Heterocyclic compounds for inducing mutated KRAS proteolysis

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer. The inventors have studied a compound useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer. The present invention has been completed by finding that a heterocyclic compound represented by formula (I) has an excellent effect of inducing mutation KRAS proteolysis, particularly an effect of inducing G12V mutation, G12D mutation, and G12C mutation KRAS proteolysis, and has a mutation KRAS inhibitory activity, particularly G12V mutation, G12D mutation, and G12C mutation KRAS inhibitory activity. The heterocyclic compound or a salt thereof according to the present invention can be used as a therapeutic agent for pancreatic cancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, and a heterocyclic compound that is excellent in inducing the degradation of mutant KRAS proteins, particularly inducing the degradation of G12V mutant, G12D mutant, and G12C mutant KRAS proteins, and is useful as a mutant KRAS inhibitor, particularly a G12V mutant, G12D mutant, and G12C mutant KRAS inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treating pancreatic 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 early detection is difficult and most cases have already metastasized, 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 levofolinate added to 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] 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).

[0004] 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 continuous 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 stronger 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 malignant (Nature Rev. Cancer, 2010, 10, p. 683-695). Furthermore, in more than 90% of pancreatic ductal adenocarcinomas, mutations can be seen in the KRAS gene, among which point mutations located in codon 12 of KRAS exon 2 account for the majority (Cancer Cell 2017, 32, p. 185-203). Therefore, KRAS plays an important role in the carcinogenesis and progression of pancreatic cancer.

[0005] As KRAS gene mutations, KRAS G12C mutations, KRAS G12D mutations, etc. are known, but G12C mutation KRAS has a high frequency in non-small cell lung cancer, but only a few percentages in pancreatic cancer (Cancer Cell 2014, 25, p.272-281), and therapeutic drugs for other KRAS mutations are expected. It is reported that G12D mutation KRAS is seen in about 34% of pancreatic cancers, the highest proportion among KRAS mutations. It is also reported that G12V mutation KRAS is seen in about 22% of pancreatic cancers, the second highest proportion among KRAS mutations, second only to G12D mutation (Nat. Rev. Cancer, 2018, 18, p.767-777).

[0006] 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 G12D mutations, but do not record the effects on G12D mutant KRAS cancers.

[0007]

[0008] In addition, Patent Documents 9, 10, and 11 disclose KRAS G12D inhibitors.

[0009] In addition, Patent Document 12 discloses a pan-KRAS inhibitor.

[0010] In recent years, as a technology to induce the degradation of target proteins, bifunctional compounds collectively referred to as PROTAC (PROteolysis-TArgeting Chimera), SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), etc. have been discovered, which are expected to be one of the new drug development models (Drug. Discov. Today Technol., 2019, 31, p15-27). Bifunctional compounds promote the formation of a complex between the target protein and the E3 ligase in the cell, and induce the degradation of the target protein by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms in the cell. The protein called E3 ligase recognizes the protein to be degraded and ubiquitinates it, thereby promoting the degradation in the proteasome.

[0011] 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. As representative examples, Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), mouse double minute 2 homolog 2 (mouse double minute 2homolog, MDM2), etc. can be cited. In particular, Patent Document 4 reports VHL, and Patent Document 5 reports CRBN.

[0012] A bifunctional compound is a compound 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 13, Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17).

[0013] Prior art literature

[0014] Patent Literature

[0015] Patent Document 1: International Publication No. 2016 / 049565

[0016] Patent Document 2: International Publication No. 2016 / 049568

[0017] Patent Document 3: International Publication No. 2017 / 172979

[0018] Patent Document 4: International Publication No. 2013 / 106643

[0019] Patent Document 5: International Publication No. 2015 / 160845

[0020] Patent Document 6: U.S. Patent Application Publication No. 2018 / 0015087

[0021] Patent Document 7: International Publication No. 2019 / 195609

[0022] Patent Document 8: International Publication No. 2020 / 018788

[0023] Patent Document 9: International Publication No. 2021 / 041671

[0024] Patent Document 10: International Publication No. 2021 / 106231

[0025] Patent Document 11: International Publication No. 2021 / 107160

[0026] Patent Document 12: International Publication No. 2022 / 132200

[0027] Patent Document 13: International Publication No. 2021 / 051034

[0028] Patent Document 14: International Publication No. 2022 / 087335

[0029] Patent Document 15: International Publication No. 2022 / 061348

[0030] Patent Document 16: International Publication No. 2022 / 148421

[0031] Patent Document 17: International Publication No. 2022 / 173032

[0032] Non-patent literature

[0033] Non-patent literature 1: Cell.Chem.Biol.,2020,27,p19-31

[0034] Non-patent document 2: ACS Cent. Sci., 2020, 6, p1367-1375 Summary of the invention

[0035] Problems to be solved by the invention

[0036] Provided is a pharmaceutical composition, for example, a heterocyclic compound that has an excellent effect of inducing the degradation of mutant KRAS proteins, particularly the effect of inducing the degradation of G12V mutant, G12D mutant, and G12C mutant KRAS proteins, and is useful as a mutant KRAS inhibitor, particularly a G12V mutant, G12D mutant, and G12C mutant KRAS inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer, particularly mutant KRAS-positive pancreatic cancer, particularly G12V mutant, G12D mutant, and G12C mutant KRAS-positive pancreatic cancer.

[0037] Methods used to solve problems

[0038] The present inventors have conducted intensive studies on compounds useful as active ingredients of pharmaceutical compositions for treating pancreatic cancer. As a result, the present inventors 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 an excellent effect of inducing the decomposition of mutant KRAS proteins, particularly an effect of inducing the decomposition of G12V mutant, G12D mutant and G12C mutant KRAS proteins, and have mutant KRAS inhibitory activity, particularly G12V mutant, G12D mutant and G12C mutant KRAS inhibitory activity, thereby completing the present invention.

[0039] 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.

[0040]

[0041] (Where,

[0042] A is CR A or N,

[0043] R A H or C 1-3 alkyl,

[0044] X 1 is -CH2- or -O-,

[0045] R 1 is a naphthyl group which may be substituted with OH or the following formula (II),

[0046]

[0047] R 1a is H, methyl, F or Cl,

[0048] R 1b is F, Cl, methyl or ethyl,

[0049] R 2 is H, halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 Alkyl, cyclopropyl or vinyl,

[0050] R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XXXV),

[0051]

[0052] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0053] R 3b H or C 1-3 alkyl,

[0054] R 3c and R 3d -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0055] R 3e For-OC 2-3 Alkylene-NR N1 R N2 ,

[0056] R 3f H, F or C 1-3 alkyl,

[0057] R 3g H or C 1-3 alkyl,

[0058] R 3h is a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which may be substituted and contains 1 to 3 nitrogen atoms,

[0059] 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

[0060] Two R on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The group of formula (XXXV) is a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and forms a spiro ring, which may be selected from the group consisting of C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or,

[0061] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6The group of formula (XXXV) is a ring consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring, which may be selected from the group consisting of C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0062] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridge structure containing 1 to 2 carbon atoms may be formed. The group of formula (XXXV) as a ring having the bridge structure may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo,

[0063] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0064] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0065] R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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,

[0066] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0067] X 3 is O or S,

[0068] X 4 is -CH2-, -CH2-CH2- or -O-CH2-,

[0069] n is 1 or 2, p is 1 or 2,

[0070] q is an integer from 1 to 8,

[0071] Among them, R 3c -(CH2) p CHR 3f -NR N1 RN2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-,

[0072] R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a Substituted pyrrolidinyl and R 4a The group consisting of substituted tetrahydrofuranyl and C 1-6 Alkyl; can be R 4b substituted piperidinyl; or may be R 4a Substituted tetrahydropyranyl,

[0073] R 4a C can be replaced by F 1-3 alkyl,

[0074] R 4b C substituted with 1 to 3 F 1-3 alkyl,

[0075] R 5 Methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C 3-6 Cycloalkylmethyl or C 3-6 Cycloalkyl,

[0076] R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or

[0077] R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 Cycloalkane or a 4- to 6-membered saturated heterocyclic ring which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,

[0078] R 7 is a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms,

[0079] W is an optionally substituted phenylene group or an optionally substituted 6-membered heteroaromatic diyl group containing 1 to 3 nitrogen atoms as ring constituent atoms,

[0080] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0081] L is -(L 1 -L 2 -L 3 -L 4 )-,

[0082] L 1 , L 2 , L 3 , L 4 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C 1-3 A group consisting of an alkylene group and C=O,

[0083] R L1 H or C 1-3 alkyl,

[0084] Z is NH or a 5-membered heteroaromatic diyl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,

[0085] Alternatively, YLZ is the following formula (XII).

[0086]

[0087] 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.

[0088] 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 mutant KRAS-positive pancreatic cancer as one embodiment, particularly a pharmaceutical composition for treating G12V mutation, G12D mutation and G12C 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 mutant KRAS-positive pancreatic cancer as one embodiment, particularly metastatic G12V mutation, G12D mutation and G12C mutation A pharmaceutical composition for treating locally advanced G12D mutation KRAS-positive pancreatic cancer as a method, in particular a pharmaceutical composition for treating locally advanced G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer; a pharmaceutical composition for treating relapsed or refractory G12D mutation KRAS-positive pancreatic cancer as a method, in particular a pharmaceutical composition for treating relapsed or refractory G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer; a pharmaceutical composition for treating G12D mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as a method, in particular a pharmaceutical composition for treating G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment. It should be noted that the pharmaceutical composition includes a therapeutic agent for pancreatic cancer containing a compound of formula (I) or a salt thereof; a therapeutic agent for mutant KRAS-positive pancreatic cancer as a mode; and particularly a therapeutic agent for G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer.

[0089] 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 and G12D 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; and a pharmaceutical composition for treating untreated and / or previously treated patients as one embodiment. A pharmaceutical composition for treating pancreatic cancer; a pharmaceutical composition for treating metastatic G12V mutation and G12D mutation KRAS-positive pancreatic cancer as a method; a pharmaceutical composition for treating locally advanced G12V mutation and G12D mutation KRAS-positive pancreatic cancer as a method; a pharmaceutical composition for treating recurrent or refractory G12V mutation and G12D mutation KRAS-positive pancreatic cancer as a method; a pharmaceutical composition for treating G12V mutation and G12D mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as a method. It should be noted that the pharmaceutical composition includes a therapeutic agent for pancreatic cancer containing a compound of formula (I) or a salt thereof; a therapeutic agent for G12V mutation and G12D mutation KRAS-positive pancreatic cancer as a method.

[0090] 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 includes a therapeutic agent for pancreatic cancer containing a compound of formula (I) or a salt thereof; as one embodiment, a therapeutic agent for G12V mutant KRAS-positive pancreatic cancer.

[0091] In addition, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients; a pharmaceutical composition for treating pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating metastatic pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced pancreatic cancer as one embodiment; a pharmaceutical composition for treating 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 G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating recurrent or refractory G12D mutant KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12D mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment. It should be noted that the pharmaceutical composition includes a therapeutic agent for pancreatic cancer containing a compound of formula (I) or a salt thereof; as one embodiment, a therapeutic agent for G12D mutant KRAS-positive pancreatic cancer.

[0092] In addition, the present invention relates to a pharmaceutical composition containing 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 G12C 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 G12C mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating locally advanced G12C mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating recurrent or refractory G12C mutation KRAS-positive pancreatic cancer as one embodiment; a pharmaceutical composition for treating G12C 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 includes a compound of formula (I) or a salt thereof for pancreatic cancer; as a therapeutic agent for G12C mutation KRAS-positive pancreatic cancer.

[0093] 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 of mutant KRAS-positive pancreatic cancer, particularly G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer, as an embodiment of metastatic pancreatic cancer, as an embodiment of locally advanced pancreatic cancer, as an embodiment of recurrent or refractory pancreatic cancer, as an embodiment of pancreatic cancer in patients who have not been treated and / or have a history of treatment, as an embodiment of metastatic mutant KRAS-positive pancreatic cancer, particularly metastatic G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer, as an embodiment of locally advanced mutant KRAS-positive pancreatic cancer, particularly locally advanced G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer, as an embodiment of recurrent or refractory mutant KRAS-positive pancreatic cancer, particularly recurrent or refractory G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer. A pharmaceutical composition for treating pancreatic cancer, as a mode of mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment, in particular metastatic G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment; a compound of formula (I) or a salt thereof for treating pancreatic cancer, as a mode of mutant KRAS-positive pancreatic cancer, in particular G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer; a compound of formula (I) or a salt thereof for treating pancreatic cancer, as a mode of mutant KRAS-positive pancreatic cancer, in particular G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer; and a method for treating pancreatic cancer, as a mode of mutant KRAS-positive pancreatic cancer, in particular G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer, comprising the step of administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0094] In addition, the present invention relates to a compound of formula (I) or a salt thereof for use in the manufacture of pancreatic cancer, G12V mutation and G12D mutation KRAS-positive pancreatic cancer as one embodiment, metastatic pancreatic cancer as one embodiment, locally advanced pancreatic cancer as one embodiment, recurrent or refractory pancreatic cancer as one embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment as one embodiment, metastatic G12V mutation and G12D mutation KRAS-positive pancreatic cancer as one embodiment, locally advanced G12V mutation and G12D mutation KRAS-positive pancreatic cancer as one embodiment, recurrent or refractory G12V mutation and G12D mutation KRAS-positive pancreatic cancer as one embodiment. Use of a pharmaceutical composition for treating pancreatic cancer, or G12V mutation and G12D 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 and G12D mutation KRAS-positive pancreatic cancer as a method; a compound of formula (I) or a salt thereof for treating pancreatic cancer, or G12V mutation and G12D mutation KRAS-positive pancreatic cancer as a method; and a method for treating pancreatic cancer, or G12V mutation and G12D 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.

[0095] 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.

[0096] 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, G12D 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 G12D mutation KRAS-positive pancreatic cancer, as an embodiment, locally advanced G12D mutation KRAS-positive pancreatic cancer, as an embodiment, recurrent or refractory G12D mutation KRAS-positive pancreatic cancer. Use of a pharmaceutical composition for treating pancreatic cancer, or G12D 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 G12D mutation KRAS-positive pancreatic cancer as a method; a compound of formula (I) or a salt thereof for treating pancreatic cancer, or G12D mutation KRAS-positive pancreatic cancer as a method; and a method for treating pancreatic cancer, or G12D 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.

[0097] 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, G12C 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 G12C mutation KRAS-positive pancreatic cancer, as an embodiment, locally advanced G12C mutation KRAS-positive pancreatic cancer, as an embodiment, recurrent or refractory G12C mutation KRAS-positive pancreatic cancer. Use of a pharmaceutical composition for treating pancreatic cancer, or G12C 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 G12C mutation KRAS-positive pancreatic cancer as a method; a compound of formula (I) or a salt thereof for treating pancreatic cancer, or G12C mutation KRAS-positive pancreatic cancer as a method; and a method for treating pancreatic cancer, or G12C 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.

[0098] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor, in particular a G12V mutation, G12D mutation and G12C mutant KRAS protein degradation inducer and / or a G12V mutation, G12D mutation and G12C mutant KRAS inhibitor; a compound of formula (I) or a salt thereof used as a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor, in particular a G12V mutation, G12D mutation and G12C mutant KRAS protein degradation inducer and / or a G12V mutation, G12D mutation and G12C mutant KRAS inhibitor; a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor, in particular a G12V mutation, G12D mutation and G12C mutant KRAS protein degradation inducer and / or a G12V mutation, G12D mutation and G12C mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0099] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a G12V mutation and G12D mutation KRAS protein degradation inducer and / or a G12V mutation and G12D mutation KRAS inhibitor; a compound of formula (I) or a salt thereof used as a G12V mutation and G12D mutation KRAS protein degradation inducer and / or a G12V mutation and G12D mutation KRAS inhibitor; and a G12V mutation and G12D mutation KRAS protein degradation inducer and / or a G12V mutation and G12D mutation KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0100] 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.

[0101] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a G12D mutant KRAS protein degradation inducer and / or a G12D mutant KRAS inhibitor; a compound of formula (I) or a salt thereof used as a G12D mutant KRAS protein degradation inducer and / or a G12D mutant KRAS inhibitor; and a G12D mutant KRAS protein degradation inducer and / or a G12D mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0102] In addition, the present invention also relates to a compound of formula (I) or a salt thereof as a G12C mutant KRAS protein degradation inducer and / or a G12C mutant KRAS inhibitor; a compound of formula (I) or a salt thereof used as a G12C mutant KRAS protein degradation inducer and / or a G12C mutant KRAS inhibitor; and a G12C mutant KRAS protein degradation inducer and / or a G12C mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

[0103] 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.

[0104] Effects of the Invention

[0105] The compound of formula (I) or a salt thereof has the effect of inducing the decomposition of mutant KRAS proteins and mutant KRAS inhibitory activity, especially the effect of inducing the decomposition of G12V mutation, G12D mutation and G12C mutation KRAS proteins and G12V mutation, G12D mutation and G12C mutation KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, especially mutant KRAS-positive pancreatic cancer, especially G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer. DETAILED DESCRIPTION

[0106] Hereinafter, the present invention will be described in detail.

[0107] 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.

[0108] “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.

[0109] 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.

[0110] 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.

[0111] Likewise, “C 2-3 The term "alkyl" refers to a linear or branched alkyl group having 2 to 3 carbon atoms, for example, ethyl, n-propyl or isopropyl, and in one embodiment, it is ethyl, in one embodiment, it is isopropyl, and in one embodiment, it is n-propyl.

[0112] “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.

[0113] “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, methylethylene, 1,1-dimethylmethylene, and the like. In one embodiment, a linear or branched C 1-3 Alkylene, as one embodiment, is methylene, ethylene or trimethylene, as one embodiment, is methylene or ethylene, as one embodiment, is methylene, as one embodiment, is ethylene. Similarly, "C 2-3 "Alkylene" refers to 2-3 A divalent group formed by removing a hydrogen atom from an alkyl group. It is a straight-chain or branched C 2-3 The alkylene group includes, for example, ethylene, trimethylene, methylmethylene, methylethylene, 1,1-dimethylmethylene, etc. In one embodiment, it is ethylene or trimethylene, in one embodiment, it is ethylene, and in one embodiment, it is trimethylene.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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 In one embodiment, the oxazolyl group is a thiazolyl group, and in another embodiment, the oxazolyl group is a triazolyl group. In addition, the "5-membered heteroarene diyl group" refers to a divalent group formed by removing any one hydrogen atom from a "5-membered heteroaryl group".

[0119] The "6-membered heteroaryl group" refers to a heterocyclic group of a 6-membered ring 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. It should be noted that the "6-membered heteroaromatic diyl group" refers to a divalent group formed by removing any one hydrogen atom from the "6-membered heteroaryl group".

[0120] “C 3-6 The term "cycloalkane" refers to a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0121] "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-membered to 6-membered saturated heterocycle" refers to a saturated hydrocarbon ring containing a 4-membered to 6-membered 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. As one embodiment of the "4-membered to 6-membered saturated heterocycle", it is a 4-membered 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 of the "4-membered to 6-membered saturated heterocycle", it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazoline, piperazine, morpholine, thiomorpholine or dioxothiomorpholine.

[0122] The "spiro ring" refers to a polycyclic ring structure in which two ring structures are bonded together by sharing a spiro atom as a quaternary carbon.

[0123] The "ring having a bridged structure" refers to a ring structure having a divalent chain structure connecting two non-adjacent atoms among the ring-constituting atoms of one ring. One embodiment of the "ring having a bridged structure" is azabicyclo[3.2.1]octane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.1]heptane or azaoxabicyclo[3.2.1]octane.

[0124] “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.

[0125] As a "replaceable C 1-6 Alkyl" and "C 1-3 One form of acceptable substituents in "alkyl" is F, OH, OCH3, N(CH3)2, C 3-6Cycloalkyl, azabicyclo[3.3.0]octyl or a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. In one embodiment, it is 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, piperidinyl which may be substituted or azabicyclo[3.3.0]octyl. In one embodiment, it is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl which may be substituted, tetrahydrofuranyl, tetrahydropyranyl which may be substituted, pyrrolidinyl which may be substituted. In one embodiment, it is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, Cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl or methylpyrrolidinyl, in one embodiment, F, OH, OCH3, (methoxymethyl)cyclopropyl, tetrahydrofuranyl or methylpyrrolidinyl, in one embodiment, F, OH or cyclopropyl, in one embodiment, F, OH or OCH3, in one embodiment, OH or OCH3, in one embodiment, F or OCH3, in one embodiment, OH, in one embodiment, F, in one embodiment, OCH3.

