Combinations of anticancer agents comprising bifunctional compounds having G12D mutant KRAS inhibitory activity

Abstract

The present invention provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent for use in the treatment of cancer, wherein the compound of formula (I) and the anti-cancer agent are as described in the specification.

Description

Technical Field

[0001] The present invention relates to a combination of specific anticancer compounds for treating cancers, such as pancreatic cancer, colorectal cancer and lung cancer, and pharmaceutical compositions and kits containing the same. Background Art

[0002] KRAS (Kirsten rat sarcoma virus) is a gene that provides instructions for producing a protein called K-Ras that is part of the RAS / MAPK pathway. This protein relays signals from outside the cell to the cell nucleus. These signals instruct the cell to grow and divide (proliferation) or to mature and adopt a specific function (differentiation).

[0003] KRAS mutations have been implicated in various malignancies, including cancers such as lung adenocarcinoma, mucinous adenomas, ductal carcinoma of the pancreas, and colorectal cancer.

[0004] Colorectal cancer is a cancer with high morbidity and mortality, with approximately 1.4 million new cases reported worldwide each year (World Cancer Report 2014). The most effective way to treat colorectal cancer is surgery, while chemotherapy, radiotherapy, etc. have made significant progress in recent years. Large-scale clinical trials conducted mainly in Europe and the United States have revealed that combination chemotherapy combining several types of anticancer agents is effective for colorectal cancer and helps tumor regression and prolong prognosis (J. Clin. Oncol., 22, pages 229-237, 2004). In addition to chemotherapy, molecular targeted drugs such as anti-VEGF (vascular endothelial growth factor) antibodies or anti-EGFR (epidermal growth factor receptor) antibodies are used as the first choice drug in combination with chemotherapy. Regarding EGFR antibody drugs, it is obvious that mutations in the RAS gene are negative predictors of action (Cancer Res., 66, pages 3992-3995, 2006), and in colorectal cancer, EGFR antibody drugs are currently only applicable to patients with wild-type RAS genes.

[0005] In addition, the number of deaths due to lung cancer accounts for 19% of all cancer-related deaths, which is the highest value, and about 1.8 million new patients are reported worldwide each year (World Cancer Report 2014). Specifically, it is reported that non-small cell lung cancer (NSCLC) patients account for 80% to 85% of those lung cancer patients (American Cancer Society, Cancer Facts and Figures, 2016). Surgical therapy is considered until a certain stage, but surgery is rarely used after this stage, and chemotherapy or radiotherapy subsequently become the main therapy. Based on cell morphology, adenocarcinoma and squamous cell carcinoma are classified as the most typical types of NSCLC. These tumors follow a similar clinical course, but adenocarcinoma is characterized by positioning around the lung.

[0006] Pancreatic cancer, which mainly includes pancreatic ductal adenocarcinoma, is a cancer with a very poor prognosis, a five-year survival rate of 10% or less (CA Cancer J. Clin., 2016, 66, pp. 7-30), and about 340,000 new cases are reported worldwide each year (GLOBOCAN 2012). The most effective therapy for treating pancreatic cancer is surgery. However, because early detection is difficult, cancer is usually metastatic, and cancer is usually inoperable. If surgery is not possible, chemotherapy or radiotherapy is used, but the survival rate is not so good. Today, FOLFIRINOX therapy (multi-drug therapy of three chemotherapy agents 5-FU, irinotecan and oxaliplatin plus levofolinate) is used as a standard therapy for pancreatic cancer. However, due to strong toxicity, individual patients must be carefully selected, such as therapy is only applied to patients with an ECOG performance status of 1 or less (J. Clin. Oncol., 2018, 36, pp. 2545-2556). As a molecular target drug, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved for combination therapy with gemcitabine. However, compared with gemcitabine alone, the extension of overall survival is only about two weeks and a satisfactory therapeutic effect has not been achieved.

[0007] RAS protein is a low molecular weight guanosine triphosphate (GTP) binding protein of about 21 kDa composed of 188 to 189 amino acids, and includes four main types of proteins (KRAS (KRAS 4A and KRAS 4B), NRAS and HRAS) produced by three genes - KRAS gene, NRAS gene and HRAS gene. RAS protein is divided into active GTP-bound type and inactive GDP-bound type. Due to ligand stimulation for membrane receptors (such as EGFR), RAS protein is activated by replacing guanosine diphosphate (GDP) with GTP. Active RAS binds to up to twenty effector proteins (such as RAF, PI3K and RALGDS) to activate downstream signal cascades. On the other hand, due to the intrinsic GTP hydrolysis (GTPase) activity, active RAS is converted into an inactive type by replacing GTP with GDP. GTPase activity is enhanced by means of GTPase activating protein (GAP). As can be seen from the above statements, RAS has the important function of a "molecular switch" in the intracellular signal transduction pathway of EGFR or the like, and plays a key role in cell growth, proliferation, angiogenesis and similar processes (Nature Rev. Cancer, 2011, 11, pp. 761-774, Nature Rev. Drug Discov., 2014, 13, pp. 828-851, Nature Rev. Drug Discov., 2016, 15, pp. 771-785).

[0008] Due to the low function of RAS as a GTPase or low responsiveness to GAP, spontaneous mutations in the RAS gene replace amino acids to produce a constant activation state, and then continuously transmit signals downstream. Excessive signaling can cause carcinogenesis or accelerate cancer growth.

[0009] For example, pancreatic ductal adenocarcinoma has been found to have a weakly shaped stage and a subsequent highly shaped stage in pancreatic intraepithelial neoplasia (PanIN), and mutations in the KRAS gene have been identified in the initial stage of PanIN. Subsequently, abnormalities occurred in tumor suppressor genes INK4A, p53, and SMAD4, leading to malignancies (Nature Rev. Cancer, 2010, 10, pages 683-695). In addition, in 90% or more cases of pancreatic ductal adenocarcinoma, mutations are seen in the KRAS gene, and most of them are spontaneous point mutations in codon 12 located in KRAS exon 2 (Cancer Cell 2017, 32, pages 185-203). As can be seen in the above statements, KRAS plays a key role in the carcinogenesis process and pancreatic cancer progression.

[0010] As mutations of the KRAS gene, KRAS G12C mutation, KRAS G12D mutation and the like are known. G12C mutant KRAS usually appears in non-small cell lung cancer, but there is a very small percentage in pancreatic cancer (Cancer Cell 2014, 25, pp. 272-281), and a therapeutic agent for another KRAS mutation is needed. G12D mutant KRAS is seen in about 34% of pancreatic cancer cases, and this ratio is reported to be the highest among KRAS mutations (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0011] WO 2016 / 049565, WO 2016 / 049568 and WO 2017 / 172979 disclose certain KRAS inhibitors and suggest that these agents are useful for cancers with mutations in KRAS codon 12. The G12D mutation is one of these mutations, but no effects on G12D mutant KRAS cancers are described.

[0012] In recent years, as a technology for inducing the degradation of target proteins, bifunctional compounds collectively referred to as PROTAC (protein hydrolysis targeting chimera) or SNIPER (specific and non-genetic IAP-dependent protein scavenger) have been found and are expected to be a novel drug development model technology (Drug. Discov. Today Technol., 2019, 31, pages 15-27). Such bifunctional compounds promote the formation of a complex of a target protein and an E3 ligase in cells, and the degradation of the target protein is induced by using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the mechanisms of intercellular protein degradation. Proteins called E3 ligases recognize proteins to be degraded to convert proteins into ubiquitin, thereby promoting degradation by means of proteasomes.

[0013] Six hundred (600) or more E3 ligases exist in organisms and are roughly divided into four types of HECT-domain E3, U-box E3, monomeric ring E3, and multi-subunit E3. E3 ligases used as bifunctional degradation inducers (which are called PROTACs, SNIPERs, or the like) are currently limited, and typical examples thereof include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). Specifically, VHL is reported in WO 2013 / 106643 and CRBN is reported in WO 2015 / 160845.

[0014] Bifunctional compounds are compounds in which a ligand of a target protein and a ligand of an E3 ligase are bound via a linker, and some bifunctional compounds for degrading KRAS protein have been reported (Cell. Chem. Biol., 2020, 27, pp. 19-31, ACS Cent. Sci., 2020, 6, pp. 1367-1375, US 2018 / 0015087, WO 2019 / 195609, WO 2020 / 018788). Summary of the invention

[0015] It has now surprisingly been found that the combination of compounds of formula (I) as defined herein with certain additional anticancer agents as defined herein represents a promising strategy for the treatment of cancer.

[0016] Without being bound by theory, it is believed that the compound of formula (I) as defined herein is a bifunctional compound and has a degradation-inducing effect on the G12D mutant KRAS protein and the G12D mutant KRAS inhibitory activity, and can be used together with an anticancer agent to treat cancer. In particular, it is believed that the combination of the compound of formula (I) and an anticancer agent causes a potent synergistic effect in treating cancer, and the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0017] Therefore, in a first aspect of the present invention, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof for use in treating cancer, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0018] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0019] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0020] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0021] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0022] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0023] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0024] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and

[0025] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0026] The second aspect of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, for use in treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0027] An alternative second aspect of the present invention is an anticancer agent or a pharmaceutically acceptable salt thereof for use in treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0028] The third aspect of the present invention is a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0029] The fourth aspect of the present invention is a pharmaceutical composition for treating cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0030] The fifth aspect of the present invention is a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof.

