Pharmaceutical compositions containing quinazoline compounds

Abstract

To provide a pharmaceutical composition for treating colon cancer and / or lung cancer. [Solution] The present inventors have investigated compounds useful as active ingredients in pharmaceutical compositions for cancer treatment, and have found that quinazoline compounds have excellent activity of inducing degradation of G12D mutant KRAS protein and inhibitory activity against G12D mutant KRAS, and that pharmaceutical compositions containing these compounds as active ingredients can be used as cancer treatment agents, thus completing the present invention. The pharmaceutical composition of the present invention containing the quinazoline compound or a salt thereof as an active ingredient can be used as a cancer treatment agent for colon cancer and / or lung cancer.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for treating colorectal cancer and / or lung cancer. The pharmaceutical composition according to the present invention contains a quinazoline compound that is effective in inducing degradation of G12D mutant KRAS protein and is useful as a G12D mutant KRAS inhibitor. [Background technology]

[0002] Colorectal cancer is a cancer with a high incidence and mortality rate worldwide, with approximately 1.4 million new cases reported annually worldwide (World Cancer Report 2014). The most effective method for treating colorectal cancer is surgery, but in recent years, there have been significant advances in chemotherapy and radiation therapy. Large-scale clinical trials conducted mainly in Europe and the United States have revealed that chemotherapy using a combination of multiple anticancer drugs is effective for colorectal cancer, contributing to tumor regression and prolonged prognosis (J. Clin. Oncol., 22, p.229-237, 2004). In addition to chemotherapy, molecular targeted drugs such as anti-VEGF (vascular endothelial growth factor) antibodies and anti-EGFR (epidermal growth factor receptor) antibodies are also used in combination with chemotherapy as first-line drugs. Regarding anti-EGFR antibody drugs, it has become clear that RAS gene mutations are a negative predictor of efficacy (Cancer Res., 66, p.3992-3995, 2006), and currently, anti-EGFR antibody drugs are only applicable to patients with wild-type RAS genes in colorectal cancer. Lung cancer is also responsible for the largest number of deaths, accounting for 19% of all cancer deaths, with approximately 1.8 million new cases reported annually worldwide (World Cancer Report 2014). Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases (American Cancer Society, Cancer Facts and Figures, 2016). Although surgical treatment is considered up to a certain stage, chemotherapy and radiotherapy are rarely indicated for subsequent stages. Based on cytomorphology, adenocarcinoma and squamous cell carcinoma are classified as the most common types of NSCLC. The clinical course of these tumors is similar, but adenocarcinoma is characterized by its peripheral location in the lung.

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

[0004] When an amino acid substitution occurs due to a mutation in the RAS gene, RAS becomes constitutively active due to its reduced function as a GTPase and its reduced response to GAP, and continues to send signals downstream. This excessive signaling leads to carcinogenesis and increased cancer proliferation. In colorectal cancer, mutations in the KRAS gene have been observed in 30-40% of cases, and point mutations in KRAS exon 2 (codons 12 and 13) are particularly common (Ann. Oncol., 27, p.1746-1753, 2016). Current anticancer drugs have not been shown to be effective against colorectal cancer with KRAS mutations, and there is a high unmet medical need in this segment. In lung cancer, mutations in the RAS gene have been observed in 32% of lung adenocarcinomas. The breakdown of mutation frequency is 96% in the KRAS gene, 3% in the NRAS gene, and 1% in the HRAS gene, and it has been reported that point mutations in KRAS exon 2 (codons 12 and 13) are common (Nature Rev. Drug Discov., 2014, 13, p.828-851).

[0005] Known KRAS gene mutations include the KRAS G12D mutation, in which glycine at codon 12 is replaced by aspartic acid, and the KRAS G12C mutation, in which glycine is replaced by cysteine. In recent years, several selective inhibitors for the G12C mutation have been developed, of which Sotorasib has been approved by the FDA as a treatment for NSCLC (Drugs, 2021, 81, p.1573-1579). On the other hand, the G12D mutation of KRAS is found in approximately 34% of pancreatic cancers, more than 10% of colorectal cancers, and approximately 4% of lung adenocarcinomas (Nat. Rev. Cancer, 2018, 18, p.767-777). Therefore, there are high expectations for therapeutic drugs for KRAS mutations other than the KRAS G12C mutation.

[0006] Patent Documents 1, 2, and 3 disclose KRAS inhibitors, and compounds represented by the following formula (A) and formula (B) are disclosed in Patent Documents 2 and 3, respectively (see the documents for the meanings of the symbols in the formulas). [ka] Patent Documents 1, 2, and 3 state that the compound is useful for cancers having mutations in codon 12 of KRAS, one of which is a G12D mutation, but do not describe its effect on G12D-mutated KRAS cancers.

[0007] In recent years, bifunctional compounds, collectively known as PROTAC (PROteolysis-TArgeting Chimera) and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), have been discovered as a technology for inducing degradation of targeted proteins, and are expected to be one of the new drug discovery modalities (Drug. Discov. Today Technol., 2019, 31, p.15-27). Bifunctional compounds promote the formation of a complex between a target protein and an E3 ligase in cells, and the degradation of the target protein is induced by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the protein degradation mechanisms in cells. A protein called E3 ligase recognizes the protein to be degraded and ubiquitinates it, which causes the degradation in the proteasome to proceed.

[0008] There are more than 600 types of E3 ligases in the body, which are roughly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, only a limited number of E3 ligases are used in bifunctional degraders, such as PROTACs and SNIPERs, and representative examples include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). In particular, VHL has been reported in Patent Document 4, and CRBN in Patent Document 5.

[0009] A bifunctional compound is a compound in which a ligand of a target protein and a ligand of E3 ligase are linked by a linker, and bifunctional compounds that degrade KRAS protein have been reported to date (Non-Patent Document 1, Non-Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 9). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2016 / 049565 [Patent Document 2] International Publication No. 2016 / 049568 [Patent Document 3] International Publication No. 2017 / 172979 [Patent Document 4] International Publication No. 2013 / 106643 [Patent Document 5] International Publication No. 2015 / 160845 [Patent Document 6] US Patent Application Publication No. 2018 / 0015087 [Patent Document 7] International Publication No. 2019 / 195609 [Patent Document 8] International Publication No. 2020 / 018788 [Patent Document 9] International Publication No. 2022 / 173032 [Non-patent literature]

[0011] [Non-Patent Document 1] Cell. Chem. Biol., 2020, 27, p19-31 [Non-Patent Document 2] ACS Cent. Sci., 2020, 6, p1367-1375 Summary of the Invention [Problem to be solved by the invention]

[0012] The object of the present invention is to provide a pharmaceutical composition for treating colon cancer and / or lung cancer. In particular, the object of the present invention is to provide a technique for treating colon cancer and / or lung cancer with a compound that is excellent in inducing degradation of G12D mutant KRAS protein and is useful as a G12D mutant KRAS inhibitor, for example. [Means for solving the problem]

[0013] Means for Solving the Problems The present inventors have conducted extensive research into compounds useful as active ingredients in pharmaceutical compositions for the treatment of cancer, with the aim of providing a pharmaceutical composition for the treatment of colorectal cancer and / or lung cancer, in particular a pharmaceutical composition for the treatment of G12D mutant KRAS-positive cancer, and as a result have found that quinazoline compounds of formula (I) have excellent effect of inducing the degradation of G12D mutant KRAS protein and have excellent inhibitory activity against G12D mutant KRAS, and that pharmaceutical compositions containing these compounds as an active ingredient are useful as pharmaceutical compositions for the treatment of colorectal cancer and / or lung cancer. Furthermore, the present inventors have discovered that bifunctional compounds of formula (I), which are characterized by linking a substituent at the 8th position of quinazoline to a ligand of E3 ligase, or by linking a substituent at the 8th position of quinazoline to a ligand of E3 ligase via a linker, have excellent effect of inducing the degradation of G12D mutant KRAS protein and activity of inhibiting G12D mutant KRAS, and that pharmaceutical compositions containing these compounds as active ingredients are useful as pharmaceutical compositions for treating colorectal cancer and / or lung cancer, thereby completing the present invention. That is, the present invention relates to a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound represented by the following formula (I) or a salt thereof and one or more pharma- ceutically acceptable excipients: [ka] In formula (I), R 1 is represented by the following formula (II) or formula (III): [ka] and R 1a and R 1bare the same or different and are H or F, R 2 is a halogen, C 1-3 alkyl, cyclopropyl, or vinyl; R 3 is represented by the following formula (IV): [ka] and R 4 C may be substituted with OCH3 1-3 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl; R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 is cycloalkyl, R 6a and R 6b are the same or different and are H or C optionally substituted with a group selected from the group consisting of F, OH and N(CH3)2; 1-3 alkyl or R 6a and R 6b together with the carbon to which they are attached to form a cyclopropyl, R 7 is H, a halogen, or a group represented by the following formula (VI), formula (VII), formula (VIII), and formula (IX): [ka] is a group selected from the group consisting of R 7a is H or C optionally substituted with OH 1-3 is alkyl, X is O, Y is phenylene or pyridinediyl; L is a bond; C 1-3 alkylene or C=O; Z is NH or the following formula (X), formula (XI) and formula (XII): [ka] or YLZ together represent a group of the following formula (XIII): [ka] It is.

