacyclononanediyl, diazacyclononanediyl or a divalent group represented by the following formula (XXI) to (XXV).

[0119]

[0120] One embodiment of the "divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms" is a pyrrolidinediyl group, a piperazinediyl group, or a divalent group represented by the following formula (XXI) or formula (XXII).

[0121]

[0122] One embodiment of the "divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms" is a pyrrolidinediyl group, a piperazinediyl group, or a divalent group represented by the following formula (XXI), formula (XXII), or formula (XXV).

[0123]

[0124] The "divalent group of a saturated heterocyclic ring containing two nitrogen atoms" refers to a divalent group of a 4- to 11-membered saturated heterocyclic group containing two nitrogen atoms as ring constituent atoms, and may be a divalent group of a saturated heterocyclic ring having a spiro ring or a condensed ring.

[0125] One embodiment of the "divalent saturated heterocyclic group containing two nitrogen atoms" is an imidazolidinediyl group, a piperazinediyl group, a diazepanediyl group, a diazacyclooctanediyl group, a diazacyclononanediyl group or a divalent group represented by the following formula (XXI) to (XXV).

[0126]

[0127] One embodiment of the "divalent saturated heterocyclic group containing two nitrogen atoms" is a piperazinediyl group or a divalent group represented by the following formula (XXI) or formula (XXII).

[0128]

[0129] One embodiment of the "saturated heterocyclic divalent group containing two nitrogen atoms" is a piperazinediyl group or a divalent group represented by the following formula (XXI), formula (XXII) or formula (XXV).

[0130]

[0131] The "heterocycle" refers to an aromatic hydrocarbon ring containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen.

[0132] Therefore, the "six-membered heterocyclic ring containing 1 to 2 nitrogen atoms" refers to a six-membered aromatic hydrocarbon ring containing 1 to 2 nitrogen atoms as ring constituent atoms, and in one embodiment, it is a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, or a triazine ring, and in one embodiment, it is a pyridine ring.

[0133] The "heteroaryl group" refers to a heterocyclic group containing, as a ring-constituting atom, a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen.

[0134] Therefore, the "5-membered heteroaryl group" refers to a 5-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0135] One embodiment of the "5-membered heteroaryl group" is a 5-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and one embodiment is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, as one embodiment, is pyrazolyl, imidazolyl, triazolyl, Azolyl or thiazolyl, as one embodiment, is pyrazolyl, imidazolyl, Azolyl or thiazolyl, as one embodiment, is pyrazolyl, imidazolyl, triazolyl or isocyanate Azolyl, as one embodiment, is pyrazolyl, Azolyl or thiazolyl, as one embodiment, is pyrazolyl, triazolyl or iso Azolyl, as an embodiment, is pyrazolyl or thiazolyl, as an embodiment, is pyrazolyl or triazolyl, as an embodiment, is pyrazolyl, as an embodiment, is imidazolyl, as an embodiment, is Azolyl, as one embodiment, is thiazolyl, as one embodiment, is triazolyl.

[0136] The "6-membered heteroaryl group" refers to a 6-membered heterocyclic group containing 1 to 3 nitrogen atoms as ring-constituting atoms. One embodiment of the "6-membered heteroaryl group" is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl, another embodiment is pyridyl or pyridazinyl, another embodiment is pyridyl or pyrimidinyl, another embodiment is pyridyl, and another embodiment is pyrimidinyl.

[0137] “Halogen” refers to F, Cl, Br and I. In one embodiment, it is F, Cl or Br, in one embodiment, it is F or Cl, in one embodiment, it is F or Br, in one embodiment, it is F, in one embodiment, it is Cl, in one embodiment, it is Br.

[0138] "Spiro" refers to a polycyclic ring structure in which two ring structures share a spiro atom as a quaternary carbon and are bonded together, and "fused ring" refers to a polycyclic ring structure in which two or more ring structures share two or more adjacent atoms constituting one ring and are bonded together. In addition, "bridged structure" refers to a divalent chain structure connecting two non-adjacent atoms in the ring-constituting atoms of one ring.

[0139] As a "replaceable C 1-6 Alkyl", "Substituted C 1-3 Alkyl" and "C 1-3 One form of acceptable substituents in "alkylene" is F, OH, OCH3, N (C 1-3 Alkyl)2, C 3-6 Cycloalkyl, azabicyclo[3.3.0]octyl or a 4- to 6-membered saturated heterocyclic group which may be substituted. In one embodiment, F, OH, OCH3, cyclopropyl, N(C 1-3 Alkyl)2, C which can be substituted by (can be substituted by F 1-3 alkyl) substituted pyrrolidinyl and tetrahydrofuranyl, as one embodiment, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, difluoroethyl, cyclopropyl which may be substituted, tetrahydrofuranyl, tetrahydropyranyl which may be substituted, morpholinyl, pyrrolidinyl which may be substituted or piperidinyl which may be substituted, as one embodiment, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl which may be substituted, tetrahydrofuranyl, tetrahydropyranyl which may be substituted, pyrrolidinyl which may be substituted, as one embodiment, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, , cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl or methylpyrrolidinyl, as an embodiment, is F, OH, OCH3, (methoxymethyl)cyclopropyl, tetrahydrofuranyl or methylpyrrolidinyl, as an embodiment, is F, OH or cyclopropyl, as an embodiment, is F, OH or OCH3, as an embodiment, is OH or OCH3, as an embodiment, is F or OCH3, as an embodiment, is OH, as an embodiment, is F, as an embodiment, is OCH3.

[0140] One embodiment of the acceptable substituents in the "5-membered heteroaryl group which may be substituted" and the "6-membered heteroaryl group which may be substituted" is a C substituted with a group selected from the group consisting of OH and OCH3. 1-3 Alkyl, -SO2CH3, halogen, OH, OCH3 or C 3-6 As one embodiment, a C cycloalkyl group may be substituted with a group selected from the group consisting of OH and OCH3. 1-3 Alkyl, as a form, is a C 1-3 Alkyl, as a method, is a C 1-3 Alkyl, as a way, is C 1-3 Alkyl or halogen, as one embodiment, is methyl, ethyl, methoxymethyl or F, as one embodiment, is methyl, ethyl or F.

[0141] As "4- to 6-membered saturated heterocyclic group which may be substituted", "pyrrolidinyl group which may be substituted", "C 3-6 One form of acceptable substituents in "cycloalkyl", "divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted" and "divalent saturated heterocyclic group containing 2 nitrogen atoms which may be substituted" is C 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 one embodiment, it is OH or methyl. In one embodiment, it is C which may be substituted with a group selected from the group consisting of F, OH and OCH3. 1-3 Alkyl, F, oxo or oxetanyl, as one embodiment, is a C substituted group which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2. 1-3 Alkyl or oxo, as one embodiment, is a C substituted group which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2. 1-3 Alkyl, as a method, is C substituted with F 1-3 Alkyl, as a form, is a C 1-3 Alkyl, as a method, is a C 1-3 Alkyl, as a form, is a C 1-3 Alkyl, as a way, is C 1-3 As one example, a C 1-3 Alkyl or oxo.

[0142] As "C 1-3One embodiment of the "alkyl" is a methyl group which may be substituted with one OH group or an ethyl group which may be substituted with 1 to 2 OH groups. For example, it is a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, or a 1,2-dihydroxyethyl group. As one embodiment, it is a methyl group, an ethyl group, or a hydroxymethyl group. As one embodiment, it is a methyl group or a hydroxymethyl group. As one embodiment, it is a hydroxymethyl group or a hydroxyethyl group. As one embodiment, it is a hydroxymethyl group. As one embodiment, it is a hydroxyethyl group.

[0143] As "C 1-6 Alkyl" and "C 1-3 One embodiment of the "alkyl" is a methyl group which may be substituted with one OCH3 or an ethyl group which may be substituted with 1 to 2 OCH3. For example, it is a methyl group, an ethyl group, a methoxymethyl group, a 1-methoxyethyl group, a 2-methoxyethyl group, or a 1,2-dimethoxyethyl group. As one embodiment, it is a methoxymethyl group or a methoxyethyl group, as one embodiment, it is a methoxymethyl group, and as one embodiment, it is a methoxyethyl group.

[0144] As "can be N(C 1-3 Alkyl)2-substituted C 1-6 One form of "alkyl" is "C 1-3 Alkyl", as a way to be replaced by 1 N(C 1-3 Alkyl)2-substituted methyl, which may be replaced by 1 N(C 1-3 Alkyl)2 substituted ethyl or 1 N(C 1-3 As one embodiment, a propyl group which may be substituted with one N(C 1-3 Alkyl)2 substituted methyl or 1 N(C 1-3 alkyl)2-substituted ethyl.

[0145] As "C 1-3 One embodiment of "alkyl" is a methyl group which may be substituted with one N(CH3)2 or an ethyl group which may be substituted with one N(CH3)2. As one embodiment, it is a methyl group, an ethyl group, a dimethylaminomethyl group or a dimethylaminoethyl group. As one embodiment, it is a methyl group or a dimethylaminomethyl group. As one embodiment, it is a dimethylaminomethyl group. As one embodiment, it is a dimethylaminoethyl group.

[0146] One embodiment of the "phenylene group which may be substituted with F or Cl" is a phenylene group which may be substituted with 1 to 2 F or Cl. Another embodiment is a phenylene group which may be substituted with 1 F, another embodiment is a phenylene group which may be substituted with 1 Cl, another embodiment is a phenylene group or a fluorophenylene group, another embodiment is a phenylene group, another embodiment is a 2-fluoro-1,4-phenylene group, and another embodiment is a 3-fluoro-1,4-phenylene group.

[0147] The "G12V mutation" refers to a mutation in which the amino acid residue corresponding to codon position 12 in the wild-type protein changes from glycine to valine.

[0148] “G12V mutant KRAS” refers to KRAS having the above-mentioned “G12V mutation”.

[0149] "Pancreatic cancer" refers to a malignant tumor formed in the pancreas. For example, it is pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. As an embodiment, it is pancreatic ductal carcinoma. As an embodiment, it is pancreatic ductal adenocarcinoma. Furthermore, as an embodiment, it is metastatic pancreatic cancer. As an embodiment, it is locally advanced pancreatic cancer. As an embodiment, it is recurrent or refractory pancreatic cancer. As an embodiment, it is pancreatic cancer in patients who have not been treated and / or have a history of treatment.

[0150] "Lung cancer" refers to a malignant tumor formed in the lung. For example, it is small cell lung cancer and non-small cell lung cancer. As an embodiment, it is small cell lung cancer. As an embodiment, it is non-small cell lung cancer. Furthermore, as an embodiment, it is metastatic lung cancer. As an embodiment, it is locally advanced lung cancer. As an embodiment, it is recurrent or refractory lung cancer. As an embodiment, it is lung cancer in patients who have not been treated and / or have a history of treatment.

[0151] "G12V mutation KRAS positive pancreatic cancer" refers to G12V mutation KRAS positive pancreatic cancer. For example, it is pancreatic cancer with KRAS G12V mutation, and it is pancreatic cancer with a high positive rate of G12V mutation KRAS. As one embodiment, it is G12V mutation KRAS positive pancreatic ductal carcinoma, and as one embodiment, it is G12V mutation KRAS positive pancreatic ductal adenocarcinoma.

[0152] "G12V mutation KRAS positive lung cancer" refers to G12V mutation KRAS positive lung cancer. For example, it is lung cancer with KRAS G12V mutation, and it is lung cancer with a high positive rate of G12V mutation KRAS. In one embodiment, it is G12V mutation KRAS positive small cell lung cancer, and in another embodiment, it is G12V mutation KRAS positive non-small cell lung cancer.

[0153] One embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.

[0154] (1-1)

[0155] A is CR A or N, R A H or C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0156] (1-2)

[0157] A is CR A or N, R A The compound of formula (I) or a salt thereof is H.

[0158] (1-3)

[0159] A is CR A or N, R A C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0160] (2-1)

[0161] X 1 -CH2-, -O- or -NR X1 -,

[0162] R X1 H or a replaceable C 1-3 alkyl,

[0163] Or, in X 1 For-NR X1 -, the R X1 and R 4 The compound of the formula (I) or a salt thereof may form an optionally substituted 4- to 6-membered saturated heterocyclic group together with the adjacent nitrogen atom.

[0164] (2-2)

[0165] X 1 -O- or -NR X1 -,

[0166] R X1 H or a replaceable C 1-3 alkyl,

[0167] Or, in X 1 For-NR X1 -, the R X1 and R 4 The compound of the formula (I) or a salt thereof may form an optionally substituted 4- to 6-membered saturated heterocyclic group together with the adjacent nitrogen atom.

[0168] (2-3)

[0169] X 1 -O- or -NR X1 -,

[0170] R X1 H or C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0171] (2-4)

[0172] X 1 The compound of formula (I) or a salt thereof is -O-.

[0173] (3-1)

[0174] R 1 is a naphthyl group which may be substituted with OH or the following formula (II) or formula (III),

[0175]

[0176] R 1a , R 1b are the same or different from each other and are H, methyl, F or Cl,

[0177] R 1c The compound of formula (I) or a salt thereof is F, Cl, methyl or ethyl.

[0178] (3-2)

[0179] R 1 is the following formula (II),

[0180]

[0181] R 1a is H, methyl, F or Cl,

[0182] R 1c The compound of formula (I) or a salt thereof is F, Cl, methyl or ethyl.

[0183] (3-3)

[0184] R 1 is the following formula (II),

[0185]

[0186] R 1a For F,

[0187] R 1c The compound of formula (I) or a salt thereof is methyl.

[0188] (4-1)

[0189] R 2 H, halogen, C 1-3 Alkyl, cyclopropyl or vinyl, the C 1-3 The compound of formula (I) or a salt thereof wherein the alkyl group may be substituted with a group selected from the group consisting of OH and OCH3.

[0190] (4-2)

[0191] R2 The compound of formula (I) or a salt thereof is cyclopropyl or vinyl.

[0192] (4-3)

[0193] R 2 The compound of formula (I) or a salt thereof is cyclopropyl.