[0031] The sixth aspect of the present invention is the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention in the preparation of a medicament for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0032] A seventh aspect of the present invention is a kit-of-parts comprising:

[0033] (A) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, and optionally one or more pharmaceutically acceptable excipients, and

[0034] (B) a pharmaceutical composition comprising an anticancer agent or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof,

[0035] The components (A) and (B) are each provided in a form suitable for administration in combination with the other component,

[0036] The kit of components is used to treat cancer.

[0037] The eighth aspect of the present invention is the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention for treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof. DETAILED DESCRIPTION OF THE INVENTION

[0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0040] Unless the context indicates otherwise, preferences and options for a given aspect, embodiment, feature or parameter of the invention are considered to be disclosed in combination with any and all preferences and options for all other aspects, features and parameters of the invention.

[0041] Where the word "about" is used herein (e.g., in the context of dosage of an active ingredient), it is understood that such variations are approximate and thus may vary from the numbers specified herein by ± 10%, e.g., ± 5% and preferably ± 2% (e.g., ± 1%).

[0042] Those skilled in the art will understand that reference to "treatment" of a particular condition adopts its standard meaning in the medical art. Specifically, such terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition or prolonging the life of the patient being treated.

[0043] As used herein, reference to a patient will refer to a living individual treated, including a mammalian (e.g., human) patient. In specific embodiments of the relevant aspects of the invention (e.g., the first, second, fourth, fifth, sixth, and eighth aspects of the invention), treatment is in a mammal (e.g., a human).

[0044] As used herein, the term therapeutically effective amount shall refer to the amount of a compound that confers a therapeutic effect on the patient being treated. The effect may be objective (i.e., measurable with the aid of some test or marker) or subjective (i.e., the individual gives an indication of the effect and / or feels the effect). For example, with respect to a cancer that forms as one or more solid tumors, the therapeutic effect may be observed as a reduction in the volume of one or more of those tumors.

[0045] For the avoidance of doubt, the compounds of formula (I) and anticancer agents as described herein may exist in solid form, and therefore the scope of the present invention includes all amorphous, crystalline and partially crystalline forms thereof, and may also exist in the form of an oil. When such compounds exist in crystalline and partially crystalline forms, such forms may include hydrates and solvates, which are included in the scope of the present invention. The compound may also be present in a solution.

[0046] Compounds for use

[0047] As described herein, in a first aspect of the present invention, there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof for use in treating cancer, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0048] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0049] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0050] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0051] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0052] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0053] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0054] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and

[0055] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0056] In a second aspect of the present invention, there is provided a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for use in treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0057] In an alternative second aspect of the present invention, there is provided an anticancer agent or a pharmaceutically acceptable salt thereof for use in treating cancer, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0058] Compound of formula (I)

[0059] The compound of formula (I) as referred to herein is a compound selected from the group consisting of:

[0060] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0061] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0062] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0063] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0064] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0065] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0066] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and

[0067] (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0068] For the avoidance of doubt, the structures of compounds of formula (I) correspond to the structures provided in Examples 1 to 8.

[0069] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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.

[0070] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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.

[0071] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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.

[0072] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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.

[0073] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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.

[0074] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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.

[0075] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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.

[0076] In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0077] In certain embodiments, the compound of formula (I) is selected from the group consisting of:

[0078] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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,

[0079] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0080] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0081] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0082] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0083] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0084] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and

[0085] (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0086] In certain embodiments, the compound of formula (I) is selected from the group consisting of:

[0087] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0088] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0089] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0090] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0091] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0092] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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,

[0093] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and

[0094] (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0095] The compound of formula (I) and the anticancer agent may have tautomers or geometric isomers depending on the type of substituents. In the present specification, the compound of formula (I) and the anticancer agent may sometimes be described as only one of the isomers, but the present invention includes tautomers or geometric isomers other than the described one, and includes isolated isomers or mixtures thereof.

[0096] The compounds of formula (I) may have one or more asymmetric carbon atoms and may therefore exist in the form of specific enantiomers and diastereomers thereof. The present invention includes the isolated enantiomers and diastereomers of the compounds of formula (I) or mixtures thereof.

[0097] Enantiomers of chiral compounds having one or more asymmetric carbon atoms can be labeled with "(R)" and "(S)" relative to each chiral point based on methods known in the art (eg, using the Cahn-Ingold-Prelog priority rules).

[0098] In certain embodiments, reference to a specific stereoisomer of a compound of Formula (I) may refer to that specific stereoisomer (e.g., the specific enantiomer or diastereomer indicated) being present in the substantial absence of other stereoisomers (i.e., stereoisomers having different configurations at one or more relevant chiral points).

[0099] In such cases, the compounds in the relevant configurations may be present in an enantiomeric excess (ee) or diastereomeric excess (de) of at least 60%, such as at least 70%, 80%, 90%, 95% or 98%, or specifically at least 99%, for example at least 99.9%, as desired.

[0100] Compounds of formula (I) may have axial chirality, which may refer to compounds having one or more axes about which substituent groups are held in a spatial arrangement that is non-superimposable with their mirror image. For the avoidance of doubt, all axial arrangements of such compounds are within the scope of the present invention.

[0101] Enantiomers of axially chiral compounds may be labeled with "M" and "P" based on methods known in the art (e.g., using the Cahn-Ingold-Prelog priority rules with the additional rule that two "close" substituents have a higher priority than distant substituents).

[0102] In certain embodiments, reference to a particular axial stereoisomer of a compound of Formula (I) may refer to the presence of that particular stereoisomer (e.g., an isomer with M-axial chirality) in the substantial absence of the corresponding opposite stereoisomer (e.g., an isomer with P-axial chirality).

[0103] In such cases, the purity of the axial stereoisomer (e.g., the M-axial isomer) of the compound of Formula (I) relative to the other axial stereoisomer (e.g., relative to the P-axial chiral isomer) is at least 70% (e.g., at least 80%, 90%, 95% or 99%).

[0104] For the avoidance of doubt, a compound having a particular stereochemistry (eg axial chirality) at a defined position may also have stereochemistry at one or more other positions and may therefore exist as mixtures of enantiomers or diastereomers with respect to the stereochemistry at those positions.

[0105] In addition, the present invention includes pharmaceutically acceptable prodrugs (which may be referred to as precursors) of compounds represented by formula (I) and anticancer agents. Pharmaceutically acceptable prodrugs will include compounds having groups that can be converted into amino, hydroxyl, carboxyl or similar groups by solvent decomposition or under physiological conditions. Examples of groups that can be used to form prodrugs include the groups described in: Prog. Med., 1985, 5, pp. 2157-2161 or "Iyakuhin no Kaihatsu (Drug Development)", Vol. 7, Bunshi-sekkei (Molecular Design), Hirokawa Shoten, 1990, pp. 163-198. Prodrugs include esters and carbamate derivatives or derivatives such as conjugates (e.g., conjugates of albumin-bound paclitaxel).

[0106] Prodrugs may be referred to as precursors of active compounds (ie, compounds of formula (I) and anticancer agents), which may refer to compounds that are metabolized to form active compounds in vivo.

[0107] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by means of known means, for example, by reacting the free acid or free base form of the compound contained in the formulation of the present invention with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., by rotary evaporation under reduced pressure, by freeze drying or by filtration). Salts can also be prepared by exchanging the counter ion of the compound in salt form contained in the formulation of the present invention with another counter ion, for example, using a suitable ion exchange resin.

[0108] Exemplary salts include those shown in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid; or with 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, or glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, or aluminum; salts with organic bases such as methylamine, ethylamine, or ethanolamine; salts with various amino acids and amino acid derivatives such as acetyleucine, lysine, and ornithine; and ammonium salts.

[0109] In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) and / or the anticancer agent is a hydrochloric acid (HCl) salt.

[0110] In addition, the present invention also includes various hydrates, solvates, crystalline polymorphs and amorphous solid forms of compounds of formula (I) and anticancer agents, and salts thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes. "Amorphous solid forms" include both forms that do not show peaks in powder X-ray diffraction (XRD) patterns and forms with low crystallinity.

[0111] Anticancer Agents

[0112] As described herein, the anticancer agent is selected from the group comprising taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, and fluoropyrimidine compounds, and prodrugs thereof.

[0113] The term "taxane" refers to a class of diterpenoid compounds that were originally derived from natural sources, such as plants of the genus Taxus, but some have been synthesized artificially. Taxanes are characterized by a taxadiene core. As used herein, taxanes include paclitaxel, docetaxel, cabazitaxel, and baccatin III.

[0114] In one embodiment, the anticancer agent is a taxane. In a specific embodiment, the taxane is paclitaxel.

[0115] Paclitaxel refers to a compound having the name [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diacetyloxy-15-[(2R,3S)-3-benzamido-2-hydroxy-3-phenylpropionyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl]benzoate and the following structure:

[0116] .

[0117] In a specific embodiment, the taxane is docetaxel.