[0014] The present invention relates to a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound represented by the following formula (I) or a salt thereof: [ka] In formula (I), R 1 is represented by the following formula (II) or formula (III): [ka] and R 1a and R 1b are the same or different and are H or F, R 2 is a halogen, C 1-3 alkyl, cyclopropyl, or vinyl; R 3 is represented by the following formula (IV): [ka] and R 4 is C 1-3 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl; R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 is cycloalkyl, R 6a and R 6b are the same or different and are H or C optionally substituted with a group selected from the group consisting of F, OH and N(CH3)2; 1-3 alkyl or R 6a and R 6b together with the carbon to which they are attached to form a cyclopropyl, R 7 is H, a halogen, or a group represented by the following formula (VI), formula (VII), formula (VIII), and formula (IX): [ka] is a group selected from the group consisting of R 7a is H or C optionally substituted with OH 1-3 is alkyl, X is O, Y is phenylene or pyridinediyl; L is a bond; C 1-3 alkylene or C=O; Z is NH or the following formula (X), formula (XI) and formula (XII): [ka] or YLZ together represent a group of the following formula (XIII): [ka] It is. Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0015] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and one or more pharma- ceutically acceptable excipients, particularly a pharmaceutical composition for treating colon cancer and / or lung cancer, particularly a pharmaceutical composition for treating G12D mutant KRAS-positive cancer. The pharmaceutical composition includes a therapeutic agent for colon cancer and / or lung cancer, particularly a G12D mutant KRAS-positive cancer, comprising a compound of formula (I) or a salt thereof. The present invention also relates to use of the compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating colon cancer and / or lung cancer, particularly G12D mutant KRAS positive cancer, use of the compound of formula (I) or a salt thereof for treating colon cancer and / or lung cancer, particularly G12D mutant KRAS positive cancer, the compound of formula (I) or a salt thereof for use in treating colon cancer and / or lung cancer, particularly G12D mutant KRAS positive cancer, and a method for treating colon cancer and / or lung cancer, particularly G12D mutant KRAS positive cancer, which comprises administering an effective amount of the compound of formula (I) or a salt thereof to a subject. The present invention also relates to a compound of formula (I) or a salt thereof which is a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor, a compound of formula (I) or a salt thereof for use as a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor, and a G12D mutant KRAS proteolysis inducer and / or a G12D mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof. The "subject" refers to a human or other animal in need of the treatment, and in one embodiment, a human in need of the prevention or treatment.

[0016] The present invention also relates to the use of a compound of formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating colon cancer and / or lung cancer, the use of a compound of formula (I) or a salt thereof for treating colon cancer and / or lung cancer, a compound of formula (I) or a salt thereof for use in treating colon cancer and / or lung cancer, a compound of formula (I) or a salt thereof for treating colon cancer and / or lung cancer, and a method for treating colon cancer and / or lung cancer comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof. Effect of the Invention

[0017] The compound of formula (I) or a salt thereof has an effect of inducing the degradation of G12D mutant KRAS protein and an activity of inhibiting G12D mutant KRAS, and can be used as an active ingredient of a pharmaceutical composition for treating colorectal cancer and / or lung cancer, in particular, G12D mutant KRAS-positive cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The present invention will be described in detail below.

[0019] In this specification, the term "optionally substituted" means unsubstituted or having 1 to 3 substituents. When having multiple substituents, the substituents may be the same or different from each other.

[0020] "C 1-3 "Alkyl" refers to a straight or branched alkyl having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl. 1-3 Alkyl is methyl, ethyl or isopropyl, in one embodiment it is methyl or ethyl, in one embodiment it is methyl or isopropyl, in one embodiment it is ethyl or isopropyl, in one embodiment it is ethyl or n-propyl, in one embodiment it is methyl, in one embodiment it is ethyl, in one embodiment it is n-propyl, and in one embodiment it is isopropyl.

[0021] "C 3-6 "Cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 "Cycloalkyl" is cyclobutyl, cyclopentyl, or cyclohexyl, in one embodiment cyclobutyl or cyclopentyl, in one embodiment cyclopentyl or cyclohexyl, in one embodiment cyclopropyl, in one embodiment cyclobutyl, in one embodiment cyclopentyl, and in one embodiment cyclohexyl.

[0022] "C 1-3 "Alkylene" means a straight or branched C 1-3 Alkylene, such as methylene, ethylene, trimethylene, propylene, methylmethylene, 1,1-dimethylmethylene, etc. 1-3 "Alkylene" is a straight or branched C 1-3 In one embodiment, it is methylene, ethylene, trimethylene or propylene. 1-3 As the "alkylene", straight or branched C 1-3 It is alkylene, and in one embodiment, it is methylene or ethylene, and in one embodiment, it is methylene, and in one embodiment, it is ethylene.

[0023] "Halogen" means F, Cl, Br and I. In one embodiment, "halogen" is F, Cl or Br, in one embodiment, F, in one embodiment, Cl, and in one embodiment, Br.

[0024] Certain embodiments of the permissible substituents for "optionally substituted pyrazolyl", "optionally substituted pyridyl" and "optionally substituted pyrimidinyl" include C 1-3 In one embodiment, the substituent is methyl or ethyl, in one embodiment, methyl, and in one embodiment, ethyl.

[0025] In the "optionally substituted pyrrolidinyl" and "optionally substituted piperidinyl", an embodiment of the permissible substituent is C optionally substituted with F. 1-3 In one embodiment, the substituent is C optionally substituted with F. 1-3 In one embodiment, it is alkyl, in one embodiment, it is methyl, ethyl, difluoroethyl, or oxetanyl, in one embodiment, it is difluoroethyl or oxetanyl, in one embodiment, it is 2,2-difluoroethyl, and in one embodiment, it is oxetanyl.

[0026] "C optionally substituted with F 1-3 In one embodiment, "alkyl" is methyl which may be substituted with F or ethyl which may be substituted with F. Examples of these are monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl. In one embodiment, "C optionally substituted with F" is 1-3 "Alkyl" is methyl, ethyl, monofluoromethyl, difluoromethyl, or difluoroethyl, in one embodiment, monofluoromethyl or difluoromethyl, in one embodiment, monofluoromethyl or difluoroethyl, in one embodiment, difluoromethyl or difluoroethyl, in one embodiment, monofluoromethyl, in one embodiment, difluoromethyl, in one embodiment, difluoroethyl, and in one embodiment, 2,2-difluoroethyl.

[0027] "C optionally substituted with OH 1-3 An embodiment of "alkyl" is methyl which may be substituted with one OH or ethyl which may be substituted with one or two OH. Examples of these are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1,2-hydroxyethyl. An embodiment of "C which may be substituted with OH" is 1-3"Alkyl" is hydroxymethyl or hydroxyethyl, and in one embodiment is hydroxymethyl, and in one embodiment is hydroxyethyl.

[0028] "C which may be substituted with OCH3 1-3 An embodiment of "alkyl" is methyl optionally substituted with one OCH3, ethyl optionally substituted with one or two OCH3, or n-propyl optionally substituted with one or two OCH3. Examples of these include methyl, ethyl, n-propyl, isopropyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 1,2-dimethoxypropyl, and 1,3-dimethoxypropyl. "C optionally substituted with OCH3" 1-3 In certain embodiments, "alkyl" is ethyl or 2-methoxypropyl, and in certain embodiments, 2-methoxypropyl. "C optionally substituted with N(CH3)2 1-3 An embodiment of "alkyl" is methyl which may be substituted with one N(CH3)2 or ethyl which may be substituted with one N(CH3)2. An embodiment is dimethylaminomethyl, and an embodiment is dimethylaminoethyl.

[0029] The term "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid.

[0030] "G12D mutated KRAS" refers to KRAS having the above-mentioned "G12D mutation."

[0031] "Colon cancer" refers to a malignant tumor occurring in the colon, and "lung cancer" refers to a malignant tumor occurring in the lung. Furthermore, "pancreatic cancer" refers to a malignant tumor occurring in the pancreas. Examples of pancreatic cancer include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, and in one embodiment, pancreatic ductal carcinoma and in another embodiment, pancreatic ductal adenocarcinoma.

[0032] In some embodiments, the colon and lung cancers are metastatic, locally advanced, recurrent and / or refractory cancers, and in some embodiments, the colon and lung cancers are in patients who have not been previously treated or have previously been treated.

[0033] In some embodiments, the colorectal cancer is colon cancer or rectal cancer, and in some embodiments, the lung cancer is small cell lung cancer or non-small cell lung cancer.

[0034] "G12D mutation KRAS positive cancer" refers to G12D mutation KRAS positive cancer, for example, KRAS G12D mutation occurs in cancer, and the positive rate of G12D mutation KRAS is high. In some embodiments, "G12D mutation KRAS positive cancer" refers to G12D mutation KRAS positive colon cancer and / or lung cancer.