[0126] As "5-membered heteroaryl which may be substituted", "6-membered heteroaryl which may be substituted", "6-membered heteroaromatic diyl which may be substituted", "C 3-6 One form of acceptable substituents among "cycloalkyl", "optionally substituted pyrazolyl", "optionally substituted pyridyl", "optionally substituted pyrimidinyl", "optionally substituted phenylene" and "optionally substituted cyclopropyl" is 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.

[0127] One embodiment of the acceptable substituents for the “optionally substituted 4- to 6-membered saturated heterocyclic group”, “optionally substituted pyrrolidinyl group”, “optionally substituted piperidinyl group”, “optionally substituted oxetanyl group”, “optionally substituted tetrahydrofuranyl group”, and “optionally substituted tetrahydropyranyl group” is C substituted with a group selected from the group consisting of F, OH, and OCH3. 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 and OCH3. 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 and OCH3. 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 way, is C 1-3 alkyl.

[0128] As "pyrrolidinediyl which may be substituted", "piperidindiyl which may be substituted", "piperazinediyl which may be substituted", "C 1-3 One form of acceptable substituents in "alkylene" is F, OH, OCH3 or a substituted C 1-3 Alkyl. In one embodiment, it is F, OH, OCH3, methyl, ethyl, hydroxymethyl or methoxymethyl. In one embodiment, it is F, OH, OCH3 or methyl.

[0129] As "C can be replaced by F 1-3 One embodiment of the "alkyl" is a methyl group which may be substituted with F or an ethyl group which may be substituted with F. For example, it is a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, or a trifluoroethyl group. As one embodiment, it is a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group, or a difluoroethyl group. As one embodiment, it is a monofluoromethyl group or a difluoromethyl group. As one embodiment, it is a monofluoromethyl group or a difluoroethyl group. As one embodiment, it is a monofluoromethyl group. As one embodiment, it is a difluoromethyl group. As one embodiment, it is a difluoroethyl group. As one embodiment, it is a 2,2-difluoroethyl group.

[0130] 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.

[0131] As "C 1-3 One embodiment of the "alkyl" is a methyl group which may be substituted with one OCH3, an ethyl group which may be substituted with 1 to 2 OCH3, or a propyl group which may be substituted with 1 to 3 OCH3. For example, it is a methyl group, an ethyl group, a methoxymethyl group, a 1-methoxyethyl group, a 2-methoxyethyl group, a 1,2-dimethoxyethyl group, or a 2-methoxypropyl group. As one embodiment, it is a methoxymethyl group or a methoxyethyl group, as one embodiment, it is a methoxymethyl group, as one embodiment, it is a methoxyethyl group, and as one embodiment, it is a 2-methoxypropyl group.

[0132] One embodiment of the "phenylene group which may be substituted with F" is a phenylene group which may be substituted with 1 to 2 F. Another embodiment is a phenylene group which may be substituted with 1 F, 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.

[0133] "Mutated KRAS" refers to KRAS with a mutation, such as G12V mutant KRAS, G12D mutant KRAS, and G12C mutant KRAS.

[0134] The "G12V mutation" refers to a mutation in which the amino acid residue corresponding to codon position 12 in the wild-type protein is converted from glycine to valine.

[0135] “G12V mutant KRAS” means KRAS having the above-mentioned “G12V mutation”.

[0136] The "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon position 12 in the wild-type protein is converted from glycine to aspartic acid.

[0137] “G12D mutant KRAS” means KRAS having the above-mentioned “G12D mutation”.

[0138] The "G12C mutation" refers to a mutation in which the amino acid residue corresponding to codon position 12 in the wild-type protein is converted from glycine to cysteine.

[0139] “G12C mutant KRAS” means KRAS having the above-mentioned “G12C mutation”.

[0140] "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.

[0141] "Mutated KRAS-positive pancreatic cancer" refers to pancreatic cancer that is mutated KRAS-positive, particularly pancreatic cancer that is G12V-mutated, G12D-mutated, and G12C-mutated KRAS-positive. For example, pancreatic cancer that has KRAS G12V mutation, G12D mutation, and G12C mutation, is a pancreatic cancer with a high positive rate of G12V mutation, G12D mutation, and G12C mutation KRAS. As one embodiment, it is mutated KRAS-positive pancreatic ductal carcinoma, particularly G12V mutation, G12D mutation, and G12C mutation KRAS-positive pancreatic ductal carcinoma, and as one embodiment, it is G12D mutation KRAS-positive pancreatic ductal adenocarcinoma, particularly G12V mutation, G12D mutation, and G12C mutation KRAS-positive pancreatic ductal adenocarcinoma.

[0142] "G12V mutation and G12D mutation KRAS positive pancreatic cancer" refers to G12V mutation and G12D mutation KRAS positive pancreatic cancer. For example, it is pancreatic cancer with KRAS G12V mutation and G12D mutation, and it is pancreatic cancer with a high positive rate of G12V mutation and G12D mutation KRAS. As one embodiment, it is G12V mutation and G12D mutation KRAS positive pancreatic ductal carcinoma, and as one embodiment, it is G12V mutation and G12D mutation KRAS positive pancreatic ductal adenocarcinoma.

[0143] "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.

[0144] "G12D mutation KRAS positive pancreatic cancer" refers to G12D mutation KRAS positive pancreatic cancer. For example, it is pancreatic cancer with KRAS G12D mutation, and it is pancreatic cancer with a high positive rate of G12D mutation KRAS. As one embodiment, it is G12D mutation KRAS positive pancreatic ductal carcinoma, and as one embodiment, it is G12D mutation KRAS positive pancreatic ductal adenocarcinoma.

[0145] "G12C mutation KRAS positive pancreatic cancer" refers to G12C mutation KRAS positive pancreatic cancer. For example, it is pancreatic cancer with KRAS G12C mutation, and it is pancreatic cancer with a high positive rate of G12C mutation KRAS. As one embodiment, it is G12C mutation KRAS positive pancreatic ductal carcinoma, and as one embodiment, it is G12C mutation KRAS positive pancreatic ductal adenocarcinoma.

[0146] One embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.

[0147] (1-1)

[0148] A is CR A or N, R A H or C 1-3 An alkyl compound or a salt thereof.

[0149] (1-2)

[0150] A is CR A or N, R A is a compound or a salt thereof wherein:

[0151] (1-3)

[0152] A is a compound or a salt thereof, wherein A is N.

[0153] (1-4)

[0154] A is a compound or a salt thereof wherein CH is represented by

[0155] (2-1)

[0156] X 1 A compound or a salt thereof which is -CH2- or -O-.

[0157] (2-2)

[0158] X 1 A compound or a salt thereof wherein -O-.

[0159] (3-1)

[0160] R 1 is a naphthyl group which may be substituted with OH or the following formula (II),

[0161]

[0162] R 1a is H, methyl, F or Cl,

[0163] R 1b A compound or a salt thereof which is F, Cl, methyl or ethyl.

[0164] (3-2)

[0165] R 1 is formula (II),

[0166] R 1a is H, methyl, F or Cl,

[0167] R 1b A compound or a salt thereof which is F, Cl, methyl or ethyl.

[0168] (3-3)

[0169] R 1 is formula (II),

[0170] R 1a is H, methyl, F or Cl,

[0171] R 1b A compound or a salt thereof in which R is methyl.

[0172] (3-4)

[0173] R 1 It is a compound represented by the following formula (II-a) or a salt thereof.

[0174]

[0175] (4-1)

[0176] R 2 is H, halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 An alkyl, cyclopropyl or vinyl compound or a salt thereof.

[0177] (4-2)

[0178] R 2 is halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 An alkyl, cyclopropyl or vinyl compound or a salt thereof.

[0179] (4-3)

[0180] R 2 For halogen, C 1-3 An alkyl, cyclopropyl or vinyl compound or a salt thereof.

[0181] (4-4)

[0182] R 2 A compound or a salt thereof which is a cyclopropyl group.

[0183] (5-1-1)

[0184] R 3A compound or a salt thereof selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XXXV).

[0185]

[0186] (5-1-2)

[0187] R 3 A compound or a salt thereof selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X) and formula (XI).

[0188]

[0189] (5-1-3)

[0190] R 3 A compound or a salt thereof selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VIII-a) and formula (X).

[0191]

[0192] (5-1-4)

[0193] R 3 A compound or a salt thereof selected from the group consisting of the following formula (III-a), formula (IV-a), formula (Va), formula (VIII-a) and formula (X).

[0194]

[0195] (5-1-5)

[0196] R 3 A compound or a salt thereof selected from the group consisting of the following formula (III-a), formula (IV-a) and formula (Va).

[0197]

[0198] (5-2-1)

[0199] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 A cycloalkyl compound or a salt thereof.

[0200] (5-2-2)

[0201] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 A cycloalkyl compound or a salt thereof.

[0202] (5-2-3)

[0203] R 3a -(CH2) p CHR 3f -NR N1 R N2 or -(CH2) p CHR 3f -OR 3gor a salt thereof.

[0204] (5-2-4)

[0205] R 3a -(CH2) p CHR 3f -NR N1 R N2 or a salt thereof.

[0206] (5-3-1)

[0207] R 3b H or C 1-3 An alkyl compound or a salt thereof.

[0208] (5-3-2)

[0209] R 3b is a compound or a salt thereof wherein R is H or methyl.

[0210] (5-3-3)

[0211] R 3b is a compound or a salt thereof wherein:

[0212] (5-4-1)

[0213] R 3c and R 3d -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6Cycloalkyl, wherein R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-compound or its salt.

[0214] (5-4-2)

[0215] R 3c -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, wherein R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV-a) 2 A compound or a salt thereof wherein -O- or -NH-.

[0216] (5-4-3)

[0217] R 3c -(CH2) p CHR 3f -NR N1 R N2 ; can be C 1-3 Alkyl-substituted pyrrolidinyl; or -NR N1 R N2 Substituted C 3-6 Cycloalkyl and X of (IV-a) 2 A compound or a salt thereof wherein -O- or -NH-.

[0218] (5-4-4)

[0219] R 3c To be available for -NR N1 R N2 Substituted C 3-6 A cycloalkyl compound or a salt thereof.

[0220] (5-4-5)

[0221] R 3d -(CH2) p CHR 3f -NR N1 R N2 Or can be selected from C 1-3 Alkyl, C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A compound or a salt thereof of a 4- to 6-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms and substituted with a group selected from the group consisting of:

[0222] (5-5-1)

[0223] R 3e For-OC 2-3 Alkylene-NR N1 R N2 or a salt thereof.

[0224] (5-6-1)

[0225] R 3f H, F or C 1-3 An alkyl compound or a salt thereof.

[0226] (5-6-2)

[0227] R 3f H or C 1-3 An alkyl compound or a salt thereof.

[0228] (5-6-3)

[0229] R 3f is a compound or a salt thereof wherein:

[0230] (5-7-1)

[0231] R 3g H or C 1-3 An alkyl compound or a salt thereof.

[0232] (5-7-2)

[0233] R 3g is a compound or a salt thereof wherein:

[0234] (5-8-1)

[0235] R 3h A compound or a salt thereof which is a 5-membered heteroaryl group which has 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and which may be substituted, or a 6-membered heteroaryl group which has 1 to 3 nitrogen atoms and which may be substituted.

[0236] (5-8-2)

[0237] R 3h A compound or a salt thereof which is a 6-membered heteroaryl group which has 1 to 3 nitrogen atoms and may be substituted.

[0238] (5-9-1)

[0239] 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

[0240] Two R on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The group of formula (XXXV) is a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and forms a spiro ring, which may be selected from the group consisting of C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0241] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 The group of formula (XXXV) is a ring consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring, which may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0242] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridge structure containing 1 to 2 carbon atoms may be formed. The group of formula (XXXV) as a ring having the bridge structure may be selected from C1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or a salt thereof.

[0243] (5-10-1)

[0244] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0245] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0246] R 3f and R N1 A compound or a salt thereof which can form, together with the carbon atom and the nitrogen atom to which they are bonded, a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0247] (5-10-2)

[0248] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0249] R N1 and R N2 These may form, together with the nitrogen atom to which they are bonded, a compound or a salt thereof which contains, as ring-constituting atoms, 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen and which may be substituted, a 4- to 6-membered saturated heterocyclic group.

[0250] (5-10-3)

[0251] R N1 and R N2 Same or different, both are C 1-3 An alkyl compound or a salt thereof.

[0252] (5-10-4)

[0253] R N1 C 1-3 Alkyl, R N2 is a compound or a salt thereof wherein:

[0254] (5-11-1)

[0255] X 2is -O-, -NH- or -N(C 1-3 alkyl)-compound or its salt.

[0256] (5-11-2)

[0257] X 2 A compound or a salt thereof which is -O-, -NH- or -N(CH3)-.

[0258] (5-11-3)

[0259] X 2 A compound or a salt thereof wherein -O- or -NH-.

[0260] (5-11-4)

[0261] X 2 A compound or a salt thereof wherein -NH-.

[0262] (5-11-5)

[0263] X 2 A compound or a salt thereof wherein -O-.

[0264] (5-12-1)

[0265] X 3 is a compound or a salt thereof wherein:

[0266] (5-12-2)

[0267] X 3 is a compound or a salt thereof.

[0268] (5-13-1)

[0269] X 4 A compound or a salt thereof which is -CH2-, -CH2-CH2- or -O-CH2-.

[0270] (5-14-1)

[0271] A compound or a salt thereof, wherein n is 1 or 2 and p is 1 or 2.

[0272] (5-14-2)

[0273] The compound or a salt thereof, wherein p is 1 or 2.

[0274] (5-14-3)

[0275] The compound wherein p is 1 or a salt thereof.

[0276] (5-14-4)

[0277] A compound or a salt thereof, wherein n is 1 or 2.

[0278] (5-14-5)

[0279] The compound wherein n is 1 or a salt thereof.

[0280] (5-15-1)

[0281] The compound or a salt thereof, wherein q is an integer of 1 to 8.

[0282] (6-1)

[0283] R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a Substituted pyrrolidinyl and R 4a The group consisting of substituted tetrahydrofuranyl and C 1-6 Alkyl; can be R 4b substituted piperidinyl; or may be R 4a Substituted tetrahydropyranyl,

[0284] R 4a C can be replaced by F 1-3 alkyl,

[0285] R 4b C substituted with 1 to 3 F 1-3 An alkyl compound or a salt thereof.

[0286] (6-2)

[0287] R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a The C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl,

[0288] R 4a C 1-3 alkyl,

[0289] R 4b C substituted with 1 to 3 F 1-3 An alkyl compound or a salt thereof.

[0290] (6-3)

[0291] R 4 can be selected from OCH3, R 4a 、N(R 4a )2. Can be R 4aThe C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl,

[0292] R 4a C 1-3 alkyl,

[0293] R 4b C substituted with 1 to 3 F 1-3 An alkyl compound or a salt thereof.

[0294] (6-4)

[0295] R 4 is a C which may be substituted by a group selected from the group consisting of OCH3 and tetrahydrofuranyl 1-6 or a tetrahydropyranyl compound or a salt thereof.

[0296] (6-5)

[0297] R 4 is a C that can be replaced by OCH3 1-6 An alkyl or tetrahydropyranyl compound or a salt thereof.

[0298] (6-6)

[0299] R 4 is a C that can be replaced by OCH3 1-6 An alkyl compound or a salt thereof.

[0300] (7-1)

[0301] R 5 Methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C 3-6 Cycloalkylmethyl or C 3-6 A cycloalkyl compound or a salt thereof.

[0302] (7-2)

[0303] R 5 is ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl or C 3-6 A cycloalkyl compound or a salt thereof.

[0304] (7-3)

[0305] R 5 The compound or its salt which is isopropyl or sec-butyl.

[0306] (7-4)

[0307] R 5 is an isopropyl compound or a salt thereof.

[0308] (8-1)

[0309] R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or

[0310] R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 A cycloalkane or a compound of a 4- to 6-membered saturated heterocyclic ring which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or a salt thereof.

[0311] (8-2)

[0312] R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or

[0313] R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 A cycloalkane compound or a salt thereof.

[0314] (8-3)

[0315] R 6a and R 6b are the same or different from each other and are H or C which may be substituted by a group selected from the group consisting of OH and N(CH3)2 1-6 An alkyl compound or a salt thereof.

[0316] (8-4)

[0317] R 6a H, R 6b C can be replaced by OH 1-6 An alkyl compound or a salt thereof.

[0318] (8-5)

[0319] R 6a H, R 6b A compound or a salt thereof which is a hydroxymethyl group.

[0320] (9-1)

[0321] R 7A compound or a salt thereof which is a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, a 5-membered heteroaryl group which may be substituted and contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms.

[0322] (9-2)

[0323] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII) and formula (XXXIII),

[0324]

[0325] R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 An alkyl compound or a salt thereof.

[0326] (9-3)

[0327] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII),

[0328]

[0329] R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 An alkyl compound or a salt thereof.

[0330] (9-4)

[0331] R 7 is a group selected from the group consisting of formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII),

[0332] R 7a , R 7b Same or different, H or C 1-3 An alkyl compound or a salt thereof.

[0333] (9-5)

[0334] R 7is a group selected from the group consisting of the following formula (XXIII), formula (XXIV) and formula (XXVIII),

[0335]

[0336] R 7a , R 7b Same or different, H or C 1-3 An alkyl compound or a salt thereof.

[0337] (9-6)

[0338] R 7 A compound or a salt thereof selected from the group consisting of the following formula (XXIII-a), formula (XXIV-a) and formula (XXVIII-a).

[0339]

[0340] (9-7)

[0341] R 7 It is a compound represented by the following formula (XXIII-a) or a salt thereof.

[0342]

[0343] (9-8)

[0344] R 7 It is a compound represented by the following formula (XXVIII-a) or a salt thereof.

[0345]

[0346] (9-9)

[0347] R 7 It is a compound represented by the following formula (XXIV-a) or a salt thereof.

[0348]

[0349] (10-1)

[0350] A compound or a salt thereof, in which W is an optionally substituted phenylene group or an optionally substituted 6-membered heteroaromatic hydrocarbon diyl group containing 1 to 3 nitrogen atoms as ring constituent atoms.

[0351] (10-2)

[0352] W is the following formula (XXXIV),

[0353]

[0354] W 1 is CH, CF, CCl or CCH3,

[0355] W 2 A compound or a salt thereof which is CH, CF, CCl, CCH3 or N.

[0356] (10-3)

[0357] W is formula (XXXIV),

[0358] W 1 For CH,

[0359] W 2 is a compound or a salt thereof wherein R is CH or N.

[0360] (10-4)

[0361] W is formula (XXXIV),

[0362] W 1 and W 2 are compounds wherein each of them is CH or a salt thereof.

[0363] (11-1)

[0364] A compound or a salt thereof in which Y is a phenylene group or a pyridinediyl group which may be substituted with F or Cl.

[0365] (11-2)

[0366] The compound or a salt thereof, wherein Y is a phenylene group which may be substituted with F or Cl.

[0367] (11-3)

[0368] The compound or a salt thereof wherein Y is a phenylene group.

[0369] (12-1)

[0370] L is -(L 1 -L 2 -L 3 -L 4 )-,

[0371] L 1 , L 2 , L 3 , L 4 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C 1-3 A group consisting of an alkylene group and C=O,

[0372] R L1 H or C 1-3 An alkyl compound or a salt thereof.

[0373] (12-2)

[0374] L is a key, C 1-3 Alkylene, C═O, or a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), and formula (XVIII),

[0375]

[0376] R L1 H or C 1-3 alkyl,

[0377] R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl,

[0378] R L is CH or N,

[0379] The compound or a salt thereof, wherein m is 1 or 2.

[0380] (12-3)

[0381] L is a bond, C=O or a group selected from the group consisting of the following formula (XIII) and formula (XIV),

[0382]

[0383] R L1 H or C 1-3 alkyl,

[0384] R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl,

[0385] The compound or a salt thereof, wherein m is 1 or 2.