[0118] Docetaxel refers to a compound having the name [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetoxy-1,9,12-trihydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylprop-2-yl)oxycarbonylamino]-3-phenylpropionyl]oxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl]benzoate and the following structure:

[0119] .

[0120] Nucleosides are the structural subunits of nucleic acids such as DNA and RNA, and are composed of a nucleobase (also called a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose).

[0121] "Fluorinated nucleosides" refer to a class of chemotherapeutic agents. As used herein, "fluorinated nucleosides" include nucleosides in which at least one of the hydrogen substituents on the nucleoside has been replaced with one or more fluorine substituents. "Fluorinated nucleosides" include gemcitabine and fludarabine.

[0122] In one embodiment, the anticancer agent is a fluorine-containing nucleoside. In a specific embodiment, the fluorine-containing nucleoside contains at least one fluorine substituent on the sugar unit of the nucleoside.

[0123] In certain embodiments, the fluorine-containing nucleoside is gemcitabine.

[0124] Gemcitabine refers to a compound having the name 4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one and the following structure:

[0125] .

[0126] As used herein, "platinum compound" refers to a platinum-based chemotherapeutic agent. A "platinum compound" is a coordination complex of platinum, such as cisplatin, oxaliplatin, carboplatin, nedaplatin, triplatinium tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0127] In one embodiment, the anticancer agent is a platinum compound. In a specific embodiment, the platinum compound is oxaliplatin.

[0128] Oxaliplatin refers to a compound having the name [(1R,2R)-cyclohexane-1,2-diamine](oxalate-O,O')platinum(II) and the following structure:

[0129] .

[0130] Camptothecin analogs refer to compounds that are structurally related to camptothecin, such as irinotecan, aminocamptothecin, 9-nitrocamptothecin (rubitecan), gimatecan, topotecan, silatecan, cositecan, exatecan, lurtotecan, and belotecan. The term "camptothecin analogs" may include compounds comprising the following substructures:

[0131] .

[0132] In one embodiment, the anticancer agent is a camptothecin analog. In a specific embodiment, the camptothecin analog is irinotecan.

[0133] Irinotecan refers to a compound having the name [(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazacyclopenta[11.8.0.02,11.04,9.015,20]heneicostan-1(21),2,4(9),5,7,10,15(20)-hepten-7-yl]4-piperidin-1-ylpiperidin-1-carboxylate and the following structure:

[0134] .

[0135] A "fluoropyrimidine" compound refers to a pyrimidine substituted with at least one fluorine substituent, and includes capecitabine, floxuridine, and fluorouracil (5-FU). One skilled in the art will appreciate that capecitabine is a prodrug of 5-FU.

[0136] In one embodiment, the anticancer agent is a fluoropyrimidine compound. In a specific embodiment, the fluoropyrimidine compound is 5-fluorouracil, also known as 5-FU.

[0137] The terms "5-fluorouracil" and "5-FU" refer to the compound having the name 5-fluoro-1H-pyrimidine-2,4-dione and the following structure:

[0138] .

[0139] cancer

[0140] As used herein, the following terms shall be understood to have the meanings as indicated.

[0141] "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.

[0142] “G12D mutant KRAS” means KRAS with a “G12D mutation”.

[0143] “G12D mutant KRAS-positive cancer” is a G12D mutant KRAS-positive cancer, and is, for example, a cancer in which the KRAS G12D mutation occurs and a cancer with a high positive rate of G12D mutant KRAS.

[0144] "Pancreatic cancer" is a malignant tumor arising in the pancreas. Examples thereof include pancreatic duct carcinoma and pancreatic duct adenocarcinoma. In one embodiment, "pancreatic cancer" is pancreatic duct carcinoma, and in one embodiment, "pancreatic cancer" is pancreatic duct adenocarcinoma.

[0145] "Colorectal cancer" is a malignant tumor that occurs in the large intestine.

[0146] "Lung cancer" is a malignant tumor that occurs in the lungs.

[0147] In one embodiment, the cancer is metastatic, locally advanced, recurrent and / or refractory cancer.

[0148] In a certain embodiment, the cancer is a cancer in a patient who has not been previously treated for the relevant condition (ie, has no medical history of prior treatment for the condition), and the patient (or specifically, the relevant cancer) can be referred to as treatment-naive.

[0149] In yet another embodiment, the cancer is in a patient who has been treated for a related condition (ie a different treatment, other than that defined in the first aspect of the invention) and has not responded or has responded inadequately to that treatment.

[0150] In one embodiment, the cancer is defined as being difficult to treat (i.e., a treatment-resistant cancer is a cancer that does not respond or responds inadequately to other medical treatments, which other medical treatments would be medical treatments other than those defined in the first aspect of the invention). A refractory cancer may have become resistant to treatment since the start of medical treatment, or the cancer cells may have acquired resistance during a course of previous medical treatment.

[0151] In a particular embodiment, the cancer is refractory to therapy with a compound of formula (I) in the absence of a combination as defined in the first aspect of the invention (i.e., wherein the prior therapy included a compound of formula (I), but wherein the therapy did not comprise treatment with an anticancer agent selected from taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs and fluoropyrimidine compounds).

[0152] In one embodiment, the cancer is pancreatic cancer. In a specific embodiment, the pancreatic cancer is pancreatic duct carcinoma or pancreatic duct adenocarcinoma.

[0153] In one embodiment, the cancer is colorectal cancer. In a specific embodiment, the colorectal cancer is colon cancer or rectal cancer.

[0154] In one embodiment, the cancer is lung cancer. In a specific embodiment, the lung cancer is small cell lung cancer or non-small cell lung cancer.

[0155] In one embodiment, the cancer is a G12D mutant KRAS-positive cancer.

[0156] In a specific embodiment, the G12D mutant KRAS-positive cancer is a G12D mutant KRAS-positive pancreatic cancer. In an alternative embodiment, the G12D mutant KRAS-positive cancer is a G12D mutant KRAS-positive colorectal cancer. In an alternative embodiment, the G12D mutant KRAS-positive cancer is a G12D mutant KRAS-positive lung cancer.

[0157] According to the second aspect of the present invention is an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the treatment further comprises administering a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0158] For the avoidance of doubt, the second aspect of the invention may have any of the specific features and embodiments described herein in relation to the first aspect of the invention, including all combinations thereof.

[0159] Pharmaceutical composition

[0160] According to the third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound and a prodrug thereof.

[0161] For the avoidance of doubt, the pharmaceutical composition of the third aspect of the invention may have any of the specific features and embodiments described herein in relation to the other (eg first and second) aspects of the invention, including all combinations thereof.

[0162] Suitable pharmaceutical compositions may be commercially available or otherwise described in the literature (see, for example, Remington, The Science and Practice of Pharmacy, 19th edition, Mack Printing Company, Easton, Pennsylvania (1995) and Martindale-The Complete Drug Reference (35th edition) and the literature mentioned herein), the entire relevant disclosure of which is incorporated herein by reference. Otherwise, the preparation of suitable compositions, and in particular the combination preparations comprising a compound of formula (I) and an anticancer agent or a pharmaceutically acceptable salt thereof, can be achieved by those skilled in the art using conventional techniques.

[0163] References to pharmaceutically acceptable excipients are understood to include pharmaceutically acceptable diluents, carriers and / or adjuvants as known to those skilled in the art.

[0164] In certain embodiments, the pharmaceutical compositions may be administered according to one or more of the modes of administration as described herein.

[0165] For the avoidance of doubt, a pharmaceutical composition as described herein may comprise one or more doses of a compound of formula (I) and / or an anticancer agent as described herein, or may comprise fractional doses of these components (in which case multiple such compositions may be administered during the course of treatment as described herein).

[0166] For the avoidance of doubt, a pharmaceutical composition as described herein may also be referred to as a pharmaceutical formulation.

[0167] According to a fourth aspect of the present invention, there is provided a pharmaceutical composition for treating cancer, comprising a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof.

[0168] For the avoidance of doubt, the pharmaceutical composition of the fourth aspect of the invention may have any of the specific features and embodiments described herein in relation to other (eg first to third) aspects of the invention, including all combinations thereof.

[0169] give

[0170] As used herein, references to methods and treatments involving a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof (both as defined in the first aspect of the invention) include sequential, separate or simultaneous administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof (including pharmaceutical compositions comprising each corresponding component) as part of a medical intervention for the treatment of the relevant disease or condition.

[0171] Thus, in certain embodiments, the two active ingredients (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof) are administered together or sufficiently close in time (optionally repeatedly) to achieve a higher beneficial effect for the patient in the course of treatment of the relevant condition, compared to when a formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a formulation comprising an anticancer agent (as defined in the first aspect of the invention) or a pharmaceutically acceptable salt thereof is administered separately (optionally repeatedly) in the absence of the other components during the same course of treatment. Determining whether a combination provides a greater beneficial effect with respect to the treatment of a particular cancer and in the course of treatment can be routinely accomplished by one skilled in the art.

[0172] In other embodiments, two compounds or compositions are given before, after and / or simultaneously (optionally repeatedly) before giving another component.When used in this context, the term "simultaneous administration" includes that the respective dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent (as defined in the first aspect of the present invention) or a pharmaceutically acceptable salt thereof are given within 2 hours of each other (e.g., within 60 minutes, 45 minutes, 30 minutes, 20 minutes or 10 minutes).