[0035] One embodiment of the compound of formula (I) or a salt thereof contained in the pharmaceutical composition of the present invention is shown below. (1)R 1 is of formula (II) or (III), and R 1a and R 1b are the same or different and are H or F, or a salt thereof. [ka] In one embodiment, R 1 is of formula (II), and R 1a is H or F. In one embodiment, R 1 is of formula (II), and R 1a In one embodiment, R 1 is of formula (II), and R 1a In one embodiment, R 1 is formula (III), and R 1a and R 1b are the same or different and are H or F, or a salt thereof. 1 is formula (III), and R 1a and R 1b and R are both H, or a salt thereof.1 is formula (III), and R 1a is H and R 1b In one embodiment, R 1 is formula (III), and R 1a and R 1b and F. In one embodiment, R 1 is formula (III), and R 1a is F and R 1b A compound or a salt thereof, wherein (2)R 2 is halogen, C 1-3 In one embodiment, R is an alkyl, cyclopropyl, or vinyl group, or a salt thereof. 2 In one embodiment, R 2 C 1-3 In one embodiment, R 2 In one embodiment, R 2 is vinyl or a salt thereof. (3)R 3 or a salt thereof, wherein [ka] (4)R 4 C, which may be substituted with OCH3 1-3 A compound or a salt thereof which is alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. 4 But, C 1-3 A compound or a salt thereof which is alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl. 4In one embodiment, R is tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, or a salt thereof. 4 In one embodiment, R is tetrahydrofuranyl, tetrahydropyranyl, or optionally substituted piperidinyl, or a salt thereof. 4 In one embodiment, R is a compound or a salt thereof, 4 C, which may be substituted with OCH3 1-3 In one embodiment, R is a compound or a salt thereof, which is alkyl, or tetrahydropyranyl. 4 In one embodiment, R 4 C may be substituted with OCH3 1-3 In one embodiment, R 4 C 1-3 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R 4 In one embodiment, R is an optionally substituted pyrazolyl or a salt thereof. 4 In one embodiment, R is an optionally substituted pyridyl or a salt thereof. 4 R is an optionally substituted pyrimidinyl, or a salt thereof. 4 In one embodiment, R is an optionally substituted pyrrolidinyl or a salt thereof. 4 In one embodiment, R is an optionally substituted piperidinyl or a salt thereof. 4 or a salt thereof, wherein (5)R 5 is ethyl, isopropyl, tert-butyl or C 3-6 In one embodiment, R 5isopropyl, tert-butyl or C 3-6 In one embodiment, R 5 In one embodiment, R 5 In one embodiment, R 5 In one embodiment, R 5 C 3-6 A compound or a salt thereof which is cycloalkyl. (6)R 6a and R 6b are the same or different and are H or may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2; 1-3 alkyl or R 6a and R 6b In one embodiment, R 6a and R 6b are the same or different and are H or may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2; 1-3 In one embodiment, R 6a and R 6b are the same or different and may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2; 1-3 In one embodiment, R 6a and R 6b In one embodiment, R 6a is H and R 6b C may be substituted with a group selected from the group consisting of F, OH, and N(CH3)2. 1-3 In one embodiment, R 6a is H and R 6b C optionally substituted with F 1-3 In one embodiment, R 6a is H and R 6b C may be substituted with OH1-3 In one embodiment, R 6a is H and R 6b C may be substituted with N(CH3)2 1-3 In one embodiment, R 6a and R 6b A compound in which, together with the carbon to which they are attached, a cyclopropyl group is formed, or a salt thereof. (7)R 7 is H, a halogen, or a group selected from the group consisting of formula (VI), formula (VII), formula (VIII) and formula (IX), or a salt thereof. [ka] In one embodiment, R 7 In one embodiment, R 7 In one embodiment, R 7 is a group selected from the group consisting of formula (VI), formula (VII), formula (VIII) and formula (IX), or a salt thereof. 7 In one embodiment, R 7 In one embodiment, R 7 In one embodiment, R 7 In one embodiment, R 7 In one embodiment, R 7 In one embodiment, R 7 or a salt thereof, wherein (8)R 7a is H or C optionally substituted with OH 1-3 In one embodiment, R 7a In one embodiment, R 7a C may be substituted with OH 1-3In one embodiment, R 7a C 1-3 A compound or a salt thereof, which is alkyl. (9) A compound or a salt thereof, wherein X is O. (10) A compound or a salt thereof in which Y is phenylene or pyridinediyl. In one embodiment, a compound or a salt thereof in which Y is 1,4-phenylene or 2,5-pyridinediyl. In one embodiment, a compound or a salt thereof in which Y is phenylene. In one embodiment, a compound or a salt thereof in which Y is 1,4-phenylene. In one embodiment, a compound or a salt thereof in which Y is pyridinediyl. In one embodiment, a compound or a salt thereof in which Y is 2,5-pyridinediyl. (11) L is a bond, C 1-3 In one embodiment, L is a bond or C 1-3 In one embodiment, a compound or a salt thereof, in which L is an alkylene. In one embodiment, a compound or a salt thereof, in which L is a bond or C=O. In one embodiment, a compound or a salt thereof, in which L is a bond. In one embodiment, a compound or a salt thereof, in which L is C 1-3 In one embodiment, the compound or a salt thereof is a compound in which L is C=O. (12) A compound or a salt thereof, wherein Z is NH or a group selected from the group consisting of the formula (X), the formula (XI) and the formula (XII). [ka] In one embodiment, the compound or a salt thereof, wherein Z is NH or a group selected from the group consisting of formula (X)-1, formula (XI)-1, and formula (XII)-1. [ka] In one embodiment, a compound or a salt thereof, in which Z is a group selected from the group consisting of formula (X), formula (XI) and formula (XII). In one embodiment, a compound or a salt thereof, in which Z is a group selected from the group consisting of formula (X)-1, formula (XI)-1 and formula (XII)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (X) or formula (XI). In one embodiment, a compound or a salt thereof, in which Z is formula (X)-1 or formula (XI)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (XI) or formula (XII). In one embodiment, a compound or a salt thereof, in which Z is formula (XI)-1 or formula (XII)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (XI)-1 or formula (XII)-1. In one embodiment, a compound or a salt thereof, in which Z is NH. In one embodiment, a compound or a salt thereof, in which Z is formula (X). In one embodiment, a compound or a salt thereof, in which Z is formula (X)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (X)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (XI). In one embodiment, a compound or a salt thereof, in which Z is formula (XI)-1. In one embodiment, a compound or a salt thereof, in which Z is formula (XI)-1. In one embodiment, the compound or a salt thereof, wherein Z is formula (XII).In one embodiment, the compound or a salt thereof, wherein Z is formula (XII)-1. (13) A compound or a salt thereof, wherein YLZ is the following formula (XIII): [ka] In one embodiment, the compound or salt thereof is a compound in which YLZ is represented by the following formula (XIII)-1: [ka] (14) A compound or a salt thereof which is a combination of any two or more of the above-mentioned (1) to (13) that are not contradictory.

[0036] As examples of specific compounds encompassed by the present invention, in one embodiment, the following compounds can be mentioned. (15) R 1 is of formula (II), and R 1a is F and R 2 is cyclopropyl, and R 3 is formula (IV), and R 4 is tetrahydropyranyl or optionally substituted piperidinyl, R 5 is isopropyl, R 6ais H and R 6b C may be substituted with OH 1-3 is alkyl, R 7 is of formula (VI), (VIII) or (IX), and R 7a C 1-3 A compound or a salt thereof, wherein: Y is phenylene, L is a bond, and Z is an alkyl group represented by the formula (XI): (16) R 1 is of formula (II), and R 1a is F and R 2 is cyclopropyl, and R 3 is formula (IV), and R 4 is tetrahydropyranyl, R 5 is isopropyl, R 6a is H and R 6b C may be substituted with OH 1-3 is alkyl, R 7 is of formula (VI) or (VIII), and R 7a C 1-3 A compound or a salt thereof, wherein: Y is 1,4-phenylene, L is a bond, and Z is an alkyl group;

[0037] As examples of specific compounds encompassed by the present invention, in one embodiment, the following compounds can be mentioned. (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter sometimes referred to as "compound A"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide (hereinafter sometimes referred to as "compound B"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound C"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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 (hereinafter sometimes referred to as "compound D"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound E"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "compound F"); (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter sometimes referred to as "compound G"), and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "Compound H"); A compound or a salt thereof selected from the group consisting of: As examples of specific compounds encompassed by the present invention, in one embodiment, the following compounds can be mentioned. (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter sometimes referred to as "compound A-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide (hereinafter, sometimes referred to as "compound B-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound C-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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 (hereinafter sometimes referred to as "compound D-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound E-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "compound F-1"); (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter, sometimes referred to as "compound G-1"), and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "compound H-1"); A compound selected from the group consisting of: As examples of specific compounds encompassed by the present invention, in one embodiment, the following compounds can be mentioned. (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter sometimes referred to as "compound A-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide (hereinafter sometimes referred to as "compound B-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound C-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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 (hereinafter sometimes referred to as "compound D-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide (hereinafter sometimes referred to as "compound E-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "compound F-2"); (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]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 (hereinafter, sometimes referred to as "compound G-2"), and (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide (hereinafter sometimes referred to as "compound H-2"); A compound selected from the group consisting of:

[0038] One aspect of the present invention is described below. (17-1) A pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G and Compound H. In another embodiment, a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G and Compound H, and one or more pharma- ceutically acceptable excipients. (17-2) A pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H. In another embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H, and one or more pharma- ceutically acceptable excipients. (17-3) A pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound selected from the group consisting of Compound A-1, Compound B-1, Compound C-1, Compound D-1, Compound E-1, Compound F-1, Compound G-1 and Compound H-1, or a salt thereof. In another embodiment, a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound selected from the group consisting of Compound A-1, Compound B-1, Compound C-1, Compound D-1, Compound E-1, Compound F-1, Compound G-1 and Compound H-1, or a salt thereof, and one or more pharma- ceutically acceptable excipients. (17-4) A pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, and compound F-1, compound G-1, and compound H-1, or a salt thereof. In another embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, and compound F-1, compound G-1, and compound H-1, or a salt thereof, and one or more pharma- ceutical acceptable excipients. (17-5) A pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, and compound F-2, compound G-2, and compound H-2, or a salt thereof. In another embodiment, a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, and compound F-2, compound G-2, and compound H-2, or a salt thereof, and one or more pharma- ceutical acceptable excipients. (17-6) A pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, and compound F-2, or a salt thereof. In another embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, and compound F-2, or a salt thereof, and one or more pharma- ceutical acceptable excipients. (17-7) A pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F. In another embodiment, a pharmaceutical composition for treating colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, and a pharma- ceutically acceptable excipient. (17-8) A pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F. In another embodiment, a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising a compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, and a pharma- ceutical acceptable excipient. (18-1) Use of a compound selected from the group consisting of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G and Compound H, or a salt thereof, in the manufacture of a pharmaceutical composition for treating colorectal cancer and / or lung cancer. (18-2) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H, or a salt thereof, in the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and / or lung cancer. (18-3) Use of a compound selected from the group consisting of Compound A-1, Compound B-1, Compound C-1, Compound D-1, Compound E-1, Compound F-1, Compound G-1 and Compound H-1, or a salt thereof, in the manufacture of a pharmaceutical composition for treating colon cancer and / or lung cancer. (18-4) Use of a compound selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1, or a salt thereof, in the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (18-5) Use of a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, or a salt thereof, in the manufacture of a pharmaceutical composition for treating colon cancer and / or lung cancer. (18-6) Use of a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, or a salt thereof, in the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (18-7) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof, in the manufacture of a pharmaceutical composition for treating colon cancer and / or lung cancer. (18-8) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof, in the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (19-1) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H for treating colon cancer and / or lung cancer. (19-2) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (19-3) A compound or a salt thereof selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1 for treating colon cancer and / or lung cancer. (19-4) A compound or a salt thereof selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1 for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (19-5) A compound or a salt thereof selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2 for treating colon cancer and / or lung cancer. (19-6) A compound or a salt thereof selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2 for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (19-7) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F for treating colon cancer and / or lung cancer. (19-8) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (20-1) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H for use in treating colon cancer and / or lung cancer. (20-2) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H for use in treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (20-3) A compound or a salt thereof selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1 for use in treating colon cancer and / or lung cancer. (20-4) A compound or a salt thereof selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1 for use in the treatment of G12D mutant KRAS-positive colon cancer and / or lung cancer. (20-5) A compound or a salt thereof selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2 for use in treating colon cancer and / or lung cancer. (20-6) A compound or a salt thereof selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, for use in the treatment of G12D mutant KRAS-positive colorectal cancer and / or lung cancer. (20-7) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F for use in treating colon cancer and / or lung cancer. (20-8) A compound or a salt thereof selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F for use in treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (21-1) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H, or a salt thereof, for treating colon cancer and / or lung cancer. (21-2) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H, or a salt thereof, for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (21-3) Use of a compound selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1, or a salt thereof, for treating colon cancer and / or lung cancer. (21-4) Use of a compound selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1, or a salt thereof, for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (21-5) Use of a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, or a salt thereof, for treating colon cancer and / or lung cancer. (21-6) Use of a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, or a salt thereof, for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (21-7) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof, for treating colon cancer and / or lung cancer. (21-8) Use of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof, for treating G12D mutant KRAS-positive colon cancer and / or lung cancer. (22-1) A method for treating colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound selected from the group consisting of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G and Compound H, or a salt thereof. (22-2) A method for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E, compound F, compound G and compound H, or a salt thereof. (22-3) A method for treating colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound or a salt thereof selected from the group consisting of Compound A-1, Compound B-1, Compound C-1, Compound D-1, Compound E-1, Compound F-1, Compound G-1 and Compound H-1. (22-4) A method for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound or a salt thereof selected from the group consisting of compound A-1, compound B-1, compound C-1, compound D-1, compound E-1, compound F-1, compound G-1 and compound H-1. (22-5) A method for treating colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound or a salt thereof selected from the group consisting of Compound A-2, Compound B-2, Compound C-2, Compound D-2, Compound E-2, Compound F-2, Compound G-2 and Compound H-2. (22-6) A method for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound selected from the group consisting of compound A-2, compound B-2, compound C-2, compound D-2, compound E-2, compound F-2, compound G-2 and compound H-2, or a salt thereof. (22-7) A method for treating colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof. (22-8) A method for treating G12D mutant KRAS-positive colon cancer and / or lung cancer, comprising administering to a subject an effective amount of a compound selected from the group consisting of compound A, compound B, compound C, compound D, compound E and compound F, or a salt thereof.

[0039] The compound of formula (I) may exist in the form of tautomers or geometric isomers depending on the type of the substituent. In this specification, the compound of formula (I) may be described in only one form of isomer, but the present invention also includes other isomers, and also includes isolated isomers or mixtures thereof. In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and therefore may have diastereomers. The present invention also includes isolated diastereomers of the compound of formula (I) or mixtures thereof.

[0040] Furthermore, the present invention also includes pharma- ceutically acceptable prodrugs of the compounds represented by formula (I). A pharma-ceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 1985, 5, p. 2157-2161 and "Drug Development", Vol. 7, Molecular Design, Hirokawa Shoten, 1990, p. 163-198.

[0041] The salt of the compound of formula (I) is a pharma- ceutically 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. For example, the salts described in Handbook of Pharmaceutical Salts Properties, Selection, and Use, by P. Heinrich Stahl, Wiley-VCH, 2008, may be mentioned. Specific examples of the salt include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine; and ammonium salts.

[0042] Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound of formula (I) and its salts. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

[0043] (manufacturing method) The compound of formula (I) and its salts can be produced by applying various known synthesis methods, utilizing the characteristics based on the basic structure or the type of substituent. In this case, depending on the type of functional group, it may be effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014, by PGM Wuts and TW Greene, and may be appropriately selected and used depending on the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary. In addition, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage from the raw material to the intermediate, similar to the above-mentioned protecting group, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Representative methods for producing the compound of formula (I) are described below. Each method can be performed by referring to the references attached to the description. The method of the present invention is not limited to the examples shown below.

[0044] The following abbreviations may be used in this specification. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, DOX: 1,4-dioxane, DMSO: dimethylsulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: palladium on carbon.

[0045] (Manufacturing method 1) [ka]

[0046] The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction. Examples of the protecting group include tert-butoxycarbonyl, benzyl, triphenylmethyl, benzyloxycarbonyl, tert-butyl(dimethyl)silyl, (trimethylsilyl)ethoxymethyl, trifluoroacetyl, allyl, tetrahydro-2H-pyran-2-yl, and methoxymethyl. This reaction is carried out by stirring under cooling or heating under reflux, usually for 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, alcohols such as MeOH and EtOH, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethers such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN, water, and mixtures thereof. The deprotection reagent is selected depending on the type of protecting group, and examples thereof include, but are not limited to, bases such as aqueous sodium hydroxide, aqueous potassium hydroxide, and aqueous lithium hydroxide, acids such as hydrochloric acid and trifluoroacetic acid, and tetra-n-butylammonium fluoride. It may be advantageous to carry out the reaction in the presence of triisopropylsilane in order to smoothly proceed with the reaction. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th ed., John Wiley & Sons Inc., 2014 When the starting compound (1) has axial asymmetry, the compound (1) may be separated and the resulting stereoisomer may be used to carry out this reaction. In addition, the compound of formula (I) or an intermediate thereof may have axial asymmetry and be obtained as a mixture of diastereomers. However, each diastereomer can be isolated by a conventional separation procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0047] The hydrochloride of the compound of formula (I) can be obtained by subjecting the compound of formula (I) to the following operations. The compound of formula (I) is dissolved in CH2Cl2 and MeOH, hydrogen chloride (4M DOX solution, 10 equivalents) is added under ice cooling, and the mixture is stirred for 30 minutes under ice cooling. The reaction mixture is concentrated under reduced pressure, diethyl ether is added to the resulting residue, and the resulting solid is filtered and dried under reduced pressure to obtain the hydrochloride salt of the compound of formula (I).

[0048] The hydrochloride of the compound of formula (I) can be obtained by carrying out the following procedure. The hydrochloride of the compound of formula (I) is purified by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution), and the fractions containing the target product are collected and made basic with saturated sodium bicarbonate aqueous solution, and then extracted with CHCl3 / MeOH (5 / 1). The combined organic layers are dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure to obtain a solid, which is washed with diethyl ether and dried under reduced pressure to obtain the compound of formula (I).

[0049] (Raw material synthesis 1) [ka]

[0050] This production method is the first method for producing compound (1)-1, which is included in the starting compound (1).

[0051] (first step) This step is a method for producing compound (1)-1 by cycloaddition reaction of compound (2) with compound (3). In this reaction, an equal amount of compound (2) and compound (3) or an excess amount of either one is used, and the mixture is 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 to heating under reflux, preferably at 0°C to 100°C, usually for 0.1 hours to 5 days. Examples of the solvent used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN, tBuOH, water, and mixtures thereof. Examples of copper salts include CuI, CuSO4, and CuOTf. Examples of reducing agents include sodium ascorbate and the like. In some cases, it may be advantageous to carry out 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), etc. in order to ensure smooth reaction. [Literature] Angew. Chem. Int. Ed. 2002, 41, p.2596-2599.

[0052] (Raw material synthesis 2) [ka]

[0053] This production method is the second method for producing compound (1)-1 contained in starting compound (1).

[0054] (first step) This step is a method for producing compound (5) by cycloaddition reaction of compound (2) with compound (4). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0055] (Second process) This step is a method for producing compound (6) by hydrolyzing compound (5). This reaction is carried out by stirring compound (5) under cooling to reflux, usually for 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, alcohols, acetone, N,N-dimethylformamide, tetrahydrofuran, etc. In addition, a mixture of the above solvents with water may be suitable for the reaction. Examples of the hydrolysis reagent include, but are not limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, trimethyltin hydroxide, etc. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0056] (Third step) This step is a method for producing compound (1)-1 by an amidation reaction between compound (6) and compound (7). In this reaction, compound (6) and compound (7) are used in equal amounts or one in an excess amount, and a mixture of these is stirred in the presence of a condensing agent in a solvent inert to the reaction under cooling to heating, preferably at −20° C. to 60° C., usually for 0.1 hours to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, N,N-dimethylformamide, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of the condensing agent include (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), etc. In some cases, it is preferable to use an additive (e.g., 1-hydroxybenzotriazole) in the reaction. In some cases, it is 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 potassium hydroxide, in order to smoothly proceed with the reaction. Alternatively, a method of converting compound (6) into a reactive derivative and then carrying out an acylation reaction can also 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, and active esters obtained by condensing with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with compound (7) can be carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, and ethers, under cooling to heating, preferably at -20°C to 120°C. [Literature] SR Sandler and W. Karo, Organic Functional Group Preparations, 2nd ed., Vol. 1, Academic Press Inc., 1991. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen)

[0057] (Raw material synthesis 3) [ka]

[0058] This process is the first process for producing the starting compound (2)-1.

[0059] (first step) This step is a method for producing compound (10) by the ipso substitution reaction of compound (8) with compound (9). In this reaction, an equal amount of compound (8) and compound (9) or an excess amount of either one is used, and the mixture is stirred in a solvent inert to the reaction or without a solvent, under cooling to reflux, preferably at 0°C to 80°C, usually for 0.1 hours to 5 days. Examples of the solvent used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN, and mixtures thereof. It may be advantageous to carry out 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 in order to smoothly proceed with the reaction.

[0060] (Second process) This step is a method for producing compound (12) by the ipso substitution reaction of compound (10) with compound (11). The reaction conditions were the same as those in the first step of Raw Material Synthesis 3.