[0194] (5-1)

[0195] R 3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and formula (XXVI),

[0196]

[0197] R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

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

[0199] R 3c and R 3d -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2)p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0200] R 3e H, F or C 1-3 alkyl,

[0201] R 3f H or C 1-3 alkyl,

[0202] R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted,

[0203] R 3h H, F or C 1-3 alkyl,

[0204] R 3i are the same or different from each other and are selected from H, OH, substituted C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NH-(which may be substituted C 1-3 Alkyl), -N-(which may be substituted C 1-3 alkyl)2, halogen, -CN and oxo, or

[0205] Two Rs on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The spiro ring of the ring in the group consisting of cycloalkane and 4- to 6-membered saturated heterocyclic ring can be selected from C 1-3 Alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or

[0206] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 A condensed ring of a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring, the condensed ring may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0207] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridged structure containing 1 to 2 carbon atoms may be formed. The ring having the bridged structure may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo,

[0208] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0209] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or

[0210] R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group.

[0211] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0212] X 3 is O or S,

[0213] X 4 is -CH2-, -CH2-CH2- or -O-CH2-,

[0214] n is 1 or 2,

[0215] p is 1 or 2,

[0216] A compound of formula (I) or a salt thereof, wherein q is 1 to 8.

[0217] (5-2)

[0218] R3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0219]

[0220] R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0221] R 3b H or C 1-3 alkyl,

[0222] R 3e H, F or C 1-3 alkyl,

[0223] R 3f H or C 1-3 alkyl,

[0224] R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted,

[0225] R 3h H, F or C 1-3 alkyl,

[0226] R N1 and RN2 Same or different, H or C 1-3 Alkyl, or

[0227] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or

[0228] R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group.

[0229] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0230] X 3 is O or S,

[0231] n is 1 or 2,

[0232] The compound of formula (I) or a salt thereof, wherein p is 1 or 2.

[0233] (5-3)

[0234] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0235]

[0236] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0237] R 3b H or C 1-3 alkyl,

[0238] R 3e For H,

[0239] R 3g is a 6-membered heteroaryl group which may be substituted,

[0240] R 3h is H or F,

[0241] R N1 and R N2 Same or different from each other, C 1-3 Alkyl, or

[0242] RN1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group,

[0243] X 2 is -O- or -NH-,

[0244] X 3 is O or S,

[0245] n is 1,

[0246] The compound of formula (I) or a salt thereof, wherein p is 1.

[0247] (5-4)

[0248] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0249]

[0250] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0251] R 3b H or C 1-3 alkyl,

[0252] R 3e For H,

[0253] R 3g is a 6-membered heteroaryl group which may be substituted,

[0254] R 3h is H or F,

[0255] R N1 and R N2 Same or different from each other, C 1-3 alkyl,

[0256] X 2 is -O- or -NH-,

[0257] X 3 is O or S,

[0258] n is 1,

[0259] The compound of formula (I) or a salt thereof, wherein p is 1.

[0260] (5-5)

[0261] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0262]

[0263] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0264] R 3b For H,

[0265] R 3e For H,

[0266] R 3g is a 6-membered heteroaryl group which may be substituted,

[0267] R 3h For F,

[0268] R N1 and R N2 Same or different from each other, C 1-3 alkyl,

[0269] X 2 is -O- or -NH-,

[0270] X 3 For O,

[0271] A compound of the formula (I) or a salt thereof, wherein n and p are both 1.

[0272] (5-6)

[0273] R 3 A compound of formula (I) or a salt thereof which is a group selected from the group consisting of the following formula (IV-1), formula (VII-1), formula (VIII-1), formula (IX), formula (X), formula (XI) and formula (XII-1).

[0274]

[0275] (6-1)

[0276] R 4 C 1-6 Alkyl, can be R 4a substituted piperidinyl or tetrahydropyranyl, the C 1-6 The alkyl group may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R4a )2. Can be R 4a substituted with a group selected from the group consisting of substituted pyrrolidinyl and tetrahydrofuranyl,

[0277] R 4a C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0278] (6-2)

[0279] R 4 may be selected from OCH3, N(R 4a )2 and can be R 4a The substituted pyrrolidinyl group is composed of a group substituted with C 1-6 alkyl,

[0280] R 4a C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0281] (6-3)

[0282] R 4 Can be OCH3 or N(C 1-3 Alkyl)2-substituted C 1-6 Alkyl, C 1-3 The compound of formula (I) or a salt thereof is alkyl-substituted piperidinyl or tetrahydropyranyl.

[0283] (6-4)

[0284] R 4 may be selected from OCH3, N(C 1-3 Alkyl)2 and can be R 4a The substituted pyrrolidinyl group is composed of a group substituted with C 1-6 Alkyl or tetrahydropyranyl,

[0285] R 4a C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0286] (7-1)

[0287] A compound of the formula (I) or a salt thereof, wherein Y is a phenylene group or a pyridinediyl group which may be substituted with F or Cl.

[0288] (7-2)

[0289] A compound of the formula (I) or a salt thereof, wherein Y is a phenylene group which may be substituted with F or Cl.

[0290] (7-3)

[0291] The compound of the formula (I) or a salt thereof, wherein Y is a phenylene group.

[0292] (8-1)

[0293] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-,

[0294] L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O,

[0295] R L1 H or C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0296] (8-2)

[0297] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-,

[0298] L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from free bonds, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O,

[0299] R L1 H or C 1-3 The compound of formula (I) or a salt thereof is alkyl.

[0300] (8-3)

[0301] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-, L contained in L 1 Bonded to Y,

[0302] L1 C 1-3 Alkylene or C=O,

[0303] L 2 is a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted,

[0304] L 3 C 1-3 Alkylene,

[0305] L 4 is a bond, -O- or -N(C 1-3 alkyl),

[0306] L 5 For key or C 1-3 The compound of formula (I) or a salt thereof is alkylene.

[0307] (8-4)

[0308] L is a group selected from the group consisting of the following formula (XXVII) to formula (XXXIV),

[0309]

[0310] With A compound of formula (I) or a salt thereof, wherein a carbon atom of

[0311] (9-1)

[0312] Z is a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX) and formula (XX),

[0313]

[0314] Ring B is a benzene ring or a 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms,

[0315] R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 ,

[0316] R Z2 H or C 1-3 alkyl,

[0317] R Z3 H or C 1-3 alkyl,

[0318] R Z4 The same or different, each is H or C 1-3 alkyl,

[0319] R Z5 C 1-3 alkyl,

[0320] Furthermore, L is bonded to the ring B of the above formula (XIII) to formula (XVIII) or the benzene ring of formula (XIX) and formula (XX),

[0321] The compound of formula (I) or a salt thereof, wherein m is 1 or 2.

[0322] (9-2)

[0323] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0324]

[0325] Ring B is a benzene ring or a 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms,

[0326] R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 ,

[0327] R Z2 H or C 1-3 alkyl,

[0328] R Z4 The same or different, each is H or C 1-3 alkyl,

[0329] R Z5 C 1-3 alkyl,

[0330] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII),

[0331] The compound of formula (I) or a salt thereof, wherein m is 1 or 2.

[0332] (9-3)

[0333] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0334]

[0335] Ring B is a benzene ring,

[0336] R Z1 H or C 1-3 alkyl,

[0337] R Z2 H or C 1-3 alkyl,

[0338] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII) or the benzene ring of the formula (XIX),

[0339] The compound of formula (I) or a salt thereof, wherein m is 1 or 2.

[0340] (9-4)

[0341] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0342]

[0343] Ring B is a benzene ring,

[0344] R Z1 For H,

[0345] R Z2 C 1-3 alkyl,

[0346] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII) or the benzene ring of the formula (XIX),

[0347] A compound of formula (I) or a salt thereof, wherein m is 1.

[0348] (9-5)

[0349] Z is a group selected from the group consisting of the following formula (XIII-1), formula (XVII-1) and formula (XIX-1),

[0350]

[0351] Furthermore, L is a compound of the formula (I) or a salt thereof, in which L is bonded to the benzene ring of the above-mentioned formula (XIII-1) and formula (XVII-1).

[0352] (9-6)

[0353] Z is the following formula (XIII) or formula (XVII),

[0354]

[0355] Ring B is a benzene ring,

[0356] Furthermore, L is bonded to the ring B of the above formulae (XIII) and (XVII),

[0357] R Z1 For H,

[0358] R Z2 C 1-3 alkyl,

[0359] A compound of formula (I) or a salt thereof, wherein m is 1.

[0360] (10-1)

[0361] G is CH or N,

[0362] When G is N, Z is a compound of formula (I) or a salt thereof of the above formula (XVII), formula (XVIII) or formula (XIX).

[0363] (10-2)

[0364] G is CH or N,

[0365] When G is N, Z is the compound of formula (I) or formula (XVII) or formula (XIX) above, or a salt thereof.

[0366] (10-3)

[0367] G is CH or N,

[0368] When G is N, Z is the compound of formula (I) of the above formula (XVII-1) or formula (XIX-1) or a salt thereof.

[0369] (10-4)

[0370] G is CH or N,

[0371] When G is N, Z is the compound of formula (I) of the above formula (XVII) or a salt thereof. (11)

[0373] A compound or a salt thereof which is a combination of any two or more of the embodiments described in (1-1) to (10-4) that are not contradictory.

[0374] Specific examples of the combination described in (11) include the following aspects.

[0375] (11-1-1)

[0376] A compound of formula (I) or a salt thereof.

[0377]

[0378] (Where,

[0379] A is CR A or N,

[0380] R A For H,

[0381] X 1 For -O-,

[0382] R 1 is the following formula (II),

[0383]

[0384] R 1a For F,

[0385] R 1c Methyl,

[0386] R 2 is cyclopropyl,

[0387] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0388]

[0389] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0390] R 3b For H,

[0391] R 3e For H,

[0392] R 3g is a 6-membered heteroaryl group which may be substituted,

[0393] R 3h For F,

[0394] R N1 and R N2 Same or different from each other, C 1-3 alkyl,

[0395] X 2 is -O- or -NH-,

[0396] X 3 For O,

[0397] n and p are both 1,

[0398] R4 may be selected from OCH3, N(R 4a )2 and can be R 4a The substituted pyrrolidinyl group is composed of a group substituted with C 1-6 alkyl,

[0399] R 4a C 1-3 alkyl,

[0400] Y is phenylene,

[0401] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-,

[0402] L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from free bonds, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O,

[0403] R L1 H or C 1-3 alkyl,

[0404] Z is the following formula (XIII) or formula (XVII),

[0405]

[0406] Ring B is a benzene ring,

[0407] Furthermore, L is bonded to the ring B of the above formulae (XIII) and (XVII),

[0408] R Z1 For H,

[0409] R Z2 C 1-3 alkyl,

[0410] m is 1,

[0411] G is CH or N,

[0412] Wherein, when G is N, Z is the above formula (XVII).

[0413] (11-1-2)

[0414] A compound of formula (I) or a salt thereof.

[0415]

[0416] (Where,

[0417] A is CR A or N,

[0418] R A H or C 1-3 alkyl,

[0419] X 1 -CH2-, -O- or -NR X1 -,

[0420] R X1 H or a replaceable C 1-3 alkyl,

[0421] Or, in X 1 For-NR X1 -, the R X1 and R 4 Together with the adjacent nitrogen atom, it may form a 4- to 6-membered saturated heterocyclic group which may be substituted,

[0422] R 1 is a naphthyl group which may be substituted with OH or the following formula (II) or formula (III),

[0423]

[0424] R 1a , R 1b are the same or different from each other and are H, methyl, F or Cl,

[0425] R 1c is F, Cl, methyl or ethyl,

[0426] R 2 H, halogen, C 1-3 Alkyl, cyclopropyl or vinyl, the C 1-3 The alkyl group may be substituted with a group selected from the group consisting of OH and OCH3,

[0427] R 3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and formula (XXVI),

[0428]

[0429] R 3a -(CH2) pCHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0430] R 3b H or C 1-3 alkyl,

[0431] R 3c and R 3d -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C3-6 Cycloalkyl,

[0432] R 3e H, F or C 1-3 alkyl,

[0433] R 3f H or C 1-3 alkyl,

[0434] R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted,

[0435] R 3h H, F or C 1-3 alkyl,

[0436] R 3i are the same or different from each other and are selected from H, OH, substituted C 1-3 Alkyl, -O-C 1-3 Alkyl, -NH- may be substituted C 1-3 Alkyl, -N-(which may be substituted C 1-3 alkyl)2, halogen, -CN and oxo, or

[0437] Two Rs on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The spiro ring of the ring in the group consisting of cycloalkane and 4- to 6-membered saturated heterocyclic ring can be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0438] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 A condensed ring of a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring, the condensed ring may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0439] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridged structure containing 1 to 2 carbon atoms may be formed. The ring having the bridged structure may be selected from C 1-3 Alkyl, -O-(C 1-3alkyl), OH, halogen and oxo,

[0440] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0441] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or

[0442] R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group.

[0443] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0444] X 3 is O or S,

[0445] X 4 is -CH2-, -CH2-CH2- or -O-CH2-,

[0446] n is 1 or 2,

[0447] p is 1 or 2,

[0448] q is 1 to 8,

[0449] R 4 C 1-6 Alkyl, can be R 4a substituted piperidinyl or tetrahydropyranyl, the C 1-6 The alkyl group may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a substituted with a group selected from the group consisting of substituted pyrrolidinyl and tetrahydrofuranyl,

[0450] R 4a C 1-3 alkyl,

[0451] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0452] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-,

[0453] L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O,

[0454] R L1 H or C 1-3 alkyl,

[0455] Z is a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX) and formula (XX),

[0456]

[0457] Ring B is a benzene ring or a 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms,

[0458] R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 ,

[0459] R Z2 H or C 1-3 alkyl,

[0460] R Z3 H or C 1-3 alkyl,

[0461] R Z4 The same or different, each is H or C 1-3 alkyl,

[0462] R Z5 C 1-3 alkyl,

[0463] Furthermore, L is bonded to the ring B of the above formula (XIII) to formula (XVIII) or the benzene ring of formula (XIX) and formula (XX),

[0464] m is 1 or 2,

[0465] G is CH or N,

[0466] Wherein, when G is N, Z is the above-mentioned formula (XVII), formula (XVIII) or formula (XIX).