[0386] (12-4)

[0387] L is a bond, C=O or a group selected from the group consisting of formula (XIII) and formula (XIV),

[0388] R L1 C 1-3 alkyl,

[0389] R L2 and R L3 All are H,

[0390] The compound wherein m is 1 or a salt thereof.

[0391] (12-5)

[0392] A compound or a salt thereof wherein L is a bond or C═O.

[0393] (12-6)

[0394] A compound or a salt thereof wherein L is a bond.

[0395] (12-7)

[0396] L is a compound wherein C═O or a salt thereof.

[0397] (13-1)

[0398] A compound or a salt thereof in which Z is NH or a 5-membered heteroarene diyl group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0399] (13-2)

[0400] A compound or a salt thereof, wherein Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII).

[0401]

[0402] (13-3)

[0403] A compound or a salt thereof, wherein Z is NH or a group selected from the group consisting of the following formula (XIX-a), formula (XX-a), formula (XXI-a) and formula (XXII-a).

[0404]

[0405] (In the formula, * indicates bonding to L.)

[0406] (13-4)

[0407] Z is a compound or a salt thereof selected from the group consisting of formula (XIX), formula (XX), formula (XXI) and formula (XXII).

[0408] (13-5)

[0409] Z is a compound or a salt thereof wherein Z is a group selected from the group consisting of formula (XIX-a), formula (XX-a), formula (XXI-a) and formula (XXII-a).

[0410]

[0411] (In the formula, * indicates bonding to L.)

[0412] (13-6)

[0413] Z is a compound of the following formula (XX) or a salt thereof.

[0414]

[0415] (13-7)

[0416] Z is a compound represented by the following formula (XX-a) or a salt thereof.

[0417]

[0418] (In the formula, * indicates bonding to L.)

[0419] (13-8)

[0420] The compound or a salt thereof, wherein Z is NH.

[0421] (14-1)

[0422] YLZ is a compound represented by the following formula (XII) or a salt thereof.

[0423]

[0424] (14-2)

[0425] YLZ is a compound represented by the following formula (XII-a) or a salt thereof.

[0426]

[0427] (In the formula, O-CH2* represents a bond to the carbon atom of O-CH2 bonded to YLZ.) (15)

[0429] A compound or a salt thereof which is a combination of any two or more of the embodiments described in (1-1) to (14-2) that are not contradictory.

[0430] Specific examples of the combination described in (15) include the following.

[0431] (16-1)

[0432] A compound of formula (I) or a salt thereof.

[0433]

[0434] (Where,

[0435] A is CR A or N,

[0436] R A H or C 1-3 alkyl,

[0437] X 1 is -CH2- or -O-,

[0438] R 1 is a naphthyl group which may be substituted with OH or the following formula (II),

[0439]

[0440] R 1a is H, methyl, F or Cl,

[0441] R 1b is F, Cl, methyl or ethyl,

[0442] R 2 is H, halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 Alkyl, cyclopropyl or vinyl,

[0443] R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XXXV),

[0444]

[0445] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C3-6 Cycloalkyl,

[0446] R 3b H or C 1-3 alkyl,

[0447] R 3c and R 3d -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0448] R 3e For-OC 2-3 Alkylene-NR N1 R N2 ,

[0449] R 3f H, F or C 1-3 alkyl,

[0450] R 3g H or C 1-3 alkyl,

[0451] R 3h is a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which may be substituted and contains 1 to 3 nitrogen atoms,

[0452] R 3i are the same or different from each other and are selected from H, OH, substituted C1-3 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

[0453] Two R on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The group of formula (XXXV) is a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and forms a spiro ring, which may be selected from the group consisting of C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0454] R present on two adjacent carbon atoms 3i These two carbon atoms can form a 3-6 The group of formula (XXXV) is a ring consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring, which may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, or

[0455] R present on two non-adjacent carbon atoms 3i Together with the two carbon atoms, a bridge structure containing 1 to 2 carbon atoms may be formed. The group of formula (XXXV) as a ring having the bridge structure may be selected from C 1-3 Alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo,

[0456] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0457] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0458] R 3f and R N1may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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,

[0459] X 2 is -O-, -NH- or -N(C 1-3 alkyl)-,

[0460] X 3 is O or S,

[0461] X 4 is -CH2-, -CH2-CH2- or -O-CH2-,

[0462] n is 1 or 2, p is 1 or 2,

[0463] q is an integer from 1 to 8,

[0464] Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-,

[0465] R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a Substituted pyrrolidinyl and R 4a The group consisting of substituted tetrahydrofuranyl and C 1-6 Alkyl; can be R 4b substituted piperidinyl; or may be R 4a Substituted tetrahydropyranyl,

[0466] R 4a C can be replaced by F 1-3 alkyl,

[0467] R 4b C substituted with 1 to 3 F 1-3 alkyl,

[0468] R 5 Methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C 3-6 Cycloalkylmethyl or C 3-6 Cycloalkyl,

[0469] R 6a and R 6bare the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or

[0470] R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 Cycloalkane or a 4- to 6-membered saturated heterocyclic ring which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,

[0471] R 7 is a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms,

[0472] W is an optionally substituted phenylene group or an optionally substituted 6-membered heteroaromatic diyl group containing 1 to 3 nitrogen atoms as ring constituent atoms,

[0473] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0474] L is -(L 1 -L 2 -L 3 -L 4 )-,

[0475] L 1 , L 2 , L 3 , L 4 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C 1-3 A group consisting of an alkylene group and C=O,

[0476] R L1 H or C 1-3 alkyl,

[0477] Z is NH or a 5-membered heteroaromatic diyl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,

[0478] Alternatively, YLZ is the following formula (XII).

[0479]

[0480] (16-2)

[0481] The compound or salt thereof according to (16-1) above, wherein

[0482] R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X) and formula (XI),

[0483]

[0484] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0485] R 3b H or C 1-3 alkyl,

[0486] R 3c and R 3d -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g, C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0487] R 3e For-OC 2-3 Alkylene-NR N1 R N2 ,

[0488] R 3f H, F or C 1-3 alkyl,

[0489] R 3g H or C 1-3 alkyl,

[0490] R 3h is a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which may be substituted and contains 1 to 3 nitrogen atoms,

[0491] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0492] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0493] R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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,

[0494] X 2is -O-, -NH- or -N(C 1-3 alkyl)-,

[0495] X 3 is O or S,

[0496] n is 1 or 2, p is 1 or 2,

[0497] Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-.

[0498] (16-3)

[0499] The compound or salt thereof according to (16-2) above, wherein

[0500] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0501] L is a key, C 1-3 Alkylene, C═O, or a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), and formula (XVIII),

[0502]

[0503] R L1 H or C 1-3 alkyl,

[0504] R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl,

[0505] R L is CH or N,

[0506] m is 1 or 2,

[0507] Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII),

[0508]

[0509] Alternatively, YLZ is the following formula (XII).

[0510]

[0511] (16-4)

[0512] The compound or salt thereof according to (16-3) above, wherein

[0513] A is CR A or N,

[0514] R A For H,

[0515] X 1 For -O-,

[0516] R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or

[0517] R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 Cycloalkanes,

[0518] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII) and formula (XXXIII),

[0519]

[0520] R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 alkyl,

[0521] W is the following formula (XXXIV),

[0522]

[0523] W 1 is CH, CF, CCl or CCH3,

[0524] W 2 It is CH, CF, CCl, CCH3 or N.

[0525] (16-5)

[0526] The compound or salt thereof according to (16-4) above, wherein

[0527] R 1is the following formula (II),

[0528]

[0529] R 1a is H, methyl, F or Cl,

[0530] R 1b is F, Cl, methyl or ethyl,

[0531] R 2 is halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 Alkyl, cyclopropyl or vinyl,

[0532] R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VIII-a) and formula (X),

[0533]

[0534] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0535] R 3b is H or methyl,

[0536] R 3c and R 3d-(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0537] R 3f H, F or C 1-3 alkyl,

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

[0539] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0540] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0541] R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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,

[0542] X 2 is -O-, -NH- or -N(C1-3 alkyl)-,

[0543] X 3 is O or S,

[0544] n is 1 or 2, p is 1 or 2,

[0545] Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-,

[0546] Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl,

[0547] L is a bond, C=O or a group selected from the group consisting of the following formula (XIII) and formula (XIV),

[0548]

[0549] R L1 H or C 1-3 alkyl,

[0550] R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl,

[0551] m is 1 or 2,

[0552] Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII),

[0553]

[0554] Alternatively, YLZ is the following formula (XII).

[0555]

[0556] (16-6)

[0557] The compound or salt thereof according to (16-5) above, wherein

[0558] R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a), formula (Va), formula (VIII-a) and formula (X),

[0559]

[0560] R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0561] R 3b is H or methyl,

[0562] R 3c -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl,

[0563] R 3f H, F or C 1-3 alkyl,

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

[0565] RN1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0566] R N1 and R N2 together with the nitrogen atom to which they are bonded, may form a substituted 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, or

[0567] R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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,

[0568] X 2 is -O- or -NH- or -N(CH3)-,

[0569] X 3 is O or S,

[0570] p is 1 or 2,

[0571] Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV-a) 2 is -O- or -NH-,

[0572] R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a The C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl,

[0573] R 4a C 1-3 alkyl,

[0574] R 4b C substituted with 1 to 3 F 1-3 alkyl,

[0575] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII),

[0576]

[0577] R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 alkyl,

[0578] Y is a phenylene group which may be substituted by F or Cl,

[0579] Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII).

[0580]

[0581] (16-7)

[0582] The compound or salt thereof according to (16-6) above, wherein

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

[0584]

[0585] R 2 is cyclopropyl,

[0586] R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a), formula (Va), formula (VIII-a) and formula (X),

[0587]

[0588] R 3a -(CH2) p CHR 3f -NR N1 R N2 or -(CH2) p CHR 3f -OR 3g ,

[0589] R 3b For H,

[0590] R 3c -(CH2) p CHR 3f -NR N1 R N2 ; can be C 1-3 Alkyl-substituted pyrrolidinyl; or, -NR N1 R N2 Substituted C 3-6Cycloalkyl,

[0591] R 3f For H,

[0592] R 3g For H,

[0593] R N1 and R N2 Same or different, H or C 1-3 Alkyl, or

[0594] R N1 and R N2 may form, together with the nitrogen atom to which they are bonded, a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,

[0595] X 2 is -O- or -NH-,

[0596] X 3 is O or S,

[0597] p is 1 or 2,

[0598] R 4 may be selected from OCH3, R 4a 、N(R 4a )2. Can be R 4a The C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl,

[0599] R 4a C 1-3 alkyl,

[0600] R 4b C substituted with 1 to 3 F 1-3 alkyl,

[0601] R 5 is isopropyl or sec-butyl,

[0602] R 6a and R 6b are the same or different from each other and are H or C which may be substituted by a group selected from the group consisting of OH and N(CH3)2 1-6 alkyl,

[0603] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII),

[0604]

[0605] R 7a , R 7b Same or different, H or C 1-3 Alkyl, W is the following formula (XXXIV),

[0606]

[0607] W 1 For CH,

[0608] W 2 is CH or N,

[0609] Y is phenylene,

[0610] L is a bond or C=O.

[0611] (16-8)

[0612] The compound or salt thereof according to (16-7) above, wherein

[0613] R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a) and formula (Va),

[0614]

[0615] R 3a -(CH2) p CHR 3f -NR N1 R N2 ,

[0616] R 3b For H,

[0617] R 3c To be available for -NR N1 R N2 Substituted C 3-6 Cycloalkyl,

[0618] R 3f For H,

[0619] R N1 and R N2 Same or different, both are C 1-3 alkyl,

[0620] X 2 is -O- or -NH-,

[0621] X 3 For O,

[0622] p is 1,

[0623] R 4 is a C that can be replaced by OCH3 1-6 alkyl,

[0624] R 5 is isopropyl,

[0625] R 6a For H,

[0626] R 6b C can be replaced by OH 1-6 alkyl,

[0627] R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV) and formula (XXVIII),

[0628]

[0629] R 7a , R 7b Same or different, H or C 1-3 alkyl,

[0630] W is the following formula (XXXIV),

[0631]

[0632] W 1 and W 2 All are CH,

[0633] L is a key,

[0634] Z is a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII).

[0635]

[0636] As examples of specific compounds included in the present invention, the following compounds can be mentioned as one embodiment.

[0637] A compound or a salt thereof selected from the group consisting of the following compounds:

[0638] 3-({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3- 1-[((2S)-2-methoxypropoxy)quinazolin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0639] 3-({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0640] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0641] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0642] 3-({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0643] (4R)-1-[(2S)-2-(4-{4-[({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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0644] 3-({6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester, and

[0645] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0646] As examples of specific compounds included in the present invention, the following compounds can be mentioned as one embodiment.

[0647] A compound or a salt thereof selected from the group consisting of the following compounds:

[0648] 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3- 1-[((2S)-2-methoxypropoxy)quinazolin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0649] 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0650] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0651] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0652] 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0653] (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0654] 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid (1S,3R)-3-(dimethylamino)cyclobutyl ester, and

[0655] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0656] As examples of specific compounds included in the present invention, the following compounds can be mentioned as one embodiment.

[0657] A compound or a salt thereof selected from the group consisting of the following compounds:

[0658] 3-({(7P)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3- 1-[((2S)-2-methoxypropoxy)quinazolin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0659] 3-({(7P)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0660] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0661] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide,

[0662] 3-({(7P)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester,

[0663] (4R)-1-[(2S)-2-(4-{4-[({(7P)-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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide,

[0664] 3-({(7P)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid (1S,3R)-3-(dimethylamino)cyclobutyl ester, and

[0665] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0666] 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.

[0667] 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.

[0668] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by 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., 1985, 5, p.2157-2161 and "Drug Development", Volume 7 Molecular Design, Hirokawa Bookstore, 1990, p.163-198 can be cited.

[0669] 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.

[0670] Furthermore, the present invention also includes various hydrates, solvates and polymorphs of the compound of formula (I) and salts thereof.

[0671] 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.

[0672] 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.

[0673] 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).

[0674] 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.

[0675] 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.

[0676] (Manufacturing method)

[0677] 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, can be appropriately selected to use according to their reaction conditions.In such method, after importing this protecting group to react, remove protecting group as required, thus can obtain desired compound.

[0678] 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.

[0679] Representative methods for producing compounds of formula (I) are described below. Each method can also be carried out with reference to the references attached to this description. It should be noted that the production method of the present invention is not limited to the examples shown below.

[0680] In this specification, the following abbreviations may be used.

[0681] 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, TFA: trifluoroacetic acid, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidino Hexafluorophosphoric acid, TBAF: tetra-n-butylammonium fluoride, DABCO: 1,4-diazabicyclo[2.2.2]octane, CDI: 1,1'-carbonyldiimidazole, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate, Tr: trityl.

[0682] (Manufacturing method 1)

[0683]

[0684] (Where R 1A , R 3A Indicates that from R 1 , R 3 A divalent group formed by removing the hydrogen from the functional group of the introduced protective group. 1 PG 2 It also includes the case where no protecting group exists.

[0685] Same as below)

[0686] The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction. 3 The NH2 contained in is subjected to an alkylation reaction to obtain the protective group. Examples of the protective group shown here include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, tert-butylsulfinyl and the like.

[0687] The deprotection reaction is usually stirred for 0.1 hours to 5 days from cooling to heating under reflux. Examples of solvents used here are not particularly limited, and include: alcohols such as MeOH, EtOH, iPrOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform; ethers such as ether, THF, DOX, 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, p-toluenesulfonic acid, and phosphoric acid.

[0688] By selecting a protecting group, deprotection can also be performed by catalytic hydrogenation. Examples of protecting groups include benzyl, p-methoxybenzyl, benzyloxycarbonyl, etc. In addition, deprotection can also be performed using a fluoride ion source 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. In addition, as PG 1 PG 2 , or protecting groups that can be deprotected under different deprotection conditions can be selected separately and the deprotection can be carried out in stages.

[0689] In the alkylation reaction, formaldehyde or an alkyl group having a formyl group is used, and in the presence of a reducing agent, in a solvent inert to the reaction, at -45°C to heating reflux, preferably at 0°C to room temperature, stirring is usually performed for 0.1 hours to 5 days. Examples of the solvent used here are not particularly limited, and examples include: alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; and mixtures thereof. As reducing agents, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like can be cited. It is sometimes preferred to carry out the reaction in the presence of a dehydrating agent such as a molecular sieve or an acid such as acetic acid, hydrochloric acid, and titanium (IV) isopropoxide complex.

[0690] As reference documents, for example, the following documents can be referred to.

[0691] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[0692] AR Katritzky and RJK Taylor, "Comprehensive Organic Functional Group Transformations II", Volume 2, Elsevier Pergamon, 2005

[0693] When the compound (1) as a raw material has axial asymmetry, the present reaction can be carried out using stereoisomers obtained by temporarily isolating the compound (1).

[0694] The hydrochloride of the compound of formula (I) can be obtained by subjecting the compound of formula (I) to a salt-forming reaction such as the following operation.

[0695] The compound of formula (I) that is believed to form a salt with hydrochloric acid from its chemical structural characteristics is dissolved in CH Cl and MeOH, hydrogen chloride (4M DOX solution, 10 equivalents) is added under ice-cooling, and stirred for 30 minutes under ice-cooling. The reaction mixture is concentrated under reduced pressure, ether is added to the residue obtained, the solid generated is filtered, and dried under reduced pressure to obtain the hydrochloride of the compound of the formula (I).

[0696] The compound of formula (I) can be obtained by subjecting the hydrochloride of the compound of formula (I) to a desalting reaction such as the following operation, but the invention is not limited to this method.

[0697] The hydrochloride of the compound of formula (I) was purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and the fractions containing the target product were collected, adjusted to alkalinity with saturated sodium bicarbonate aqueous solution, and extracted with CHCl3 / MeOH (5 / 1). The combined organic layer was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the obtained solid was washed with ether and dried under reduced pressure to obtain the compound of formula (I).

[0698] (Raw material synthesis 1)

[0699]

[0700] This production method is a first method for producing compound (1)-1 contained in the raw material compound (1).

[0701] (First step)

[0702] This step is a method for producing compound (1)-1 by a cycloaddition reaction of compound (2) and compound (3).

[0703] In this reaction, the compound (2) and the compound (3) are used in equal amounts or in excess of one of them, and the mixture thereof is preferably stirred in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or without a solvent, under cooling or heating under reflux, preferably at 0°C to 100°C, for usually 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; DMF, DMSO, ethyl acetate, MeCN, tBuOH, water; and mixtures thereof. Examples of the copper salt include CuI, CuSO4, and copper (I) trifluoromethanesulfonate (CuOTf). Examples of the reducing agent include sodium ascorbate, etc. Conducting the reaction in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) or the like may be advantageous in that the reaction proceeds smoothly.

[0704] [literature]

[0705] Angew.Chem.Int.Ed.2002,41,p.2596-2599.

[0706] It should be noted that the PG of compound (2) can also be used. 2 This reaction is carried out by subjecting the compound obtained by first subjecting it to a deprotection reaction.

[0707] (Raw material synthesis 2)

[0708]

[0709] (In the formula, R represents C 1-3 Alkyl. The same applies below)

[0710] This production method is a second method for producing compound (1)-1 contained in the raw material compound (1).

[0711] (First step)

[0712] This step is a method for producing compound (5) by cycloaddition reaction of compound (2) and compound (4).

[0713] The reaction conditions were the same as those in the first step of the starting material synthesis 1.

[0714] (Second step)

[0715] This step is a method for producing compound (6) by hydrolyzing compound (5).

[0716] This reaction is carried out by stirring compound (5) 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, by using a mixed solvent of the above solvent and water, it 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.

[0717] As references for this reaction, for example, the following documents can be referred to.

[0718] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0719] Angew.Chem.Int.Ed.2005,44,p.1378-1382.

[0720] (Third step)

[0721] This step is a method for producing compound (1)-1 by amidation reaction of compound (6) and compound (7).

[0722] In the present reaction, compound (6) and compound (7) 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 (benzotriazol-1-yloxy)tripyrrolidinophosphodiesterase; (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), 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.

[0723] Alternatively, a method of converting compound (6) 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 reacting with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained by reacting 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 (7) 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.