[0173] In certain embodiments, two compounds or compositions are administered sequentially (optionally repeatedly). When used in this context, the term "administered sequentially" includes a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent (as defined in the first aspect of the present invention) or a pharmaceutically acceptable salt thereof, administered at intervals of 2 hours to 7 days (e.g., 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days or 6 days) from each other.

[0174] For the avoidance of doubt, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) may be administered prior to the administration of the anticancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same). Alternatively, the anticancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) may be administered prior to the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same).

[0175] In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt (or a pharmaceutical composition comprising it) and the formulation comprising an anticancer agent or its pharmaceutically acceptable salt (or a pharmaceutical composition comprising it) are administered sequentially, such as wherein the second drug is administered after determining that treatment with the first drug is effective. Methods for determining the effectiveness of the first drug are known to those skilled in the art.

[0176] Those skilled in the art will appreciate that the compounds and pharmaceutical formulations as defined herein may be administered by oral administration of tablets, pills, capsules, granules, powders, liquids or other formulations, or by parenteral administration of intra-articular, intravenous, intramuscular or other injections, transmucosal agents or inhalations.

[0177] As solid compositions for oral administration, tablets, powders, granules or other preparations are used. In such solid compositions, one or two or more active ingredients are mixed with at least one inactive excipient. The composition may contain inactive additives according to common methods, such as lubricants, disintegrants, stabilizers, dissolution aids. Tablets or pills may be coated with a sugar coating or a film soluble in the stomach or intestines as needed.

[0178] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and contain commonly used inactive diluents, such as purified water or EtOH (ethanol). Liquid compositions may contain adjuvants other than inactive diluents, such as solubilizers, wetting agents or suspending agents, sweeteners, flavoring agents, aromatics or preservatives.

[0179] Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents include distilled water for injection or physiological saline. Examples of non-aqueous solvents are alcohols, such as EtOH. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. These compositions are sterilized, for example, by filtering through a bacteria-retaining filter, incorporating a microbicide or irradiating. In addition, such compositions can be produced in the form of a sterile solid composition, which is dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0180] Transmucosal medicaments, such as inhalants or nasal agents, are used in solid, liquid or semisolid forms and can be produced according to conventional known methods. For example, known excipients and additional pH adjusting agents, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. Administration can be carried out by means of using a suitable device for inhalation or insufflation. For example, the medicament can be administered in the form of a powder of a single compound form or a formulated mixture, or in the form of a solution or suspension combined with a pharmaceutically acceptable carrier using a known device, such as a metering and administration inhalation device, or a nebulizer. Dry powder inhalers, etc. can be used for single administration or multiple administration, and dry powders or capsules containing powders can be used. Alternatively, the medicament can use a suitable propellant, for example, suitable gas, such as chlorofluoroalkane or carbon dioxide, in the form of a pressurized aerosol spray, etc.

[0181] In one embodiment, the compounds and compositions as described herein are administered orally, intraarticularly, intravenously, intramuscularly, transmucosally, or by inhalation. In a specific embodiment, the compounds and compositions as described herein are administered intravenously.

[0182] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally or by means of inhalation, such as intravenously.

[0183] In one embodiment, the anticancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally, or by inhalation, such as orally or intravenously (depending on the anticancer agent used).

[0184] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially via the same route of administration (eg, intravenously).

[0185] In alternative embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent or a pharmaceutically acceptable salt thereof are administered sequentially via different routes of administration. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered intravenously and the anticancer agent or a pharmaceutically acceptable salt thereof may be administered orally.

[0186] dose

[0187] Those skilled in the art will be able to determine suitable (ie, therapeutically effective) dosages of compounds of formula (I) and anticancer agents as described herein using conventional techniques and reference to the relevant literature thereon (such as relevant marketing authorizations and / or drug formularies).

[0188] For the avoidance of doubt, references herein to uses, compounds for use, methods, combinations, compositions and kits of parts shall include the agents used herein in their therapeutically effective amounts.

[0189] Exemplary dosages of compounds of Formula (I) and anticancer agents as described herein are as follows.

[0190] In the case of oral administration, the daily dose of the compound of formula (I) and / or the anticancer agent may appropriately be about 0.001 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and the dose may be administered once or divided into two to four times a day (e.g., twice, three times or four times a day).

[0191] In the case of intravenous administration, the daily dose of the compound of formula (I) and / or the anticancer agent may be appropriately about 0.0001 to 10 mg / kg body weight, and administered once or divided into multiple times a day (eg, twice, three times or four times a day).

[0192] In addition, the daily dose of the transmucosal agent is about 0.001 to 100 mg / kg body weight, and is administered once or divided into multiple times a day (for example, twice, three times, or four times a day).

[0193] It will be understood by those skilled in the art that the dosage is appropriately determined on an individual basis, taking into account the patient's symptoms, age, sex, and the like.

[0194] Treatment

[0195] According to the fifth aspect of the present invention is a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0196] For the avoidance of doubt, the method of the fifth aspect of the invention may have any of the specific features and embodiments described above for other (eg first to fourth) aspects of the invention, including all combinations thereof.

[0197] Use in the preparation of medicines

[0198] The sixth aspect of the present invention is the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention in the preparation of a medicament for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0199] For the avoidance of doubt, the use of the sixth aspect of the invention may have any of the specific features and embodiments described above for other (eg first to fifth) aspects of the invention, including all combinations thereof.

[0200] Component Set

[0201] According to a seventh aspect of the present invention, there is provided a kit of parts comprising:

[0202] (A) a pharmaceutical composition comprising: a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, and

[0203] (B) a pharmaceutical composition comprising: an anticancer agent or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof,

[0204] The components (A) and (B) are each provided in a form suitable for administration in combination with the other component,

[0205] The kit of components is used to treat cancer.

[0206] As used herein, reference to components being administered in conjunction with one another is contemplated herein as the sequential, separate or simultaneous administration of such components as part of a medical intervention directed to treating a related disease or condition as described herein.

[0207] In an alternative seventh aspect of the present invention, there is provided a kit of parts comprising:

[0208] (I) one of the components (A) or (B) as described in the seventh aspect of the present invention, and

[0209] (II) instructions for using the component in combination with the other of the two components,

[0210] The kit of components is used to treat cancer.

[0211] For the avoidance of doubt, the kit of parts of the seventh aspect of the invention may have any of the specific features and embodiments described above for other (eg first to sixth) aspects of the invention, including all combinations thereof.

[0212] For therapeutic use

[0213] In an eighth aspect of the present invention, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof for treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

[0214] For the avoidance of doubt, the use of the eighth aspect of the invention may have any of the specific features and embodiments described above for other (eg first to seventh) aspects of the invention, including all combinations thereof.

[0215] Preparation of compounds / compositions

[0216] Pharmaceutical compositions, combination products and kits as described herein may be prepared according to standard and / or accepted pharmaceutical practice.

[0217] Therefore, in another aspect of the present invention, there is provided a method for preparing a pharmaceutical composition as described herein, the method comprising combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent, both as described herein, with one or more pharmaceutically acceptable excipients.

[0218] In a further aspect of the invention there is provided a process for preparing a combination product or kit of parts as defined above. The process comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof, both as described herein, and an anticancer agent.

[0219] As used herein, reference to combining will mean that two components are suitable for administration in conjunction with each other.

[0220] Thus, with respect to the method of preparing a kit of parts as defined above, by "combining" the two components with each other, the present invention encompasses two components of the kit of parts which may:

[0221] (i) are provided as separate formulations (ie, independent of each other) which are subsequently combined together for use in combination with each other in a combination therapy; or

[0222] (ii) The separate components are packaged and presented together as a "combination package" for use in conjunction with each other in a combination therapy.

[0223] The compounds described herein, including compounds of formula (I) and pharmaceutically acceptable salts thereof, and anticancer agents described herein, can be prepared according to techniques well known to those skilled in the art, such as those described in the examples provided below and / or those provided in the public literature for each such compound.

[0224] Certain compounds as described herein, such as anticancer agents as described herein and pharmaceutical compositions containing the same are commercially available from sources known to those skilled in the art.

[0225] Formula (I) compound and its salt can be produced by using various known synthesis methods based on its basic structure or substituent type. Here, depending on the type of functional group, as a production technology, it is sometimes effective to replace the functional group with a suitable protective group (a group that can be easily converted into a functional group) in the process from raw materials to intermediates. The example of the protective group includes the protective group described in PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", the 5th edition, John Wiley & Sons Inc., 2014 and the group appropriately selected from such protective groups is used according to the reaction conditions. In such methods, the reaction is carried out under the condition of introducing a protective group, and the protective group is then removed as needed, so that the desired compound can be obtained.

[0226] In addition, the prodrug of the compound of formula (I) can be produced by introducing a specific group in the process of raw materials to intermediates with respect to the above protecting groups or by further reacting the obtained compound of formula (I). This reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation or dehydration.

[0227] Isolation and purification are carried out by applying conventional chemical operations, such as extraction, fractional crystallization or various types of fractional chromatography.