[0467] (11-2)

[0468] The compound or salt thereof according to (11-1-2) above, wherein

[0469] X 1 -O- or -NR X1 -,

[0470] R X1 H or a replaceable C 1-3 alkyl,

[0471] Or, in X 1 For-NR X1 -, the R X1 and R 4 Together with the adjacent nitrogen atom, it may form a 4- to 6-membered saturated heterocyclic group which may be substituted,

[0472] R 1 is the following formula (II),

[0473]

[0474] R 1a is H, methyl, F or Cl,

[0475] R 1c is F, Cl, methyl or ethyl,

[0476] R 2 is cyclopropyl or vinyl,

[0477] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0478]

[0479] R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NRN1 R N2 and-NR N1 R N2 A 4- to 6-membered saturated heterocyclic group substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0480] R 3b H or C 1-3 alkyl,

[0481] R 3e H, F or C 1-3 alkyl,

[0482] R 3f H or C 1-3 alkyl,

[0483] R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted,

[0484] R 3h H, F or C 1-3 alkyl,

[0485] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0486] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or

[0487] R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group.

[0488] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0489] X 3 is O or S,

[0490] n is 1 or 2,

[0491] p is 1 or 2,

[0492] Y is a phenylene group which may be substituted by F or Cl,

[0493] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0494]

[0495] Ring B is a benzene ring or a 6-membered heterocyclic ring containing 1 to 2 nitrogen atoms,

[0496] R Z1 H, C 1-3 Alkyl, -O-(C 1-3 Alkyl), -NR Z4 2. -CONR Z4 2 or -NR Z4 COR Z5 ,

[0497] R Z2 H or C 1-3 alkyl,

[0498] R Z4 The same or different, each is H or C 1-3 alkyl,

[0499] R Z5 C 1-3 alkyl,

[0500] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII),

[0501] m is 1 or 2,

[0502] G is CH or N,

[0503] When G is N, Z is the above-mentioned formula (XVII) or formula (XIX).

[0504] (11-3)

[0505] The compound or salt thereof according to (11-2) above, wherein

[0506] X 1 -O- or -NR X1 -,

[0507] R X1 H or C 1-3 alkyl,

[0508] R 3is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0509]

[0510] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0511] R 3b H or C 1-3 alkyl,

[0512] R 3e For H,

[0513] R 3g is a 6-membered heteroaryl group which may be substituted,

[0514] R 3h is H or F,

[0515] R N1 and R N2 Same or different from each other, C 1-3 Alkyl, or

[0516] R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group,

[0517] X 2 is -O- or -NH-,

[0518] X 3 is O or S,

[0519] n is 1,

[0520] p is 1,

[0521] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0522]

[0523] Ring B is a benzene ring,

[0524] R Z1 H or C 1-3 alkyl,

[0525] R Z2 H or C 1-3 alkyl,

[0526] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII) or the benzene ring of the formula (XIX),

[0527] m is 1 or 2,

[0528] G is CH or N,

[0529] When G is N, Z is the above-mentioned formula (XVII) or formula (XIX).

[0530] (11-4)

[0531] The compound or salt thereof according to (11-2) above, wherein

[0532] A is CR A or N,

[0533] R A For H,

[0534] X 1 For -O-,

[0535] R 1 is the following formula (II),

[0536]

[0537] R 1a For F,

[0538] R 1c Methyl,

[0539] R 2 is cyclopropyl,

[0540] R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),

[0541]

[0542] R 3a -(CH2) p CHR 3e -NR N1 R N2 ,

[0543] R 3b H or C 1-3 alkyl,

[0544] R 3e For H,

[0545] R 3gis a 6-membered heteroaryl group which may be substituted,

[0546] R 3h is H or F,

[0547] R N1 and R N2 Same or different from each other, C 1-3 alkyl,

[0548] X 2 is -O- or -NH-,

[0549] X 3 is O or S,

[0550] n is 1,

[0551] p is 1,

[0552] R 4 may be selected from OCH3, N(C 1-3 Alkyl)2 and can be R 4a The substituted pyrrolidinyl group is composed of a group substituted with C 1-6 Alkyl or tetrahydropyranyl,

[0553] R 4a C 1-3 alkyl,

[0554] Y is phenylene,

[0555] L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-, L contained in L 1 Bonded to Y,

[0556] L 1 C 1-3 Alkylene or C=O,

[0557] L 2 is a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted,

[0558] L 3 C 1-3 Alkylene,

[0559] L 4 is a bond, -O- or -N(C 1-3 alkyl),

[0560] L 5 For key or C 1-3 Alkylene,

[0561] Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),

[0562]

[0563] Ring B is a benzene ring,

[0564] R Z1 H or C 1-3 alkyl,

[0565] R Z2 H or C 1-3 alkyl,

[0566] Furthermore, L is bonded to the ring B of the above formula (XIII) or (XVII) or the benzene ring of the formula (XIX),

[0567] m is 1 or 2.

[0568] (11-5)

[0569] The compound or salt thereof according to (11-4) above, wherein

[0570] R 3 is a group selected from the group consisting of the following formula (IV-1), formula (VII-1), formula (VIII-1), formula (IX), formula (X), formula (XI) and formula (XII-1),

[0571]

[0572] L is a group selected from the group consisting of the following formula (XXVII) to formula (XXXIV),

[0573]

[0574] With The carbon atom of is bonded to Y,

[0575] Z is a group selected from the group consisting of the following formula (XIII-1), formula (XVII-1) and formula (XIX-1),

[0576]

[0577] Furthermore, L is bonded to the benzene ring of the above formula (XIII-1) and formula (XVII-1),

[0578] G is CH or N,

[0579] When G is N, Z is the above-mentioned formula (XVII-1) or formula (XIX-1).

[0580] As examples of specific compounds included in the present invention, the following compounds or salts thereof can be mentioned as one embodiment.

[0581] 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,

[0582] (2S)-1-{6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinane-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.

[0583] As examples of specific compounds included in the present invention, the following compounds or salts thereof can be mentioned as one embodiment.

[0584] 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,

[0585] (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinane-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.

[0586] As examples of specific compounds included in the present invention, the following compounds or salts thereof can be mentioned as one embodiment.

[0587] 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,

[0588] (2S)-1-{(7P)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinane-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.

[0589] The compound of formula (I) may exist in tautomers and geometric isomers depending on the type of substituents. In this specification, the compound of formula (I) is sometimes described as only one form of isomer, but the present invention also includes other isomers, and also includes isolated products of isomers or mixtures thereof.

[0590] In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and diastereomers may exist based on this. The present invention also includes separated products of diastereomers of the compound of formula (I) or mixtures thereof.

[0591] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compounds shown in formula (I). Pharmaceutically acceptable prodrugs refer to compounds having groups that can be converted into amino, hydroxyl, carboxyl, etc. by solvolysis or under physiological conditions. As the groups forming the prodrug, for example, Prog. Med., 5, 2157-2161 (1985) and the groups described in "Development of Drugs" (Hirokawa Bookstore, 1990) Volume 7 Molecular Design 163-198 can be cited.

[0592] In addition, the salt of the compound of formula (I) refers to a pharmaceutically acceptable salt of the compound of formula (I), and may form an acid addition salt or a salt with a base depending on the type of the substituent. Examples thereof include salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specifically, examples include: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetyleucine, lysine, and ornithine; ammonium salts, etc.

[0593] Furthermore, the present invention also includes various hydrates, solvates and polymorphs of the compound of formula (I) and salts thereof.

[0594] In addition, the present invention includes all compounds of formula (I) or salts thereof labeled with one or more radioactive or non-radioactive isotopes acceptable in pharmaceutical sciences. Examples of preferred isotopes for isotope labeling of the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N, etc.), oxygen ( 15 O. 17 O and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), sulfur ( 35 S, etc.) isotopes.

[0595] The compounds of the present invention labeled with isotopes can be used in studies such as tissue distribution of drugs and / or substrates. For example, tritium ( 3 H), carbon 14 ( 14 C) and other radioactive isotopes are used for this purpose.

[0596] Replacement with a heavier isotope, such as replacement of hydrogen with deuterium ( 2H) is sometimes therapeutically advantageous due to improved metabolic stability (e.g., increased in vivo half-life, reduced dosage, reduced drug interactions).

[0597] Positron-emitting isotopes ( 11 C. 18 F. 15 O and 13 N, etc.) can be used in positron emission tomography (PET) experiments to test substrate receptor occupancy.

[0598] The isotope-labeled compounds of the present invention can be generally produced by conventional methods known to those skilled in the art or by the same production methods as in Examples or Production Examples using an appropriate isotope-labeled reagent instead of an unlabeled reagent.

[0599] (Manufacturing method)

[0600] The compound of formula (I) and its salt can utilize the feature based on the kind of its basic structure or substituent, and various known synthetic methods are applied to manufacture.At this moment, according to the kind of functional group, sometimes in advance, the functional group is replaced with suitable protecting group (the group that can be easily converted into the functional group) in the stage from raw material to intermediate, and this is effective in manufacturing technology.As such protecting group, for example, PGM Wuts and TW Greene write, " Greene's Protective Groups in Organic Synthesis ", the 5th edition, John Wiley & Sons Inc., the protecting group recorded in 2014 etc. can be enumerated, and use can be appropriately selected according to their reaction conditions.In such method, after importing this protecting group to react, removing protecting group as required, thus can obtain desired compound.

[0601] Pharmaceutically acceptable prodrugs refer to compounds having groups that can be converted into amino, hydroxyl, carboxyl, etc. by solvolysis or under physiological conditions. Examples of prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985), "Drug Development" (Hirokawa Bookstore, 1990), Vol. 7, Molecular Design, 163-198.

[0602] In addition, the prodrug of the compound of formula (I) can be prepared by introducing a specific group from the raw material to the intermediate stage or using the obtained compound of formula (I) to further react, as with the above-mentioned protecting group. The reaction can be carried out by applying a method known to those skilled in the art such as common esterification, amidation, dehydration, etc.

[0603] Representative methods for producing the compounds of formula (I) are described below. Each method can also be carried out with reference to the references attached to the description. It should be noted that the production method of the present invention is not limited to the examples shown below.

[0604] In this specification, the following abbreviations may be used.

[0605] DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropanol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, Pd / C: palladium supported on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidino Hexafluorophosphate, PyAOP: (7-azabenzotriazol-1-yloxy)tripyrrolidino Hexafluorophosphoric acid, SFC: supercritical fluid chromatography, NMM: N-methylmorpholine, CDI: 1,1'-carbonyldiimidazole, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea 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.

[0606] (Manufacturing method 1)

[0607]

[0608] (Wherein, -L 35 - indicates the -L contained in -L- 3 -L 4 -L 5 -. The same applies below.)

[0609] The production method is to produce a compound of formula (I) wherein A is N, -L contained in -L- 1 - is CO, -L 2 - is -N(R L2 )- or a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, -L 3 -L 4 -L 5 -for-L 35 -、RL2 H or C 1-6 A method for producing a compound of formula (I-1) having an alkyl group.

[0610] This reaction is a reaction in which an amide compound is obtained by using an equal amount or an excess amount of one of the compounds (1) and (2) and stirring the mixture thereof in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days in the presence of a condensing agent. Examples of solvents are not particularly limited, and include: 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-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenylphosphoryl azide (DPPA), etc. The method of using an additive (e.g., 1-hydroxybenzotriazole) is sometimes preferred for the reaction. The method of 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 is sometimes advantageous in terms of making the reaction proceed smoothly.

[0611] Alternatively, a method of converting compound (1) into a reactive derivative and then subjecting it to an acylation reaction may be used. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate or the like, and active esters obtained by condensation with 1-hydroxybenzotriazole or the like. The reaction of these reactive derivatives with compound (2) may be carried out in a solvent inert to the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether under cooling or heating, preferably at -20°C to 120°C.

[0612] [literature]

[0613] SR Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, Volume 1, Academic Press Inc., 1991

[0614] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0615] (Manufacturing method 2)

[0616]

[0617] (PG 71 Represents R 1 The NH protecting group contained in R 11 Indicates that from R 1 A divalent group formed by removing H from the NH contained in it. The same applies to the following.)

[0618] This production method is another production method of the compound of formula (I).

[0619] The compound of formula (I) can also be obtained by subjecting compound (3) to a deprotection reaction. Examples of the protecting group shown here include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl and the like.

[0620] The deprotection reaction is carried out by stirring from cooling to heating under reflux, usually for 0.1 hours to 5 days. Examples of solvents used here are not particularly limited, and include: alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform; ethers such as ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN or water; and mixtures thereof. Examples of deprotection reagents are not particularly limited, and include acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, and phosphoric acid.

[0621] By selecting a protecting group, deprotection can also be carried out by catalytic hydrogenation. Examples of protecting groups include benzyl, p-methoxybenzyl, benzyloxycarbonyl, etc. In addition, deprotection can also be carried out using fluoride ion sources such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl (dimethyl) silyl, (trimethylsilyl) ethoxymethyl, etc. Furthermore, examples of protecting groups that can be deprotected under alkaline conditions include acetyl, trifluoroacetyl, benzoyl, etc.

[0622] As reference documents, for example, the following documents can be referred to.

[0623] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[0624] AR Katritzky and RJK Taylor, "Comprehensive Organic Functional Group Transformations II", Volume 2, Elsevier Pergamon, 2005

[0625] (Manufacturing method 3)

[0626]

[0627] The present production method is a method for producing a compound of formula (I-2) wherein A is N in the compound of formula (I) by reacting compound (4) with compound (5).

[0628] In this reaction, compound (4) and compound (5) are used in equal amounts or in excess of one of them, and the mixture thereof is stirred in the presence of a condensing agent in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days. Examples of solvents are not particularly limited, and include: aromatic hydrocarbons such as 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, PyAOP, etc. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate is sometimes advantageous in terms of making the reaction proceed smoothly.

[0629] Alternatively, the compound (I-2) can be obtained by converting compound (4) into a reactive derivative in which the hydroxyl group at position 4 of compound (4) is converted into a chloro group using a chlorinating agent 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 solvent inert to the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether under cooling or heating, preferably at -20°C to 120°C.

[0630] (Manufacturing method 4)

[0631]

[0632] The production method is to convert -L contained in -L- in the compound of formula (I) into 1 - is CO, -L 2 - is -N(R L2 )- or a substituted divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms and -L 3 -L4 -L 5 -for-L 35 -、R L2 H or C 1-6 A method for producing a compound of formula (I-3) having an alkyl group.

[0633] In this reaction, the compound (I-3) can be obtained by subjecting the compound (69) and the compound (2) to the same reaction conditions as in Production Method 1.