[0724] [literature]

[0725] SR Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, Volume 1, Academic Press Inc., 1991

[0726] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0727] (Raw material synthesis 3)

[0728]

[0729] (Where R 3B Indicates NR 3aa R 3bb , OR 3cc , R 3dd , P.G. 1A PG 3 Represents a protecting group. 3B Indicates that from NR 3a R 3b , OR 3c , R 3d A divalent group formed by removing H from any of the functional groups into which a protecting group can be introduced and the functional groups into which a carbonyl group or a carboxyl group can be introduced. 1 Can have PG 2 . The same applies below)

[0730] This production method is a second method for producing compound (1)-2 contained in the raw material compound (1).

[0731] (First step)

[0732] This step is a method for producing compound (9) by cycloaddition reaction of compound (8) and compound (3).

[0733] The reaction conditions were the same as those in the first step of the starting material synthesis 1.

[0734] (Second step)

[0735] This step is a method for producing compound (10) by subjecting compound (9) to a deprotection reaction.

[0736] The reaction conditions are the same as those for the deprotection reaction in Preparation Method 1.

[0737] (Third step)

[0738] This step is a method for preparing compound (1)-2 by adding compound (11) after reacting compound (10) with a carbonylating agent or by an amidation reaction of compound (10) with compound (12).

[0739] This step is carried out by reacting the compound (10) with an equal amount or an excess amount of a carbonylation agent in a solvent inert to the reaction, under cooling or heating, preferably at -20°C to 80°C, usually for about 0.1 hour to about 1 day. Next, an equal amount or an excess amount of the compound (11) is added to the obtained reaction mixture, and the mixture is reacted under cooling or heating, preferably at -20°C to 80°C, for about 0.1 hour to 1 day. Examples of the carbonylation agent include 1,1'-carbonyldiimidazole, 4-nitrophenyl chloroformate, diphosgene, triphosgene, phenyl chloroformate, and the like. 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, tetrahydrofuran, dioxane, and dimethoxyethane; N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, or a mixture thereof. It should be noted that the reaction may be carried out in the presence of a base such as triethylamine, which is sometimes advantageous in terms of making the reaction proceed smoothly.

[0740] The reaction conditions for the amidation reaction of compound (10) and compound (12) are the same as those in the third step of the starting material synthesis 2.

[0741] [literature]

[0742] SR Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, Volume 2, Academic Press Inc., 1991

[0743] (Raw material synthesis 4)

[0744]

[0745]

[0746] (In the formula, PG 4PG 5 Represents a protecting group. LG Represents C 1-12 Alkyl, LG 1 represents a leaving group, and BLG represents a boronic acid group or a trifluoroborate group protected by a boronic acid protecting group such as a boronic acid group or a boronic acid pinacol ester group (hereinafter sometimes referred to as a boronic acid group, etc.). Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, etc.

[0747] The present production method is a method for producing compound (2)-1 contained in the raw material compound (2).

[0748] (First step)

[0749] This step is a method for producing compound (14) by hydrolyzing compound (13).

[0750] This reaction is carried out by stirring compound (13) under cooling or heating under reflux for 0.1 hour to 5 days. As examples of solvents used here, there are no particular restrictions, and alcohols, acetone, DMF, THF, etc. can be cited. In addition, by setting a mixed solvent of the above solvent and water, it is sometimes preferred for the reaction. As examples of hydrolysis reagents, there are no particular restrictions, and sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, etc. can be cited.

[0751] As references for this reaction, for example, the following documents can be referred to.

[0752] The Chemical Society of Japan edited "Experimental Chemistry Lectures (5th Edition)" Volume 16 (2005) (Maruzen)

[0753] Angew.Chem.Int.Ed.2005,44,p.1378-1382.

[0754] (Second step)

[0755] This step is a method for producing compound (15) by protecting the hydroxyl group of compound (14) with a protecting group.

[0756] As an example, when the protection is performed using a tert-butyl group, the reaction is carried out by stirring the compound (14) under cooling or heating under reflux for usually 0.1 hour to 5 days. Examples of solvents used herein are not particularly limited, and include ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; tBuOH, DMF, etc. Examples of tert-butyl protecting agents are not particularly limited, and include isobutylene, 2-tert-butyl-1,3-diisopropylisourea, etc.

[0757] Alternatively, compound (15) can be produced by a dehydration condensation reaction of compound (14) and tBuOH.

[0758] As references for this reaction, for example, the following documents can be referred to.

[0759] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[0760] Org.Lett.,2012,14,17,p.4678-4681

[0761] (Third step)

[0762] This step is to react compound (15) with R LG A method for preparing compound (16) by in-situ substitution reaction of -SH.

[0763] As the R used here LG Examples of -SH include C 1-12 In this reaction, the compound (15) and R are used in equal amounts or in excess. LG -SH, and the mixture of these is stirred in a solvent inert to the reaction or without a solvent, under cooling or heating reflux, preferably at 0°C to 80°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; DMF, DMAc, DMSO, ethyl acetate, MeCN; and mixtures thereof. It is sometimes advantageous to conduct the reaction in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (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 in order to facilitate the reaction.

[0764] (Step 4)

[0765] This step is to react compound (16) with PG 5 A method for preparing compound (17) by in-situ substitution reaction of -OH. 5 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.

[0766] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0767] (Fifth step)

[0768] This step is to react compound (17) with a 2 A method for preparing compound (18) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[0769] 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.

[0770] In this reaction, compound (17) and a compound containing R are used in equal amounts or 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 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-dimethylimidazolin-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, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, etc. 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 that the reaction proceeds smoothly. In addition, heating the mixture by irradiating microwaves may be advantageous in allowing the reaction to proceed smoothly.

[0771] [literature]

[0772] J.Am.Chem.Soc.,2005,127,p.4685-4696

[0773] Org.Lett.2011,13,p.3948-3951

[0774] Org.Lett.2012,14,p.1278-1281

[0775] Compound (18) (wherein R 2 is hydrogen).

[0776] [literature]

[0777] J.Org.Chem.,1977,42,p.3491-3494

[0778] Tetrahedron Letters 2013,54,5207-5210

[0779] (Sixth step)

[0780] This step is a method for preparing compound (20) by Suzuki-Miyaura coupling reaction of compound (18) and compound (19).

[0781] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0782] When compound (18) 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.

[0783] (Step 7)

[0784] This step is a method for producing compound (21) by oxidation reaction of compound (20).

[0785] In this reaction, compound (22) 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.

[0786] [literature]

[0787] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 17, Maruzen, 2004

[0788] When compound (21) has axial asymmetry, it may be obtained as a mixture of stereoisomers. Each stereoisomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0789] In addition, in order to be able to react with the protective group PG introduced later 1 Under different deprotection conditions, compound (21) may be subjected to the deprotection reaction to obtain PG 2 Convert to other protecting groups.

[0790] The reaction conditions of the deprotection reaction used here are the same as those in the step described in Preparation Method 1.

[0791] Next, as the transformed PG 2 Examples of the protecting group include tetrahydro-2H-pyran-2-yl and the like.

[0792] As references for this reaction, for example, the following documents can be referred to.

[0793] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[0794] (Step 8)

[0795] This step is a method for producing compound (22) by deprotecting compound (21) using a catalytic hydrogenation reaction.

[0796] This reaction can be carried out by stirring the compound (21) in a solvent inert to the reaction such as MeOH, EtOH, ethyl acetate, THF, etc., under a hydrogen atmosphere at normal pressure to increased pressure in the presence of a metal catalyst and under cooling to heating, preferably at room temperature for 1 hour to 5 days. As the metal catalyst, palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plates and platinum oxide, and nickel catalysts such as reduced nickel and Raney nickel can be used.

[0797] (Step 9)

[0798] This step is a method for preparing compound (24) by reacting compound (22) with compound (23).

[0799] In this reaction, the compound (22) and the compound (23) are used in equal amounts or in excess of one of them, and the mixture thereof is reacted 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.

[0800] As references for this reaction, for example, the following documents can be referred to.

[0801] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 14, Maruzen, 2005

[0802] In addition, for compound (24), 1 Halogenation of a compound having a considerable portion of hydroxyl groups can produce LG 1 The halogenating agent used here is not particularly limited, and examples thereof include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, and the like.

[0803] As references for this reaction, for example, the following documents can be referred to.

[0804] The Chemical Society of Japan, "Experimental Chemistry Lectures", 5th edition, Volume 13, Maruzen, 2004

[0805] Furthermore, for compound (24), LG 1 LG can be produced by sulfonylation of a compound having a considerable portion of hydroxyl groups in the presence of a base. 1 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.

[0806] As references for this reaction, for example, the following documents can be referred to.

[0807] Synthesis 1999,9,p.1633-1636

[0808] (Step 10)

[0809] This step is a method for preparing compound (26) by an in-situ substitution reaction of compound (24) and compound (25).

[0810] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0811] (Step 11)

[0812] This step is a method for producing compound (27) by subjecting compound (26) to a deprotection reaction.

[0813] The reaction conditions are the same as those in the step described in Production Method 1.

[0814] (Step 12)

[0815] This step is a method for preparing compound (2)-1 by reacting compound (27) with compound (28).

[0816] In this reaction, compound (27) and compound (28) 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, and the like. 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 allowing the reaction to proceed smoothly.

[0817] (Raw material synthesis 5)

[0818]

[0819] This production method is a method for producing the starting material compound (26).

[0820] (First step)

[0821] This step is a method for preparing compound (28) by an in-situ substitution reaction between compound (15) and compound (25).

[0822] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0823] Alternatively, compound (28) can be produced by subjecting compound (25) to a halogen-containing compound and then subjecting it to a negishi coupling reaction with compound (15).

[0824] (Second step)

[0825] This step is to react compound (28) with PG 5 A method for preparing compound (29) by in-situ substitution reaction of -OH.

[0826] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0827] (Third step)

[0828] This step is to react compound (29) with a 2 A method for preparing compound (30) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[0829] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0830] Compound (30) (wherein R 2 is hydrogen).

[0831] [literature]

[0832] J.Org.Chem.,1977,42,p.3491-3494

[0833] Tetrahedron Letters 2013,54,5207-5210

[0834] (Step 4)

[0835] This step is a method for preparing compound (31) by Suzuki-Miyaura coupling reaction of compound (30) and compound (19).

[0836] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0837] (Fifth step)

[0838] This step is a method for producing compound (32) by deprotecting compound (31) through catalytic hydrogenation reaction.

[0839] The reaction conditions are the same as those in the eighth step of the starting material synthesis 4.

[0840] (Sixth step)

[0841] This step is a method for preparing compound (26) by reacting compound (32) with compound (23).

[0842] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[0843] (Raw material synthesis 6)

[0844]

[0845] This production method is a method for producing the raw material compound (2)-1.

[0846] (First step)

[0847] This step is a method for producing compound (33) by subjecting compound (31) to a deprotection reaction.

[0848] The reaction conditions are the same as those in the step described in Production Method 1.

[0849] When compound (31) has axial asymmetry, it may be obtained as a mixture of stereoisomers. Each stereoisomer can be isolated by a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0850] In addition, in order to be able to react with the protective group PG introduced later 1 Under different deprotection conditions, compound (31) may be subjected to deprotection reaction and PG 2 Convert to other protecting groups.

[0851] (Second step)

[0852] This step is a method for preparing compound (34) by reacting compound (33) with compound (28).

[0853] The reaction conditions are the same as those in the twelfth step of the starting material synthesis 4.

[0854] (Third step)

[0855] This step is a method for producing compound (35) by deprotecting compound (34) using a catalytic hydrogenation reaction.

[0856] The reaction conditions are the same as those in the eighth step of starting material synthesis 4.

[0857] (Step 4)

[0858] This step is a method for preparing compound (2)-1 by reacting compound (35) with compound (23).

[0859] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[0860] (Raw material synthesis 7)

[0861]

[0862] The present production method is a method for producing compound (8)-1 contained in the raw material compound (8).

[0863] (First step)

[0864] This step is a method for preparing compound (37) by chlorination reaction of compound (36).

[0865] In this reaction, the compound (36) and the chlorinating agent are used in equal amounts or in excess of one of them, and the mixture is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or heating to reflux, preferably at 60° C. or heating to reflux, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane, etc. Examples of the chlorinating agent include phosphorus oxychloride, thionyl chloride, etc. It is sometimes advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA or NMM in order to facilitate the reaction.

[0866] (Second step)

[0867] This step is to react compound (37) with R LG A method for preparing compound (38) by in-situ substitution reaction of -SH.

[0868] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0869] (Third step)

[0870] This step is to react compound (38) with PG 5 A method for preparing compound (39) by in-situ substitution reaction of -OH.

[0871] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0872] (Step 4)

[0873] This step is a method for preparing compound (41) by an in situ substitution reaction between compound (39) and compound (40).

[0874] In this reaction, the compound (39) and the compound (40) 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, N-methylmorpholine (NMM), 1,4-diazabicyclo[2.2.2]octane (DABCO), and tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate may be advantageous in that the reaction proceeds smoothly.

[0875] (Fifth step)

[0876] This step is to react compound (41) with a 2 A method for preparing compound (42) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[0877] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0878] (Sixth step)

[0879] This step is a method for preparing compound (43) by Suzuki-Miyaura coupling reaction of compound (42) and compound (19).

[0880] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0881] (Step 7)

[0882] This step is a method for producing compound (44) by oxidation reaction of compound (43).

[0883] The reaction conditions are the same as those in the seventh step of the starting material synthesis 4.

[0884] (Step 8)

[0885] This step is a method for producing compound (45) by deprotecting compound (44) using a catalytic hydrogenation reaction.

[0886] The reaction conditions are the same as those in the eighth step of starting material synthesis 4.

[0887] (Step 9)

[0888] This step is a method for preparing compound (46) by reacting compound (45) with compound (23).

[0889] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[0890] (Step 10)

[0891] This step is a method for preparing compound (8)-1 by an in-situ substitution reaction between compound (46) and compound (25).

[0892] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0893] (Raw material synthesis 8)

[0894]

[0895] The present production method is a method for producing compound (8)-1 contained in the raw material compound (8).

[0896] (First step)

[0897] This step is a method for preparing compound (47) by an in situ substitution reaction of compound (44) and compound (25).

[0898] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0899] (Second step)

[0900] This step is a method for producing compound (48) by deprotecting compound (47) using a catalytic hydrogenation reaction.

[0901] The reaction conditions are the same as those in the eighth step of starting material synthesis 4.

[0902] (Third step)

[0903] This step is a method for preparing compound (8)-1 by reacting compound (48) with compound (23).

[0904] (Raw material synthesis 9)

[0905]

[0906] This production method is a method for producing the starting material compound (47).

[0907] (First step)

[0908] This step is a method for preparing compound (49) by an in situ substitution reaction between compound (37) and compound (25).

[0909] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0910] Alternatively, compound (49) can be produced by subjecting compound (25) in which the hydrogen atom is converted to halogen to a negishi coupling reaction with compound (37).

[0911] (Second step)

[0912] This step is to react compound (49) with PG 5 A method for preparing compound (50) by in-situ substitution reaction of -OH.

[0913] The reaction conditions are the same as those in the third step of starting material synthesis 4.

[0914] (Third step)

[0915] This step is a method for preparing compound (51) by an in situ substitution reaction between compound (50) and compound (40).

[0916] The reaction conditions are the same as those in the fourth step of starting material synthesis 7.

[0917] (Step 4)

[0918] This step is to react compound (51) with a 2 A method for preparing compound (52) by Suzuki-Miyaura coupling reaction of a boronic acid derivative such as a -boronic acid group.

[0919] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0920] (Fifth step)

[0921] This step is a method for preparing compound (47) by Suzuki-Miyaura coupling reaction of compound (52) and compound (19).

[0922] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0923] (Raw material synthesis 10)

[0924]

[0925] The present production method is a method for producing compound (2)-2 contained in the raw material compound (2).

[0926] (First step)

[0927] This step is a method for producing compound (53) by subjecting compound (47) to a deprotection reaction.

[0928] The reaction conditions are the same as those for the deprotection reaction in Preparation Method 1.

[0929] (Second step)

[0930] This step is a method for producing compound (54) by adding compound (11) after reacting compound (53) with a carbonylating agent or by amidation reaction of compound (53) with compound (12).

[0931] The reaction conditions are the same as those in the third step of the starting material synthesis 3.

[0932] (Third step)

[0933] This step is a method for producing compound (55) by deprotecting compound (54) using a catalytic hydrogenation reaction.

[0934] The reaction conditions are the same as those in the eighth step of starting material synthesis 4.

[0935] (Step 4)

[0936] This step is a method for preparing compound (2)-2 by reacting compound (55) with compound (23).

[0937] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[0938] (Raw material synthesis 11)

[0939]

[0940] (In the formula, PG 6 represents a protecting group. )

[0941] This production method is a method for producing the raw material compound (3).

[0942] (First step)

[0943] This step is a method for preparing Compound (58) by amidation reaction of Compound (56) and Compound (57).

[0944] The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0945] (Second step)

[0946] This step is a method for producing compound (59) by subjecting compound (58) to a deprotection reaction.

[0947] The reaction conditions are the same as those in the step described in Production Method 1.

[0948] (Third step)

[0949] This step is a method for preparing compound (3) by reacting compound (59) with a diazo transfer reagent.

[0950] In this reaction, compound (59) is treated with an equal amount or an excess amount of a diazo transfer reagent in a solvent inert to the reaction under cooling or heating, preferably at 0°C to 50°C, for usually 0.1 hour to 3 days. Examples of the diazo transfer reagent are not particularly limited, and examples thereof include trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or a salt thereof, 2-azido-1,3-dimethylimidazole Hexafluorophosphate (ADMP), etc. It is sometimes advantageous to carry out the reaction in the presence of an organic base such as TEA, 4-dimethylaminopyridine (DMAP), 2,6-lutidine, or a catalytic amount of a copper salt such as CuSO4. Examples of solvents include halogenated hydrocarbons such as THF and dichloromethane; MeCN, alcohols, water; and mixtures thereof.

[0951] [literature]

[0952] J.Org.Chem.2012,77,p.1760-1764

[0953] Nature 2019,574,p.86-89

[0954] Org.Biomol.Chem.2014,12,p.4397-4406

[0955] (Raw material synthesis 12)

[0956]

[0957]

[0958] (where LG 2 represents a leaving group. )

[0959] The present production method is a method for producing the raw material compound (1)-3 contained in the raw material compound (1).

[0960] (First step)

[0961] This step is a method for preparing Compound (61) by reacting Compound (32) with Compound (60).

[0962] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[0963] (Second step)

[0964] This step is a method for producing Compound (62) by subjecting Compound (61) to a deprotection reaction.

[0965] The reaction conditions are the same as those in the step described in Production Method 1.

[0966] (Third step)

[0967] This step is a method for preparing Compound (63) by reacting Compound (62) with Compound (28).

[0968] The reaction conditions are the same as those in the twelfth step of the starting material synthesis 4.

[0969] (Step 4)

[0970] This step is a method for preparing compound (2)-3 by hydrolyzing compound (63).

[0971] The reaction conditions are the same as those in the second step of the starting material synthesis 2.

[0972] (Fifth step)

[0973] This step is a method for preparing compound (1)-3 by amidation reaction of compound (2)-3 with compound (59).

[0974] The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0975] (Raw material synthesis 13)

[0976]

[0977] (In the formula, PG 7 represents a protecting group for NH. )

[0978] This production method is a method for producing a raw material compound (1)-4 contained in a raw material compound (1). Here, L of the raw material compound (1)-4 is shown. 2 NR L1 , pyrrolidinediyl, piperidinediyl or piperazinediyl.

[0979] (First step)

[0980] This step is a method for preparing Compound (65) by amidation reaction of Compound (59) and Compound (64).

[0981] The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0982] (Step 2, Step 3)

[0983] This step is a method for producing compound (1)-4 by subjecting the compound obtained by deprotection reaction of compound (65) to an amidation reaction with compound (2)-3.

[0984] The reaction conditions of the deprotection reaction are the same as those in the step described in Production Method 1.

[0985] The reaction conditions of the amidation reaction are the same as those in the third step of the starting material synthesis 2.

[0986] (Raw material synthesis 14)

[0987]

[0988] (where LG 3 Represents a leaving group. When Z is NH, A 1 represents a hydrogen atom, A 2 represents a halogen, and Z is a 5-membered heteroaromatic hydrocarbon diyl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, A 1 When A is a group selected from the group consisting of Cl, Br and I, 2 Indicates boronic acid group, etc., A 1 When A is a boronic acid group, 2 represents a group selected from the group consisting of Cl, Br and I. )

[0989] The present production method is a method for producing the starting compound (1)-5 contained in the starting compound (1).