[0228] Various types of isomers can be produced by selecting appropriate raw material compounds or can be separated using the differences in biochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods for racemates (e.g., fractional crystallization for inducing racemates into diastereomeric salts with optically active bases or acids, chromatography using chiral columns or the like, or similar methods) and can also be produced from appropriate optically active raw material compounds.

[0229] In addition, the compound of formula (I) or its intermediate sometimes has axial chirality and is obtained as a mixture of axial stereoisomers, and each axial stereoisomer can be separated by separation using a common separation operation such as octadecylsilane (ODS) column chromatography or silica gel column chromatography.

[0230] Advantages of the present invention

[0231] Treatments as described herein may have the following advantages: they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, and / or have a better treatment profile than treatments known in the prior art for the same condition.

[0232] Without being bound by theory, it is believed that the compound of formula (I) has an inducing degradation effect on G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and can be used together with an anticancer agent to act synergistically in the treatment of cancer, especially G12D mutant KRAS-positive cancer. The anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof. DETAILED DESCRIPTION

[0233] Examples

[0234] The preparation method of the compound of formula (I) will be described in further detail below based on examples. It should be noted that the present invention is not limited to the compounds described in the following examples. The preparation method of the raw material compound is also shown in the preparation examples. The preparation method of the compound of formula (I) is not limited to the preparation method of the specific example described below, and the compound of formula (I) can also be produced by means of a combination of such preparation methods or methods obvious to those skilled in the art.

[0235] In case of inconsistency between nomenclature and compound structure as depicted graphically, the latter prevails (unless contradicted by any experimental details that may be given and / or unless clear from the context).

[0236] For the purpose of convenience, the concentration mol / L is shown as M. For example, 1 M sodium hydroxide aqueous solution means 1 mol / L sodium hydroxide aqueous solution.

[0237] abbreviation

[0238] The following abbreviations may be used herein.

[0239] DMF: N,N-dimethylformamide

[0240] DMAc: N,N-dimethylacetamide

[0241] THF: Tetrahydrofuran

[0242] MeCN: Acetonitrile

[0243] MeOH: Methanol

[0244] EtOH: ethanol

[0245] DOX: 1,4-dioxane

[0246] DMSO: dimethyl sulfoxide

[0247] TEA: triethylamine

[0248] DIPEA: N,N-diisopropylethylamine

[0249] tBuOK: Potassium tert-butoxide

[0250] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0251] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0252] PdCl2(dppf)·CH2Cl2:[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct

[0253] Pd / C: Palladium / Carbon

[0254] Preparation Example

[0255] Preparation Example 1

[0256] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL) and THF (500 mL) was cooled with an ice bath, followed by addition of DIPEA (240 mL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (48 g), and the mixture was 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 volume of the solution became about 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered 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.

[0257] Preparation Example 2

[0258] To a mixture of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL) and DABCO (1.15 g) was added cesium carbonate (50.3 g) with stirring at room temperature in an argon atmosphere, and the mixture was stirred at room temperature overnight. About 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 filtered, washed with water and dried under reduced pressure overnight 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.

[0259] Preparation Example 3

[0260] To a mixture of (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxacyclohexane-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.9 g), benzyl alcohol (2.37 g) and THF (40 mL) was added tBuOK (2.54 g) under argon stream with ice bath cooling, and the mixture was stirred at the same temperature for 1.5 hours. Ice water and saturated aqueous ammonium chloride solution were added to the reaction mixture, the mixture 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 obtained residue. The mixture was stirred for a while, and the precipitated solid was filtered 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.

[0261] Preparation Example 4

[0262] In an argon atmosphere, a mixture of tert-butyl (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxacyclohexane-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), cyclopropylboronic acid (1.27 g), tripotassium phosphate (5.67 g) and PdCl2(dppf)·CH2Cl2 (600 mg) was stirred at 100° C. for 3 hrs. After the reaction mixture was cooled to room temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium chloride solution was added to the obtained 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 obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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.

[0263] Preparation Example 5

[0264] Tert-butyl (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxacyclohexan-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 g) were added. A mixture of 2-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (0.2 g), DOX (40 mL) and water (8 mL) was degassed and replaced with argon under stirring at room temperature, and then the mixture was stirred at 100° C. in an argon atmosphere for 2.5 hours. Water (about 150 mL) was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium 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 (basic silica gel, hexane / ethyl acetate) to obtain fractions containing: (1) a low-polarity diastereomeric mixture (peak-1 and peak-2; peak-1 and peak-2 have the same axial chirality) and (2) a high-polarity diastereomeric mixture (peak-3 and peak-4; peak-3 and peak-4 have the same axial chirality), respectively. Among these fractions, the fraction containing a low-polarity diastereomeric mixture (peak-1 and peak-2, same axial chirality) was collected to obtain (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-carboxylic acid tert-butyl ester (1.42 g) as a foamy solid. In addition, fractions containing a high polarity diastereomeric mixture (peak-3 and peak-4, same axial chirality) were collected to obtain (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-carboxylic acid tert-butyl ester (1.37 g) as a foamy solid. The low polarity diastereomeric mixture was used for the subsequent reaction.

[0265] Preparation Example 6

[0266] To a MeOH (200 mL) solution of the low polar diastereomeric mixture (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexane-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexane-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (10 g) obtained in Preparation Example 11 was added 10% Pd / C (50% wet, 2 g), and the reaction mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The resulting reaction mixture was filtered through a celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure, and the obtained 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-carboxylic acid tert-butyl ester (8.11 g) as a foamy solid.

[0267] Preparation Example 7

[0268] To a mixture of (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-carboxylic acid tert-butyl ester (7.48 g), DMF (70 mL) and 1-(chloromethyl)-4-ethynylbenzene (1.9 g) was added cesium carbonate (6.2 g) with stirring at room temperature, and the mixture was stirred at 60° C. in an argon atmosphere for 2 hours. To the reaction mixture cooled to room temperature were added ice water and a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Subsequently, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and the obtained solid was filtered to give (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 (8.12 g) as a foamy solid.

[0269] Preparation Example 8

[0270] To tert-butyl (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 (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) were added at room temperature. mL) was added anhydrous copper (II) sulfate (389 mg), and the mixture was 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 layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (1S, 4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexane-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-carboxylic acid tert-butyl ester (5.62 g).

[0271] Preparation Example 12

[0272] To a solution 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-(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 (3.97 g) in 1,2-dichloroethane (60 mL) was added trimethyltin(IV) hydroxide (3.35 g) at room temperature, and the mixture was stirred at 80°C for 18 hrs. After the mixture was cooled to room temperature, hydrochloric acid (1 M, 60 mL) was added, and the mixture was extracted with CHCl 3 / MeOH (9 / 1). The organic layer was washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate 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]hept-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 as a solid (3.26 g).

[0273] Preparation Example 13

[0274] Under ice-cooling, to (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-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 monohydrochloride (60 mg), DIPEA (70 μL) and DMF (3 mL) were added. HATU (70 mg) was added to a mixture of 4-nitropropene (2-nitropropene) and 4-nitropropene (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (6 ... -(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-carboxylic acid tert-butyl ester (173 mg).

[0275] Preparation Example 14

[0276] To a solution of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (5.01 g) in DMAc (80 mL) was added 4-methyl-1,3-thiazole (2.88 mL) and potassium acetate (3.11 g) at room temperature, and the mixture was degassed and filled with argon three times. Palladium acetate (356 mg) was added at room temperature and the mixture was stirred at 100° C. for 16 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added, and insoluble matter was removed by filtration through a celite pad. Water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. 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 filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give tert-butyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.66 g) as a solid.

[0277] Preparation Example 15

[0278] In an argon atmosphere, to a mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (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) was added PdCl2(dppf)·CH2Cl2 (1.14 g), and the mixture was stirred at 100° C. for 16 hours. After the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.74 g) as a solid.

[0279] Preparation Example 17

[0280] To a solution of tert-butyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.41 g) in CH2Cl2 (50 mL) and MeOH (50 mL) was added hydrochloric acid (4M DOX solution, 20 mL) dropwise under ice-bath cooling, and the mixture was stirred at room temperature for 6 hours. Diethyl ether was added to the reaction mixture, and the resulting solid was filtered, washed with diethyl ether and dried under reduced pressure to give (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol n·hydrochloride (2.12 g) as a solid. The filtrate was concentrated and dried under reduced pressure to give (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol n·hydrochloride (2.01 g) as a solid.

[0281] Preparation Example 18

[0282] To a solution of tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.34 g) in CH2Cl2 (25 mL) and MeOH (25 mL) was added hydrochloric acid (4M DOX solution, 25.6 mL) at -20°C to -10°C, and the mixture was 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 hydrochloride (3.06 g) as a solid.

[0283] Preparation Example 20

[0284] To a mixture of (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.12 g), (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (1.76 g) and DMF (22 mL) was added DIPEA (4.7 mL) under ice-cooling, and then HATU (3.02 g) was added dropwise under ice-cooling to maintain the internal temperature below 5°C. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Under ice-cooling, water (120 mL), a saturated aqueous sodium chloride solution (50 ml) and ethyl acetate were added, and the aqueous layer was extracted three times with ethyl acetate, and then extracted three times with ethyl acetate / isopropanol (9 / 1). The combined organic layer was washed with a saturated aqueous sodium chloride solution, 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 (CHCl 3 / MeOH) to give tert-butyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-carboxylate (3.09 g) as an oil.