[0634] (Raw material synthesis 1)

[0635]

[0636] (where LG 2 LG 4 LG 6 LG 7 LG 8 and LG 81 The same or different from each other, respectively represent leaving groups. 4 Indicates the protective group of OH, PG 7 and PG 71 Respectively represent R 1 The NH protecting group contained in R 11 Indicates that from R 1 The NH contained in the PG is freed from the H to form a divalent group. 8 Represents a protecting group that can be deprotected by catalytic hydrogenation reaction conditions, PG 81 Indicates a protecting group for COOH. 4 PG 7 PG 71 PG 8 and PG 81 It is also possible to select protecting groups that can be deprotected under different deprotection conditions and perform deprotection in stages. LG2 Represents C 1-12 Alkyl, BLG represents a boronic acid group or a trifluoroborate group protected by a boronic acid protecting group such as a boronic acid group or a boronic acid pinacol ester group (hereinafter sometimes referred to as a boronic acid group, etc.). Examples of the leaving group shown here include Cl, Br, I, methanesulfonyloxy, p-toluenesulfonyloxy, etc. The same applies to the following.)

[0637] This production method is a first method for producing compound (1) which is a starting compound of production method 1.

[0638] (First step)

[0639] This step is a method for producing compound (7) from compound (6).

[0640] This reaction is carried out by stirring compound (6) under cooling to heating reflux for 0.1 hour to 5 days. As the example of the solvent used here, it is not particularly limited, and alcohols, acetone, DMF, THF etc. can be listed. In addition, by setting the mixed solvent of the above-mentioned solvent and water, it is sometimes preferred for reaction. As the example of the reagent used in this reaction, it is not particularly limited, and sodium hydroxide aqueous solution, potassium hydroxide aqueous solution etc. can be listed.

[0641] As references for this reaction, for example, the following documents can be referred to.

[0642] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0643] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0644] (Second step)

[0645] This step is a method for producing compound (8) by protecting the hydroxyl group of compound (7) with a protecting group.

[0646] As an example, when the protection is performed by using a tert-butyl group, the reaction is carried out by stirring the compound (7) in the presence of a tert-butyl protecting agent under cooling or heating under reflux for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; tBuOH, DMF, etc. Examples of the tert-butyl protecting agent are not particularly limited, and include isobutylene, 2-tert-butyl-1,3-diisopropylisourea, etc.

[0647] Alternatively, compound (8) can also be produced by a dehydration condensation reaction of compound (7) and tBuOH.

[0648] As references for this reaction, for example, the following documents can be referred to.

[0649] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[0650] Org. Lett., 2012, 14, 17, p.4678-4681

[0651] (Third step)

[0652] This step is to react compound (8) with R LG2 A method for producing compound (10) by in-situ substitution reaction of -SH.

[0653] As the R used here LG2 Examples of -SH include C 1-12 Alkyl mercaptan, for example ethyl mercaptan, dodecanethiol.

[0654] In this reaction, the compound (8) and the compound (9) are used in equal amounts or in excess of one of them, and the mixture thereof is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or under heating reflux, preferably at 0°C to 80°C, for usually 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN; and mixtures thereof. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate is sometimes advantageous in terms of making the reaction proceed smoothly.

[0655] (Step 4)

[0656] This step is to react compound (10) with PG as compound (11). 8 A method for preparing compound (12) by in-situ substitution reaction of -OH. 8 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol.

[0657] The reaction conditions are the same as those in the third step of the raw material synthesis 1.

[0658] (Fifth step)

[0659] This step is to react compound (12) with a compound (13) containing R 2 A method for producing compound (14) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as -boronic acid group.

[0660] Examples of the boronic acid group and the like used herein are not particularly limited, and examples thereof include a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol boric acid ester salt group, and a trifluoroborate salt group.

[0661] In this reaction, compound (12) and a compound containing R are used in equal amounts or one of them is used in excess. 2-boronic acid derivatives such as boronic acid groups, and a mixture of these is stirred in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating reflux, preferably at 20°C to 140°C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include: halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropanol, butanol, and pentanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water; and mixtures thereof. As bases, inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide can be listed. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf)·CH2Cl2, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and the like. Conducting the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, or 1,1'-bis(diphenylphosphino)ferrocene may be advantageous in terms of smoothing the reaction. In addition, heating the mixture by microwave irradiation may be advantageous in terms of smoothing the reaction.

[0662] [literature]

[0663] J. Am. Chem. Soc., 2005, 127, p.4685-4696

[0664] Org. Lett. 2011, 13, p.3948-3951

[0665] Org. Lett. 2012, 14, p.1278-1281

[0666] In addition, LG 6 When the compound (12) is a halogen atom, the compound (14) (where R 2 is hydrogen).

[0667] [literature]

[0668] J. Org. Chem., 1977, 42, p.3491-3494

[0669] Tetrahedron Letters 2013, 54, 5207-5210

[0670] (Sixth step)

[0671] This step is a method for preparing compound (16) by Suzuki-Miyaura coupling reaction of compound (14) and compound (15).

[0672] The reaction conditions are the same as those in the fifth step of the raw material synthesis 1.

[0673] When compound (16) has axial asymmetry, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0674] (Step 7)

[0675] This step is a method for producing compound (17) by oxidation reaction of compound (16).

[0676] In this reaction, compound (16) is treated with an equal amount or an excess of an oxidizing agent in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 80°C, for usually 0.1 hour to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is preferably used. Examples of solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, potassium monopersulfate (Oxone), active manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.

[0677] [literature]

[0678] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 17, Maruzen, 2004

[0679] It should be noted that when compound (17) has axial asymmetry, it may be obtained as a mixture of stereoisomers. Each stereoisomer can be isolated by performing conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography, resolution using SFC using a chiral column, etc.

[0680] (Step 8)

[0681] This step is a method for preparing compound (19) by an in-situ substitution reaction of compound (17) and compound (18).

[0682] The reaction conditions are the same as those in the third step of the raw material synthesis 1.

[0683] (Step 9)

[0684] This step is a method for producing compound (20) by deprotecting compound (19) using a catalytic hydrogenation reaction.

[0685] The reaction can be carried out as follows: Compound (19) is stirred for 1 hour to 5 days in a hydrogen atmosphere, at normal pressure to pressure, in a solvent inert to the reaction such as MeOH, EtOH, ethyl acetate, etc., in the presence of a metal catalyst, under cooling or heating, preferably at room temperature. As the metal catalyst, palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plates and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel are used.

[0686] (Step 10)

[0687] This step is a method for producing compound (22) from compound (20) and compound (21).

[0688] This reaction is carried out by using compound (20) and compound (21) in equal amounts or in excess of one of them, and reacting the mixture in the presence of a base in a solvent inert to the reaction under cooling or heating under reflux, preferably at 0°C to 80°C, for usually 0.1 hour to 5 days. The solvent used here is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Examples of the base are not particularly limited, and examples thereof include: organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. It is sometimes advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.

[0689] As references for this reaction, for example, the following documents can be referred to.

[0690] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 14, Maruzen, 2005

[0691] In addition, for compound (21), 81 Halogenation of a compound having a considerable portion of hydroxyl groups can produce LG 81 The halogenating agent used here is not particularly limited, and examples thereof include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, and the like.

[0692] As references for this reaction, for example, the following documents can be referred to.

[0693] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 13, Maruzen, 2004

[0694] Furthermore, for compound (21), LG 81 LG can be produced by sulfonylation of a compound having a considerable portion of hydroxyl groups in the presence of a base. 81 The example of the sulfonylating agent used here is not particularly limited, and examples thereof include methanesulfonyl chloride, p-toluenesulfonyl chloride, and methanesulfonic anhydride. The example of the base is not particularly limited, and examples thereof include TEA, DIPEA, pyridine, and tetramethylethylenediamine.

[0695] As references for this reaction, for example, the following documents can be referred to.

[0696] Synthesis 1999, 9, p.1633-1636

[0697] (Step 11)

[0698] This step is to carry out the protection of compound (22) i.e. PG 4 and PG 7 Deprotection of PG 71 Protect R 11 A method for preparing compound (23) by deprotecting the NH group contained in the compound.

[0699] The reaction conditions are the same as those in the step described in Preparation Method 2. In addition to Compound (22) and the deprotecting agent, a PG 71 The reaction is carried out using a protecting reagent for protecting the NH group.

[0700] (Step 12)

[0701] This step is a method for producing compound (24) by reacting compound (23) with compound (5).

[0702] The reaction conditions are the same as those in Preparation Method 3.

[0703] (Step 13)

[0704] This step is a method for producing compound (1) by subjecting compound (24) to a deprotection reaction.

[0705] The reaction conditions are the same as those in the step described in Production Method 2.

[0706] (Raw material synthesis 2)

[0707]

[0708] (In the formula, PG 82 Represents C 1-3 Alkyl. The same applies below.)

[0709] This production method is to produce a compound (3) which is a raw material compound of production method 2, wherein A is N and -L- 1 - is CO, -L 2 - is -N(R L2 )- or a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, -L 3 -L 4 -L 5 -for-L 35 -、R L2 H or C 1-6 The first method of preparing an alkyl compound (3-1).

[0710] (First step)

[0711] This step is a method for preparing compound (26) by reacting compound (25) with compound (5).

[0712] The reaction conditions are the same as those in Preparation Method 3.

[0713] (Second step)

[0714] This step is a method for producing compound (27) by hydrolyzing compound (26) under basic conditions.

[0715] The reaction is carried out by stirring compound (26) under cooling or heating under reflux for 0.1 hour to 5 days. Examples of solvents used herein are not particularly limited, and include alcohols, acetone, DMF, THF, etc. In addition, a mixed solvent of the above solvent and water is sometimes preferred for the reaction. Examples of hydrolysis reagents are not particularly limited, and include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, trimethyltin hydroxide, etc.

[0716] As references for this reaction, for example, the following documents can be referred to.

[0717] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0718] Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0719] (Third step)

[0720] This step is a method for producing compound (3-1) by subjecting compound (27) and compound (2) to an amidation reaction.

[0721] The reaction conditions are the same as those in the step described in Production Method 1.

[0722] (Raw material synthesis 3)

[0723]

[0724] This production method is to produce a compound (3) which is a raw material compound of production method 2, wherein A is N and -L- 1 - is CO, -L 2 - is -N(R L2 )- or a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, -L 3 -L 4 -L 5 -for-L 35 -、R L2 H or C 1-6 The second method for preparing the alkyl compound (3-1).

[0725] (First step)

[0726] This step is a method for preparing compound (29) from compound (20) and compound (28).

[0727] The reaction conditions are the same as those in the tenth step of starting material synthesis 1.

[0728] (Second step)

[0729] This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction.

[0730] The reaction conditions are the same as those in the second step of the starting material synthesis 2.

[0731] (Third step)

[0732] This step is a method for producing compound (31) by subjecting compound (30) and compound (2) to an amidation reaction.

[0733] The reaction conditions are the same as those in the step described in Production Method 1.

[0734] (Step 4)

[0735] This step is to remove the protective group of compound (31), namely PG 4 and PG 7 Deprotection of PG 71 Protect R 11A method for preparing compound (32) by deprotecting the NH group contained in the compound.

[0736] The reaction conditions are the same as those in the step described in Preparation Method 2. In addition to compound (31) and the deprotecting agent, a PG 71 The reaction is carried out using a protecting reagent for protecting the NH group.

[0737] (Fifth step)

[0738] This step is a method for producing compound (3-1) by reacting compound (32) with compound (5).

[0739] The reaction conditions are the same as those in Preparation Method 3.

[0740] (Raw material synthesis 4)

[0741]

[0742] (In the formula, -L'- represents the -L contained in -L- 1 -L 2 -L 3 -, -R Z Indicates -CHO or -CH2-LG 81 , P.G. 83 represents the protecting group of NH bonded to L'. Here, R L ' is H or C 1-3 Alkyl, or a divalent group that can form a saturated heterocyclic ring containing 1 to 2 nitrogen atoms together with the adjacent nitrogen atom and L'.

[0743] This production method is to produce -L contained in -L- in compound (4) which is a raw material compound in production method 3. 4 - is -N(R L’ )-、-L 5 - is a compound (4-1) wherein - is -CH2-.

[0744] (First step)

[0745] This step is a method for producing compound (34) from compound (20) and compound (33).

[0746] The reaction conditions are the same as those in the tenth step of starting material synthesis 1.

[0747] (Second step)

[0748] This step is a method for producing compound (35) by subjecting compound (34) to a deprotection reaction.

[0749] The reaction conditions are the same as those in the step described in Production Method 2.

[0750] (Third step)

[0751] This step is a step of obtaining compound (4-1) from compound (35) and compound (36), wherein -R Z When -CHO is used, it is obtained by reductive amination. Z -CH2-LG 81 When, it is obtained by alkylation reaction.

[0752] -R Z When -CHO is used, the compound (35) and the compound (36) are used in equal amounts or in excess of one of the equivalents, and the reaction is carried out in the presence of a reducing agent and acetic acid in a solvent inert to the reaction under ice cooling to room temperature, usually with stirring for 1 hour to 5 days. Examples of the reducing agent used here are not particularly limited, and include NaBH(OAc)3, 2-methylpyridine borane, NaBH3CN, and the like. The solvent used here is not particularly limited, and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; ether solvents such as THF, diethyl ether, and DOX; alcohol solvents such as MeOH and EtOH; or MeCN, and the like can be used.

[0753] -R Z -CH2-LG 81 The reaction conditions are the same as those in the tenth step of raw material synthesis 1.

[0754] (Raw material synthesis 5)

[0755]

[0756] (In the formula, PG 41 Represents the protecting group of NH, R 31 Represents R 3a -N(R 3b )CO-、R 3c -OCO- or R 3d -CO-. )

[0757] This production method is to produce a compound (1) which is a raw material compound of production method 1 wherein R 3 is Formula (IV), Formula (V) or Formula (VI) and X 3 A method for preparing a compound (52) wherein the compound is O.

[0758] (First step)

[0759] This step is to react compound (6) with compound (9), namely R LG2 A method for preparing compound (37) by in-situ substitution reaction of -SH.

[0760] The reaction conditions are the same as those in the third step of the starting material synthesis 1.