[0061] (Third step) This process involves the reaction of compound (12) with PG 3 This method produces compound (13) by ipso substitution reaction with --OH. The PG used here 3 Examples of -OH include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions were the same as those in the first step of Raw Material Synthesis 3.

[0062] (Fourth step) This process involves the reaction of compound (13) with R 2 The compound (14) is produced by Suzuki coupling reaction with a boronic acid derivative containing a 2-methyl-2-propanediol group. Examples of the boronic acid derivative used here include, but are not limited to, boronic acid, boronic acid ester, boronic acid pinacol ester, triol borate salt, and trifluoroborate salt. This reaction is carried out by reacting compound (13) with R 2 A mixture of these is stirred in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20° C. to 140° C., usually for 0.1 hours to 5 days. Examples of the solvent used here are not particularly limited, but include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water, and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, etc. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium(3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, etc. In some cases, it is advantageous to carry out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, etc. In some cases, it is advantageous to heat the mixture by microwave irradiation in order to carry out the reaction smoothly. [Literature] J. Am. Chem. Soc., 2005, 127, p.4685-4696

[0063] (Fifth step) This step is a method for producing compound (16) by Suzuki coupling reaction of compound (14) and compound (15). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 3.

[0064] (Sixth step) This step is a method for producing compound (17) by deprotection of compound (16) through catalytic hydrogenation reaction. This reaction can be carried out by stirring compound (16) under a hydrogen atmosphere at normal to elevated pressure in a reaction-inert solvent such as MeOH, EtOH, ethyl acetate, etc., in the presence of a metal catalyst, under cooling to heating, preferably at room temperature, for 1 hour to 5 days. Examples of the metal catalyst that can be used include palladium catalysts such as Pd / C and palladium black, platinum catalysts such as platinum plate and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, etc.

[0065] (Seventh step) This step is a method for producing compound (2)-1 by reacting compound (17) with compound (18). This reaction is carried out by using an equal amount of compound (17) and compound (18) or an excess amount of either one, and reacting the mixture in the presence of a base in a solvent inert to the reaction under cooling to reflux, preferably at 0° C. to 80° C., usually for 0.1 hours to 5 days. The solvent used here is not particularly limited, but 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, but 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 may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures", 5th edition, Vol. 14, Maruzen, 2005, edited by the Chemical Society of Japan

[0066] (Raw material synthesis 4) [ka]

[0067] This is the second method for producing the starting compound (16).

[0068] (first step) This process involves the reaction of compound (10) with R LG This is a method for producing compound (19) by ipso substitution reaction with —SH. LG An example of -SH is C 1-12 Alkyl thiols, such as ethanethiol and dodecanethiol, can be mentioned. The reaction conditions were the same as those in the first step of Raw Material Synthesis 3.

[0069] (Second process) This process involves the reaction of compound (19) with PG 3 This is a method for producing compound (20) by ipso substitution reaction with -OH. 3 Examples of -OH include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions were the same as those in the first step of Raw Material Synthesis 3.

[0070] (Third step) This process involves the reaction of compound (20) with R 2 This method involves the Suzuki coupling reaction of a boronic acid derivative containing a group to produce compound (21). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 3.

[0071] (Fourth step) This step is a method for producing compound (22) by Suzuki coupling reaction of compound (21) and compound (15). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 3.

[0072] (Fifth step) This step is a method for producing compound (23) by oxidation reaction of compound (22). In this reaction, compound (22) is treated with an equivalent or excess amount of an oxidizing agent in a solvent inert to the reaction under cooling to heating, preferably at -20°C to 80°C, for usually 0.1 hours to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used. Examples of the solvent include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, oxone, activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, etc. [Literature] "Experimental Chemistry Lectures", 5th edition, Vol. 17, Maruzen, 2005, edited by the Chemical Society of Japan

[0073] (Sixth step) This step is a method for producing compound (16) by the ipso substitution reaction of compound (23) with compound (24). The reaction conditions were the same as those in the first step of Raw Material Synthesis 3.

[0074] (Raw material synthesis 5) [ka]

[0075] This process is a process for producing the starting compound (3).

[0076] (first step) This step is a method for producing compound (26) by an amidation reaction between compound (7) and compound (25). The reaction conditions were the same as those in the third step of Raw Material Synthesis 2.

[0077] (Second process) This step is a method for producing compound (27) by subjecting compound (26) to a deprotection reaction. The reaction conditions are the same as those described in Production Method 1.

[0078] (Third step) This step is a method for producing compound (29) by an amidation reaction between compound (27) and compound (28). The reaction conditions were the same as those in the third step of Raw Material Synthesis 2.

[0079] (Fourth step) This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction. The reaction conditions are the same as those described in Production Method 1.

[0080] (Fifth step) This step is a method for producing compound (3) by reacting compound (30) with a diazo transfer reagent. In this reaction, compound (30) is treated with an equivalent or excess amount of a diazo transfer reagent in a solvent inert to the reaction, under cooling to heating, preferably at 0°C to 50°C, usually for 0.1 hours to 3 days. Examples of diazo transfer reagents include, but are not limited to, trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or a salt thereof, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP), etc. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, 4-dimethylaminopyridine (DMAP), 2,6-lutidine, etc., or a catalytic amount of copper salt such as CuSO4. Examples of solvents include halogenated hydrocarbons such as THF and dichloromethane, MeCN, alcohols, water, and mixtures thereof. [Literature] J. Org. Chem. 2012, 77, p.1760-1764 Nature 2019, 574, p.86-89 Org. Biomol. Chem. 2014, 12, p.4397-4406

[0081] The compound of formula (I) is isolated and purified as a free compound, a salt thereof, a hydrate, a solvate, or a polymorphic substance. The salt of the compound of formula (I) can also be produced by subjecting the compound to a conventional salt-forming reaction. Isolation and purification are carried out by applying conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing the difference in physicochemical properties between isomers. For example, optical isomers can be obtained by a general optical resolution method of a racemate (e.g., fractional crystallization leading to a diastereomeric salt with an optically active base or acid, chromatography using a chiral column, etc.), or can be produced from an appropriate optically active starting compound.

[0082] The compounds of formula (I) according to the present invention can be used for the treatment of colon cancer and / or lung cancer, in particular G12D mutant KRAS positive cancer.

[0083] Pharmaceutical compositions containing one or more of the compounds of formula (I) or salts thereof as active ingredients can be prepared by using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers, and by commonly used methods. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intra-articular, intravenous, or intramuscular injections, transmucosal agents, or inhalants.

[0084] As a solid composition for oral administration, tablets, powders, granules, etc. are used. In such a solid composition, one or more active ingredients are mixed with at least one inactive excipient. The composition may contain inactive additives such as lubricants, disintegrants, stabilizers, and dissolution aids according to the usual method. Tablets or pills may be coated with sugar coating or a film of a gastric or enteric material, if necessary. The liquid composition for oral administration includes pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and includes commonly used inert diluents, such as purified water or EtOH ethanol. The liquid composition may contain, in addition to the inert diluent, auxiliary agents such as solubilizers, wetting agents, and suspending agents, sweeteners, flavors, aromatics, and preservatives.

[0085] Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, alcohols such as EtOH. Such compositions may further contain isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. Alternatively, these can be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0086] Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be prepared according to a conventionally known method. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. may be appropriately added. For administration, a suitable device for inhalation or insufflation can be used. For example, known devices such as metered dose inhalation devices and nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or in combination with a pharma- ceutically acceptable carrier as a solution or suspension. Dry powder inhalers and the like can be for single or multiple administrations, and can utilize dry powders or powder-containing capsules. Alternatively, the agent can be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0087] In the case of oral administration, the daily dosage is usually about 0.001 to 100 mg / kg per body weight, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg, and is administered once or in two to four divided doses. In the case of intravenous administration, the daily dosage is usually about 0.0001 to 10 mg / kg per body weight, and is administered once or in multiple divided doses per day. In the case of transmucosal administration, the daily dosage is about 0.001 to 100 mg / kg per body weight, and is administered once or in multiple divided doses per day. The dosage is appropriately determined according to individual cases, taking into consideration symptoms, age, sex, etc.

[0088] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0089] The compound of formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, or may be administered separately, consecutively, or at a desired time interval. The preparation for simultaneous administration may be a combination drug or may be formulated separately. EXAMPLES

[0090] The method for producing the compound of formula (I) will be described in more detail below based on the examples. Note that the present invention is not limited to the compounds described in the following examples. Also, the methods for producing the raw material compounds are shown in the respective production examples. Also, the method for producing the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can be produced by a combination of these production methods or a method obvious to a person skilled in the art.

[0091] In the present specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0092] For convenience, the concentration (mol / L) is expressed as M. For example, 1M sodium hydroxide solution means a 1 mol / L aqueous solution of sodium hydroxide.

[0093] Manufacturing Example 1 After cooling a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) on ice, DIPEA (240 mL), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (48 g) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total amount of the solution was about 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the obtained solution and stirred at room temperature. The precipitated solid was collected by filtration to obtain tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (123 g) as a solid.

[0094] Manufacturing Example 2 To a mixture of (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL), and DABCO (1.15 g), cesium carbonate (50.3 g) was added while stirring at room temperature, and the mixture was stirred overnight at room temperature under an argon atmosphere. Approximately 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was collected by filtration while washing with water and dried overnight under reduced pressure to give tert-butyl (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (32.8 g) as a solid.

[0095] Production Example 5 Under an argon atmosphere, tert-butyl (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.9 g), benzyl alcohol (2.37 g), and THF (40 mL) were added with tBuOK (2.54 g) under ice cooling and stirred at the same temperature for 1.5 hours. Ice water and saturated aqueous ammonium chloride solution were added to the reaction mixture, which was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixed solvent of hexane / ethyl acetate (6 / 1) was added to the resulting residue and stirred for a while. The precipitated solid was collected by filtration and dried to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.8 g) as a solid.