[0285] Preparation Example 21

[0286] 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) was added DIPEA (7.8 mL) under ice-cooling, and then HATU (4.5 g) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. Under ice-cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate / isopropanol (9 / 1). The combined organic layers were washed with a saturated aqueous sodium chloride solution, 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 (CHCl 3 / MeOH) to give 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.

[0287] Preparation Example 23

[0288] To a solution of tert-butyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-1-carboxylate (3.09 g) in CH2Cl2 (18 mL) and MeOH (18 mL) was added hydrochloric acid (4M DOX solution, 17 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 5 hours. The reaction mixture was concentrated and dried under reduced pressure to obtain (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide n·hydrochloride (2.92 g) as a solid.

[0289] Preparation Example 24

[0290] To a solution of 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) in CH2Cl2 (35 mL) and MeOH (30 mL) was added hydrochloric acid (4M DOX solution, 28 mL) at -20 to -10°C, and the mixture was 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.

[0291] Preparation Example 26

[0292] 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) was added DIPEA (6.2 mL), followed by dropwise addition of HATU (3.61 g) under ice-bath cooling. The mixture was stirred under ice-bath cooling for 1 hour and at room temperature for 1 hour. Under ice-bath cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, followed by extraction with ethyl acetate / isopropanol (9 / 1). 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 filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 / 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.

[0293] Preparation Example 29

[0294] 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 CH2Cl2 (35 mL) and MeOH (35 mL) was added hydrochloric acid (4M DOX solution, 20 mL) at -20°C to -15°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give 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.

[0295] Preparation Example 33

[0296] 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), a solution of 2-azido-1,3-dimethylimidazolium hexafluorophosphate (1.06 g) in MeCN (5 mL) was added dropwise over 10 minutes or longer under ice-cooling, and the mixture was stirred under ice-cooling for 5 hours. 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 layers were dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate 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.

[0297] Preparation Example 37

[0298] 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'-di-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 in an argon atmosphere. The reaction solution cooled to room temperature was diluted with ethyl acetate, and the mixture was filtered through a celite pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution, 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 obtain 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.

[0299] Preparation Example 38

[0300] In an argon atmosphere, palladium (II) acetate (200 mg) was added to a mixture of {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamic acid tert-butyl ester (3.21 g), 5-bromo-1,3-thiazole-4-carboxylic acid methyl ester (2.6 g), tripotassium phosphate (3.8 g), dicyclohexyl (2',6'-dimethoxydiphenyl-2-yl) phosphine (730 mg), DOX (30 mL) and water (6 mL) at room temperature, and the mixture was stirred at 100° C. for 3 hours. After the mixture was cooled to room temperature, ethyl acetate was added, and the mixture was washed with water and a saturated sodium chloride aqueous solution. After the organic layer was dried over anhydrous magnesium 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 methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.48 g) as a solid.

[0301] Preparation Example 39

[0302] 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 CH2Cl2 (20 mL) under ice-bath cooling, and the mixture was stirred for 1 hour under ice-bath cooling. Under ice-bath cooling, the reactant was quenched with MeOH, and 10% aqueous sodium potassium tartrate solution (60 mL) and CHCl3 were added, and the mixture was stirred overnight. The mixture was separated into layers, the aqueous layer was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling. Water was added and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was 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.

[0303] Preparation Example 41

[0304] 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) was added boron trifluoride-diethyl ether complex (26 μL), and the mixture was stirred at room temperature for 1 hour. TEA (66 μL) was added to the mixture, and the mixture was 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 obtain tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.09 g) as a solid.

[0305] Preparation Example 42

[0306] To a solution of (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (300 mg) and 1,3-oxazolidin-2-one (183 mg) in DOX (1.69 mL) were added copper (I) iodide (32 mg), rac-(1R,2R)-cyclohexane-1,2-diamine (20 μL) and potassium carbonate (290 mg) 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 a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (4R)-tert-butyl 2,2-dimethyl-4-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,3-oxazolidine-3-carboxylate (120 mg) as a solid.

[0307] Preparation Example 48

[0308] To a mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (350 mg) and CH2Cl2 (7 mL) was added meta-chloroperbenzoic acid (about 30% water content, 100 mg) with stirring under ice-bath cooling. The reaction mixture was stirred for 1.5 hours under ice-bath cooling, and diluted with CH2Cl2, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain sulfur oxide. The obtained sulfur oxide was mixed with (S)-2-methoxypropanol (45 mg) and THF (4 mL). KOtBu (80 mg) was added to the mixture under ice methanol bath cooling, and the mixture was stirred at room temperature in an argon atmosphere for 1 hour. Ice water and aqueous ammonium chloride solution were added to the reaction mixture, and the product was extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. 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) to obtain (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (280 mg) as a foamy solid.

[0309] Preparation Example 51

[0310] MeOH (3 mL) was added to (1S, 4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (211 mg) and 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added under stirring at room temperature. Subsequently, the mixture was stirred at room temperature in an argon atmosphere for 1 hour. Ice and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. 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) to give the lower polar diastereomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (single axial stereoisomer, 87 mg) and the high polar diastereomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (single axial stereoisomer, 59 mg) as a solid. The low polar diastereomer was used for the subsequent reaction.

[0311] Preparation Example 52

[0312] To a solution of (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (80 mg) in t-BuOH (0.7 mL), THF (0.7 mL) and water (0.7 mL) were added (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (53 mg), sodium ascorbate (33 mg) and CuI (12 mg), and the mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, a solution of EDTA disodium salt in water was added. The mixture was extracted three times with CH 2 Cl 2 , and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (102 mg) as a foamy solid.

[0313] Preparation Example 57

[0314] 1,1',1''-(chloromethanetriyl)triphenyl (335 g) was added to a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL) and CH2Cl2 (1880 mL) at room temperature. And the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into ice water (1.5 L), and the organic layer and the aqueous layer were separated. The aqueous layer was extracted three times with CH2Cl2 (400 mL). The combined organic layer was dried over anhydrous sodium sulfate. Subsequently, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue for grinding (0 ° C, 2 hours), and then 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) was obtained as a solid by filtration collection and drying under reduced pressure.

[0315] Preparation Example 58

[0316] To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL) was added lithium diisopropylamide (2 M THF solution, 214.28 mL) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 hours. Iodomethane (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to quench the reactant, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate. Then, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 mL) / petroleum ether (50 mL) was added to the obtained residue for trituration, and then 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) was obtained as a solid by filtration and drying under reduced pressure.

[0317] Preparation Example 59

[0318] To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g) and DOX (1000 mL) was added palladium acetate (4.52 g) at room temperature under a nitrogen atmosphere. After the reaction mixture was degassed and filled with nitrogen three times each time, the mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. After cooling to ambient temperature, water (1500 mL) was added, and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layers were dried over anhydrous sodium sulfate, and then insoluble materials were removed by filtration. Activated carbon (50 g) was added to the resulting solution, and the solution was stirred at 20 ° C for 1 hour and filtered, while washing three times with ethyl acetate (50 ml). The filtrate was concentrated. Methanol (200 mL) was added to the resulting residue for grinding, and the resulting solid was filtered and dried under reduced pressure to obtain 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0319] Preparation Example 60

[0320] In an argon atmosphere, bis(tri-tert-butylphosphine)palladium(0) (18 mg) was added to a mixture of 4-methyl-1,3-oxazole-5-carboxylic acid (178 mg), tetra-n-butylammonium chloride (195 mg), (4R)-tert-butyl 4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL), and the mixture was stirred at 170° C. under microwave irradiation for 30 minutes. The mixture was cooled to room temperature and then diluted with ethyl acetate, and insoluble matter was removed by filtration through a celite pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium 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 (CHCl 3 / MeOH) to give tert-butyl (4R)-2,2-dimethyl-4-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-1,3-oxazolidine-3-carboxylate (215 mg) as a solid.

[0321] In the following table, "PEx" means "Preparation Example" and "PSyn" indicates that other preparation examples were also prepared using the same method as "PEx" in the same column of the table (i.e., "PEx" was prepared using the same method as the method used to prepare the preparation example value indicated in the "PEx" column).

[0322] Structure: chemical formula (compounds with "*" in the chemical formula indicate that the compound is a single axial stereoisomer). n HCl: n hydrochloride ("n HCl" indicates that the compound is a monohydrochloride to a trihydrochloride), Data: biochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified, [M+H] + ), ESI-: m / z values ​​in mass spectrometry (ionization method ESI, [MH] unless otherwise specified) - ), NMR: δDMSO-d6 1 Peak value (ppm) in H-NMR (500 MHz), NMR (100°C): δ in DMSO-d6 at 100°C 1 Peak value (ppm) in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: doublet of doublets (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum) (e.g.: br s).

[0323] Table 1

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] Examples

[0342] The following are examples of compounds of formula (I) and their characteristics.

[0343] In the following examples, an asterisk indicates that the compound is a single axial stereoisomer.