[0761] (Second step)

[0762] This step is a method for preparing compound (38) by an in-situ substitution reaction of compound (37) and compound (11).

[0763] The reaction conditions are the same as those in the fourth step of starting material synthesis 1.

[0764] (Third step)

[0765] This step is to react compound (38) with a protected group PG 41 A method for preparing compound (40) by in situ substitution reaction of compound (39) having a protected amino group.

[0766] In this reaction, compound (38) and compound (39) are used in equal amounts or in excess of one of them, and the mixture thereof is stirred in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 60°C, for usually 0.1 hour to 5 days. Examples of the solvent are not particularly limited, and include: aromatic hydrocarbons such as toluene; halogenated hydrocarbons such as dichloromethane; DMF, DMSO, ethyl acetate, MeCN; and mixtures thereof. Conducting the reaction in the presence of an organic base such as TEA, DIPEA or NMM, or an inorganic base such as potassium carbonate, sodium carbonate or cesium carbonate is sometimes advantageous in terms of making the reaction proceed smoothly.

[0767] (Step 4)

[0768] This step is to react compound (40) with compound (13) containing R 2 A method for preparing compound (41) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as -boronic acid group.

[0769] The reaction conditions are the same as those in the fifth step of the starting material synthesis 1.

[0770] (Fifth step)

[0771] This step is a method for preparing compound (42) by Suzuki-Miyaura coupling reaction of compound (41) and compound (15).

[0772] The reaction conditions are the same as those in the fifth step of the starting material synthesis 1.

[0773] When compound (42) has axial asymmetry, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0774] (Sixth step)

[0775] This step is a method for producing compound (43) by oxidation reaction of compound (42).

[0776] The reaction conditions are the same as those in the seventh step of the starting material synthesis 1.

[0777] When compound (43) has axial asymmetry, it may be obtained as a mixture of stereoisomers. The individual stereoisomers can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography, or resolution using SFC using a chiral column.

[0778] (Step 7)

[0779] This step is a method for preparing compound (44) by an in situ substitution reaction of compound (43) and compound (18).

[0780] The reaction conditions are the same as those in the third step of the starting material synthesis 1.

[0781] (Step 8)

[0782] This step is a method for producing Compound (45) by deprotecting Compound (44) using a catalytic hydrogenation reaction.

[0783] The reaction conditions are the same as those in the ninth step of the starting material synthesis 1.

[0784] (Step 9)

[0785] This step is a method for preparing compound (46) from compound (45) and compound (21).

[0786] The reaction conditions are the same as those in the tenth step of starting material synthesis 1.

[0787] (Step 10)

[0788] This step is a method for producing compound (47) by subjecting compound (46) to a deprotection reaction.

[0789] The reaction conditions are the same as those in the step described in Production Method 2.

[0790] (Step 11)

[0791] This step is a step of obtaining compound (51) by subjecting compound (47) to urea formation reaction using compound (48), urea formation reaction using compound (49), and amidation reaction using compound (50).

[0792] In the ureidation reaction using compound (48) and the carbamate reaction using compound (49), compound (48) or compound (49) is used in an equal amount or an excess amount of one of them relative to compound (47), and the mixture thereof is stirred in a solvent inert to the reaction under cooling or heating, preferably at -20°C to 60°C, in the presence of a condensing agent for usually 0.1 hour to 5 days. Examples of the solvent are not particularly limited, and include: 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 the condensing agent include CDI, triphosgene, bis(4-nitrophenyl) carbonate, 4-nitrophenyl chloroformate, and the like. The use of an additive (e.g., 1-hydroxybenzotriazole, dimethylaminopyridine) is sometimes preferred for the reaction. Conducting the reaction in the presence of an organic base such as TEA, DIPEA or NMM, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide may be advantageous in that the reaction proceeds smoothly.

[0793] The reaction conditions for the amidation reaction using compound (50) are the same as those in the step described in Production Method 1.

[0794] (Step 12)

[0795] This step is a method for producing Compound (52) by subjecting Compound (51) to a deprotection reaction.

[0796] The reaction conditions are the same as those in the step described in Production Method 2.

[0797] (Raw material synthesis 6)

[0798]

[0799] This production method is a second method for producing compound (1) which is a starting compound of production method 1.

[0800] (First step)

[0801] This step is a method for producing Compound (53) by deprotecting Compound (17) using a catalytic hydrogenation reaction.

[0802] The reaction conditions are the same as those in the ninth step of the starting material synthesis 1.

[0803] (Second step)

[0804] This step is a method for preparing compound (54) from compound (53) and compound (21).

[0805] The reaction conditions are the same as those in the tenth step of starting material synthesis 1.

[0806] (Third step)

[0807] This step is a method for preparing compound (55) by an in situ substitution reaction of compound (54) and compound (18).

[0808] The reaction conditions are the same as those in the third step of the starting material synthesis 1.

[0809] (Step 4)

[0810] This step is a method for producing compound (56) by subjecting compound (55) to a deprotection reaction.

[0811] The reaction conditions are the same as those in the step described in Production Method 2.

[0812] (Fifth step)

[0813] This step is a method for preparing compound (57) by reacting compound (56) with compound (5).

[0814] The reaction conditions are the same as those in Preparation Method 3.

[0815] (Sixth step)

[0816] This step is a method for producing compound (1) by subjecting compound (57) to a deprotection reaction.

[0817] The reaction conditions are the same as those in the step described in Production Method 2.

[0818] (Raw material synthesis 7)

[0819]

[0820] This production method is to produce a compound (3) which is a raw material compound of production method 2, wherein A is N, -L contained in -L- 1 - is CO, -L 2 - is -N(R L2 )- or a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, -L 3 -L 4 -L 5 -for-L 35 -、R L2 H or C 1-6 A method for preparing an alkyl compound (61).

[0821] (First step)

[0822] This step is a method for producing compound (58) by subjecting compound (29) to a deprotection reaction.

[0823] The reaction conditions are the same as those in the step described in Production Method 2.

[0824] (Second step)

[0825] This step is a method for preparing compound (59) by reacting compound (58) with compound (5).

[0826] The reaction conditions are the same as those in Preparation Method 3.

[0827] (Third step)

[0828] This step is a method for producing compound (60) by subjecting compound (59) to a deprotection reaction.

[0829] The reaction conditions are the same as those in the second step of the starting material synthesis 2.

[0830] (Step 4)

[0831] This step is a method for producing Compound (61) by subjecting Compound (60) and Compound (2) to an amidation reaction.

[0832] The reaction conditions are the same as those in the step described in Production Method 1.

[0833] (Raw material synthesis 8)

[0834]

[0835] This production method is a method for producing compound (69) which is a starting compound in production method 4.

[0836] (First step)

[0837] This step is a method for preparing compound (62) by an in situ substitution reaction between compound (38) and compound (5).

[0838] The reaction conditions are the same as those in the third step of the starting material synthesis 5.

[0839] (Second step)

[0840] This step is to react compound (62) with a compound (13) containing R 2 A method for preparing compound (63) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[0841] The reaction conditions are the same as those in the fifth step of the starting material synthesis 1.

[0842] (Third step)

[0843] This step is a method for preparing compound (64) by Suzuki-Miyaura coupling reaction of compound (63) and compound (15).

[0844] The reaction conditions are the same as those in the fifth step of the starting material synthesis 1.

[0845] When compound (64) has axial asymmetry, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0846] (Step 4)

[0847] This step is a method for producing compound (65) by oxidation reaction of compound (64).

[0848] The reaction conditions are the same as those in the seventh step of the starting material synthesis 1.

[0849] It should be noted that when compound (65) has axial asymmetry, it may be obtained as a mixture of stereoisomers. The individual stereoisomers can be isolated by conventional resolution operations, such as resolution using ODS column chromatography or silica gel column chromatography, or resolution using SFC using a chiral column.

[0850] (Fifth step)

[0851] This step is a method for preparing compound (66) by an in situ substitution reaction of compound (65) and compound (18).

[0852] The reaction conditions are the same as those in the third step of the starting material synthesis 1.

[0853] (Sixth step)

[0854] This step is a method for preparing Compound (67) by deprotecting Compound (66) using a catalytic hydrogenation reaction.

[0855] The reaction conditions are the same as those in the ninth step of the starting material synthesis 1.

[0856] (Step 7)

[0857] This step is a method for preparing compound (68) from compound (67) and compound (21).

[0858] The reaction conditions are the same as those in the tenth step of starting material synthesis 1.

[0859] (Step 8)

[0860] This step is a method for preparing Compound (69) by subjecting Compound (68) to a deprotection reaction.

[0861] The reaction conditions are the same as those in the step described in Production Method 2.

[0862] (Raw material synthesis 9)

[0863]

[0864] (where LG CB represents the leaving group, PG CB Indicates L 2 The protecting group of NH contained in it. )

[0865] This production method is to produce the compound (2) which is the raw material compound of the production method 1: -L 2 - is a divalent group of a saturated heterocyclic ring containing two nitrogen atoms which may be substituted, -L 35 - is a compound (2-1) wherein - is -CH2-.

[0866] (First step)

[0867] This step is a method for preparing compound (72) by Suzuki-Miyaura coupling reaction of compound (70) and compound (71).

[0868] The reaction conditions are the same as those in the fifth step of the starting material synthesis 1.

[0869] (Second step)

[0870] This step is a method for preparing Compound (73) as an aldehyde from Compound (72).

[0871] This reaction is a reaction in which compound (72) and osmium tetroxide are reacted in the presence of an organic base in a solvent inert to the reaction under cooling to room temperature to obtain the corresponding 1,2-diol compound, and then a periodic acid is added to the reaction mixture to oxidize the 1,2-diol, thereby obtaining compound (73) as an aldehyde. Examples of the solvent used here include alcohols such as tBuOH; ethers such as THF, DOX, and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, and xylene; acetone; and mixed solvents thereof with water. In addition, examples of the organic base used here include pyridine, 2,6-lutidine, and the like, and examples of the periodic acid used here include sodium periodate, periodic acid, and the like.

[0872] (Third step)

[0873] This step is a method for preparing Compound (75) by reductive amination reaction using Compound (73) and Compound (74) as an amine compound.

[0874] Reaction conditions and starting materials In the third step of synthesis 4 -R Z The same as -CHO.

[0875] (Step 4)

[0876] This step is a reaction in which compound (2-1) is obtained by subjecting compound (75) to a deprotection reaction.

[0877] The reaction conditions are the same as those in Preparation Method 2.

[0878] The pharmacological activity of the compound of formula (I) was confirmed by the following test.

[0879] Experimental Example 1 Evaluation of RAS G12V degradation effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[0880] The RASG12V degrading effect of the test compound was evaluated by measuring the expression level of RASG12V using the cell ELISA method.

[0881] PA-TU-8902 cells (DSMZ, ACC 179) were cultured at 1.5 x 10 4 Each 36 μL of each cell was inoculated in a 384-well plate (Greiner Bio-One) in the form of 10 cells. The cell culture conditions were DMEM medium (Sigma-Aldrich) containing 10% fetal bovine serum (Cytiva) at 37°C in the presence of 5% CO2.

[0882] The next day, the test compound (10 points in the range of final concentration 3 μM to 0.1 nM), the compound of Example No. 7 with a final concentration of 3 μM as a positive control, and the solvent of the test compound, i.e., dimethyl sulfoxide (DMSO) as a negative control, were diluted 100-fold with fresh culture medium, 4 μL were added to each well, and cultured for 24 hours.

[0883] The next day, the culture supernatant was removed, 20 μL of 4% paraformaldehyde phosphate buffer (FUJIFILM Wako) was added to each well, and the cells were fixed by standing 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 standing at room temperature for 10 minutes, the supernatant was removed, 25 μL of PBS was added to each well, and the supernatant was removed to wash each well, and the operation was performed twice in total. Subsequent washing operations were performed in the same manner. Then, the supernatant was removed, 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; ThermoFisher Scientific) was added to each well, and after standing at room temperature for 10 minutes, 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 standing at room temperature for 30 minutes, the supernatant was removed by centrifugation, and 15 μL of a solution diluted with Can Get Signal Solution 2 (TOYOBO) using anti-Ras (G12V mutation specific) antibody (Ras (G12V Mutant Specific) (D2H12) Rabbit mAb; Cell Signaling Technology; 500-fold dilution) and anti-β-actin antibody (Anti-betaActin antibody; Abcam; 5000-fold dilution) as primary antibodies was added to each well, and the mixture was left standing at 4°C overnight.

[0884] The next day, the supernatant was removed by centrifugation and washed with PBS. The supernatant was removed by centrifugation, and 15 μL of a solution obtained by diluting the 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) as the secondary antibody 1000 times with Can Get Signal Solution 2 was added to each well. After standing at room temperature for 1 hour, the supernatant was removed by centrifugation and washed with PBS. After removing the supernatant, the plate was directly air-dried at room temperature for more than 2 hours, and the fluorescence signals at 700nm and 800nm ​​were measured using Aerius (Li-COR Biosciences).

[0885] The RAS G12V signal value corrected by the signal value of β-actin 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 decomposition rate of RAS G12V was calculated. The decomposition rate at the compound concentration showing the highest decomposition effect was set to Dmax, and the 50% decomposition value (DC) of RAS G12V was calculated by Sigmoid-Emax model nonlinear regression analysis based on the decomposition rate until the compound concentration showing Dmax. 50 The results of several test compounds of formula (I) are shown in the following table.

[0886] [Table 1]

[0887]

[0888] Experimental Example 2 Evaluation of ERK phosphorylation inhibition on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[0889] The ERK phosphorylation inhibitory effect of the test compound was evaluated by measuring the phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is located downstream of KRAS signaling, by cell ELISA.

[0890] PA-TU-8902 cells were plated at 5.0 x 10 3 The cells were inoculated in a 384-well plate at 36 μL / well. Cell culture was performed under the same conditions as in Test Example 1.