[0096] Production Example 8 Under an argon atmosphere, a mixture of (1S,4S)-tert-butyl 5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropyl borate (1.27 g), tripotassium phosphate (5.67 g), and PdCl2(dppf)·CHCl2 (600 mg) was stirred at 100°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and the solution was concentrated under reduced pressure. A saturated aqueous solution of sodium chloride was added to the resulting residue, and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.8 g) as a foamy solid.

[0097] Manufacturing Example 11 (1S,4S)-tert-butyl 5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.15 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.92 g), tripotassium phosphate (4.1 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.12 A mixture of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.2 g), DOX (40 mL), and water (8 mL) was degassed and argon-purged while stirring at room temperature, and then stirred at 100°C under an argon atmosphere for 2.5 hours. Water (approximately 150 mL) was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and a fraction containing (1) a low-polarity diastereomeric mixture (peak-1 and 2. Peak-1 and 2 have the same axial chirality) and (2) a high-polarity diastereomeric mixture (peak-3 and 4. Peak-3 and 4 have the same axial chirality) was obtained. Fractions containing the less polar diastereomeric mixture (peak-1,2, identical axial chirality) were collected to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.42 g) as a foamy solid.In addition, fractions containing a highly polar diastereomeric mixture (peak-3,4, identical axial chirality) were collected to give (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.37 g) as a foamy solid.

[0098] Manufacturing Example 14 A mixture of diastereomers with low polarity obtained in Production Example 11, (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (10 g) was added to MeOH (200 mL) solution, and 10% Pd / C (50% water content, 2 g) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The resulting reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (8.11 g) as a foamy solid.

[0099] Manufacturing Example 22 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (7.48 g), DMF (70 mL), 1-(chloromethyl)-4-ethynylbenzene (1.9 g) was added with cesium carbonate (6.2 g) while stirring at room temperature, and stirred at 60 ° C. for 2 hours under argon atmosphere. Ice water and saturated aqueous ammonium chloride solution were added to the reaction mixture cooled to room temperature, and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and the resulting solid was collected by filtration to give (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (8.12 g) as a foamy solid.

[0100] Manufacturing Example 32 (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.3 g) in CHCl(13 mL) was added m-chloroperbenzoic acid (about 30% water content, 358 mg) under ice cooling and stirred at the same temperature for 2 hours. A 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture under ice cooling. The aqueous layer and the organic layer were separated, and the obtained aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.32 g) as an oil.

[0101] Manufacturing Example 34 To a mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (1.32 g), DMAc (15 mL), and 4-ethyl-3-hydroxypyridine (525 mg), cesium carbonate (1.9 g) and DABCO (160 mg) were added at room temperature, and the mixture was stirred at 80°C for 2 hours and at 100°C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-[(4-ethylpyridin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (774 mg) as an oil.

[0102] Manufacturing Example 40 (1S,4S)-tert-butyl 5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (4.24 g), (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 (2.30 g), sodium ascorbate (1.45 g), tert-butyl alcohol (35 mL), THF (35 mL), and water (35 mL). Anhydrous copper(II) sulfate (389 mg) was added to the mixture of 1 mL of ethyl acetate at room temperature and stirred at room temperature for 2.5 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-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-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.62 g) was obtained as a solid.

[0103] Manufacturing Example 51 Under an argon atmosphere, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-thiazol-5-yl)phenyl]ethyl}carbamoyl] A mixture of tert-butyl 2-[(1-{[2-(trimethylsilyl)ethoxy]carbonyl}piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.1 g), THF (22 mL), and tetra-n-butylammonium fluoride (1M THF solution, 2.57 mL) was added with acetic acid (90 μL) at room temperature and stirred at 60° C. for 15 hours. After cooling to room temperature, ethyl acetate and a saturated aqueous ammonium chloride solution were added and the mixture was separated. The aqueous layer was extracted with ethyl acetate / methanol (10 / 1), and the combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-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-[(piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (951 mg) as a solid.

[0104] Manufacturing Example 52 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-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-[(piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (250 mg), oxetan-3-one (43 To a mixture of (1S,4S)-5-(6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-thiazolyl)-2-yl]- ... To obtain tert-butyl 2-{[1-(oxetan-3-yl)piperidin-4-yl]oxy}quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (220 mg) as a solid.

[0105] Manufacturing Example 53 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-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-[(piperidin-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (250 mg), 2,2-difluoroethyl trifluoromethanesulfonate (124 A mixture of (1S,4S)-5-(6-cyclopropyl-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxypropyl]oxy}-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]oxy} ... Tert-butyl 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}quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (196 mg) was obtained as a solid.

[0106] Manufacturing Example 54 To a solution of methyl (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-methylbutanoate (190 mg) in CHCl (12 mL) was added thionyl chloride (500 μL) under ice-cooling under an argon atmosphere, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with DMF (7 mL), (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (450 mg), and cesium carbonate (260 mg) under ice cooling, and stirred overnight at 60° C. under an argon atmosphere. The reaction mixture was filtered through Celite, and the residue on the Celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S, 4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-({2-[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (670 mg) as a foamy solid.

[0107] Manufacturing Example 56 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-({2-[(2S)-1-methoxy-3-methyl-1-oxobutan-2-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (670 mg) in MeOH (7 mL) was added with aqueous sodium hydroxide (1M, 2.5 mL) under ice cooling and stirred at room temperature for 3 days. After neutralization with hydrochloric acid (1M, 2.5 mL) under ice cooling, CHCl3 and water were added to separate the mixture, and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH), and then purified again by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain (2S)-2-{5-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}-3-methylbutanoic acid (372 mg) as a foamy solid.

[0108] Manufacturing Example 61 (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (3.97 g) in 1,2-dichloroethane (60 mL) solution, trimethyltin(IV) hydroxide (3.35 g) was added at room temperature and stirred at 80 ° C. for 18 hours. After cooling to room temperature, hydrochloric acid (1M, 60 mL) was added and the mixture was extracted with CHCl3 / MeOH (9 / 1). The organic layer was washed with 1M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (3.26 g) as a solid.

[0109] Manufacturing Example 63 (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (150 mg), 3-{4-[(1R)-1-amino-2-hydroxyethyl]phenyl}-1,3-oxazolidin-2-one n-hydrochloride (60 mg), DIPEA (70 μL), DMF (3 To the mixture of 1 mL of 1,000 ml ... The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (173 mg) as a solid.

[0110] Manufacturing Example 66 A mixture of (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (6.5 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (7.6 g), triphenylphosphine (0.53 g), potassium acetate (4.9 g), DOX (120 mL) and palladium acetate (0.23 g) was degassed and replaced with argon gas, and stirred overnight at 115 ° C. The reaction solution was cooled to room temperature and filtered through Celite while washing with a small amount of dioxane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-[8-(benzyloxy)-6-cyclopropyl-2-[(oxan-4-yl)oxy]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (5.47 g) as a foamy solid.

[0111] Manufacturing Example 67 (1S,4S)-tert-butyl 5-[8-(benzyloxy)-6-cyclopropyl-2-[(oxan-4-yl)oxy]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.52 g), (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (0.84 g), tripotassium phosphate (1.85 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.15 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (0.27 g), DOX (20 mL), and water (4 mL) were added in that order, and the mixture was degassed and replaced with argon gas while stirring at room temperature, and then stirred at 90°C for 5 hours under an argon atmosphere. The mixture was further stirred at 100°C for 7 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain a fraction containing (1) the less polar diastereomer (peak-1) and (2) the more polar diastereomer (peak-2). The fractions containing the less polar diastereomer (peak-1) were collected to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (580 mg) as a foamy solid.In addition, fractions containing the more polar diastereomer (peak-2) were collected to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (360 mg) as a foamy solid.

[0112] Manufacturing Example 68 Under a nitrogen atmosphere, cesium carbonate (180 mg) and chloro(methoxy)methane (35 μL) were added to a solution of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-(3-fluoro-5-hydroxy-2-methylphenyl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl (250 mg) in DMF (5 mL) under ice cooling, and the mixture was stirred at room temperature for 15 hours. Cesium carbonate (260 mg) and chloro(methoxy)methane (50 μL) were added under ice cooling, and the mixture was stirred at room temperature for another 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then insoluble matter was removed by filtration and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[3-fluoro-5-(methoxymethoxy)-2-methylphenyl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (186 mg) as an oil.

[0113] Manufacturing Example 69 Under an argon atmosphere, PdCl2(dppf)·CHCl2(1.14 g) was added to a mixture of N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate tert-butyl (4.43 g), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.67 g), potassium carbonate (3.87 g), DOX (80 mL) and water (8 mL), and the mixture was stirred at 100°C for 16 hours. After cooling to room temperature, ethyl acetate was added, filtered through Celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate tert-butyl (3.74 g) as a solid.

[0114] Manufacturing Example 71 To a solution of tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.34 g) in CHCl (25 mL) and MeOH (25 mL), hydrogen chloride (4M DOX solution, 25.6 mL) was added under cooling to -20 to -10°C and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol n-hydrochloride (3.06 g) as a solid.

[0115] Manufacturing Example 73 To a mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol n-hydrochloride (3.43 g), (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.81 g) and DMF (40 mL), DIPEA (7.8 mL) was added under ice cooling, and then HATU (4.5 g) was added little by little under ice cooling, and the mixture was stirred for 1 hour under ice cooling and at room temperature for 1 hour. Under ice cooling, water, saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate / isopropyl alcohol (9 / 1), and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain tert-butyl (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (5.01 g) as an oil.

[0116] Manufacturing Example 76 To a solution of (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl (5.01 g) in CHCl (35 mL) and MeOH (30 mL), hydrogen chloride (4M DOX solution, 28 mL) was added under cooling to -20 to -10°C and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide n-hydrochloride (4.71 g) as a solid.