[0344] Example 1: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexane-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

[0345]

[0346] Under ice-cooling, 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 (5.61 g) and CH2Cl2 (60 mL) were added. mL) was added trifluoroacetic acid (27 mL), and the mixture was then stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate aqueous solution was added to the residue. The mixture was extracted three times with CHCl3 / MeOH (5 / 1), and the organic layer subsequently combined was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by means of ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Saturated sodium bicarbonate aqueous solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl3 / MeOH (5 / 1). The combined organic layer was 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 resulting product, and the mixture was stirred at 80°C for 10 minutes and stirred overnight at room temperature. Hexane (70 mL) was added and the mixture was stirred at room temperature for 1 hour. Then, the obtained solid was filtered, washed with isopropyl acetate / hexane (1 / 1), and dried under reduced pressure at 40°C overnight to give the title compound (3.01 g) as a solid.

[0347] ESI+:1117.3;

[0348] NMR (100℃):0.48-0.68 (4H, m), 0.77 (3H, br d), 1.07 (3H, br d),1.35-1.43 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97 (1H, m),1.98-2.10 (3H, m), 2.01 (3H, d), 2.10-2.21 (1H, m), 2.45 (3H, s), 2.50-2.59(1H, m), 3.06 (1H, dd), 3.13 (1H, d), 3.35-3.45 (2H, m), 3.57-3.64 (1H, m),3.65-3.75 (3H, m), 3.75-3.79 (1H, m), 3.80-3.90 (3H, m), 4.16 (1H, dd), 4.35(1H, br s), 4.41-4.48 (1H, m), 4.48-4.56 (1H, m), 4.78-4.84 (2H, m), 4.84-4.95 (1H, m), 5.13 (1H, br s), 5.17-5.24 (1H, m), 5.24-5.31 (2H, m), 6.82(2H, d), 7.30 (1H, d), 7.38-7.44 (4H, m), 7.44-7.48 (2H, m), 7.61 (2H, br d), 8.00 (1H, br d), 8.43 (1H, br s), 8.88 (1H, s), 12.75 (1H, br s).

[0349] Example 2: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexan-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 trihydrochloride

[0350]

[0351] Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-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}ethan-1-ol dihydrochloride (25 mg) and DMF (1 mL) were added to the mixture under ice-cooling. To a mixture of 4-nitro-1-yl (2-nitro-2-yl)-4-nitropropene (5-nitropropene) (2-nitro-1-yl)-2-nitropropene (5-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (

[0352] ESI+:1133.3.

[0353] Example 3: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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

[0354]

[0355] Under ice-cooling, 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), CH2Cl2 (2 In a mixture of 4M DOX solution (0.988 mL) and MeOH (2 mL), hydrochloric acid (4M DOX solution, 0.988 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, CHCl and saturated sodium bicarbonate aqueous solution were added, and the mixture was stirred for a moment. Subsequently, the aqueous layer was extracted with CHCl / MeOH (5 / 1), and the combined organic layer was dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl / MeOH), and then purified by means of ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fractions containing the target compound were combined, alkalized with saturated sodium bicarbonate aqueous solution, and then extracted twice with CHCl / MeOH (5 / 1). The combined organic layer was dried over anhydrous sodium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with diethyl ether and dried under reduced pressure to obtain the title compound (74 mg) in a solid state.

[0356] ESI+:1105.7.

[0357] Example 4: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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

[0358]

[0359] This compound was prepared using a method analogous to that provided in Example 5 below.

[0360] ESI+:1100.4;

[0361] NMR (100℃):0.48-0.68 (4H, m), 0.77 (3H, br d), 1.03-1.10 (3H, m), 1.35-1.44 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97 (1H, m),1.98-2.10 (3H, m), 2.01 (3H, d), 2.11-2.24 (1H, m), 2.50-2.60 (1H, m), 3.06(1H, dd), 3.14 (1H, d), 3.36-3.44 (2H, m), 3.56-3.64 (1H,m), 3.65-3.75 (3H,m), 3.77 (1H, br s), 3.80-3.92 (6H, m), 4.16 (1H, dd), 4.36 (1H, br s), 4.41-4.48 (1H, m), 4.49-4.57 (1H, m), 4.73-4.84 (2H, m), 4.87-4.96 (1H, m), 5.13(1H, br s), 5.17-5.24 (1H, m), 5.24-5.32 (2H, m), 6.31 (1H, d), 6.82 (2H, d),7.30 (1H, d), 7.38-7.45 (5H, m), 7.45 (1H, d), 7.47 (1H, br s), 7.61 (2H, brd), 8.01 (1H, br d), 8.43 (1H, s), 12.75 (1H, br s).

[0362] Example 5: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexane-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

[0363]

[0364] The mixture was stirred for 20 minutes under ice-cooling for 5 minutes to obtain tert-butyl (1S,4S)-5-(6-cyclopropyl-8-{[4-(1-{(2S)-1-[(2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamoyl)-4-hydroxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]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 (5.72 g) g) trifluoroacetic acid (27 mL) was added dropwise to a solution in CH2Cl2 (55 mL), and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution and CHCl3 / MeOH (9 / 1) were added to the residue. The mixture was extracted three times with CHCl3 / MeOH (9 / 1), and the organic layer subsequently combined was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by means of ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Saturated sodium bicarbonate aqueous solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl3 / MeOH (9 / 1). The combined organic layer was 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. EtOH was added to the resulting product, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the resulting precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to a solid (2.98 g).

[0365] ESI+:1114.5;

[0366] NMR (100℃):0.48-0.68 (4H, m), 0.77 (3H, br d), 1.03-1.10 (3H, m), 1.30 (3H, t), 1.35-1.43 (1H, m), 1.66-1.77 (3H, m), 1.87 (1H, br d), 1.89-1.97 (1H, m), 1.98-2.10 (3H, m), 2.01 (3H, d), 2.11-2.20 (1H, m), 2.50-2.60(1H, m), 3.06 (1H, dd), 3.13 (1H, d), 3.35-3.45 (2H, m), 3.57-3.64 (1H, m),3.65-3.75 (3H, m), 3.75-3.79 (1H, m), 3.80-3.93 (3H, m), 4.11 (2H, q), 4.16(1H, dd), 4.35 (1H, br s), 4.41-4.48 (1H, m), 4.49-4.57 (1H, m), 4.78-4.84(2H, m), 4.87-4.96 (1H, m), 5.12 (1H, br s), 5.17-5.24 (1H, m), 5.24-5.32(2H, m), 6.27 (1H, d), 6.82 (2H, d), 7.30 (1H, d), 7.35-7.40 (2H, m), 7.40-7.48 (5H, m), 7.61 (2H, br d), 8.01 (1H, br d), 8.43 (1H, s), 12.75 (1H, brs).

[0367] Example 6: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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

[0368]

[0369] To a mixture of (1S,4S)-5-{6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (98 mg) and CH2Cl2 (3 mL) was added trifluoroacetic acid (1 mL) under cooling in an ice-methanol bath. The mixture was stirred at room temperature for 2 hours in an argon atmosphere. The resulting reaction mixture was concentrated under reduced pressure, and ice, saturated aqueous sodium bicarbonate solution and CHCl / MeOH (10 / 1) were added to the residue. The mixture was stirred for 10 minutes and then extracted with CHCl / MeOH (10 / 1), and the combined organic layers were then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting product was dissolved in MeOH and concentrated, dried under reduced pressure to give the title compound (73 mg) as a solid.

[0370] ESI+:1105.7;

[0371] NMR (100℃):0.48-0.68 (4H, m), 0.77 (3H, br d), 1.04-1.10 (3H, m), 1.14 (3H, d), 1.35-1.43 (1H, m), 1.74 (1H, br d), 1.87 (1H, br d), 1.89-1.97(1H, m), 2.00 (3H, d), 2.01-2.10 (1H, m), 2.10-2.32 (1H, m), 2.45 (3H, s),2.45-2.60 (1H, m), 3.06 (1H, dd), 3.14 (1H, d), 3.30 (3H, s), 3.60 (1H, brd), 3.65-3.78 (5H, m), 3.84 (1H, dd), 4.16 (1H, dd), 4.28 (1H, dd), 4.32-4.38(2H, m), 4.45 (1H, br t), 4.52 (1H, br t), 4.78-4.85 (2H, m), 4.86-4.94 (1H,m), 5.14 (1H, br s), 5.28 (2H, d), 6.83 (2H, d), 7.30 (1H, d), 7.37-7.43 (4H,m), 7.45 (1H, d), 7.47 (1H, s), 7.59 (2H, br d), 8.00 (1H, br d), 8.42 (1H, s), 8.88 (1H, s), 12.75 (1H, br s).

[0372] Example 7: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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

[0373]

[0374] This compound was prepared using a method analogous to that provided in Example 6 above.