[0891] The next day, the test compound (9 points in the range of final concentrations of 3μM to 0.3nM), trametinib (MEK inhibitor) at a final concentration of 300nM as a positive control, and DMSO, the solvent of the test compound as a negative control, were diluted 100 times with fresh culture medium, and 4μL was added to each well, and cultured for 24 hours. After culture, 30μL of 30% glyoxal solution (40% glyoxal [NAKALI TESQUE] diluted with PBS) was added to each well immediately, and the cells were fixed by standing at room temperature for 1 hour and 30 minutes. Then, the plate was centrifuged (110×g, 7 seconds, and centrifugation was performed under this condition unless otherwise specified), the supernatant was removed, and 20μL of PBS containing 0.1% Triton X-100 was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation, and the same operation was repeated. Then, 20 μL of PBS containing 0.5% SDS was added to each well, and the cells were centrifuged after standing at room temperature for 30 minutes to remove the supernatant. Next, 20 μL of blocking solution (Intercept Blocking Buffer) was added to each well and allowed to stand at room temperature for 1 hour. The supernatant was removed by centrifugation, and 15 μL of a phosphorylated antibody of ERK (Thr202 / Tyr204) (Phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology) diluted 2500 times with blocking solution was added to each well as a primary antibody, and allowed to stand overnight at 4°C.

[0892] The next day, the plate was centrifuged, the supernatant was removed, and 50 μL of PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 was diluted 20 times with ion exchange water before use) was added to each well, and each well was washed by centrifugation to remove the supernatant. Washing was performed a total of 3 times. After washing, 15 μL of anti-rabbit antibody diluted 1000 times with blocking solution was added to each well as a secondary antibody, and allowed to stand at room temperature for 1 hour. The plate was centrifuged, the supernatant was removed, and each well was washed 3 times in the same manner after reacting with the primary antibody in PBS containing 0.05% Tween-20. Centrifugation after the third wash was performed at 171×g for 17 seconds. After removing the supernatant, the plate was directly air-dried at room temperature for more than 3 hours, and the fluorescence signal at 800 nm was measured using Aerius.

[0893] The signal value when DMSO was added was set as 0% inhibition, and the signal value when 300 nM trametinib was added was set as 100% inhibition. The 50% inhibition value (IC 50).

[0894] Experimental Example 3 Evaluation of the anchorage-independent cell proliferation inhibitory effect on the human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[0895] The anchorage-independent cell proliferation inhibitory effect of the test compound was evaluated by spheroid three-dimensional culture.

[0896] PA-TU-8902 cells were plated at 5 × 10 2 The cells were inoculated in a low-adhesion U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite Co., Ltd.) at 36 μL / well. The cell culture was performed under the same conditions as in Experimental Example 1.

[0897] The next day, the test compound (final concentration range 3μM to 0.1nM, 8 to 10 points) and the solvent of the test compound as a negative control, DMSO, were diluted 100 times with fresh culture medium, and 4μL was added to each well. After culturing at 37°C for 6 days in the presence of 5% CO2, 20μL of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring for 1 hour at room temperature using a plate mixer (FINEPCR), the luminescent signal was measured using ARVO X3 (PerkinElmer).

[0898] The signal value in the case of DMSO treatment was set as 0% inhibition, and the signal value in the case of medium alone without cells was set as 100% inhibition. The 50% inhibition value (IC 50 ). The results of several test compounds of formula (I) are shown in the following table. For Example No. 17, the inhibition rate at 30 nM was calculated. It should be noted that 50% inhibition @ 30 nM means that the test compound has 50% inhibitory activity at a concentration of 30 nM.

[0899] [Table 2-1]

[0900]

[0901] [Table 2-2]

[0902]

[0903] Experimental Example 4 Evaluation of the inhibitory effect on anchorage-independent cell proliferation of human KRAS G12V mutation-positive lung adenocarcinoma line LCLC-97TM1

[0904] The anchorage-independent cell proliferation inhibitory effect of the test compound was evaluated by spheroid three-dimensional culture.

[0905] LCLC-97TM1 cells (DSMZ, ACC 388) were cultured at 7.5 x 10 2 The cells were seeded in a low-adhesion U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite Co., Ltd.) at 36 μL / well. The cell culture conditions were RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[0906] The next day, the test compound (final concentration range 10 μM to 0.1 nM, 9 points) and the solvent of the test compound as a negative control, DMSO, were diluted 100 times with fresh culture medium, and 4 μL was added to each well. After culturing at 37°C for 6 days 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), the luminescent signal was measured using ARVO X3 (PerkinElmer).

[0907] The signal value in the case of DMSO treatment was set as 100% survival rate, and the signal value in the case of medium alone without cells was set as 0% survival rate. The 50% survival value (IC50) was calculated by Sigmoid-Emax model nonlinear regression analysis.

[0908] Experimental Example 5 Evaluation of the anti-tumor effect in mice bearing the human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[0909] PA-TU-8902 cells were cultured under the same conditions as in Experimental Example 1. PA-TU-8902 cells were recovered, suspended in PBS, and 2 equal amounts of VitroGel Hydrogel Matrix (The Well Bioscience Company) were added to prepare a 1.0-3.0×10 7 / mL, and the cell suspension was implanted subcutaneously in 4-6 week old male nude mice (BALB / c-nu (nu / nu), Charles River, Japan) at a volume of 100 μL. About 2 weeks after implantation, the mice were divided into groups so that the tumor volume and body weight were approximately equal, and the test compound was administered from the next day. The test was conducted under the conditions of 5 mice in each solvent group and test compound administration group. The compound was dissolved in a solvent composed of 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 Chemical), and 1M sodium hydroxide aqueous solution (Kanto Chemical) at a liquid volume ratio of 4:84.4:1.1:1:9:0.5. The test compound dissolved in the solvent or the solvent was administered into the tail vein. The administration was once or twice a week for up to 3 weeks. Tumor diameter and body weight were measured twice a week. Tumor volume was calculated using the following formula.

[0910] [Tumor volume (mm 3 )] = [longer diameter of the tumor (mm)] x [shorter diameter of the tumor (mm)] 2 x 0.5

[0911] The tumor growth inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition and the tumor volume of the solvent group on the last 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% reduction, and the tumor volume 0 was set as 100% reduction, and the tumor reduction rate (%) of the test compound was calculated.

[0912] Experimental Example 6 Evaluation of the anti-tumor effect in mice bearing the human G12V mutant KRAS-positive lung adenocarcinoma line LCLC-97TM1

[0913] Cell culture was performed under the same conditions as in Experimental Example 4. LCLC-97TM1 cells were recovered, suspended in PBS, and 2 times the amount of VitroGel Hydrogel Matrix (The Well Bioscience) was added to prepare 3.0×10 6 / 100μL, and the cell suspension was implanted subcutaneously into male nude mice (BALB / c-nu(nu / nu), Charles River, Japan) aged 4 to 6 weeks. About 2-3 weeks after implantation, the mice were divided into groups so that the tumor volumes were roughly equal between the groups, and the test compound was started. The experiment was conducted with 5 mice in each solvent group and test compound administration group. For the solvent group, the solvent was administered intravenously, and for the test compound administration group, a solution of the test compound dissolved in the solvent was administered intravenously. The solvent used was the same as that in Experimental Example 5. The drug was administered once a week, for a total of 2 times. Tumor diameter and body weight were measured twice a week. The following formula is used to calculate the tumor volume.

[0914] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] x [short diameter of tumor (mm)] 2 x 0.5

[0915] The tumor growth inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition and the tumor volume of the solvent group on the last 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% reduction, and the tumor volume 0 was set as 100% reduction, and the tumor reduction rate (%) of the test compound was calculated.

[0916] According to the results of the above test, the effect of inducing the decomposition of G12V mutant KRAS was confirmed for several compounds of formula (I). In addition, the cell proliferation inhibitory effect on human G12V mutant KRAS positive pancreatic cancer and / or lung cancer strains was confirmed for several compounds of formula (I). In addition, the anti-tumor effect in human G12V mutant KRAS positive lung cancer strain-bearing mice was confirmed for several compounds of formula (I). Therefore, the compound of formula (I) can be used to treat pancreatic cancer and / or lung cancer, especially KRAS G12V mutation-positive pancreatic cancer and / or lung cancer, etc.

[0917] The pharmaceutical composition containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, ie, pharmaceutical excipients or pharmaceutical carriers.

[0918] Administration may be any of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intra-articular, intravenous, intramuscular, transmucosal, and inhalants.

[0919] As solid compositions for oral administration, tablets, powders, granules, etc. can be used. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The composition can contain inert additives such as lubricants, disintegrants, stabilizers, and dissolution aids according to conventional methods. Tablets or pills can be coated with sugar coatings or films of gastric soluble or enteric soluble substances as needed.

[0920] The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, etc., and contains a commonly used inert diluent, such as purified water or EtOH. In addition to the inert diluent, the liquid composition may also contain auxiliary agents such as solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0921] Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. As aqueous solvents, for example, distilled water for injection or physiological saline are contained. As non-aqueous solvents, for example, alcohols such as EtOH are contained. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. They are sterilized, for example, by filtering through a bacteria-retaining filter, by the combination of a bactericide or by irradiation. In addition, they can also be made into sterile solid compositions and dissolved or suspended in sterile water or a sterile injection solvent before use.

[0922] Inhalants or transmucosal agents such as nasal agents can use solid, liquid or semi-solid substances and can be manufactured according to the methods known in the past. For example, known excipients, pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. Apparatus for appropriate inhalation or blowing can be used for administration. For example, known apparatuses or sprayers such as metered dosing inhalation apparatuses can be used to administer the compound alone or in the form of a powder of a mixture forming a formula, or in combination with a pharmaceutically acceptable carrier in the form of a solution or suspension. Dry powder inhalers, etc. can be inhalers for one or more administrations, and dry powders or capsules containing powders can be used. Alternatively, it can be a pressurized aerosol spray using a suitable propellant, such as a suitable gas such as chlorofluoroalkane or carbon dioxide.

[0923] In the case of oral administration, the daily dosage is about 0.001 to 100 mg / kg per unit body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, which is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dosage is about 0.0001 to 10 mg / kg per unit body weight, which is administered once a day or divided into multiple times. In addition, as a transmucosal agent, about 0.001 to 100 mg / kg per unit body weight is administered once a day or divided into multiple times. The dosage can be appropriately determined according to the symptoms, age, gender, etc. and according to the respective circumstances.

[0924] Although it varies depending on the administration route, dosage form, administration site, and the type of excipients or additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0925] The compound of formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of formula (I) is believed to be effective. The combined use can be simultaneous administration, or separate administration continuously or at intervals of desired time. The preparation for simultaneous administration can be a compounding agent, or it can be separately formulated.

[0926] Example

[0927] The following is a further detailed description of the preparation method of the compound of formula (I) based on the examples. It should be noted that the present invention is not limited to the compounds described in the following examples. In addition, the preparation method of the raw material compound is shown in the preparation example. In addition, the preparation method of the compound of formula (I) is not limited to the preparation method of the specific embodiments shown below, and the compound of formula (I) can also be prepared by the combination of these preparation methods or by a method obvious to those skilled in the art.

[0928] In addition, in this specification, naming software, such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.), may be used to name compounds.

[0929] In addition, for the sake of convenience, the concentration mol / L is expressed as M. For example, 1M sodium hydroxide aqueous solution means 1 mol / L sodium hydroxide aqueous solution.

[0930] Production Example 1

[0931] 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (30.9 g) was suspended in THF (310 mL), and sodium hydroxide (1M aqueous solution, 147 mL) was added dropwise under ice cooling so that the internal temperature was below 12°C, and stirred under ice cooling for 2 hours. The reaction solution was poured into a conical flask containing hydrogen chloride (1M aqueous solution, 147 mL) and water (700 mL) under ice cooling, and stirred at room temperature for 2 hours. The insoluble matter was filtered out while washing with water, and dried under reduced pressure at 40°C overnight to obtain 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (24.6 g) as a solid.

[0932] Production Example 2

[0933] Under nitrogen atmosphere, 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise to a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (24.6 g) and THF (260 mL) heated to 60°C over 15 minutes, and stirred at the same temperature for 2.5 hours. The mixture was cooled to room temperature naturally, and the insoluble matter was filtered out while washing with THF (500 mL). The filtrate was concentrated, and MeOH (210 mL) was added to the obtained solid, stirred at room temperature for 1 hour, and suspended and washed. The insoluble matter was filtered out using MeOH (100 mL) to obtain 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[0934] Production Example 3

[0935] At room temperature, ethanethiol (5 mL) and DABCO (11 g) were added to a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (29 g) in dichloromethane (300 mL), and stirred overnight at room temperature under an argon atmosphere. Under ice cooling, water was added to stop the reaction. Chloroform was added, and the organic layer and the aqueous layer were separated by liquid separation, and the aqueous layer was extracted 3 times with chloroform. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-bromo-4-tert-butoxy-2-(ethylthio)-8-fluoro-6-iodoquinazoline (32 g) as a solid.

[0936] Production Example 4

[0937] Under ice cooling, tBuOK (10 g) was added to a solution of 7-bromo-4-tert-butoxy-2-(ethylthio)-8-fluoro-6-iodoquinazoline (32 g) and (1S)-1-phenylethane-1-ol (11 mL) in THF (400 mL), and stirred under ice cooling for 1 hour under an argon atmosphere. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride under ice cooling. Water and ethyl acetate were added, the organic layer and the aqueous layer were separated, the organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g) as an oil.

[0938] Production Example 5

[0939] 7-Bromo-4-tert-butoxy-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g), cyclopropylboronic acid (7.5 g), PdCl2(dppf)·CH2Cl2 (7.6 g), potassium phosphate (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 solution was allowed to return to room temperature and then diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazoline (22.9 g) as an oily substance.

[0940] Production Example 6

[0941] 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 to 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazoline (14.21 g), and the mixture was degassed and replaced with argon several times, and then heated and stirred at 50° C. in an argon atmosphere overnight. The reaction suspension was cooled naturally and filtered through Celite (registered trademark) while washing with ethyl acetate to remove gray insoluble matter. The filtrate was concentrated to about 1 / 4 under reduced pressure, and then water was added and extracted twice with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline as a solid (a diastereoisomer mixture of about 3.3:1 from axial asymmetry, 16.44 g).