[0990] (First step)

[0991] This step is a method for preparing compound (68) by an in situ reaction of compound (66) and compound (67) or a Buchwald-Hartwig amination reaction when Z is NH.

[0992] The reaction conditions of the in situ reaction are the same as those of the fourth step of the starting material synthesis 7.

[0993] As references for the Buchwald-Hartwig amination reaction, for example, the following documents can be referred to.

[0994] J.Am.Chem.Soc.,2020,142,p.15027-15037

[0995] In addition, this step is a method for preparing compound (68) by Suzuki-Miyaura coupling reaction of compound (66) and compound (67) when Z is a 5-membered heteroaryl group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.

[0996] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[0997] Here, as references for the reaction when Z is the formula (XXIX), for example, the following documents can be referred to.

[0998] J.Org.Chem.,2000,65,p.1516-1524

[0999] Chemical Communications 2014,50,p.1867-1870

[1000] Bioorg.Med.Chem.Lett.,2001,11,p.2061-2065

[1001] (Second step)

[1002] This step is a method for preparing Compound (69) by reacting Compound (68) with Compound (32).

[1003] The reaction conditions are the same as those in the ninth step of the starting material synthesis 4.

[1004] Alternatively, this step can also be carried out by reacting compound (68) with LG 3 A compound in which a considerable portion of the hydroxyl groups is reacted with the compound (32) to produce the compound (69).

[1005] Here, as references for the Mitsunobu reaction, for example, the following documents can be referred to.

[1006] Chem.Asian J.2007,2,p.1340-1355

[1007] (Third step)

[1008] This step is a method for producing compound (70) by hydrolyzing compound (69).

[1009] The reaction conditions are the same as those in the second step of the starting material synthesis 2.

[1010] (Step 4)

[1011] This step is a method for preparing compound (1)-4 by amidation reaction of compound (70)-1 and compound (71).

[1012] The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[1013] (Raw material synthesis 15)

[1014]

[1015] (Where R 6aa , R 6bb Indicates that from R 6a , R 6b A divalent group formed by removing the hydrogen from the functional group that has introduced a protecting group. 9 PG 10 PG 11 The same or different from each other, representing a hydrogen atom or a protecting group, PG12 Represents a protecting group, A 3 represents a hydrogen atom, a carboxyl group, a boronic acid group, etc.)

[1016] This production method is a method for producing the starting material compound (56).

[1017] (First step)

[1018] This step is in A 3 When it is a hydrogen atom, for example, R 7 This is a method for preparing compound (74) by subjecting compound (73) of formula (XXIII) to a Mizoroki-Heck reaction with compound (72).

[1019] In this reaction, the compound (72) and the compound (73) 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 in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20°C to 140°C, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolin-2-one, ethyl acetate, water; and mixtures thereof. Examples of the base include bases such as potassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, etc. In addition, heating the mixture by irradiating with microwaves may be advantageous in that the reaction proceeds smoothly.

[1020] As references for the reaction, for example, the following documents can be referred to.

[1021] Synthesis 2020,52,p.2521-2527

[1022] PNAS 2016, 113, p.7124-7129

[1023] Or, for example, by R 7 A method for producing compound (74) by Ullmann reaction of compound (73) selected from the group consisting of formula (XXVI), formula (XXVIII) and formula (XXXIII) with compound (72).

[1024] As references for the reaction, for example, the following documents can be referred to.

[1025] Angew.Chem.Int.Ed.,2003,42,p.5400-5449

[1026] In addition, this step is in A 3 When it is a carboxyl group, for example, R 7 A method for producing compound (74) by decarboxylation coupling reaction of compound (73) of formula (XXIV) with compound (72).

[1027] As references for the reaction, for example, the following documents can be referred to.

[1028] Science, 2006, 313, p.662-664

[1029] Furthermore, this step is in A 3 For example, when R 7 A method for preparing compound (74) by Suzuki-Miyaura coupling reaction of compound (73) of formula (XXIII) and compound (72).

[1030] The reaction conditions are the same as those in the fifth step of starting material synthesis 4.

[1031] (Second step)

[1032] This step is a method for producing compound (56) by subjecting compound (74) to a deprotection reaction.

[1033] The reaction conditions are the same as those in the step described in Production Method 1.

[1034] (Raw material synthesis 16)

[1035]

[1036] (In the formula, A 5 represents a group selected from the group consisting of Cl, Br, mesylate and triflate, LG 3 represents a leaving group. )

[1037] The present production method is a method for producing the starting compound (68)-1 and the starting compound (68)-2 contained in the starting compound (68).

[1038] (First step)

[1039] This step is a method for preparing Compound (78) by reacting Compound (75) with Compound (77).

[1040] As references for the reaction, for example, the following documents can be referred to.

[1041] Chem.Commun.,2014,50,15,p.1867-1870

[1042] (Second step)

[1043] This step is a method for preparing compound (78) by reacting compound (77) with glyoxylic acid using an aryl-substituted tosylmethyl isocyanide (TosMIC) reagent.

[1044] As references for the reaction, for example, the following documents can be referred to.

[1045] J.Org.Chem.,2000,65,5,p.1516-1524

[1046] J.Am.Chem.Soc.,2007,129,3,p.490-491

[1047] (Third step)

[1048] This step is a method for preparing compound (68)-1 by Suzuki-Miyaura coupling reaction of compound (78) with an alkoxymethylboronic acid derivative, followed by a deprotection reaction under acidic conditions.

[1049] The reaction conditions of the Suzuki-Miyaura coupling reaction are the same as those in the fifth step of the starting material synthesis 4.

[1050] Examples of the alkoxymethylboronic acid derivative used herein include (2-trimethylsilyl)-ethoxymethyl potassium trifluoroborate.

[1051] As references for the reaction, for example, the following documents can be referred to.

[1052] Org.Lett.,2008,10,11,p.2135-2128

[1053] Org.Lett.,2011,13,15,p.3948-3951

[1054] The reaction conditions of the subsequent deprotection reaction under acidic conditions are the same as those in the step described in Production Method 1. Examples of the acid used here include trifluoroacetic acid and the like.

[1055] As references for deprotection reactions, for example, the following documents can be referred to.

[1056] PGM Wuts and TW Greene, “Greene's Protective Groups in Organic Synthesis”, 5th edition, John Wiley & Sons Inc., 2014

[1057] In this step, compound (68)-1 can be prepared by Suzuki-Miyaura coupling reaction of compound (78) with an acetoxymethylboronic acid derivative.

[1058] As references for the reaction, for example, the following documents can be referred to.

[1059] Org.Lett.,2012,14,5,p.1278-1281

[1060] (Step 4)

[1061] This step is a method for preparing compound (80) by reacting compound (79) with compound (77).

[1062] In this reaction, the compound (79) and the compound (77) are used in equal amounts or in excess of one of them, and the mixture is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling or heating to reflux, preferably at room temperature or heating to reflux, for usually 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as dichloromethane; DMF, DMSO, ethyl acetate, MeCN, etc. It is sometimes advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA or NMM or an inorganic base such as potassium carbonate, sodium carbonate or cesium carbonate in order to facilitate the reaction.

[1063] (Fifth step)

[1064] This step is a method for preparing compound (68)-2 by Suzuki-Miyaura coupling reaction of compound (80) with an alkoxymethylboronic acid derivative, followed by a deprotection reaction under acidic conditions.

[1065] The reaction conditions were the same as those in the third step of the starting material synthesis 16.

[1066] In this step, compound (68)-2 can be prepared by Suzuki-Miyaura coupling reaction of compound (80) with an acetoxymethylboronic acid derivative.

[1067] The compound of formula (I) is isolated and purified as a free compound, a salt, a hydrate, a solvate, a polymorph, or an amorphous solid. The salt of the compound of formula (I) can also be produced by a salt-forming reaction according to a conventional method.

[1068] Isolation and purification can be carried out by common chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, etc.

[1069] Various isomers can be produced by selecting appropriate raw material compounds, or can be separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods of racemates (e.g., fractional crystallization directed to stereoisomer salts with optically active bases or acids, chromatography using chiral columns, etc.), or can be produced from appropriate optically active raw material compounds.

[1070] In addition, the compound of formula (I) or its intermediate may have axial asymmetry and be obtained as a mixture of stereoisomers. Each stereoisomer can be isolated by conventional resolution operation, for example, resolution using octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

[1071] The pharmacological activity of the compound of formula (I) was confirmed by the following test.

[1072] Test Example 1-1 Evaluation of RAS G12V degradation effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[1073] The RASG12V degrading effect of the test compound was evaluated by measuring the expression level of RASG12V using the cell ELISA method.

[1074] PA-TU-8902 cells (DSMZ, ACC 179) were cultured at 1.5 × 10 4 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.

[1075] The next day, the test compound (final concentration range 3 μM to 0.1 nM, 10 points), Example Compound 17 with a final concentration of 1 μM as a positive control, and dimethyl sulfoxide (DMSO), the solvent of the test compound as a negative control, were diluted 100-fold with fresh culture medium, 4 μL were added to each well, and cultured for 24 hours.

[1076] 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 a total of 2 times. The subsequent washing operations were implemented in the same way. Then, the supernatant was removed, and 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 prepared by diluting the primary antibodies, 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-beta Actin antibody; Abcam; 5000-fold dilution) with Can Get Signal Solution 2 (TOYOBO) was added to each well and the mixture was allowed to stand at 4°C overnight.

[1077] 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).

[1078] 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 Example Compound 17 was added at a final concentration of 1 μM was set to 100%, and the degradation rate of RAS G12V was calculated. 50% degradation value (DC 50 ) is calculated using Sigmoid-Emax model nonlinear regression analysis. Dmax represents the decomposition rate at the compound concentration that shows the highest decomposition effect. The results of several test compounds of formula (I) are shown in the following table.

[1079] [Table 1-1]

[1080] Ex <![CDATA[DC 50 (nM)]]> Ex <![CDATA[DC 50 (nM)]]> 1 31 18 69 2 18 19 26 4 45 20 48 5 26 21 35 6 22 23 112(Dmax=62%) 9 21 25 14 11 13 26 19 12 37 29 8 13 11 35 23 14 10 40 76 15 89 41 30 17 41 42 30

[1081] Test Example 1-2 Evaluation of RAS G12D degradation in human KRAS G12D mutation-positive pancreatic cancer line AsPC-1

[1082] The RAS G12D expression level was measured by the cell ELISA method, and the RAS G12D degrading effect of the test compound was evaluated in the same manner as in Test Example 1-1.

[1083] AsPC-1 cells (ATCC, CRL-1682) were cultured at 2.0×10 4 36 μL of each cell was inoculated in a 384-well plate. Cell culture conditions were RPMI-1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum at 37°C in the presence of 5% CO 2 .

[1084] The next day, the test compound (final concentration range 3 μM to 0.1 nM, 10 points) and DMSO, the solvent of the test compound as a negative control, were diluted 100-fold with fresh culture medium, 4 μL each was added to each well, and cultured for 24 hours.

[1085] The next day, the same method as in Test Example 1-1 was used from the immobilization of the cells to the addition of the blocking solution. 20 μL of blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) was added to each well. After standing at room temperature for 30 minutes, the supernatant was removed by centrifugation. To the wells serving as the positive control, a solution obtained by diluting the anti-β-actin antibody (1000-fold dilution) as the primary antibody with the blocking solution was added, and to the other wells, 15 μL of a solution obtained by diluting the anti-Ras (G12D mutation-specific) antibody (Ras (G12D Mutant Specific) (D8H7) Rabbit mAb; Cell Signaling Technology; 1000-fold dilution) and the anti-β-actin antibody (1000-fold dilution) with the blocking solution was added, and the mixture was allowed to stand overnight at 4°C.

[1086] 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 and anti-mouse IgG antibody as the secondary antibody 1000 times with a blocking solution 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 signal at 700nm and 800nm ​​was measured using Aerius.

[1087] The RAS G12D degradation rate was calculated by setting the RAS G12D signal value corrected by the β-actin signal value when DMSO was added as 0% and the RAS G12D signal value under the condition of staining with anti-β-actin antibody alone as 100%. 50 ) was calculated using Sigmoid-Emax model nonlinear regression analysis. The results of several test compounds of formula (I) are shown in the table below.

[1088] [Table 1-2]

[1089] Ex <![CDATA[DC 50 (nM)]]> Ex <![CDATA[DC 50 (nM)]]> 1 5 18 26 2 5 19 4 4 20 20 16 5 6 21 8 6 5 23 1 9 5 25 3 11 4 26 6 12 3 29 21 13 6 35 16 14 2 40 47 15 146 41 3 17 11 42 6

[1090] Experimental Example 2 Evaluation of ERK phosphorylation inhibition on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902

[1091] 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.

[1092] PA-TU-8902 cells were plated at 5.0 x 10 3 The cells were seeded in a 384-well plate (Greiner Bio-One) at 36 μL / well. The cell culture conditions were the same as those in Test Example 1-1.

[1093] The next day, the test compound (9 points in the range of final concentration of 3 μM to 0.3 nM), trametinib (MEK inhibitor) at a final concentration of 300 nM 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 4 μL was added to each well, and cultured for 24 hours. After culture, 30 μL of 30% glyoxal solution (40% glyoxal [NAKALI TESQUE Co., Ltd.] was diluted with PBS) was added to each well quickly, and the cells were fixed by standing at room temperature for 1 hour and 30 minutes. The plate was then centrifuged (110×g, 7 seconds, and centrifugation was performed under this condition unless otherwise specified), the supernatant was removed, and 20 μL 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 further repeated. Then, add 20 μL of PBS containing 0.5% SDS to each well, let stand at room temperature for 30 minutes, centrifuge and remove the supernatant. Next, add 20 μL of blocking solution (InterceptBlocking Buffer) to each well and let stand at room temperature for 1 hour. Remove the supernatant by centrifugation, add 15 μL of ERK (Thr202 / Tyr204) phosphorylation antibody (Phospho-p44 / 42MAPK (Erk1 / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology) diluted 2500 times with blocking solution as the primary antibody to each well, and let stand at 4°C overnight.

[1094] 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 the supernatant was removed by centrifugation to wash each well. Washing was performed a total of 3 times. After washing, 15 μL of anti-rabbit IgG 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 using 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.

[1095] 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 The results of several test compounds of formula (I) are shown in the following table.

[1096] [Table 2]

[1097] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 19 18 33 2 16 19 31 4 48 20 34 5 8 21 19 6 7 23 107 9 12 25 13 11 14 26 15 12 18 29 15 13 9 35 11 14 10 40 53 15 42 41 24

[1098] 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 or the human KRAS G12D mutation-positive pancreatic cancer line AsPC-1 or the human KRAS G12C mutation-positive pancreatic cancer line MIA PaCa-2

[1099] The anchorage-independent cell proliferation inhibitory effect of the test compound was evaluated by spheroid three-dimensional culture.

[1100] PA-TU-8902 cells, AsPC-1 cells, or MIA PaCa-2 cells (RIKEN BRC, RCB2094) were cultured at 5 × 10 2 The cells were plated in a low-adhesion U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite Co., Ltd.) at 36 μL / well. PA-TU-8902 cells were cultured under the same conditions as in Experiment 1-1, AsPC-1 cells were cultured under the same conditions as in Experiment 1-2, and MIA PaCa-2 cells were cultured using RPMI-1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2.

[1101] The next day, the test compound (final concentration range 3μM to 0.3nM, 6 to 9 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).

[1102] 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.

[1103] [Table 3]

[1104] Ex <![CDATA[PA-TU-8902 IC 50 (nM)]]> <![CDATA[AsPC-1 IC 50 (nM)]]> <![CDATA[MIA PaCa-2IC 50 (nM)]]> 1 57 28 11 2 33 11 12 3 160 NT NT 4 72 38 22 5 29 8 5 6 32 14 7 7 81 NT NT 8 102 NT NT 9 53 19 9 10 69 NT NT 11 45 11 13 12 36 17 20 13 36 18 13 14 47 19 10 15 161 126 6 16 261 NT NT 17 46 16 10 18 69 32 26 19 58 16 27 20 63 68 14 21 60 43 11 22 65 NT NT 23 182 9 17 24 125 NT NT 25 41 14 16 26 41 15 7 27 122 NT NT 28 159 NT NT 29 63 25 5 30 235 NT NT 31 67 NT NT 32 105 NT NT 33 103 NT NT 34 109 NT NT 35 32 10 5 36 143 NT NT 37 78 NT NT 38 177 NT NT 39 52 NT NT 40 100 62 20 41 52 29 23 42 32 10 9 43 61 NT NT

[1105] NT = not determined.

[1106] Experimental Example 4 Evaluation of the anti-tumor effect in mice bearing human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902 or human KRASG12D mutation-positive pancreatic cancer line PK-59

[1107] PA-TU-8902 cells or PK-59 cells (RIKEN BRC, RCB1901) were cultured in DMEM medium or RPMI-1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. PA-TU-8902 cells or PK-59 cells were recovered, suspended in PBS, and two equal amounts of VitroGel Hydrogel Matrix (The WellBioscience) were added to prepare 1.0-2.0×10 7 / mL, and the obtained cell suspension was implanted subcutaneously in 4-6 week old male nude mice (BALB / c-nu (nu / nu), The Jackson Laboratory Japan, Inc.) at a volume of 100 μL. About 2 weeks after implantation, the groups were divided into groups in a manner that the tumor volume and body weight between the groups were roughly equal, and the test compound was administered from the next day. The solvent group and the test compound administration group were tested with 5 mice each. The solvent used was a solution obtained by dissolving ethanol (FUJIFILM Wako Co., Ltd.), (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) aqueous solution (ROQUETTE Co., Ltd.), and HCO-40 (Nikko Chemical Co., Ltd.) in a ratio of 4%, 0.5%, and 9% in 5% glucose solution (Otsuka Pharmaceutical Co., Ltd.), and the solvent was used to dissolve the compound. The test compound or solvent dissolved in the solvent was administered into the tail vein. Administer once or twice a week for 2 weeks. Tumor diameter and body weight were measured twice a week. The tumor volume was calculated using the following formula.

[1108] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5

[1109] 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 administration as 100% inhibition and the tumor volume of the solvent group on the last measurement day as 0%. The results of several test compounds of formula (I) are shown in the table below.

[1110] [Table 4-1]

[1111]

[1112] [Table 4-2]

[1113]

[1114] As a result of the above test, it was confirmed that several compounds of formula (I) have G12V mutant KRAS decomposition effect and G12D mutant KRAS decomposition effect (Test Examples 1-1, 1-2). Furthermore, it was confirmed that several compounds of formula (I) have an inhibitory effect on the phosphorylation of ERK located downstream of the KRAS signal (Test Example 2). In addition, it was confirmed that several compounds of formula (I) have a cell proliferation inhibitory effect on human G12V mutant KRAS positive pancreatic cancer strains, human G12D mutant KRAS positive pancreatic cancer strains and human G12C mutant KRAS positive pancreatic cancer strains (Test Example 3). In addition, it was confirmed that several compounds of formula (I) have anti-tumor effects in mice bearing human G12V mutant KRAS positive pancreatic cancer strains or human G12D mutant KRAS positive pancreatic cancer strains (Test Example 4). Therefore, the compound of formula (I) can be used for the treatment of pancreatic cancer, especially KRAS-positive pancreatic cancer with mutations, especially G12V mutation, G12D mutation and G12C mutation KRAS-positive pancreatic cancer, etc.

[1115] 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.

[1116] 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.

[1117] 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.

[1118] 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.

[1119] 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.

[1120] 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 chlorofluoroalkanes or carbon dioxide.

[1121] 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.

[1122] 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.

[1123] 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.

[1124] Example

[1125] 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.

[1126] In addition, in this specification, naming software, such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.), may be used to name compounds.

[1127] 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.

[1128] The "amorphous solid form" described in this specification includes both forms showing no peak in a powder X-ray diffraction (XRD) pattern and forms having a low degree of crystallinity.

[1129] Production Example 1

[1130] 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, and the internal temperature was kept 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 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.