[0375] ESI+:1102.8;

[0376] NMR (100℃):0.48-0.68 (4H, m), 0.77 (3H, br d), 1.07 (3H, d), 1.14(3H, d), 1.30 (3H, t), 1.35-1.43 (1H, m), 1.75 (1H, br d), 1.85-1.98 (2H, m),2.00 (3H, d), 2.01-2.10 (1H, m), 2.42-2.51 (1H, m), 2.51-2.60 (1H, m), 3.07(1H, dd), 3.16 (1H, d), 3.30 (3H, s), 3.60 (1H, br d), 3.65-3.78 (4H, m),3.80 (1H, br s), 3.84 (1H, br dd), 4.07-4.15 (2H, m), 4.17 (1H, dd), 4.28(1H, dd), 4.32-4.39 (2H, m), 4.42-4.48 (1H, m), 4.52 (1H, br t), 4.73-4.85(2H, m), 4.87-4.96 (1H, m), 5.14 (1H, br s), 5.28 (2H, br d), 6.27 (1H, d),6.83 (2H, d), 7.30 (1H, d), 7.35-7.40 (2H, m), 7.40-7.49 (5H, m), 7.59 (2H,br d), 8.01 (1H, br d), 8.42 (1H, s), 12.75 (1H, br s).

[0377] Example 8: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide

[0378]

[0379] This compound was prepared using a method analogous to that provided in Example 6 above.

[0380] ESI+:1089.9.

[0381] Biological Examples

[0382] Example A: In vivo combination therapy with SOC in xenograft mice derived from the human KRAS G12D mutation-positive PK-59 pancreatic cancer cell line

[0383] PK-59 cells (RIKEN, catalog number RCB1901) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. 6- to 8-week-old female nude mice (BALB / c nude mice, from Beijing Vital River Laboratory Animal Technology Co., Ltd) were subcutaneously inoculated with PK-59 cells (3×10 6 ) in 0.2 mL DPBS (containing 50% BD Matrigel (Corning Incorporated)) to form tumors. Animals were randomized and treatment began on day 7 after tumor inoculation, when the average tumor size reached approximately 120 mm 3 . Animals were assigned to groups based on tumor volume using Excel-based randomization software that performed stratified randomization. Each group consisted of 5 mice. Test articles were administered as shown in Table 2. Solvent A was prepared by mixing 4% by volume of ethanol, 1% by volume of 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% by volume of polyoxyethylene hydrogenated castor oil (HCO-40) in a 5% glucose solution. The compound of Example 1 was dissolved therein. Gemcitabine and Abraxane™ (Abraxane™, nanoparticle albumin-bound (nab) paclitaxel) were dissolved in saline. Tumor size and body weight were measured two to three times a week. Tumor volume was calculated using the following formula.

[0384] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5.

[0385] The tumor growth inhibition (TGI) rate (%) of the test compound in each group was calculated using the following formula: TGI (%) = [1-(Ti-T1) / (Vi-V1)] × 100; Ti is the average tumor volume of the treatment group on a given day, T1 is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day as Ti, and V1 is the average tumor volume of the vehicle group on the first day of treatment.

[0386] Table 2

[0387]

[0388] As shown in the test results described in Table 2, the compound of Example 1 in combination with gemcitabine or Aberystokes™ showed anti-tumor activity in mice carrying human pancreatic cancer cells with KRAS G12D mutation, indicating that the combination with the compound of Example 1 is superior to gemcitabine or Aberystokes™ monotherapy for the treatment of G12D mutant KRAS-positive pancreatic cancer.

[0389] Example B: In vivo combination therapy with SOC in xenograft mice derived from a human KRAS G12D mutation-positive GP2d colorectal cancer cell line

[0390] GP2d cells (European Collection of Authenticated Cell Cultures, catalog number 95090714) were cultured in DMEM medium supplemented with 10% fetal bovine serum (2 mM glutamine) at 37°C in an atmosphere of 5% CO2 in air. Female nude mice (BALB / c nude mice, from Beijing Vital River Laboratory Animal Technology Co., Ltd) aged 6 to 8 weeks were subcutaneously inoculated with GP2d cells (3×10 6 ) in 0.2 mL DPBS (containing 50% BD Matrigel (Corning Incorporated)) to form tumors. Animals were randomized and treatment began on day 10 after tumor inoculation, when the average tumor size reached approximately 150 mm 3 . Animals were assigned to groups based on their tumor volume using Excel-based randomization software that performed stratified randomization. Each group consisted of 5 mice. Test articles were administered as shown in Table 3. Solvent A was prepared by mixing 4% by volume of ethanol, 1% by volume of 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% by volume of HCO-40 in a 5% glucose solution. The compound of Example 1 was dissolved therein. 5-FU and irinotecan were dissolved in saline. Oxaliplatin was dissolved in 5% glucose. Tumor size and body weight were measured twice to three times a week. Tumor volume was calculated using the following formula.

[0391] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5.

[0392] The TGI rate (%) of the test compound in each group was calculated using the following formula: TGI (%) = [1-(Ti-T1) / (Vi-V1)] × 100; Ti is the average tumor volume of the treatment group on a given day, T1 is the average tumor volume of the treatment group on the first day of treatment, Vi is the average tumor volume of the vehicle control group on the same day as Ti, and V1 is the average tumor volume of the vehicle group on the first day of treatment.

[0393] Table 3

[0394]

[0395] As shown in the test results described in Table 3, the compound of Example 1 in combination with 5-FU, irinotecan or oxaliplatin showed anti-tumor activity in mice carrying human colorectal cancer cells with a KRAS G12D mutation, indicating that the combination with the compound of Example 1 is superior to 5-FU, irinotecan or oxaliplatin monotherapy for the treatment of G12D mutant KRAS-positive colorectal cancer.

[0396] Example C: In vivo combination therapy with docetaxel in KRAS G12D mutation-positive human lung cancer patient-derived xenograft mice

[0397] Female nude mice aged 4 to 6 weeks (control: NMRI-Foxn1nu, from Charles River) were kept in a warehouse and subcutaneously inoculated with tumors derived from human lung cancer patients (model name: LXFA 2204 (from Charles River)). Animals were assigned to groups based on the tumor volume of the animals using Excel-based randomization software that performs stratified randomization. Each group consisted of 8 mice. Test articles were given as shown in Table 4. Solvent A was prepared by mixing 4% by volume of ethanol, 1% by volume of 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% by volume of HCO-40 in a 5% glucose solution. The compound of Example 1 was dissolved therein. Docetaxel was dissolved in a 0.9% NaCl solution. Tumor diameter and weight volume were measured twice a week. Tumor volume was calculated using the following formula.

[0398] [Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 ×0.5.

[0399] The tumor growth inhibition (TGI) rate (%) of the test compound was calculated, with the test compound-treated group having 100% inhibition of tumor volume one day before the start of treatment and the vehicle group having 0% inhibition of tumor volume at the end of 3 weeks after the first treatment.

[0400] The following results were obtained (Table 4).

[0401] Table 4.

[0402]

[0403] As shown in the test results described in Table 4, the anti-tumor activity of the compound of Example 1 in combination with docetaxel in human G12D mutant KRAS-positive lung cancer cell line tumor-bearing mice indicates that the combination with the compound of Example 1 may be superior to docetaxel monotherapy.

[0404] Industrial Applicability

[0405] The present invention is excellent in anti-tumor activity and can be used to treat G12D mutant KRAS-positive cancers, especially G12D mutant KRAS-positive pancreatic cancer, colorectal cancer and / or lung cancer, etc.

Claims

1. A combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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]hept-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]hept-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]hept-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]hept-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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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, and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in claim 1, for use in treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, the anticancer agent being selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

3. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 and an anticancer agent or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof. The pharmaceutical composition according to claim 3 , which is used for treating cancer.

5. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof.

6. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as claimed in claim 1 for treating cancer, wherein the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds, and prodrugs thereof.

7. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the manufacture of a medicament for treating cancer, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof.

8. A kit of parts comprising: (A) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, and optionally one or more pharmaceutically acceptable excipients, and (B) a pharmaceutical composition comprising an anticancer agent or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, wherein the anticancer agent is selected from the group consisting of a taxane compound, a fluorinated nucleoside, a platinum compound, a camptothecin analog, a fluoropyrimidine compound, and a prodrug thereof, The components (A) and (B) are each provided in a form suitable for administration in combination with the other component, The kit of components is used to treat cancer.

9. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of any one of claims 1 to 8, wherein the anticancer agent is a taxane compound.

10. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 9, wherein the taxane compound is paclitaxel.

11. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 9, wherein the taxane compound is docetaxel.

12. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of any one of claims 1 to 8, wherein the anticancer agent is a fluorinated nucleoside.

13. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 12, wherein the fluorinated nucleoside is gemcitabine.

14. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of any one of claims 1 to 8, wherein the anticancer agent is a platinum compound.

15. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 14, wherein the platinum compound is oxaliplatin.

16. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of any one of claims 1 to 8, wherein the anticancer agent is a camptothecin analog.

17. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 16, wherein the camptothecin analog is irinotecan.

18. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use, or kit of parts for use of any one of claims 1 to 8, wherein the anticancer agent is a fluoropyrimidine compound.

19. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use or kit of parts for use of claim 18, wherein the fluoropyrimidine compound is 5-FU.

20. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use, or kit of parts for use of any one of claims 1 to 19, wherein the cancer is pancreatic cancer.

21. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use, or kit of parts for use of any one of claims 1 to 19, wherein the cancer is colorectal cancer.

22. The compound for use, pharmaceutical composition for use, pharmaceutical composition for use, method, use, or kit of parts for use of any one of claims 1 to 19, wherein the cancer is lung cancer.

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