[0117] Manufacturing Example 79 To a mixture of (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide n-hydrochloride (3.81 g), N-(tert-butoxycarbonyl)-L-valine (2.16 g) and DMF (45 mL), DIPEA (6.2 mL) was added, and then HATU (3.61 g) was added little by little under ice cooling, and the mixture was stirred for 1 hour under ice cooling and at room temperature for 1 hour. Under ice cooling, water, saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate / isopropyl alcohol (9 / 1), and the combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 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 (4.43 g) as a solid.

[0118] Manufacturing Example 83 To a 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 (4.43 g) in CHCl (35 mL) and MeOH (35 mL), hydrogen chloride (4M DOX solution, 20 mL) was added under cooling to -20 to -15°C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide n-hydrochloride (4.21 g) as a solid.

[0119] Manufacturing Example 88 A solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (1.06 g) in MeCN (5 mL) was added dropwise over 10 minutes to a mixture of L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide n-hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), and MeCN (20 mL) under ice cooling, and the mixture was stirred for 5 hours under ice cooling. Water, a saturated aqueous sodium chloride solution, and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give (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 (1.07 g) as a solid.

[0120] Manufacturing Example 93 To a mixture of L-valine methyl ester hydrochloride (1.96 g), MeCN (45 mL), and DIPEA (5 mL), 4-bromo-2-(bromomethyl)benzoic acid methyl ester (3.00 g) was added under water cooling, and the temperature was slowly raised to 80°C and stirred at 80°C for 2 days. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / ethyl acetate) to obtain (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-methylbutanoic acid methyl ester (2.86 g) as a solid.

[0121] Manufacturing Example 94 Under an argon atmosphere, palladium acetate (41 mg) was added to a mixture of (2S)-2-(5-bromo-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-3-methylbutanoate (600 mg), potassium (2-trimethylsilyl)-ethoxymethyltrifluoroborate (876 mg), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (151 mg), sodium carbonate (390 mg), DOX (9 mL) and water (1.8 mL) at room temperature, and the mixture was stirred at 130°C for 4 hours under microwave irradiation. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was filtered through Celite and washed with ethyl acetate. Water was added to the obtained filtrate to separate the layers, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain the coupling reaction product (600 mg). Trifluoroacetic acid (2.1 mL) was added to a solution of the coupling reaction product in CHCl (4.2 mL) under ice cooling and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain methyl (2S)-2-[5-(hydroxymethyl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]-3-methylbutanoate (190 mg) as a solid.

[0122] Manufacturing Example 95 Under an argon atmosphere, 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoic acid ethyl ester (190 mg), 4-bromobenzyl alcohol (100 mg), PdCl2(dppf)·CHCl2(45 mg), and tripotassium phosphate (227 mg) were added with DOX (2 mL) and water (0.4 mL) and stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the Celite was washed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain ethyl 2-{4-[4-(hydroxymethyl)phenyl]-1H-pyrazol-1-yl}-3-methylbutanoate (157 mg) as an oil.

[0123] Manufacturing Example 96 Under an argon atmosphere, a solution of 2,2,6,6-tetramethylpiperidine (4.4 mL) in THF (80 mL) was added dropwise to n-butyllithium (1.57 M hexane solution, 15.2 mL) while cooling with dry ice-MeOH refrigerant (-78°C), and stirred for 1 hour under ice cooling (light yellow solution). The reaction mixture was cooled with dry ice-MeOH refrigerant, and a solution of (3-bromo-5-fluorophenoxy)(tert-butyl)di(methyl)silane (5.21 g) in THF (20 mL) was added, and stirred at the same temperature for 1 hour. Methyl iodide (2.2 mL) was added dropwise to the reaction mixture, and stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was stirred while warming to room temperature. Ethyl acetate was added to the reaction mixture for extraction, and the organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3-bromo-5-fluoro-4-methylphenoxy)(tert-butyl)di(methyl)silane (5.13 g) as an oil.

[0124] Manufacturing Example 97 To a mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (500 mg), N-methyl-2-nitrobenzenesulfonamide (376 mg), tri-n-butylphosphine (0.51 mL) and THF (7 mL), 1,1'-azobis(N,N-dimethylformamide) (353 mg) was added little by little under ice cooling, and the mixture was stirred at room temperature for 8 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Insoluble matter was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain tert-butyl {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate (667 mg) as a solid.

[0125] Manufacturing Example 98 Under an argon atmosphere, palladium acetate (29 mg) was added to a mixture of tert-butyl {(1R)-1-(4-bromophenyl)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]ethyl}carbamate (665 mg), 4-methyl-1,3-thiazole (235 μL), potassium acetate (253 mg) and DMAc (13 mL), and the mixture was stirred at 100° C. for 16 hours. After cooling to room temperature, ethyl acetate and water were added, and the insoluble matter was filtered through Celite. The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (268 mg) as a solid.

[0126] Manufacturing Example 99 Under an argon atmosphere, 4-tert-butylbenzenethiol (82 μL) was added to a mixture of {(1R)-2-[methyl(2-nitrobenzene-1-sulfonyl)amino]-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate tert-butyl (130 mg), potassium carbonate (84 mg) and DMF (1.3 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate tert-butyl (60 mg) as an oil.

[0127] Manufacturing Example 100 To a mixture of {(1R)-2-(methylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}tert-butyl carbamate (55 mg) and THF (1 mL), formaldehyde (37% aqueous solution, 26 μL) was added under ice cooling, and the mixture was stirred for 10 minutes under the same conditions. Sodium triacetoxyborohydride (67 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. After dilution with CHCl3, a saturated aqueous solution of sodium bicarbonate was added and the mixture was stirred for a while, and the aqueous layer was separated. The aqueous layer was extracted with CHCl3 / MeOH (5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the mixture was concentrated under reduced pressure to obtain {(1R)-2-(dimethylamino)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}tert-butyl carbamate (75 mg) as an oil.

[0128] Manufacturing Example 102 A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL) and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred overnight at 100°C under an argon atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g) as an oil.

[0129] Manufacturing Example 103 Under an argon atmosphere, tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g), 5-bromo-1,3-thiazole-4-carboxylic acid methyl ester (2.6 g), tripotassium phosphate (3.8 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (730 mg), DOX (30 mL) and water (6 mL) were added with palladium acetate (200 mg) at room temperature and stirred at 100°C for 3 hours. After cooling to room temperature, ethyl acetate was added and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.48 g) as a solid.

[0130] Manufacturing Example 104 Under nitrogen atmosphere, diisobutylaluminum hydride (1M toluene solution, 11 mL) was added dropwise to a solution of methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.01 g) in CHCl (20 mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. MeOH was added to stop the reaction under ice cooling, and 10% aqueous sodium potassium tartrate solution (60 mL) and CHCl3 were added and stirred overnight. The layers were separated, the aqueous layer was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), sodium borohydride (350 mg) was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Water was added, and the mixture was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl [(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]carbamate (588 mg) as a solid.

[0131] Manufacturing Example 106 To a mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g), 2,2-dimethoxypropane (3.3 mL) and acetone (15 mL), boron trifluoride diethyl ether complex (26 μL) was added and stirred at room temperature for 1 hour. TEA (66 μL) was added and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.09 g) as a solid.

[0132] Manufacturing Example 107 To a solution of (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate tert-butyl (300 mg) and 1,3-oxazolidin-2-one (183 mg) in DOX (1.69 mL), copper iodide (32 mg), racemic-(1R,2R)-cyclohexane-1,2-diamine (20 μL), and potassium carbonate (290 mg) were added at room temperature. The mixture was stirred at 140°C for 2 hours and at 150°C for 1 hour under microwave irradiation. Ethyl acetate and water were added, and the mixture was filtered through Celite. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,3-oxazolidine-3-carboxylate tert-butyl (120 mg) as a solid.

[0133] Manufacturing Example 109 To a solution of 1-(4-bromophenyl)-2-fluoroethanone (2.7 g) and (S)-2-methylpropane-2-sulfinamide (3.03 g) in THF (27 mL), tetraisopropyl orthotitanate (11.1 g) was added and stirred at 40°C for 12 hours. BH3·THF complex (1 M THF solution, 18.4 mL) was added under ice cooling (0-5°C) and stirred for 2 hours. After adding water to stop the reaction, the mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, after which the insoluble matter was filtered off and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain (S)-N-[(1R)-1-(4-bromophenyl)-2-fluoroethyl]-2-methylpropane-2-sulfinamide (3.2 g) as an oil.

[0134] The compounds shown in the following table were produced in the same manner as in the above-mentioned Production Examples. The production method, structure and physicochemical data of each Production Example compound are shown in the following table.

[0135] Example 8 A mixture of (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-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-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-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.61 g) and CHCl (60 mL) was added to trifluoroacetic acid (27 mL) was added under cooling (internal temperature: -5°C or less), and then stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the residue, extracted three times with CHCl3 / MeOH (5 / 1), and the combined organic layers were dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by ODS column chromatography (MeCN / 0.1% aqueous formic acid solution). A saturated aqueous sodium bicarbonate solution was added to the fraction containing the target product, and extracted three times with CHCl3 / MeOH (5 / 1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain the product. Isopropyl acetate (70 mL) was added to the obtained product, and the mixture was stirred at a bath temperature of 80°C for 10 minutes, and then stirred at room temperature overnight.Hexane (70 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration, washed with isopropyl acetate / hexane (1 / 1), and then dried overnight at 40° C. under reduced pressure to give (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 (3.01 g) as a solid.

[0136] Example 7 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 (1.04 g) was dissolved in CHCl(9 mL) and MeOH(9 mL), and hydrogen chloride (4M DOX solution, 3 mL) was added under ice cooling and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried under reduced pressure to give (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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 n-hydrochloride (1.04 g) as a solid.

[0137] Example 20 A mixture of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg), CHCl (2 mL) and MeOH (2 Hydrogen chloride (4M DOX solution, 0.988 mL) was added to the mixture of 100 mL of 1,0 ... After filtering off the insoluble matter, the mixture was concentrated under reduced pressure to obtain a solid. The solid was washed with diethyl ether and dried under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide (74 mg) as a solid.