[1131] Production Example 2

[1132] 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). MeOH (210 mL) was added to the solid obtained by concentrating the filtrate, stirred at room temperature for 1 hour, and suspended and washed. The insoluble matter was filtered out with MeOH (100 mL) to obtain 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[1133] Production Example 3

[1134] 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.

[1135] Production Example 4

[1136] Under argon atmosphere, under ice cooling, bis(trimethylsilyl)amide lithium (1M THF solution, 160mL) was added to a suspension of 2-acetamide-4-bromo-3-fluoro-5-iodobenzoic acid methyl ester (21.5g) in THF (250mL) using a dropping funnel for 20 minutes. Then, under argon atmosphere, stirred at 40°C for 1 hour. Water was added under ice cooling to stop the reaction, 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. To the collected aqueous layer, hydrogen chloride (1M aqueous solution, 200mL) was slowly added under ice cooling, and a solid was precipitated. The insoluble matter was filtered out, washed with water and MeOH, and dried overnight at 50°C under reduced pressure, resulting in 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (17.7g) as a solid.

[1137] Production Example 5

[1138] Under a nitrogen atmosphere, DIPEA (30 mL) was added dropwise to a suspension of 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (21.24 g) in sulfonyl chloride (95.2 mL) for 5 minutes under ice cooling, 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. The insoluble matter was filtered out with water / MeCN (5 / 1, 250 mL), and 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (18.95 g) was obtained as a solid.

[1139] Production Example 6

[1140] In dichloromethane (300mL) suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (29g), at room temperature add ethanethiol (5mL) and DABCO (11g), under argon atmosphere, stir at room temperature overnight.Add water under ice cooling and make reaction stop.Add chloroform, by liquid separation operation, organic layer and water layer are separated, and chloroform is extracted water layer 3 times.The organic layer collected is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-bromo-4-tert-butoxy-2-(ethylthio)-8-fluoro-6-iodoquinazoline (32g) as solid.

[1141] Production Example 7

[1142] 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 stirred overnight at room temperature under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture for dilution, and 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 chromatography (chloroform / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-8-fluoro-6-iodo-2-[( 4-( ...

[1143] Production Example 8

[1144] 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 and dried under reduced pressure to obtain 7-bromo-4-chloro-2-(ethylthio)-8-fluoro-6-iodoquinoline (4.33 g) as a solid.

[1145] Production Example 9

[1146] Under ice cooling, tBuOK (10 g) was added to a THF (400 mL) solution of 7-bromo-4-tert-butoxy-2-(ethylthio)-8-fluoro-6-iodoquinazoline (32 g) and (1S)-1-phenylethane-1-ol (11 mL), and stirred for 1 hour under ice cooling under an argon atmosphere. The reaction was stopped by adding a saturated aqueous ammonium chloride solution 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 sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate), and 7-bromo-4-tert-butoxy-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g) was obtained as an oil.

[1147] Production Example 12

[1148] 7-Bromo-4-chloro-2-(ethylthio)-8-fluoro-6-iodoquinoline (4.3 g) was dissolved in THF (40 mL) under a nitrogen atmosphere, (1S)-1-phenylethane-1-ol (1.28 mL) was added at room temperature, tBuOK (1.14 g) was added in an ice-salt bath, and stirred at the same temperature for 3 hours. Ice and ethyl acetate were added to a saturated aqueous ammonium chloride solution, the reaction mixture was injected therein, and then stirred and extracted twice with ethyl acetate. The combined organic layer was washed with a 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 (hexane / ethyl acetate) to obtain 7-bromo-4-chloro-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (4.85 g) as an oil.

[1149] Production Example 13

[1150] 1-(tert-butoxycarbonyl)-3-hydroxyazetidine (1 g) was dissolved in DMAc (10 mL), tBuOK (600 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 10 minutes to prepare an alkoxide solution. 7-Bromo-4-chloro-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (2.12 g) was dissolved in DMAc (10 mL), and the prepared alkoxide solution was added dropwise in an ice-salt bath under an argon atmosphere, and 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, and the insoluble matter was filtered out. The obtained solid was purified by silica gel column chromatography (hexane / chloroform to 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.

[1151] Production Example 14

[1152] 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.

[1153] Production Example 17

[1154] Under an argon atmosphere, a mixture of tert-butyl 3-({7-bromo-2-(ethylthio)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (2.48 g), cyclopropylboronic acid (500 mg), PdCl2(dppf)·CH2Cl2 (300 mg), potassium phosphate (2.9 g), MeCN (40 mL), and water (8 mL) was stirred at 90°C for 6 hours. After naturally cooling to room temperature, ethyl acetate and water were added, and Celite (registered trademark) was filtered. The filtrate was extracted with ethyl acetate, and the combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtering out the desiccant, it was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / chloroform) to obtain tert-butyl 3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (2.09 g) as a foamy solid.

[1155] Production Example 18

[1156] 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, and after powdering (0°C, 2 hours), it was filtered out and dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

[1157] Production Example 19

[1158] 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, and then 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, and after powdering, it 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.

[1159] Production Example 20

[1160] To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL), palladium acetate (II) (4.52 g) was added at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and filled with nitrogen three times each, and then stirred at 100 ° C for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added and extracted 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, and the mixture was stirred at 20° C. for 1 hour, and filtered while rinsing with ethyl acetate (50 mL) three times. The filtrate was concentrated, 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.

[1161] Production Example 21

[1162] To 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylthio)-8-[(1S)-1-phenylethoxy]quinazoline (14.21 g) were added 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), and the mixture was degassed and replaced with argon several times, followed by heating and stirring at 50° C. in an argon atmosphere overnight. The reaction suspension after natural cooling was filtered through Celite (registered trademark) while washing with ethyl acetate to remove the 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).

[1163] Production Example 24

[1164] Tert-butyl 3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (4.98 g) was dissolved in DOX (100 mL), and 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (5.7 g), palladium (II) acetate (238 mg), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (1 g), barium hydroxide (4.3 g) and water (10 mL) were added at room temperature, and the mixture was stirred at 50° C. for 1 hour under an argon atmosphere. At the same temperature, 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1 g) was added to the reaction mixture, and stirred at 50°C for 1 hour under an argon atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added, filtered through Celite (registered trademark), washed with ethyl acetate, water was added to the filtrate, and extracted twice with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (hexane / chloroform) to obtain 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 as a foamy solid (a diastereoisomer mixture of about 3.5:1 from an axial asymmetry, 5.98 g).

[1165] Production Example 25

[1166] 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 diastereomeric 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 stirred at room temperature overnight. The insoluble material, 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 diastereomer mixture of about 1:1 derived from axial asymmetry, 1.82 g), was filtered out while being washed 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.

[1167] Production Example 27

[1168] 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 diastereomer mixture of about 1:1 from axial asymmetry, 9.45 g). 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).

[1169] Production Example 29

[1170] 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 (2.93 g) was suspended in MeOH (30 mL), and methanesulfonic acid (1.1 mL) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes and stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with chloroform / iPrOH (9 / 1), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in THF (40 mL), and 4-methylbenzene-1-sulfonic acid monohydrate (740 mg) and 3,4-dihydro-2H-pyran (3 mL) were added at room temperature, and the mixture was stirred at room temperature overnight. Basic silica gel was added to the reaction mixture, which was concentrated, and the residue was purified by basic silica gel column chromatography (hexane / chloroform) to obtain (7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinoline (1.65 g).

[1171] Production Example 30

[1172] (7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinoline (1.65 g) was dissolved in DMF (15 mL), TEA (825 μL) and N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (750 mg) were added under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling in a nitrogen atmosphere. Water was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The resulting powder was filtered out and dried under reduced pressure to obtain 3-({(7M)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( [(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (2.11 g).

[1173] Production Example 31

[1174] 3-({(7M)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-1-( 2-(Trimethylsilyl)ethyl azetidine-1-carboxylate (2.1 g) was dissolved in dichloromethane (50 mL), and m-chloroperbenzoic acid (containing about 30% water, 1.6 g) was added under ice-cooling, followed by stirring at the same temperature for 30 minutes. An aqueous sodium thiosulfate solution was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, followed by extraction twice with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-({(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-( [(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (1.57 g).

[1175] Production Example 33

[1176] Under argon atmosphere, sodium bicarbonate (1.55 g) and 10% Pd / C (containing about 50% water, 994 mg) were added to a 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 (3 g) in MeOH (70 mL) and THF (70 mL) at room temperature. The mixture was stirred overnight at room temperature and pressure under a hydrogen atmosphere. After replacement with argon, the reaction mixture was filtered through Celite (registered trademark) using chloroform / iPrOH (4 / 1, 100 mL) and EtOH / water (10 / 1, 100 mL) and concentrated. Ethyl acetate was added to the residue, washed with water and a saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. Filtration and concentration gave 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (2.7 g) as a foamy solid.

[1177] Production Example 36

[1178] 3-({(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-( 2-(Trimethylsilyl)ethyl azetidine-1-carboxylate (1.57 g) was dissolved in MeOH (20 mL) and THF (20 mL), and 10% Pd / C (containing about 50% water, 800 mg) was added at room temperature, and the mixture was stirred overnight at room temperature and pressure under a hydrogen atmosphere. 10% Pd / C (containing about 50% water, 1200 mg) was added at room temperature, and the mixture was further stirred overnight at room temperature and pressure under a hydrogen atmosphere. The reaction mixture was replaced with argon, Celite (registered trademark) and chloroform were added, and the mixture was filtered through Celite (registered trademark), washed with chloroform, and the filtrate was concentrated to obtain 3-({(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-(

[0063] The mixture was mixed with 2-(trimethylsilyl)ethyl azetidine-1-carboxylate (1.42 g) and 1-(4-(6-(4-(6-nitro-1-yl)-1H-indazol-4-yl)-8-hydroxyquinolin-4-yl}oxy)azetidine-1-carboxylate.

[1179] Production Example 37

[1180] 4-tert-Butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (8.25 g) was dissolved in DMF (50 mL), cesium carbonate (14 g) and 1-(chloromethyl)-4-ethynylbenzene (1.95 g) were added at room temperature, and stirred overnight at room temperature under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazoline (6.07 g) as a solid.

[1181] Production Example 40

[1182] 3-({(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-( 2-(trimethylsilyl)ethyl azetidine-1-carboxylate (1.41 g) was dissolved in DMF (30 mL), cesium carbonate (3.2 g) and 1-(chloromethyl)-4-ethynylbenzene (0.32 g) were added at room temperature, and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Water was added to the reaction mixture, extracted twice with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (hexane / chloroform) to obtain 3-({(7M)-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(

[0063] The mixture was mixed with 2-(trimethylsilyl)ethyl 1H-indazol-4-yl]quinolin-4-yl}oxy)azetidine-1-carboxylate (1.19 g).

[1183] Production Example 41

[1184] To a solution of 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazoline (2 g) and (2S)-2-methoxypropane-1-ol (0.35 mL) in THF (30 mL), tBuOK (340 mg) was added under ice cooling, and stirred under ice cooling for 30 minutes under an argon atmosphere. Saturated aqueous ammonium chloride solution was added under ice cooling to stop the reaction. Water and ethyl acetate were added, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazoline (2.09 g) as a foamy solid.

[1185] Production Example 50

[1186] To a solution of (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazoline (2.09 g) in THF (25 mL) were added 4-methylbenzene-1-sulfonic acid monohydrate (380 mg) and 3,4-dihydro-2H-pyran (0.5 mL) under ice cooling, and the mixture was stirred at room temperature overnight under an argon atmosphere. After adding TEA (2 mL) under ice cooling, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-4-ol (1.35 g).

[1187] Production Example 58

[1188] (2S)-2-methoxypropane-1-ol (70 mg) was dissolved in THF (2 mL), tBuOK (85 mg) was added at room temperature, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere to prepare an alkoxide solution. 3-({(7S)-6-cyclopropyl-2-(ethylsulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( 2-(trimethylsilyl)ethyl azetidine-1-carboxylate (400mg) was dissolved in THF (8mL), and the prepared alkoxide solution was added in a MeOH ice bath and stirred at the same temperature for 30 minutes under a nitrogen atmosphere. Water was injected into the reaction mixture, extracted twice with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate), and 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [((2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (361 mg).

[1189] Production Example 63

[1190] Under ice cooling, DIPEA (15 mL) and bis(4-nitrophenyl carbonate) (5.8 g) were added to a DMF (60 mL) solution of [(1s, 3s)-3-hydroxycyclobutyl] tert-butyl carbamate (3.6 g), and stirred at room temperature for 1 hour under an argon atmosphere. Benzyl azetidine-3-ylcarbamate (3 g) was added under ice cooling, and stirred at room temperature for 2 hours under an argon atmosphere. Under ice cooling, the reaction 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 washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure, the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate), and 3-{[(benzyloxy)carbonyl]amino}azetidine-1-carboxylic acid (1s, 3s)-3-[(tert-butoxycarbonyl)amino]cyclobutyl ester (4.81 g) was obtained as a solid containing impurities.

[1191] Production Example 67

[1192] Under ice cooling, 2-[( To a THF (30 mL) solution of [(2-(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((

[0134] (4-(4-(4-(4-(2-((4-((2-( ...

[1193] Production Example 74

[1194] Under ice cooling, DIPEA (4.1 mL) and triphosgene (630 mg) were added to a solution of N,N-dimethyl-3-azetidine methylamine dihydrochloride (1100 mg) in dichloromethane (30 mL), and stirred at room temperature for 1 hour under a nitrogen atmosphere. Benzyl azetidine-3-ylcarbamate (1.5 g), pyridine (1 mL) and 4-(dimethylamino)pyridine (150 mg) were added under ice cooling, and stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH), and (1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidine-3-yl)benzyl carbamate (2050 mg) was obtained as an oily substance containing impurities.

[1195] Production Example 76

[1196] Under ice cooling, DIPEA (2.6 mL) and thiophosgene (0.29 mL) were added to a solution of N,N-dimethyl-3-azetidine methylamine dihydrochloride (700 mg) in dichloromethane (20 mL), and stirred at room temperature for 1 hour under an argon atmosphere. Azetidine-3-ylcarbamic acid tert-butyl ester (780 mg), pyridine (0.6 mL), 4-(dimethylamino) pyridine (90 mg) were added under ice cooling, and stirred at room temperature for 2 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate), and (1-{3-[(dimethylamino) methyl] azetidine-1-thiocarbonyl} azetidine-3-yl) carbamic acid tert-butyl ester (432 mg) was obtained as an oil.

[1197] Production Example 77

[1198] To azetidine-3-yl (methyl) benzyl carbamate (2.4g), 4- (dimethylamino) butyric acid hydrochloride (2.19g) DMF (30mL) suspension, DIPEA (8.6mL) was added under ice cooling, and stirred at room temperature for 5 minutes under a nitrogen atmosphere. HATU (4.56g) was added under ice cooling, and stirred overnight at room temperature under a nitrogen atmosphere. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted 5 times with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (chloroform / MeOH), it was purified by basic silica gel column chromatography (hexane / ethyl acetate), and {1- [4- (dimethylamino) butyryl] azetidine-3-yl} methyl benzyl carbamate (2504mg) was obtained as an oil.

[1199] Production Example 78

[1200] To a DMF (5 mL) solution of [(1r, 3r)-3-hydroxycyclobutyl]carbamic acid tert-butyl ester (200 mg) and 2-chloro-N, N-dimethylacetamide (143 mg), sodium hydride (60%, dispersed in liquid paraffin, 85 mg) was added under ice cooling, and stirred overnight at room temperature under a nitrogen atmosphere. Water was added at room temperature, and extracted three times 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, the residue was purified by silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH) to obtain tert-butyl {(1r, 3r)-3-[2-(dimethylamino)-2-oxoethoxy]cyclobutyl}carbamate (131 mg) as a solid.

[1201] Production Example 79

[1202] At room temperature, 10% Pd / C (about 50% water content, 1.5 g) was added to a solution of 3-{[(benzyloxy)carbonyl]amino}azetidine-1-carboxylic acid (1s, 3s)-3-[(tert-butoxycarbonyl)amino]cyclobutyl ester (4.81 g) in THF (50 mL) and MeOH (50 mL), and the mixture was stirred overnight at room temperature and pressure under a hydrogen atmosphere. After replacement with argon, a small amount of Celite (registered trademark) and aqueous EtOH were added, and then stirred at room temperature for 10 minutes. Celite (registered trademark) was filtered using aqueous EtOH, toluene was added to the filtrate, and it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / MeOH / 28% ammonia water), and 3-aminoazetidine-1-carboxylic acid (1s, 3s)-3-[(tert-butoxycarbonyl)amino]cyclobutyl ester (2.19 g) was obtained as a solid.

[1203] Production Example 84

[1204] Under ice cooling, 3-{[tert-butyldi(methyl)silyl]oxy}-N-{2-[( To a solution of 1.96 g of azetidine-1-carboxamide (1.96 g) in THF (25 mL) was added TBAF (1 M THF solution, 11 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain 3-hydroxy-N-{2-[(

[0147] (4-(4-(4-((4-((2-( ...

[1205] Production Example 85

[1206] At room temperature, TFA (3 mL) was added to a solution of tert-butyl (1-{[2-(dimethylamino)ethyl]carbamoyl}azetidine-3-yl)carbamate (1100 mg) in dichloromethane (15 mL), and stirred at room temperature for 6 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain 3-amino-N-[2-(dimethylamino)ethyl]azetidine-1-carboxamide n (trifluoroacetic acid) salt (3000 mg) as an oil.

[1207] Production Example 86

[1208] Under ice cooling, hydrogen chloride (4M DOX solution, 14 mL) was added to a solution of tert-butyl [(3S)-1-{[2-(dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl](methyl)carbamate (1600 mg) in dichloromethane (16 mL) and MeOH (16 mL), and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain (3S)-N-[2-(dimethylamino)ethyl]-3-(methylamino)pyrrolidine-1-carboxamide hydrochloride (1800 mg) as a foamy solid.

[1209] Production Example 89

[1210] Under nitrogen atmosphere, at room temperature, to a solution of tert-butyl {(1r,3r)-3-[2-(dimethylamino)-2-oxoethoxy]cyclobutyl}carbamate (131 mg) in THF (10 mL) was added borane dimethyl sulfide complex (2M THF solution, 361 μL), and stirred at room temperature for 8 hours. Under nitrogen atmosphere, borane dimethyl sulfide complex (2M THF solution, 361 μL) was added at room temperature, and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution were added at room temperature, and extracted three times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH), and tert-butyl {(1r,3r)-3-[2-(dimethylamino)ethoxy]cyclobutyl}carbamate (115 mg) was obtained as a solid.

[1211] Production Example 91

[1212] To a solution of (2R)-2-amino-2-(6-chloropyridin-3-yl)ethane-1-ol dihydrochloride (3.58 g) in MeOH (10 mL) and TEA (10 mL) was added di-tert-butyl dicarbonate (4.77 g), and the mixture was stirred at 25° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / MeOH), and tert-butyl [(1R)-1-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate (4.3 g) was obtained as a solid.

[1213] Production Example 92

[1214] Under a nitrogen atmosphere, boron trifluoride ether complex (520 μL) was added to a suspension of tert-butyl [(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (20 g) and 2,2-dimethoxypropane (66 mL) in acetone (300 mL), and the mixture was stirred at room temperature for 1 hour. TEA (1.3 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- Tert-butyl oxazolidine-3-carboxylate (21.4 g).

[1215] Production Example 94

[1216] (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- Tert-butyl oxazolidine-3-carboxylate (3 g) was suspended in DMSO (10 mL), and 1,2,4-triazole (1.4 g), copper (I) iodide (315 mg), 8-quinolinol (495 mg), and potassium carbonate (2.4 g) were added at room temperature, and stirred at 150°C overnight under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,3- Tert-butyl oxazolidine-3-carboxylate (2.45 g).

[1217] Production Example 97

[1218] At room temperature, 4-methyl-1,3-thiazole (2.88 mL) and potassium acetate (3.11 g) were added to a solution of tert-butyl [(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (5.01 g) in DMAc (80 mL), and degassing and argon replacement were performed three times each. Palladium (II) acetate (356 mg) was added at room temperature, and the mixture was stirred at 100° C. for 16 hours under an argon atmosphere. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and insoluble matter was removed by filtration through Celite (registered trademark). Water was added to the filtrate, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.66 g) as a solid.