[0942] Production Example 7

[0943] 4-tert-Butoxy-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (a diastereoisomer mixture of about 3.7:1 due to axial asymmetry, 22.6 g) was dissolved in dichloromethane (300 mL), and m-chloroperbenzoic acid (about 30% water content, 15 g) was added under ice cooling (internal temperature: 5-10°C), and stirred at room temperature for 2 hours under a nitrogen atmosphere. Under ice cooling, an aqueous solution (300 mL) of sodium thiosulfate pentahydrate (14 g) and a saturated aqueous sodium bicarbonate solution (300 mL) were added to the reaction mixture, and after stirring at room temperature for 30 minutes, the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. iPrOH (600 mL) was added to the obtained residue, and the mixture was stirred at room temperature overnight. The generated insoluble matter was filtered out, washed with iPrOH, and dried under reduced pressure to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline as a solid (a mixture of diastereomers with an axial asymmetry of about 1:1, 9.5 g, Preparation Example 7-2). The filtrate was concentrated to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline as a foamy solid (a single diastereomer with an undetermined axial asymmetric configuration, 15.5 g, Preparation Example 7-1).

[0944] Production Example 8

[0945] In an ice-MeOH bath, tBuOK (254 mg) was added to a THF (20 mL) solution of 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (1386 mg) and (2S)-2-methoxypropane-1-ol (189 μL), and the mixture was stirred at the same temperature for 30 minutes under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution 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 a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 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 oily substance.

[0946] Production Example 9

[0947] 1,1',1''-(chloromethanetriyl)triphenyl (335 g) was added to a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL), and dichloromethane (1880 mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1.5 L), the organic layer and the aqueous layer were separated, and the aqueous layer was extracted three times with dichloromethane (400 mL). The combined organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the obtained residue to powderize (0°C, 2 hours), and then filtered and dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

[0948] Production Example 10

[0949] To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL), lithium diisopropylamide (2M THF solution, 214.28 mL) was added at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 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 stop the reaction, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 mL) / petroleum ether (50 mL) was added to the obtained residue to powderize, and the mixture was filtered out and dried under reduced pressure to obtain 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) as a solid.

[0950] Production Example 11

[0951] 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'-bis-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL), palladium (II) acetate (4.52 g) was added at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and nitrogen filled three times each, and then stirred at 100°C for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added, and extraction was performed three times with ethyl acetate (900 mL). The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. Activated carbon (50 g) was added to the obtained solution, stirred at 20°C for 1 hour, and filtered while rinsing with ethyl acetate (50 mL) three times. The filtrate was concentrated under reduced pressure, and MeOH (200 mL) was added to the obtained residue to powderize it, which was collected by filtration and dried under reduced pressure to obtain 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.

[0952] Production Example 12

[0953] Sodium bicarbonate (1.62 g) and 10% Pd / C (about 50% water content, 609 mg) were added 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), and the mixture was stirred at room temperature and pressure for 3 hours under a hydrogen atmosphere. 10% Pd / C (about 50% water content, 304 mg) was added, and the mixture was stirred at room temperature and pressure for 3 hours under a hydrogen atmosphere. Celite (registered trademark) filtration was performed 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 obtain 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.

[0954] Production Example 13

[0955] To a DMF (10 mL) 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) was added DIPEA (1036 μL), tert-butyl 4-(chloromethyl)benzoate (515 mg), and cesium carbonate (2220 mg) in sequence at room temperature, and the mixture was stirred at room temperature for 4 hours 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 a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 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.

[0956] Production Example 14

[0957] 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) at room temperature, 4-methylbenzene-1-sulfonic acid monohydrate (216 mg) and 3,4-dihydro-2H-pyran (1.08 mL) were added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Saturated aqueous sodium bicarbonate solution 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 obtain 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid tert-butyl ester (966 mg).

[0958] Production Example 17

[0959] 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, the mixture was stirred at 50°C for 5 hours. Hydrogen chloride (1 M aqueous solution, 1000 μL) and water were added, and the mixture was extracted with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 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 oily substance.

[0960] Production Example 20

[0961] Under ice cooling, CDI (8.9 g) was added to a solution of N,N-dimethylethylenediamine (6 mL) in THF (50 mL) under ice cooling, and stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and iPrOH (50 mL) and azetidine-3-ol hydrochloride (5 g) were added to the residue at room temperature, and stirred at 80°C for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH / 28% ammonia water) to obtain N-[2-(dimethylamino)ethyl]-3-hydroxyazetidine-1-carboxamide (9.67 g) as an oil.

[0962] Production Example 21

[0963] At room temperature, 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a solution of tert-butyl 4-[((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, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. A solution of azetidine-3-carbonitrile mono(trifluoroacetic acid) 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. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-[({(7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid tert-butyl ester (73.1 mg).

[0964] Production Example 22

[0965] At room temperature, 4-[({(7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a mixture of tert-butyl benzoate (72 mg) and dichloromethane (2 mL), TFA (0.4 mL) was added, and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, and chloroform and a saturated aqueous sodium bicarbonate solution were added to the residue, and the mixture was extracted with chloroform / iPrOH (4 / 1). The organic layer was washed with a saturated aqueous sodium chloride solution, 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 obtain 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.

[0966] Production Example 29

[0967] At room temperature, 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( PyBOP (80 mg) and cesium carbonate (50 mg) were added to a solution of tert-butyl 4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (50 mg) in THF (5 mL), 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 obtain 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid tert-butyl ester (80 mg).

[0968] Production Example 30

[0969] At room temperature, 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a solution of tert-butyl 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]benzoate (80 mg) in dichloromethane (5 mL) was added TFA (1 mL), followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain 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.

[0970] Production Example 38

[0971] 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), 4-methylbenzene-1-sulfonic acid monohydrate (66 mg) was added at room temperature, and the mixture was stirred at room temperature overnight under an argon atmosphere. Saturated aqueous sodium bicarbonate solution was added at room temperature, extracted twice with chloroform / iPrOH (4 / 1), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 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 oily substance.

[0972] Production Example 40

[0973] 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) was added TFA (1.5 mL) 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 a saturated sodium bicarbonate aqueous solution was added to the fraction containing a peak on the less polar side, followed by extraction twice with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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.

[0974] Production Example 43

[0975] 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), cesium carbonate (130 mg) and PyBOP (210 mg) were added at room temperature, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (S)-azetidine-2-carboxamide (67 mg) and cesium carbonate (220 mg) were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Water and chloroform were added to the reaction mixture, and the mixture was 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 peak on the low polarity side were collected and concentrated. The residue was dissolved in MeCN / water, and after adding a saturated aqueous sodium bicarbonate solution, it was extracted twice with chloroform / iPrOH (9 / 1). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 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.

[0976] Production Example 51

[0977] 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) in dichloromethane (2.5 mL) and N-methyl-2-pyrrolidone (5 mL), and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (424 mg) was added, and stirred at room temperature for 16 hours. Water and saturated aqueous sodium bicarbonate solution were added, and stirred briefly. Extracted twice with ethyl acetate, the combined organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering out the desiccant, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / iPrOH) to obtain 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.

[0978] Production Example 52

[0979] Hydrogen chloride (4M DOX solution, 8 mL) was added to a mixture of (2S)-4-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl}-2-methylpiperazine-1-carboxylic acid tert-butyl ester (490 mg) and dichloromethane (10 mL), and the mixture was stirred at room temperature overnight under an argon atmosphere. Isopropyl ether was added to suspend the mixture, and the insoluble matter was filtered out and dried under reduced pressure to obtain 3-(3-methyl-5-{[(3S)-3-methylpiperazin-1-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione hydrochloride (450 mg) as a solid.

[0980] Production Example 53

[0981] 1-(6-Bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (4143 mg), potassium vinyl trifluoroborate (6869 mg), PdCl2(dppf)·CH2Cl2 (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 cooled to room temperature and then water was added, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, 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 obtain 1-(6-vinyl-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (3565 mg) as a solid.

[0982] Production Example 54

[0983] 1-(6-vinyl-1-methyl-1H-indazol-3-yl)-1,3-diazinane-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 slowly 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 solution were added, and the mixture was extracted with ethyl acetate 5 times. The organic layer was washed with saturated aqueous sodium chloride solution 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 with hexane / ethyl acetate (2 / 1) to obtain 3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbaldehyde (1344 mg) as a solid.

[0984] Production Example 62

[0985] To a mixture of tert-butyl 6-{[3-(2,4-dioxo-1,3-diazinane-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 under ice-cooling, and the mixture was 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 obtain 1-{6-[(2,6-diazaspiro[3.3]heptane-2-yl)methyl]-1-methyl-1H-indazol-3-yl}-1,3-diazinane-2,4-dione (68 mg) as a foamy solid.

[0986] Production Example 65

[0987] Trimethyl orthoacetate (32 mL) was added 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, and the mixture was stirred overnight at 110° C. under an argon atmosphere. After the reaction mixture was returned to room temperature, MeOH was added to suspend the mixture. The insoluble matter was filtered off and dried overnight at 50° C. under reduced pressure to obtain methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) as a solid.

[0988] Production Example 66

[0989] Under argon atmosphere, under ice cooling, bis(trimethylsilyl)amide lithium (1M THF solution, 160 mL) was added dropwise to a suspension of methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) in THF (250 mL) using a dropping funnel over 20 minutes. Then, the mixture was stirred at 40°C for 1 hour under argon atmosphere. Under ice cooling, water was added to stop the reaction, the mixture was diluted with ethyl acetate and water, the organic layer and the aqueous layer were separated by liquid separation, and the organic layer was extracted with water twice. Under ice cooling, hydrogen chloride (1M aqueous solution, 200 mL) was slowly added to the collected aqueous layer, resulting in the precipitation of solids. The insoluble matter was filtered out, washed with water and MeOH, and dried overnight at 50°C under reduced pressure to obtain 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (17.7 g) as a solid.

[0990] Production Example 67

[0991] Under nitrogen atmosphere, under ice cooling, DIPEA (30 mL) was added dropwise to a suspension of 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (21.24 g) in phosphorus oxychloride (95.2 mL) for 5 minutes, and stirred at 110°C for 2 hours. After the reaction mixture was cooled to room temperature naturally, MeCN (100 mL) was added and stirred for 30 minutes under ice cooling. Insoluble matter was filtered out using MeCN (100 mL). The obtained solid was suspended in MeCN (50 mL) and ice water (200 mL) and stirred for 30 minutes. Insoluble matter was filtered out using water / MeCN (5 / 1, 250 mL), and 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (18.95 g) was obtained as a solid.

[0992] Production Example 68

[0993] 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 stirred at 40°C for 2 hours. Ethyl mercaptan (850 μL) was added, and stirred at 60°C for 4 hours. After cooling to room temperature, water (200 mL) was added, and stirred at room temperature for 30 minutes. The insoluble matter was filtered off and dried under reduced pressure to obtain 7-bromo-4-chloro-2-(ethylthio)-8-fluoro-6-iodoquinoline (4.33 g) as a solid.

[0994] Production Example 70

[0995] 1-(tert-Butyloxycarbonyl)-3-hydroxyazetidine (1 g) was dissolved in DMAc (10 mL), tBuOK (600 mg) was added under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes to prepare an alkoxide. 7-Bromo-4-chloro-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (2.12 g) was dissolved in DMAc (10 mL), the prepared alkoxide solution was added dropwise in an ice-salt bath under 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. After filtering out the insoluble matter, the obtained solid was purified by silica gel column chromatography (hexane / chloroform / MeOH) to obtain tert-butyl 3-({7-bromo-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (2.48 g) as a foamy solid.

[0996] Production Example 73

[0997] MeOH (120 mL) was added to tert-butyl 3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (a diastereoisomer mixture of about 3.5:1 from axial asymmetry, 5.98 g), and the mixture was stirred at 50°C for 1 hour and then at room temperature overnight. The insoluble matter, tert-butyl 3-({6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (a diastereoisomer mixture of about 1:1 from axial asymmetry, 1.82 g), was filtered while washing with MeOH, and the filtrate was concentrated under reduced pressure to obtain the target tert-butyl 3-({(7M)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (a single diastereomer, 3.43 g) as a foamy solid.

[0998] Production Example 74

[0999] Tert-butyl 3-({(7M)-6-cyclopropyl-2-(ethylthio)-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, and stirred at the same temperature for 2 hours. Sodium thiosulfate aqueous solution was added under ice-cooling, and after stirring at room temperature for 30 minutes, the mixture was extracted twice with chloroform, and the combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain 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.

[1000] Production Example 79

[1001] Under ice cooling, CDI (130 mg) was added to a solution of N,N-dimethylethylenediamine (90 μL) in THF (3 mL), and the mixture was stirred for 1 hour under a nitrogen atmosphere. 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 at 90° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain 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.

[1002] Production Example 88

[1003] Under ice cooling, DIPEA (2 mL) and methanesulfonyl chloride (650 μL) were added to a solution of (3S)-4-{[4-(hydroxymethyl)phenyl]methyl}-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1730 mg) in dichloromethane (20 mL), and stirred under ice cooling for 1 hour under a nitrogen atmosphere, and stirred at room temperature overnight. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The organic layers were combined, washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-4-{[4-(chloromethyl)phenyl]methyl}-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1550 mg) as a solid.

[1004] Production Example 89

[1005] At room temperature, 4-hydroxytetrahydropyran (1.45 mL), DABCO (120 mg) and cesium carbonate (7 g) were added 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), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture for dilution, and the insoluble matter was filtered out through Celite (registered trademark). Saturated aqueous ammonium chloride solution was added to the filtrate, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-8-fluoro-6-iodo-2-[( 4-( ...

[1006] Production Example 97

[1007] Under ice cooling, TFA (2 mL) was added to a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (330 mg) in dichloromethane (10 mL), and after stirring at room temperature for 1 hour under a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure to prepare an amine. At room temperature, in another flask, 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[( To a solution of tert-butyl benzoate (300 mg) in MeCN (10 mL) was added TEA (120 μL) and PyAOP (440 mg), and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. A solution of the prepared amine and TEA (1.1 mL) in MeCN (5 mL) was added at room temperature, and the mixture was stirred at room temperature 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), and 4-[({(7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(

[0147] tert-butyl 4-(4-(4-yl)oxy)quinazolin-8-yl}oxy)methyl]benzoate (222 mg).

[1008] Production Example 99

[1009] Under a nitrogen atmosphere, copper (I) iodide (4.07 g), N,N'-dimethylethylenediamine (4.59 mL), and potassium phosphate (13.59 g) were added to a solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (5 g) and tert-butyl(3-iodophenoxy)di(methyl)silane (7.85 g) in 1,4-dioxane (200 mL), and the mixture was stirred at 120°C for 16 hours. Water was added to the reaction mixture, and the mixture was 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 obtain 1-(3-{[tert-butyldi(methyl)silyl]oxy}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (8 g) as an oily substance.