[0138] Example 18 Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (65 mg), (2R)-2-amino-2-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethane-1-ol n-hydrochloride (25 mg), DMF (1 To the mixture of 10 mL of 1,000 ml ... Diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to give (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide n-hydrochloride (43 mg) as a solid. Example 48 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]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 was prepared in the same manner as described in WO 2022 / 173032. Example 70 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide was prepared in the same manner as described in WO 2022 / 173032.

[0139] The compounds shown in the following table were produced in the same manner as in the above-mentioned Examples, and the structures and physicochemical data of the compounds in the following table are also shown.

[0140] In addition, the following abbreviations may be used in the tables below. PEx: Production Example number, Ex: Example number, PSyn: Production Example number produced by a similar method, Syn: Example number produced by a similar method (for example, Syn: 8 indicates that it was produced by a similar method to Example 8, and Syn: 18# indicates that the hydrochloride salt obtained by production by a similar method to Example 18 was desalted.), Str: Chemical structure (a compound with an "*" in the chemical structure indicates that the compound is single with respect to axial or central asymmetry. n HCl: n-hydrochloride (compounds with a production example number indicate monohydrochloride to trihydrochloride, and compounds with an example number indicate monohydrochloride to pentahydrochloride), DAT: physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified) + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise noted [MH] - ), NMR: in DMSO-d 1 H-NMR (500 MHz) peak δ value (ppm), NMR (100°C): 100°C in DMSO-d 1 δ value (ppm) of peak in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad line (spectrum) (e.g., br s).

[0141] [Table 1-1]

[0142] [Table 1-2]

[0143] [Table 1-3]

[0144] [Table 1-4]

[0145]

Table 1-5

[0146]

Table 1-6

[0147]

Table 1-7

[0148]

Table 1-8

[0149]

Table 1-9

[0150]

Table 1-10

[0151]

Table 1-11

[0152]

Table 1-12

[0153]

Table 1-13

[0154]

Table 1-14

[0155]

Table 1-15

[0156]

Table 1-16

[0157]

Table 1-17

[0158]

Table 1-18

[0159]

Table 1-19

[0160]

Table 1-20

[0161]

Table 1-21

[0162]

Table 1-22

[0163]

Table 1-23

[0164]

Table 1-24

[0165]

Table 1-25

[0166]

Table 1-26

[0167]

Table 1-27

[0168]

Table 1-28

[0169]

Table 1-29

[0170]

Table 1-30

[0171]

Table 1-31

[0172]

Table 1-32

[0173]

Table 1-33

[0174]

Table 1-34

[0175]

Table 1-35

[0176]

Table 1-36

[0177]

Table 1-37

[0178]

Table 1-38

[0179]

Table 1-39

[0180]

Table 1-40

[0181]

Table 1-41

[0182]

Table 2-1

[0183]

Table 2-2

[0184]

Table 2-3

[0185]

Table 2-4

[0186]

Table 2-5

[0187]

Table 2-6

[0188]

Table 2-7

[0189]

Table 2-8

[0190]

Table 2-9

[0191]

Table 2-10

Table 2-11

[0192]

Table 3-1

[0193]

Table 3-2

Table 3-3

[0194] Test Example A: Evaluation of antitumor activity in mice bearing human G12D mutant KRAS-positive colon cancer line GP2d GP2d cells (ECACC, 95090714) were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 2 mM L-glutamine at 37°C in the presence of 5% CO2. GP2d cells were harvested and suspended in PBS, and an equal volume of Matrigel (Corning) was added to the suspension. The cells were then cultured at 3.0x10 cells per mouse. 6 The cell suspension, prepared at 200μL / cell, was subcutaneously implanted into 6-8 week old female nude mice (BALB / c nude mice, Beijing Vital River Laboratory Animal Technology Co., Ltd). Approximately 1 week after implantation, the mice were divided into groups so that the tumor volumes were almost equal between the groups, and the administration of the test compound was started. The test was performed with 5 mice each in the solvent group and the test compound administration group, and the solvent was administered to the solvent group, and the test compound dissolved in the solvent was administered to the test compound administration group, via the tail vein. The solvent was prepared by mixing 4% ethanol, 1% 50% (2-hydroxypropyl)-β-cyclodextrin, 9% polyoxyethylene hydrogenated castor oil (HCO-40), and 86% 5% glucose solution by volume. The administration was once a week, a total of three times. The tumor diameter and body weight were measured 2-3 times a week. The following formula was used to calculate the tumor volume. [Tumor volume (mm 3 )] = [Long axis of tumor (mm)] x [Short axis of tumor (mm)] 2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated by setting the tumor volume of the test compound administration group on the first day of administration as 100% inhibition, and the tumor volume of the vehicle group 3 weeks after the first administration as 0% inhibition. [Table 4]

[0195] Test Case B: Evaluation of antitumor activity in tumor-bearing mice derived from G12D mutant KRAS-positive human lung cancer patients Female nude mice aged 4-6 weeks (Crl:NMRI-Foxn1nu, Charles River) were stocked and tumors derived from human lung cancer patients (model name: LXFA 2204 (Charles River)) were subcutaneously implanted. Approximately one month after implantation, the mice were divided into groups and the administration of the test compound was started. The test was performed with 8 mice in each of the vehicle group and the test compound administration group. The vehicle was administered to the vehicle group, and the test compound dissolved in the vehicle was administered to the test compound administration group via the tail vein. The vehicle was prepared by mixing 4% ethanol, 1% 50% (2-hydroxypropyl)-β-cyclodextrin, 9% polyoxyethylene hydrogenated castor oil (HCO-40), and 86% 5% glucose solution by volume. The test compound group was administered twice a week, a total of six times. The tumor size and body weight were measured twice a week. The following formula was used to calculate the tumor volume. [Tumor volume (mm 3 )] = [Longest diameter of tumor (mm)] x [Shortest diameter of tumor (mm)] 2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated by taking the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition, and the tumor volume of the solvent group 3 weeks after the first administration as 0% inhibition. In addition, when the tumor volume of the test compound administration group was lower than the tumor volume on the day before the start of administration, the tumor regression rate (%) of the test compound was calculated by taking the tumor volume on the day before the start of administration as 0% regression, and a tumor volume of 0 as 100% regression. [Table 5] [Industrial Applicability]

[0196] The compound of the present invention or a salt thereof has an excellent effect of inducing the degradation of G12D mutant KRAS protein and is useful as a G12D mutant KRAS inhibitor. It can be used as an active ingredient of a pharmaceutical composition, for example, as an active ingredient of a pharmaceutical composition for treating colorectal cancer and / or lung cancer.

Claims

1. A pharmaceutical composition for treating colon cancer and / or lung cancer, comprising: The following formula (I): 【Chemistry 1】 [In the formula, R 1 is represented by the following formula (II) or formula (III): 【Chemistry 2】 and R 1a and R 1b are the same or different and are H or F, R 2 is a halogen, C 1-3 alkyl, cyclopropyl, or vinyl; R 3 is represented by the following formula (IV): 【Chemistry 3】 and R 4 is C 1-3 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl; R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 is cycloalkyl, R 6a and R 6b are the same or different and are H or are F, OH and N(CH 3 ) 2 C, which may be substituted with a group selected from the group consisting of 1-3 alkyl or R 6a and R 6b together with the carbon to which they are attached to form a cyclopropyl, R 7 is H, a halogen, or a group represented by the following formulas (VI), (VII), (VIII), and (IX): 【Chemistry 4】 is a group selected from the group consisting of R 7a is H or C optionally substituted with OH 1-3 is alkyl, X is O, Y is phenylene or pyridinediyl; L is a bond; C 1-3 alkylene or C=O; Z is NH or the following formula (X), formula (XI) and formula (XII): 【Chemistry 5】 or YLZ is a group selected from the group consisting of the following formula (XIII): 【Chemistry 6】 is] or a salt thereof and one or more pharma- ceutical compositions comprising the compound of formula (I) or a salt thereof and one or more pharma- ceutically acceptable excipients.

2. The compound of formula (I) or a salt thereof (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The pharmaceutical composition of claim 1, selected from the group consisting of:

3. The compound of formula (I) or a salt thereof is (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The pharmaceutical composition according to claim 1 or 2, selected from the group consisting of:

4. The compound of formula (I) or a salt thereof is (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The pharmaceutical composition according to claim 1 or 2, selected from the group consisting of:

5. In the preparation of a pharmaceutical composition for treating colon cancer and / or lung cancer, 【Chemistry 7】 [In the formula, R 1 is represented by the following formula (II) or formula (III): 【Chemistry 8】 and R 1a and R 1b are the same or different and are H or F, R 2 is a halogen, C 1-3 alkyl, cyclopropyl, or vinyl; R 3 is represented by the following formula (IV): 【Chemistry 9】 and R 4 is C 1-3 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl; R 5 is ethyl, isopropyl, tert-butyl, or C 3-6 is cycloalkyl, R 6a and R 6b are the same or different and are H or are F, OH and N(CH 3 ) 2 C, which may be substituted with a group selected from the group consisting of 1-3 alkyl or R 6a and R 6b together with the carbon to which they are attached to form a cyclopropyl, R 7 is H, a halogen, or a group represented by the following formulas (VI), (VII), (VIII), and (IX): 【Chemistry 10】 is a group selected from the group consisting of R 7a is H or C optionally substituted with OH 1-3 is alkyl, X is O, Y is phenylene or pyridinediyl; L is a bond, C 1-3 alkylene or C=O; Z is NH or the following formula (X), formula (XI) and formula (XII): 【Chemistry 11】 or YLZ is a group selected from the group consisting of the following formula (XIII): 【Chemistry 12】 is] Use of the compound or a salt thereof.

6. A compound of formula (I) or a salt thereof, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The use according to claim 5, selected from the group consisting of:

7. A compound of formula (I) or a salt thereof, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The use according to claim 5 or 6, selected from the group consisting of:

8. A compound of formula (I) or a salt thereof, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]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, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)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, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and Those salts, The use according to claim 5 or 6, selected from the group consisting of:

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