[1219] Production Example 100

[1220] Under ice cooling, hydrogen chloride (4M DOX solution, 20 mL) was added in small amounts to a solution of {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamic acid tert-butyl ester (4.41 g) in dichloromethane (50 mL) and MeOH (40 mL), and stirred at room temperature for 6 hours. Diethyl ether was added to the reaction mixture, and the solid was filtered out, washed with diethyl ether, and dried under reduced pressure to obtain (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethane-1-ol n hydrochloride (2.12 g) as a solid. The filtrate was concentrated under reduced pressure, dried by heating under reduced pressure, and (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethane-1-ol n hydrochloride (2.01 g) was obtained as a solid.

[1221] Production Example 101

[1222] Under ice cooling, (4R)-2,2-dimethyl-4-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1,3- Hydrogen chloride (4M DOX solution, 11 mL) was added to a solution of tert-butyl oxazolidine-3-carboxylate (1.54 g) in dichloromethane (15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain (2R)-2-amino-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethane-1-ol hydrochloride (1.1 g) as a solid.

[1223] Production Example 106

[1224] A suspension of tert-butyl [(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (15 g) in dichloromethane (100 mL) was cooled with ice, TEA (9 mL) and methanesulfonyl chloride (4.4 mL) were added, and the mixture was stirred at the same temperature for 1 hour under an argon atmosphere. A saturated aqueous sodium bicarbonate solution was added, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain (2R)-2-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]ethyl methanesulfonate (19 g) as a solid.

[1225] Production Example 107

[1226] A mixture of (2R)-2-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]ethyl methanesulfonate (13 g), dimethylamine (9.5 M aqueous solution, 37 mL), and THF (30 mL) was stirred at room temperature for 1 hour and stirred at 50° C. overnight. The reaction mixture was cooled to room temperature naturally, and then water was added, extracted with chloroform, 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 (chloroform / MeOH) to obtain tert-butyl [(1R)-1-(4-bromophenyl)-2-(dimethylamino)ethyl]carbamate (7.89 g) as a solid.

[1227] Production Example 110

[1228] Add (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3- tert-Butyl oxazolidine-3-carboxylate (3 g), 4-methyl-1,3- Azole-5-carboxylic acid (2.16 g), tetra-n-butylammonium chloride (2.34 g), cesium carbonate (4.11 g), bis(tri-tert-butylphosphine)palladium (0) (225 mg), N-methyl-2-pyrrolidone (30 mL), stirred at 160 ° C for 1 hour under argon atmosphere. The reaction mixture was cooled naturally to room temperature, ethyl acetate and water were added, filtered through Celite (registered trademark), and the filtrate was extracted 3 times with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]-1,3- Tert-butyl oxazolidine-3-carboxylate (1.51 g).

[1229] Production Example 112

[1230] Under ice cooling, HATU (13.8 g) was added to a DMF (150 mL) solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (10 g), (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethane-1-ol hydrochloride (9.3 g) and DIPEA (21 mL), and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was diluted with ethyl acetate and water under ice cooling, and the organic layer and the aqueous layer were separated by a liquid separation operation. The organic layer was washed twice with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (16.47 g) as a foamy solid.

[1231] Production Example 113

[1232] Under ice cooling, DIPEA (4 mL) and HATU (2.2 g) were added to a suspension of (2R)-2-amino-2-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethan-1-ol hydrochloride (1.1 g) and N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (3 g) in dichloromethane (20 mL), and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (1.77 g) as a solid.

[1233] Production Example 118

[1234] To a solution of sodium azide (4 g) in methyl tert-butyl ether (70 mL), water (60 mL) and MeCN (10 mL) was added 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-yl trifluoromethanesulfonate under ice cooling. (14.8g), stirred at room temperature for 1 hour. Use methyl tert-butyl ether and water to transfer to a separatory funnel, separate the organic layer and the aqueous layer, wash the organic layer with water once, and prepare a solution of an azidation reagent. Under ice cooling, TFA (23mL) was added to a dichloromethane (200mL) solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (16.47g), and after stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure. Under ice cooling, DMSO (150mL), water (30mL), and potassium bicarbonate (12.5g) were added to the residue, and stirred under ice cooling for 10 minutes. Under ice cooling, the prepared solution of the azidation reagent was added dropwise from the separatory funnel to the reaction mixture, and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and water, and the organic layer and the aqueous layer were separated by a separation operation. The organic layer was washed twice 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 (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (11.6 g) as a foamy solid.

[1235] Production Example 119

[1236] To a mixture of sodium azide (373 mg), methyl tert-butyl ether (6 mL) and water (6 mL) was added 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazole-3-yl trifluoromethanesulfonate under ice cooling. (2304 mg) and MeCN (0.3 mL), stirred at the same temperature for 30 minutes, and allowed to stand at room temperature for 1 hour. The aqueous layer was removed with a pipette to prepare a solution of an azidating agent. TFA (3 mL) was added to a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (2417 mg) in dichloromethane (15 mL), stirred overnight at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and water (3 mL), and potassium bicarbonate (7026 mg) and the prepared solution of the azidating agent were added using methyl tert-butyl ether (3 mL) at room temperature. Stirred at room temperature for 3 hours, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution were added at room temperature, and extracted 6 times with chloroform / iPrOH (4 / 1). The organic layer was 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 (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (1503 mg) as a solid.

[1237] Production Example 123

[1238] To a MeOH (5 mL) solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-N-{(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide (1.89 g) was added hydrogen chloride (4M DOX solution, 5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain L-valyl-(4R)-N-{(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide hydrochloride (2.14 g) as a solid.

[1239] Production Example 124

[1240] Under an argon atmosphere, a mixture of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (1.76 g), (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethane-1-ol hydrochloride (2.12 g), and DMF (22 mL) was ice-cooled, and DIPEA (4.7 mL) and HATU (3.02 g) were added in small amounts each time so that the internal temperature was maintained below 5°C. The reaction mixture was stirred for 1 hour under ice-cooling and for 1 hour at room temperature. The reaction mixture was ice-cooled, and water (120 mL) and a saturated aqueous sodium chloride solution (50 mL) were added, followed by extraction with ethyl acetate three times. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The aqueous layer was extracted three times with ethyl acetate / iPrOH (9 / 1), and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layers were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain tert-butyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-carboxylate (3.09 g) as an oily substance.

[1241] Production Example 125

[1242] Tert-butyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-carboxylate (38.5 g) was dissolved in EtOH (100 mL), and methanesulfonic acid (26 mL) was added at room temperature, followed by stirring at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (27.01 g) as a solid.

[1243] Production Example 129

[1244] Under ice cooling, CDI (55 mg) was added to a solution of N-(tert-butoxycarbonyl)-N-methyl-1,2-ethylenediamine (60 mg) in THF (3 mL), and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was added with (7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( A solution of (2-{[(2S)-2-methoxypropoxy]-8-[(1S)-1-phenylethoxy]quinoline (100 mg) in iPrOH (3 mL) was stirred at 90° C. overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate to hexane / chloroform, and then chloroform / MeOH) to obtain (2-{[3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( [(1S)-1-phenylethoxy]quinolin-4-yl}oxy)azetidine-1-carbonyl]amino}ethyl)methylcarbamic acid tert-butyl ester (117 mg).

[1245] Production Example 132

[1246] Potassium carbonate (1.6 g), copper (II) sulfate pentahydrate (67 mg), and 1H-imidazole-1-sulfonyl=azido=mono(tetrafluoroborate) salt (715 mg) were added to a solution of L-valyl-(4R)-N-{(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide hydrochloride (1.34 g) in iPrOH (13 mL) and water (2 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. iPrOH was added to the reaction mixture, and the mixture was filtered through Celite (registered trademark) and washed with iPrOH, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform / MeOH) and then purified by silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-N-{(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide (725 mg) as a foamy solid.

[1247] Production Example 133

[1248] 8-(Benzyloxy)-4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( [(4- ...

[1249] To a portion of the obtained product (4 g) and a dichloromethane (20 mL) solution of triisopropylsilane (3.29 mL), TFA (4.74 mL) was added at 0°C and stirred at 25°C for 18 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted three times with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The reaction was carried out again under the same conditions, and the crude products obtained from the two batches were combined and purified twice by silica gel column chromatography (dichloromethane / MeOH). The residue was suspended in dichloromethane (24 mL), stirred at 25°C for 12 hours, the insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by supercritical fluid chromatography (Cellulose-2 column, 0.1% ammonia water / MeOH), and the fractions containing the peak on the high polarity side were collected to obtain the product (single diastereomer, 2.8 g).

[1250] To a portion of the obtained product (500 mg) and a dichloromethane (5 mL) solution of 3,4-dihydro-2H-pyran (127 μL), 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added, and the mixture was stirred at 25°C for 52 hours. Water was added to the reaction mixture, and it was extracted three times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. It was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain (7M)-8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(

[0267] (4-( ...

[1251] Production Example 134

[1252] Under ice cooling, (7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( PyBOP (560 mg) and cesium carbonate (340 mg) were added to a solution of 1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-ol (380 mg) in THF (15 mL), and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. 3-Aminoazetidine-1-carboxylic acid (1s, 3s)-3-[(tert-butoxycarbonyl)amino]cyclobutyl ester (600 mg) and DIPEA (1.3 mL) were added under ice cooling, and the mixture was stirred at 50° C. for 1 hour under an argon atmosphere. The reaction mixture was filtered through Celite (registered trademark) using chloroform. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( [(tert-butoxycarbonyl)amino]cyclobutyl]-2-[(((tert-butoxycarbonyl)amino)-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (573 mg).

[1253] Production Example 162

[1254] At room temperature, 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( To a solution of (1s,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl azetidine-1-carboxylate (573 mg), (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (320 mg) and sodium ascorbate (320 mg) in tBuOH (5 mL), water (5 mL) and THF (5 mL) was added copper (II) sulfate pentahydrate (170 mg), and the mixture was stirred at room temperature for 1 hour. Disodium ethylenediaminetetraacetate (1.2 g) was added at room temperature, and after stirring at room temperature for 1 hour, a saturated sodium bicarbonate aqueous solution was added, and chloroform was used to filter through Celite (registered trademark). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / MeOH) to obtain 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( 3-[(tert-butoxycarbonyl)amino]cyclobutyl 8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (773 mg).

[1255] Production Example 186

[1256] At room temperature, 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( To a mixture of tBuOH (1 mL), THF (1 mL) and water (1 mL) were added anhydrous copper (II) sulfate (25 mg) and sodium ascorbate (66 mg), and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Basic silica gel was added to the reaction mixture, and the mixture was concentrated. The residue was purified by basic silica gel column chromatography (hexane / chloroform to chloroform / MeOH) to obtain 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( 4-{[((2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (197 mg).

[1257] Production Example 188

[1258] To a solution of tert-butyl 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (700 mg) and (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (350 mg) in tBuOH (5 mL), THF (10 mL) and water (5 mL) were added anhydrous copper (II) sulfate (126 mg) and sodium ascorbate (350 mg) at room temperature, the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Basic silica gel was added to the reaction mixture, followed by concentration. The residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated under reduced pressure.

[1259] The residue was dissolved in MeOH (10 mL), and methanesulfonic acid (469 μL) was added at room temperature, followed by stirring under a nitrogen atmosphere at room temperature for 30 minutes and at 40° C. for 4 hours. DIPEA (1.4 mL) was added to the reaction mixture at room temperature, and the reaction mixture was concentrated. The residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (723 mg) as a solid.

[1260] Production Example 190

[1261] For 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( 2-(trimethylsilyl)ethyl 2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate (47 mg) and (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- To a solution of tBuOH (1 mL), THF (1 mL) and water (1 mL) was added anhydrous copper sulfate (II) (11 mg) and sodium ascorbate (30 mg) at room temperature, and the mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere. Basic silica gel was added to the reaction mixture, and the mixture was concentrated. The residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated.

[1262] The residue was dissolved in THF (3 mL), TBAF (1 M THF solution, 300 μL) was added at room temperature, and the mixture was stirred at 40° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide (54 mg).

[1263] Production Example 192

[1264] Under ice cooling, 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( Methanesulfonic acid (2 mL) was added to a solution of (1s,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl azetidine-1-carboxylate (773 mg) in iPrOH (15 mL), and the mixture was stirred at 40°C for 4 hours. After adding TEA (15 mL) under ice-cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (1s,3R)-3-aminocyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (769 mg) as a solid.

[1265] Production Example 193

[1266] Under ice cooling, 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( To a solution of 2-(trimethylsilyl)ethyl azetidine-1-carboxylate (195 mg) in THF (4 mL), TBAF (1 M THF solution, 300 μL) was added, and the mixture was stirred at room temperature for 1 hour. TBAF (1 M THF solution, 300 μL) was further added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(

[0267] The product was prepared by mixing 1H-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (157 mg).

[1267] Production Example 195

[1268] At room temperature, 4-{[(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( To a solution of 2-(trimethylsilyl)ethyl piperidine-1-carboxylate (317 mg) in THF (6 mL), TBAF (1 M THF solution, 800 μL) and acetic acid (30 μL) were added, and the mixture was stirred at 60° C. for 15 hours under argon atmosphere. After naturally cooling to room temperature, chloroform / MeOH (5 / 1) and saturated aqueous ammonium chloride solution were added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(

[0267] The product was prepared by mixing 1-[(((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((

[1269] Production Example 196

[1270] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( alkyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline methyl ester (820 mg) was dissolved in 1,2-dichloroethane (15 mL), trimethyltin hydroxide (681 mg) was added, and the mixture was stirred at 85° C. for 24 hours. Water, saturated aqueous ammonium chloride solution, and saturated aqueous sodium chloride solution were added at room temperature, and the mixture was extracted five times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(

[0134] 2-(4-( ...

[1271] Production Example 197

[1272] At room temperature, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( To a solution of (4-(1H-pyrazol-1-yl)phenyl)ethane-1-ol (50 mg) in dichloromethane (5 mL) were added HATU (27 mg), DIPEA (64 μL) and (2R)-2-amino-2-[4-(1H-pyrazol-1-yl)phenyl]ethane-1-ol hydrochloride (26 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / ethyl acetate to chloroform / MeOH) to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(

[0267] N-(4-(1H-pyrazol-1-yl)phenyl)ethyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-L-prolinamide (34 mg).

[1273] Production Example 198

[1274] Under ice cooling, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( To a solution of (1H-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (50 mg) in DMF (2 mL) were added DIPEA (40 μL) and 2,2-difluoroethyl trifluoromethanesulfonate (15 μL), and the mixture was stirred at the same temperature for 1 hour under an argon atmosphere. A saturated aqueous sodium chloride solution and chloroform / MeOH (4 / 1) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(

[0147] The product was prepared by mixing 1-[(4-(4-methyl-1,3-thiazol-5-yl)-1H-(4-(4-methyl-1,3-thiazol-5-yl)phenyl)ethyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (58.5 mg).

[1275] Production Example 199

[1276] At room temperature, 4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( To a solution of methyl]benzoate (81 mg) in THF (1 mL) and MeCN (1 mL), sodium hydroxide (1 M aqueous solution, 500 μL) was added, and the mixture was stirred at 50° C. for 5 hours. Hydrogen chloride (1 M aqueous solution, 0.5 mL) 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 under reduced pressure to obtain 4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (72 mg).

[1277] The compounds shown in the table below 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 table below.

[1278] It is to be noted that the axially asymmetric configurations of Production Example Compounds 27, 33, 37, 196, 197, and 199 were confirmed as follows.

[1279] Preparation Example 27 (7M)-4-tert-Butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline

[1280] Preparation Example 33 (7M)-4-tert-Butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol

[1281] Preparation Example 37 (7M) -4-tert-Butoxy-6-cyclopropyl-2-(ethylsulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazoline

[1282] Preparation Example 196 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( 4-( ...

[1283] Preparation Example 197 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( [(1R)-2-hydroxy-1-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-L-prolinamide

[1284] Preparation Example 199 4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( [(2S)-2-methoxypropoxy]quinazolin-8-yl)methyl]benzoic acid

[1285] Example 1

[1286] Under ice cooling, 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3- Methanesulfonic acid (180 μL) was added to a solution of (1s,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl azetidine-1-carboxylate (95 mg) in iPrOH (5 mL), and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was diluted with chloroform, filtered through a short column filled with basic silica gel using chloroform / MeOH (9 / 1), and the filtrate was concentrated under reduced pressure.

[1287] To the residue, THF (5 mL), formaldehyde (37% aqueous solution, 50 μL), sodium triacetoxyborohydride (60 mg) were added under ice cooling, and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution was added under ice cooling to stop the reaction. Dilute with chloroform / iPrOH (3 / 1), separate the organic layer and the aqueous layer by liquid separation operation, and extract the aqueous layer 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN / 0.1% formic acid aqueous solution), and the fractions containing the target were collected. After dilution with chloroform / iPrOH (3 / 1) at room temperature, saturated sodium bicarbonate aqueous solution was added. The organic layer and the aqueous layer were separated by liquid separation operation, and the aqueous layer was extracted 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane / iPrOH (10 / 1), and hexane was added to precipitate a solid. The insoluble matter was filtered out, washed with water, and dried at 50°C overnight under reduced pressure to obtain 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

[0145] The mixture was mixed with (1S,3R)-3-(dimethylamino)cyclobutyl azetidine-1-carboxylate (33.9 mg).

[1288] Example 2

[1289] Under ice cooling, 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( Methanesulfonic acid (0.13 mL) was added to a solution of (1s,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl azetidine-1-carboxylate (52 mg) in iPrOH (5 mL), and the mixture was stirred at 50°C for 4 hours. The reaction mixture was diluted with chloroform and then filtered through a short column packed with basic silica gel using chloroform / MeOH (9 / 1), and the filtrate was concentrated under reduced pressure.

[1290] To the residue, THF (5 mL), formaldehyde (37% aqueous solution, 30 μL), sodium triacetoxyborohydride (40 mg) were added under ice cooling, and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution was added under ice cooling to stop the reaction. Dilute with chloroform / iPrOH (3 / 1), separate the organic layer and the aqueous layer by liquid separation operation, and extract the aqueous layer 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN / 0.1% formic acid aqueous solution), and the fractions containing the target were collected. After dilution with chloroform / iPrOH (3 / 1) at room temperature, saturated sodium bicarbonate aqueous solution was added. The organic layer and the aqueous layer were separated by liquid separation operation, and the aqueous layer was extracted 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of dichloromethane / iPrOH (10 / 1), and hexane was added, whereby a solid precipitated. The insoluble matter was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. overnight to obtain (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (38.2 mg) as a solid.

[1291] Example 5

[1292] To a mixture of N,N-dimethyl-3-azetidinylmethylamine dihydrochloride (60 mg) in dichloromethane (3 mL) was added DIPEA (220 μL) and triphosgene (31 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was collected using a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated.

[1293] The residue was dissolved in MeOH (2 mL), and methanesulfonic acid (100 μL) was added at room temperature, and stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated and purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated. The residue was dissolved in MeCN and water, and a saturated sodium bicarbonate aqueous solution was added, and extracted three times with chloroform / iPrOH (9 / 1), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in ethyl acetate, and the insoluble matter was collected by filtration and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (33 mg) as a solid.

[1294] Example 6

[1295] To a mixture of N,N-dimethyl-3-azetidinylmethylamine dihydrochloride (68 mg) in dichloromethane (3 mL) was added DIPEA (250 μL) and triphosgene (35 mg) under ice cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (4R)-1-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was collected using a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated.

[1296] The residue was dissolved in MeOH (3 mL), and methanesulfonic acid (150 μL) was added at room temperature, and stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated and purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated. The residue was dissolved in MeCN and water, and a saturated sodium bicarbonate aqueous solution was added, and extracted three times with chloroform / iPrOH (9 / 1), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in ethyl acetate, the insoluble matter was collected by filtration and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide (30 mg).