[1010] Production Example 100

[1011] TBAF (1M THF solution, 30.3 mL) was added to a THF (90 mL) solution of 1-(3-{[tert-butyldi(methyl)silyl]oxy}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (8.9 g), and the atmosphere was replaced with nitrogen three times, followed by stirring at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed four times with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was suspended in ethyl acetate (30 mL) and stirred, and the insoluble matter was filtered out and dried under reduced pressure. The obtained solid was suspended in MeCN / water (2 / 1, 200 mL) and freeze-dried to obtain 1-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (6.2 g) as a solid.

[1012] Production Example 101

[1013] Potassium iodide (560 mg) and potassium carbonate (635 mg) were added to a DMF (10 mL) solution of 1-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1 g) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 115°C, 2-bromo-1,1-dimethoxyethane (468 μL) was added, and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was filtered with MeCN, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (MeCN / 0.05% TFA aqueous solution) to obtain 1-[3-(2,2-dimethoxyethoxy)phenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (940 mg) as a solid.

[1014] Production Example 102

[1015] Hydrogen chloride (2M aqueous solution, 5.55 mL) was added to a solution of 1-[3-(2,2-dimethoxyethoxy)phenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (920 mg) in acetone (9.2 mL), and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and freeze-dried to obtain (3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinane-1-yl}phenoxy)acetaldehyde (889 mg) as a solid.

[1016] Production Example 104

[1017] A mixture of tert-butyl 9-[2-(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinane-1-yl}phenoxy)ethyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (180 mg) and trifluoromethanesulfonic acid (180 μL) was replaced with nitrogen three times and stirred at 65° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was combined with the crude product of the similar reaction (using 270 mg of the starting material), dissolved in MeCN (5 mL), and purified by reverse phase chromatography (MeCN / 0.05% TFA aqueous solution) to obtain 1-{3-[2-(3,9-diazaspiro[5.5]undecane-3-yl)ethoxy]phenyl}-1,3-diazinane-2,4-dione n(trifluoromethanesulfonic acid) salt (350 mg) as a solid.

[1018] The compounds shown in the following table were produced in the same manner as in the production examples described above. The production method, structure and physicochemical data of the compounds in each production example are shown in the following table.

[1019] Example 2

[1020] 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 at room temperature overnight. Ethyl acetate, water and a saturated sodium chloride aqueous solution were added, the mixture was extracted with ethyl acetate, and the obtained 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). Saturated sodium bicarbonate aqueous solution was added to the target fraction, extracted twice with chloroform / iPrOH (4 / 1), and 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.

[1021] Example 3

[1022] TFA (0.4 mL) was added to [(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-( The mixture was stirred overnight at room temperature in a mixture of tert-butyl 2-[(2S)-2-methoxypropoxy]quinazoline-4-yl}-3-fluoropiperidin-4-yl]carbamate (58 mg) and dichloromethane (1.2 mL). The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Saturated sodium bicarbonate aqueous solution was added to the target fraction, extracted twice with chloroform / iPrOH (4 / 1), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained solid was washed with hexane and dried under reduced pressure to obtain 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.

[1023] Example 5

[1024] 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-diazinane-2,4-dione hydrochloride (34 mg), DIPEA (82 μL) and DMF (3 mL), and stirred at room temperature overnight. Ethyl acetate, water and a saturated sodium chloride aqueous solution were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and a saturated sodium bicarbonate aqueous solution was added to the target fraction, extracted three times with chloroform / iPrOH (4 / 1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in MeCN / water and freeze-dried to obtain (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(2S)-4-{[3-(2,4-dioxo-1,3-diazinane-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.

[1025] Embodiment 20

[1026] PyBOP (63 mg) and cesium carbonate (40 mg) were added 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-diazinane-2,4-dione (45 mg) in THF (5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (S)-azetidine-2-carboxamide (25 mg) and DIPEA (90 μL) were added at room temperature, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution 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 obtain (2S)-1-{(7M)-6-cyclopropyl-8-({4-[(4-{[3-(2,4-dioxo-1,3-diazinane-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.

[1027] The Example compounds shown in the table below were produced in the same manner as the production methods of the Examples shown above. The production methods and physicochemical data of the Example compounds are shown in the table below.

[1028] In addition, in the following tables, the following abbreviations may be used.

[1029] PEx: manufacturing example number, Ex: example number, PSyn: manufacturing example number manufactured by the same method, Syn: example number manufactured by the same method (for example, Syn 1 means manufactured by the same method as Example 1.), Str: chemical formula (the compound with "#" in the chemical formula represents a diastereoisomer mixture with an axial asymmetry of 3:1 to 5:1 of the compound. The compound with "##" in the chemical formula represents a compound with a single axial asymmetry, but the stereochemistry is not determined. The compound with "###" in the chemical formula represents a compound with an axial asymmetry of 3:1 to 5:1 of the compound, but the stereochemistry is not determined.). n HCl: n hydrochloride (indicates that the compound with the manufacturing example number is monohydrochloride to trihydrochloride.), n TfOH: n trifluoromethanesulfonic acid (indicates that the compound with the manufacturing example number is monotrifluoromethanesulfonate to tri(trifluoromethanesulfonate).), DAT: physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] when no statement is given) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, [MH] when no statement is made - ), NMR: DMSO-d6 at 27°C 1 δ value (ppm) of the peak of H-NMR (500 MHz), NMR (90°C): 1 δ value (ppm) of H-NMR (500 MHz) peak, s: singlet (spectrum), d: doublet (spectrum), dd: doublet of doublet (spectrum), ddd: doublet of doublet of doublet (spectrum), t: triplet (spectrum), dt: doublet of triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum).

[1030] [Table 3-1]

[1031]

[1032] [Table 3-2]

[1033]

[1034] [Table 3-3]

[1035]

[1036] [Table 3-4]

[1037]

[1038] [Table 3-5]

[1039]

[1040] [Table 3-6]

[1041]

[1042] [Table 3-7]

[1043]

[1044] [Table 3-8]

[1045]

[1046] [Table 3-9]

[1047]

[1048] [Table 3-10]

[1049]

[1050] [Table 3-11]

[1051]

[1052] [Table 3-12]

[1053]

[1054] [Table 3-13]

[1055]

[1056] [Table 3-14]

[1057]

[1058] [Table 3-15]

[1059]

[1060] [Table 3-16]

[1061]

[1062] [Table 3-17]

[1063]

[1064] [Table 3-18]

[1065]

[1066] [Table 3-19]

[1067]

[1068] [Table 3-20]

[1069]

[1070] [Table 3-21]

[1071]

[1072] [Table 3-22]

[1073]

[1074] [Table 3-23]

[1075]

[1076] [Table 3-24]

[1077]

[1078] [Table 3-25]

[1079]

[1080] [Table 4-1]

[1081]

[1082] [Table 4-2]

[1083]

[1084] [Table 4-3]

[1085]

[1086] [Table 4-4]

[1087]

[1088] [Table 5-1]

[1089]

[1090] [Table 5-2]

[1091]

[1092] [Table 5-3]

[1093]

[1094] [Table 5-4]

[1095]

[1096] [Table 5-5]

[1097]

[1098] [Table 5-6]

[1099]

[1100] [Table 5-7]

[1101]

[1102] [Table 5-8]

[1103]

[1104] [Table 6-1]

[1105]

[1106] [Table 6-2]

[1107]

[1108] Industrial Applicability

[1109] The compound of the present invention or a salt thereof has an excellent effect of inducing degradation of G12V mutant KRAS protein, is useful as a G12V mutant KRAS inhibitor, and can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating pancreatic cancer and / or lung cancer.

Claims

1. A compound of formula (I) or a salt thereof, In formula (I), A is CR A or N, R A H or C 1-3 alkyl, X 1 -CH2-, -O- or -NR X1 -, R X1 H or a replaceable C 1-3 alkyl, Or, in X 1 For-NR X1 -, the R X1 and R 4 Together with the adjacent nitrogen atom, it may form a 4- to 6-membered saturated heterocyclic group which may be substituted, R 1 is a naphthyl group which may be substituted with OH or the following formula (II) or formula (III), R 1a , R 1b are the same or different from each other 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, the C 1-3 The alkyl group may be substituted with a group selected from the group consisting of OH and OCH3, R 3 is a group selected from the group consisting of the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and formula (XXVI), R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3b H or C 1-3 alkyl, R 3c and R 3d -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3e H, F or C 1-3 alkyl, R 3f H or C 1-3 alkyl, R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted, R 3h H, F or C 1-3 alkyl, R 3i are the same or different from each other and are selected from H, OH, substituted C 1-3 Alkyl, -O-C 1-3 Alkyl, -NH- may be substituted C 1-3 Alkyl, -N-(which may be substituted C 1-3 alkyl)2, halogen, -CN and oxo, or Two Rs on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The spiro ring of the ring in the group consisting of cycloalkane and 4- to 6-membered saturated heterocyclic ring can be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 A condensed ring of a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring, the condensed ring may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridged structure containing 1 to 2 carbon atoms may be formed. The ring having the bridged structure may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, R N1 and R N2 Same or different, H or C 1-3 Alkyl, or R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group. X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, 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 C 1-6 Alkyl, can be R 4a substituted piperidinyl or tetrahydropyranyl, the C 1-6 The alkyl group may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a substituted with a group selected from the group consisting of substituted pyrrolidinyl and tetrahydrofuranyl, R 4a C 1-3 alkyl, Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-, L 1 , L 2 , L 3 , L 4 , L 5 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, a C 1-3 A group consisting of an alkylene group and C=O, R L1 H or C 1-3 alkyl, Z is a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX) and formula (XX), Ring B is a benzene ring or a 6-membered heterocyclic ring 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 , R Z2 H or C 1-3 alkyl, R Z3 H or C 1-3 alkyl, R Z4 The same or different, each is H or C 1-3 alkyl, R Z5 C 1-3 alkyl, Furthermore, L is bonded to the ring B of the formula (XIII) to the formula (XVIII) or the benzene ring of the formula (XIX) and the formula (XX), m is 1 or 2, G is CH or N, in, When G is N, Z is the above-mentioned formula (XVII), formula (XVIII) or formula (XIX).

2. The compound or salt thereof according to claim 1, wherein X 1 -O- or -NR X1 -, R X1 H or a replaceable C 1-3 alkyl, Or, in X 1 For-NR X1 -, the R X1 and R 4 Together with the adjacent nitrogen atom, it may form a 4- to 6-membered saturated heterocyclic group which may be substituted, R 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 formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R 3a -(CH2) p CHR 3e -NR N1 R N2 ; -(CH2) p CHR 3e -OR 3f ; can be selected from 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 substituted by a 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 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3b H or C 1-3 alkyl, R 3e H, F or C 1-3 alkyl, R 3f H or C 1-3 alkyl, R 3g C 3-6 cycloalkyl, 5-membered heteroaryl which may be substituted, 6-membered heteroaryl which may be substituted, or 4- to 6-membered saturated heterocyclic group which may be substituted, R 3h H, F or C 1-3 alkyl, R N1 and R N2 Same or different, H or C 1-3 Alkyl, or R N1 and R N2 Together with the nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 Together with the carbon atom and nitrogen atom to which they are bonded, they may form a substituted 4- to 6-membered saturated heterocyclic group. X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, n is 1 or 2, p is 1 or 2, Y is a phenylene group which may be substituted by F or Cl, Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX), Ring B is a benzene ring or a 6-membered heterocyclic ring 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 , R Z2 H or C 1-3 alkyl, R Z4 The same or different, each is H or C 1-3 alkyl, R Z5 C 1-3 alkyl, Furthermore, L is bonded to the ring B of the formula (XIII) or (XVII), m is 1 or 2, G is CH or N, When G is N, Z is the above formula (XVII) or formula (XIX).

3. The compound or salt thereof according to claim 2, wherein A is CR A or N, R A For H, X 1 For -O-, R 1 is the following formula (II), R 1a For F, R 1c Methyl, R 2 is cyclopropyl, R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R 3a -(CH2) p CHR 3e -NR N1 R N2 , R 3b H or C 1-3 alkyl, R 3e For H, R 3g is a 6-membered heteroaryl group which may be substituted, R 3h is H or F, R N1 and R N2 Same or different from each other, C 1-3 alkyl, X 2 is -O- or -NH-, X 3 is O or S, n is 1, p is 1, R 4 may be selected from OCH3, N(C 1-3 Alkyl)2 and can be R 4a The substituted pyrrolidinyl group is composed of a group substituted with C 1-6 Alkyl or tetrahydropyranyl, R 4a C 1-3 alkyl, Y is phenylene, L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-, L contained in L 1 Bonded to Y, L 1 C 1-3 Alkylene or C=O, L 2 is a divalent group of a saturated heterocyclic ring containing 1 to 2 nitrogen atoms which may be substituted, L 3 C 1-3 Alkylene, L 4 is a bond, -O- or -N(C 1-3 alkyl)-, L 5 For key or C 1-3 Alkylene, Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX), Ring B is a benzene ring, R Z1 H or C 1-3 alkyl, R Z2 H or C 1-3 alkyl, Furthermore, L is bonded to the ring B of the formula (XIII) or (XVII) or the benzene ring of the formula (XIX), m is 1 or 2.

4. The compound or salt thereof according to claim 3, wherein R 3 is a group selected from the group consisting of the following formula (IV-1), formula (VII-1), formula (VIII-1), formula (IX), formula (X), formula (XI) and formula (XII-1), L is a group selected from the group consisting of the following formula (XXVII) to formula (XXXIV), having The carbon atom of is bonded to Y, Z is a group selected from the group consisting of the following formula (XIII-1), formula (XVII-1) and formula (XIX-1), Furthermore, L is bonded to the benzene ring of the formula (XIII-1) and the formula (XVII-1), G is CH or N, When G is N, Z is the above-mentioned formula (XVII-1) or formula (XIX-1).

5. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for treating pancreatic cancer and / or lung cancer.

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

8. The compound or salt thereof according to claim 1, for use in treating pancreatic cancer and / or lung cancer.

9. Use of the compound or salt thereof according to claim 1 in treating pancreatic cancer and / or lung cancer.

10. A method for treating pancreatic cancer and / or lung cancer, comprising the step of administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

Images