[1297] Embodiment 11

[1298] Under ice cooling, 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutane-2 -yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-aminocyclobutyl ester (769 mg) in THF (15 mL) solution was added with formaldehyde (37% aqueous solution, 0.4 mL) and sodium triacetoxyborohydride (500 mg), and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added under ice cooling to stop the reaction. Dilute with chloroform / iPrOH (3 / 1) at room temperature, separate the organic layer and the aqueous layer by liquid separation operation, and extract the aqueous layer 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified twice by ODS chromatography (0.1% formic acid MeCN / 0.1% formic acid aqueous solution), and the fractions containing the target product were collected. Chloroform / iPrOH (3 / 1) and saturated sodium bicarbonate aqueous solution were added at room temperature. The organic layer and the aqueous layer were separated by liquid separation operation, and the aqueous layer was extracted three times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate / iPrOH (10 / 1), and hexane was added to precipitate a solid. The insoluble matter was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. overnight to obtain (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (370 mg) as a solid.

[1299] Example 12

[1300] N,N-Dimethylethylenediamine (230 μL) was dissolved in THF (15 mL), and CDI (335 mg) was added under ice-cooling, followed by stirring at room temperature for 1 hour. Under ice-cooling, a solution of (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (720 mg) in iPrOH (15 mL) was added, and the mixture was stirred at room temperature for 30 minutes and at 50°C for 1 hour. The reaction mixture was cooled naturally, saturated sodium bicarbonate aqueous solution was added, extracted three times with chloroform / iPrOH (9 / 1), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated to about 10 mL. Saturated sodium bicarbonate aqueous solution was added to the residue, and stirred at room temperature for 1 hour. The insoluble matter was collected by filtration, washed with water, and dried at 40°C under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (501 mg) as a solid.

[1301] Example 13

[1302] Triphosgene (215 mg) was dissolved in dichloromethane (30 mL), and (1s,3s)-3-(dimethylamino)cyclobutane-1-ol (265 mg) and DIPEA (1.28 mL) were added under ice-cooling, and the mixture was stirred under ice-cooling for 20 minutes and at room temperature for 30 minutes under a nitrogen atmosphere to prepare a solution of an activated body. To a mixture of (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (800 mg) in dichloromethane (20 mL) was added dropwise the prepared solution of the activated product under ice-cooling, and the mixture was stirred under ice-cooling under a nitrogen atmosphere for 30 minutes. Piperidine (160 μL) was added under ice cooling, and the mixture was stirred for 10 minutes under ice cooling and at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform / iPrOH (9 / 1). The organic layer was collected using a phase separator and concentrated. The residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated to about 5 mL. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was stirred at room temperature for 1 hour. The insoluble material was collected by filtration and dried under reduced pressure to obtain (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylate as a solid (635 mg).

[1303] Embodiment 14

[1304] N,N-Dimethyl-3-azetidinemethanamine dihydrochloride (47 mg) was suspended in dichloromethane (2 mL), DIPEA (200 μL) and triphosgene (24 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (90 mg) was added under ice-cooling, and the mixture was stirred under ice-cooling under a nitrogen atmosphere for 1 hour. In another flask, N, N-dimethyl-3-azetidine methylamine dihydrochloride (47 mg) was suspended in dichloromethane (2 mL), DIPEA (200 μL) and triphosgene (24 mg) were added under ice cooling, and stirred at room temperature for 1 hour under a nitrogen atmosphere. It was added to the reaction mixture under ice cooling, stirred under ice cooling for 1 hour under a nitrogen atmosphere, and stirred at room temperature for 30 minutes. Piperidine (60 μL) was added under ice cooling, stirred under ice cooling for 10 minutes and stirred at room temperature for 30 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, extracted 3 times with chloroform / iPrOH (9 / 1), the organic layer was collected using a phase separator, and concentrated. The residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated. The residue was dissolved in MeCN / water, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with chloroform / iPrOH (9 / 1). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidine-3-yl]]]-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-3-yl]]]-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidine-3-yl]]]-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-3-yl]]-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl} ... -yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (28 mg).

[1305] Embodiment 15

[1306] At room temperature, (4R)-1-{(2S)-2-[4-(4-{[(6-cyclopropyl-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( To a solution of (1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (76 mg) in dichloromethane (3 mL) was added TFA (300 μL), and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and THF (3 mL), ice, and a saturated aqueous sodium bicarbonate solution (3 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted 3 times with chloroform / MeOH (10 / 1) and filtered using a phase separator. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH) to obtain (4R)-1-[(2S)-2-{4-[4-({[6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(

[0267] -4-{[1-(pyrimidin-2-yl)azetidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (37 mg).

[1307] Embodiment 28

[1308] Under ice cooling, (4R)-1-{(2S,3S)-2-[4-(4-{[(6-cyclopropyl-4-{[(3S)-1-{[2-(dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl]oxy}-7-[6-fluoro-5-methyl-1-( To a solution of dichloromethane (10 mL) of 1H-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (260 mg) was added TFA (0.3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (5 mL), saturated aqueous sodium bicarbonate solution was added under ice cooling, and stirred for 30 minutes under ice cooling. The reaction mixture was diluted with chloroform and water, the organic layer and the aqueous layer were separated by a liquid separation operation, and the aqueous layer was extracted 3 times with chloroform / iPrOH (3 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN / 0.1% formic acid aqueous solution), and the fractions containing the peak on the low polarity side were collected and concentrated under reduced pressure until the liquid volume reached 2-5 mL. Under ice cooling, saturated sodium bicarbonate aqueous solution was added to the residue, resulting in the precipitation of solids. The insoluble matter was collected by filtration, washed with water, and then dried under reduced pressure at 50° C. overnight to obtain (4R)-1-{(2S,3S)-2-[4-(4-{[(6-cyclopropyl-4-{[(3S)-1-{[2-(dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl)oxy]methyl}phenyl)-1H-1,2,3-triazol-1-yl]-3-methylpentanoyl}-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide as a solid (single diastereomer with undetermined axial asymmetric configuration, 41.2 mg).

[1309] Embodiment 34

[1310] At room temperature, 3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( To a mixture of THF (1 mL), tBuOH (1 mL) and water (1 mL) were added (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (21 mg), sodium ascorbate (19 mg) and anhydrous copper (II) sulfate (7 mg). The mixture was stirred at room temperature for 2 hours under an argon atmosphere, and disodium ethylenediaminetetraacetate (15 mg) and ethyl acetate (about 5 mL) were added to the reaction mixture, followed by vigorous stirring at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution were added, and the mixture was extracted three times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform / MeOH).

[1311] The obtained residue was dissolved in dichloromethane (1 mL), TFA (1 mL) was added at room temperature and stirred for 3 hours. The reaction mixture was concentrated, THF (3 mL) and saturated sodium bicarbonate aqueous solution were added to the residue and stirred for 1 hour. Saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution were added, and the reaction mixture was extracted 3 times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), the target fraction was collected, and after adding saturated sodium bicarbonate aqueous solution, it was extracted 3 times with chloroform / iPrOH (4 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(dimethylamino)ethyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate (12 mg) as a solid.

[1312] Embodiment 39

[1313] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( alkyl-2-yl)-1H-indazol-4-yl]-2-[( A mixture of (4-(4-methyl-1,3-thiazol-5-yl)phenyl)propan-1-ol (50 mg), (3S)-3-amino-3-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propan-1-ol hydrochloride (30 mg), HATU (30 mg) and dichloromethane (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH).

[1314] TFA (75 μL) was added to a solution of the obtained solid in dichloromethane (3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (3 mL). A saturated aqueous sodium bicarbonate solution was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Chloroform and water were added to the reaction mixture, and the mixture was separated using a phase separator, and the aqueous layer was extracted 3 times with chloroform / MeOH (4 / 1). The filtrate was concentrated under reduced pressure, and the residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated. To the residue was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted twice with chloroform / iPrOH (5 / 1). The collected organic layers were concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(

[0145] The mixture was mixed with 1-[(4-(4-methyl-1,3-thiazol-5-yl)phenyl]propyl]-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1S)-3-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propyl}-L-prolinamide (14.8 mg).

[1315] Embodiment 40

[1316] Under ice cooling, 4-[({6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-( To a DMF (2 mL) solution of benzoic acid (29 mg) was added L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (26 mg), DIPEA (60 μL), and PyBOP (25 mg), and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. Saturated sodium bicarbonate aqueous solution and chloroform / MeOH (7 / 1) were added to the reaction mixture, and the mixture was extracted twice with chloroform / MeOH (7 / 1) using a phase separator. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH).

[1317] The obtained foamy solid was dissolved in dichloromethane (3 mL), TFA (220 μL) was added at room temperature, and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, THF (3 mL), ice, and saturated sodium bicarbonate aqueous solution (3 mL) were added to the residue, and stirred at room temperature for 1 hour. The reaction mixture was extracted 3 times with chloroform / MeOH (7 / 1), filtered using a phase separator, and concentrated under reduced pressure. The residue was purified by ODS chromatography (MeOH / aqueous ammonium bicarbonate solution) to obtain N-{4-[({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]quinazolin-8-yl}oxy)methyl]benzoyl}-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (5 mg) as a solid.

[1318] Embodiment 41

[1319] To (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2- To a solution of hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (80 mg) and 4-(dimethylamino)butyric acid hydrochloride (25 mg) in DMF (2 mL) were added DIPEA (90 μL), 1-hydroxybenzotriazole (15 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21 mg), and the mixture was stirred overnight at room temperature under an argon atmosphere. Chloroform / iPrOH (4 / 1) was added, and water and a saturated sodium chloride aqueous solution were added, the organic layer and the aqueous layer were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution). A saturated sodium bicarbonate aqueous solution was added to the target fraction, and the mixture was extracted twice with chloroform / iPrOH (4 / 1), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-({1-[4-(dimethylamino)butanoyl]azetidin-3-yl}oxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide (28 mg) as a solid.

[1320] Embodiment 43

[1321] At room temperature, (2-{[3-({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-( To a solution of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (40 mg) in tBuOH (1 mL), THF (1 mL) and water (1 mL) were added anhydrous copper (II) sulfate (13 mg) and sodium ascorbate (33 mg), and the mixture was stirred at room temperature for 20 minutes under a nitrogen atmosphere. Basic silica gel was added to the reaction mixture, which was concentrated, and the residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated.

[1322] The residue was dissolved in MeOH (2 mL), and methanesulfonic acid (50 μL) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes and at 50° C. for 6 hours. The reaction mixture was concentrated and purified by ODS chromatography (MeCN / 0.1% formic acid aqueous solution), and the target fraction was concentrated. The residue was dissolved in MeCN / water, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted twice with chloroform / iPrOH (9 / 1), and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated.

[1323] The residue was suspended in THF (2 mL), and formaldehyde (37% aqueous solution, 50 μL) and sodium triacetoxyborohydride (45 mg) were added at room temperature, and stirred at room temperature for 10 minutes, and then water (0.1 mL) was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with chloroform / iPrOH (9 / 1), and the combined organic layer was separated with a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform / MeOH), and the target fraction was concentrated. The residue was suspended in water, filtered and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (15 mg) as a solid.

[1324] 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.

[1325] It should be noted that the axially asymmetric configurations of Example Compounds 15, 28, 39, and 40 were confirmed to be as follows.

[1326] Example Compound 15 (4R)-1-[(2S)-2-{4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [(1-(pyrimidin-2-yl)azetidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-1H-1,2,3-triazol-1-yl}-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

[1327] Example Compound 28 (4R)-1-[(2S,3S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-{[(3S)-1-{[2-(dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylpentanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

[1328] Example Compound 39 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[( [(1S)-3-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propyl]-L-prolinamide

[1329] Example Compound 40 N-{4-[({(7M)-6-cyclopropyl-...

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 is -CH2- or -O-, R 1 is a naphthyl group which may be substituted with OH or the following formula (II), R 1a is H, methyl, F or Cl, R 1b is F, Cl, methyl or ethyl, R 2 is H, halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 Alkyl, cyclopropyl or vinyl, R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XXXV), R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g 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 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3e For-OC 2-3 Alkylene-NR N1 R N2 , R 3f H, F or C 1-3 alkyl, R 3g H or C 1-3 alkyl, R 3h is a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which may be substituted and contains 1 to 3 nitrogen atoms, 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 R on the same carbon atom 3i It can form a carbon atom with the adjacent carbon atom selected from C 3-6 The group of formula (XXXV) is a ring selected from the group consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and forms a spiro ring, which may be selected from the group consisting of 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 The group of formula (XXXV) is a ring consisting of a cycloalkane and a 4- to 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring, which 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 bridge structure containing 1 to 2 carbon atoms may be formed. The group of formula (XXXV) as a ring having the bridge 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, may form a substituted 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, or R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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, 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 an integer from 1 to 8, in, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a Substituted pyrrolidinyl and R 4a The group consisting of substituted tetrahydrofuranyl and C 1-6 Alkyl; can be R 4b substituted piperidinyl; or may be R 4a Substituted tetrahydropyranyl, R 4a C can be replaced by F 1-3 alkyl, R 4b C substituted with 1 to 3 F 1-3 alkyl, R 5 Methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C 3-6 Cycloalkylmethyl or C 3-6 Cycloalkyl, R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 Cycloalkane or a 4- to 6-membered saturated heterocyclic ring which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, R 7 is a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which contains 1 to 3 nitrogen atoms, W is an optionally substituted phenylene group or an optionally substituted 6-membered heteroaromatic diyl group containing 1 to 3 nitrogen atoms as ring constituent atoms, 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 1 , L 2 , L 3 , L 4 are the same or different from each other, and are selected from a free bond, -O-, -NR L1 -, pyrrolidinediyl which may be substituted, piperidinediyl which may be substituted, piperazinediyl which may be substituted, C 1-3 A group consisting of an alkylene group and C=O, R L1 H or C 1-3 alkyl, Z is NH or a 5-membered heteroaromatic diyl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, Alternatively, YLZ is the following formula (XII), 2. The compound or salt thereof according to claim 1, wherein R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X) and formula (XI), R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g 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 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3e For-OC 2-3 Alkylene-NR N1 R N2 , R 3f H, F or C 1-3 alkyl, R 3g H or C 1-3 alkyl, R 3h is a 5-membered heteroaryl group which may be substituted and contains 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group which may be substituted and contains 1 to 3 nitrogen atoms, 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, may form a substituted 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, or R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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, 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, Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-.

3. The compound or salt thereof according to claim 2, wherein Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl, L is a key, C 1-3 Alkylene, C═O, or a group selected from the group consisting of the following formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), and formula (XVIII), R L1 H or C 1-3 alkyl, R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl, R L is CH or N, m is 1 or 2, Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII), Alternatively, YLZ is the following formula (XII), 4. The compound or salt thereof according to claim 3, wherein A is CR A or N, R A For H, X 1 For -O-, R 6a and R 6b are the same or different from each other and are H or a C which may be substituted by a group selected from the group consisting of F, OH, OCH3 and N(CH3)2 1-6 Alkyl, or R 6a , R 6b Together with the carbon to which they are bonded, they can form substitutable C 3-6 Cycloalkanes, R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII) and formula (XXXIII), R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 alkyl, W is the following formula (XXXIV), W 1 is CH, CF, CCl or CCH3, W 2 It is CH, CF, CCl, CCH3 or N.

5. The compound or salt thereof according to claim 4, wherein R 1 is the following formula (II), R 1a is H, methyl, F or Cl, R 1b is F, Cl, methyl or ethyl, R 2 is halogen, C which may be substituted by a group selected from the group consisting of OH and OCH3 1-3 Alkyl, cyclopropyl or vinyl, R 3 is a group selected from the group consisting of the following formula (III), formula (IV), formula (V), formula (VIII-a) and formula (X), R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 5- 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3b is H or methyl, R 3c and R 3d -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 A 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, which is substituted by a group selected from the group consisting of 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3f H, F or C 1-3 alkyl, R 3g H 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, may form a substituted 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, or R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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, 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, Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, Y is a phenylene group or a pyridinediyl group which may be substituted by F or Cl, L is a bond, C=O or a group selected from the group consisting of the following formula (XIII) and formula (XIV), R L1 H or C 1-3 alkyl, R L2 and R L3 The same or different, H, F, OH, OCH3 or substituted C 1-3 alkyl, m is 1 or 2, Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII), Alternatively, YLZ is the following formula (XII), 6. The compound or salt thereof according to claim 5, wherein R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a), formula (Va), formula (VIII-a) and formula (X), R 3a -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3b is H or methyl, R 3c -(CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; can be C 1-3 Alkyl-substituted pyrrolidinyl; may be C 1-3 Alkyl substituted piperidinyl; or, may be selected from C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 The groups consisting of the group substituted with C 3-6 Cycloalkyl, R 3f H, F or C 1-3 alkyl, R 3g H 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, may form a substituted 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, or R 3f and R N1 may form, together with the carbon atom and the nitrogen atom to which they are bonded, a substituted 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, X 2 is -O- or -NH- or -N(CH3)-, X 3 is O or S, p is 1 or 2, Among them, R 3c -(CH2) p CHR 3f -NR N1 R N2 When X of formula (IV-a) 2 is -O- or -NH-, R 4 may be selected from F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )2. Can be R 4a The C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl, R 4a C 1-3 alkyl, R 4b C substituted with 1 to 3 F 1-3 alkyl, R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII), R 7a , R 7b The same or different, H or C which can be replaced by OH 1-3 alkyl, Y is a phenylene group which may be substituted by F or Cl, Z is NH or a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII), 7. The compound or salt thereof according to claim 6, wherein R 1 is the following formula (II-a), R 2 is cyclopropyl, R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a), formula (Va), formula (VIII-a) and formula (X), R 3a -(CH2) p CHR 3f -NR N1 R N2 or -(CH2) p CHR 3f -OR 3g , R 3b For H, R 3c -(CH2) p CHR 3f -NR N1 R N2 ; can be C 1-3 Alkyl-substituted pyrrolidinyl; or -NR N1 R N2 Substituted C 3-6 Cycloalkyl, R 3f For H, R 3g For H, R N1 and R N2 Same or different, H or C 1-3 Alkyl, or R N1 and R N2 may form, together with the nitrogen atom to which they are bonded, a 4- to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X 2 is -O- or -NH-, X 3 is O or S, p is 1 or 2, R 4 may be selected from OCH3, R 4a 、N(R 4a )2. Can be R 4a The C substituted group is a group consisting of substituted pyrrolidinyl and tetrahydrofuranyl 1-6 Alkyl; can be R 4b substituted piperidinyl; or tetrahydropyranyl, R 4a C 1-3 alkyl, R 4b C substituted with 1 to 3 F 1-3 alkyl, R 5 is isopropyl or sec-butyl, R 6a and R 6b are the same or different from each other and are H or C which may be substituted by a group selected from the group consisting of OH and N(CH3)2 1-6 alkyl, R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVIII) and formula (XXXIII), R 7a , R 7b Same or different, H or C 1-3 alkyl, W is the following formula (XXXIV), W 1 For CH, W 2 is CH or N, Y is phenylene, L is a bond or C=O.

8. The compound or salt thereof according to claim 7, wherein R 3 is a group selected from the group consisting of the following formula (III-a), formula (IV-a) and formula (Va), R 3a -(CH2) p CHR 3f -NR N1 R N2 , R 3b For H, R 3c To be available for -NR N1 R N2 Substituted C 3-6 Cycloalkyl, R 3f For H, R N1 and R N2 Same or different, both are C 1-3 alkyl, X 2 is -O- or -NH-, X 3 For O, p is 1, R 4 is a C that can be replaced by OCH3 1-6 alkyl, R 5 is isopropyl, R 6a For H, R 6b C can be replaced by OH 1-6 alkyl, R 7 is a group selected from the group consisting of the following formula (XXIII), formula (XXIV) and formula (XXVIII), R 7a , R 7b Same or different, H or C 1-3 alkyl, W is the following formula (XXXIV), W 1 and W 2 All are CH, L is a key, Z is a group selected from the group consisting of the following formula (XIX), formula (XX), formula (XXI) and formula (XXII), 9. The compound or salt thereof according to claim 1, wherein The compound of formula (I) is selected from the group consisting of: 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3- 1-[((2S)-2-methoxypropoxy)quinazolin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester, 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3- oxazol-5-yl)phenyl]ethyl}-L-prolinamide, 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylic acid (1s,3R)-3-(dimethylamino)cyclobutyl ester, (4R)-1-[(2S)-2-(4-{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]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-1-carboxylic acid (1S,3R)-3-(dimethylamino)cyclobutyl ester, and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3-[(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

10. 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 10, which is a pharmaceutical composition for treating pancreatic cancer.

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

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

14. Use of the compound or salt thereof according to claim 1 in treating pancreatic cancer.

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

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