Anticancer drug combinations containing bifunctional compounds with G12D mutant KRAS inhibitory activity

Abstract

Provided herein is a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is a bifunctional compound having G12D mutant KRAS inhibitory activity, and an anticancer agent for use in the treatment of cancer, wherein the compound of formula (I) and the anticancer agent are as described herein.

Description

[Technical Field]

[0001] The present invention relates to combinations of specific anti-cancer compounds, and pharmaceutical compositions and kits containing them, for use in the treatment of cancers such as pancreatic, colon and lung cancer. [Background technology]

[0002] KRAS (Kirsten Rat Sarcoma Virus) is a gene that provides instructions for making a protein called K-Ras, which is part of the RAS / MAPK pathway. This protein relays signals from outside the cell to the cell's nucleus. These signals tell the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate).

[0003] KRAS mutations have been implicated in a variety of malignancies, including cancers such as lung adenocarcinoma, mucinous adenoma, pancreatic ductal carcinoma, and colorectal cancer. Colorectal cancer is a cancer with a high incidence and mortality rate, with approximately 1.4 million new cases reported annually worldwide (World Cancer Report 2014). While surgery remains the most effective treatment for colorectal cancer, chemotherapy and radiation therapy have also made significant advances in recent years. Large-scale clinical trials conducted primarily in Europe and the United States have demonstrated that combination chemotherapy, which combines several anticancer drugs, is effective against colorectal cancer, contributing to tumor regression and prolonged prognosis (J. Clin. Oncol., 22, pp. 229–237, 2004). In addition to chemotherapy, molecularly targeted drugs such as anti-VEGF (vascular endothelial growth factor) antibodies and anti-EGFR (epidermal growth factor receptor) antibodies are often used in combination with chemotherapy as first-line treatments. Regarding EGFR antibody drugs, it is clear that mutations in the RAS gene are a negative predictor of efficacy (Cancer Res., 66, pp. 3992-3995, 2006), and in colorectal cancer, EGFR antibody drugs are currently only applicable to patients with wild-type RAS genes.

[0004] Additionally, lung cancer accounts for 19% of all cancer deaths, the highest rate, with approximately 1.8 million new cases reported annually worldwide (World Cancer Report 2014). Specifically, non-small cell lung cancer (NSCLC) patients are reported to account for 80-85% of lung cancer cases (American Cancer Society, Cancer Facts and Figures, 2016). While surgical treatment is considered up to a certain stage, chemotherapy and radiation therapy become the secondary treatments. Based on cytomorphology, adenocarcinoma and squamous cell carcinoma are the most common types of NSCLC. While these tumors share a similar clinical course, adenocarcinoma is characterized by its location in the lung periphery.

[0005] Pancreatic cancer, primarily pancreatic ductal adenocarcinoma, has an extremely poor prognosis, with a 5-year survival rate of less than 10% (CA Cancer J.Clin., 2016, 66, pp. 7–30), and approximately 340,000 new cases are reported annually worldwide (GLOBOCAN 2012). The most effective treatment for pancreatic cancer is surgery. However, because early detection is difficult, pancreatic cancer often metastasizes, making it inoperable. In inoperable cases, chemotherapy and radiation therapy are used, but survival rates are poor. Currently, FOLFRINOX therapy (a combination therapy of 5-FU, irinotecan, and oxaliplatin with the addition of levofolinate) is the standard treatment for pancreatic cancer. However, due to its strong toxicity, patients must be carefully selected; for example, this therapy should only be used on patients with an ECOG performance status of 1 or less (J. Clin. Oncol., 2018, 36, pp. 2545-2556). As a molecular targeted drug, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved in combination with gemcitabine. However, the overall survival benefit was only about two weeks compared to gemcitabine alone, and no satisfactory therapeutic effect was achieved.

[0006] RAS proteins are small guanosine triphosphate (GTP)-binding proteins of approximately 21 kDa composed of 188–189 amino acids. RAS proteins include four major types (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) produced by three genes: KRAS, NRAS, and HRAS. RAS proteins are divided into active GTP-bound and inactive GDP-bound forms. RAS proteins are activated by ligand stimulation of cell membrane receptors, such as EGFR, by replacing guanosine diphosphate (GDP) with GTP. Active RAS binds to up to 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signaling cascades. Meanwhile, active RAS is converted to its inactive form by replacing GTP with GDP through its intrinsic GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). As can be seen from the above, RAS plays an important role as a "molecular switch" in intracellular signaling pathways such as EGFR, and plays an extremely important role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev.Cancer, 2011, 11, pp. 761-774; Nature Rev.Drug Discov., 2014, 13, pp. 828-851; Nature Rev.Drug Discov., 2016, 15, pp. 771-785).

[0007] Spontaneous mutations in the RAS gene result in amino acid substitutions that reduce RAS function as a GTPase and its response to GAPs, resulting in a constitutively activated state, which then transmits signals downstream. This excessive signaling can lead to oncogenesis and accelerated cancer growth.

[0008] For example, pancreatic ductal adenocarcinoma (PDA) has been shown to develop through a weakly dysplastic stage followed by a strongly dysplastic stage in pancreatic intraepithelial neoplasia (PanIN). Mutations in the KRAS gene are already present in early-stage PanIN. Subsequently, abnormalities in the tumor suppressor genes INK4A, p53, and SMAD4 lead to malignant progression (Nature Rev. Cancer, 2010, 10, pp. 683-695). Furthermore, mutations in the KRAS gene are present in over 90% of PDA cases, the majority of which are spontaneous point mutations at codon 12 in KRAS exon 2 (Cancer Cell, 2017, 32, pp. 185-203). As can be seen from the previous section, KRAS plays a crucial role in the oncogenesis and development of pancreatic cancer.

[0009] Known mutations in the KRAS gene include the KRAS G12C mutation and the KRAS G12D mutation. The G12C mutation occurs frequently in non-small cell lung cancer, but occurs in a small percentage of pancreatic cancer (Cancer Cell 2014, 25, pp. 272-281). Therefore, therapeutic agents for other KRAS mutations are desired. The G12D mutation is reported to be found in approximately 34% of pancreatic cancer cases, the highest rate among KRAS mutations (Nat. Rev. Cancer 2018, 18, pp. 767-777).

[0010] WO2016 / 049565, WO2016 / 049568 and WO2017 / 172979 disclose certain KRAS inhibitors and state that these agents are useful for cancers with mutations in KRAS codon 12. The G12D mutation is one such mutation, but there is no description of their effects on G12D-mutated KRAS cancers.

[0011] In recent years, bifunctional compounds, collectively known as PROTACs (proteolysis-targeting chimeras) or SNIPERs (specific and nongenetic IAP-dependent protein erasers), have been discovered as a technique for inducing target protein degradation and are expected to become a novel drug discovery modality (Drug.Discov.Today Technol., 2019, 31, pp. 15-27). Such bifunctional compounds promote the formation of a complex between the target protein and an E3 ligase in cells, and the degradation of the target protein is induced using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases recognize proteins to be degraded and convert them to ubiquitin, thereby promoting degradation by the proteasome.

[0012] More than 600 E3 ligases exist in living organisms, and they can be broadly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. Currently, only a limited number of E3 ligases are used as bifunctional degraders, known as PROTACs and SNIPERs. Representative examples include von Hippel-Lindau (VHL), cerebron (CRBN), inhibitor of apoptosis proteins (IAPs), and mouse double minute 2 homolog (MDM2). Specifically, VHL was reported in WO2013 / 106643, and CRBN was reported in WO2015 / 160845.

[0013] A bifunctional compound is a compound in which a ligand of a target protein and a ligand of an E3 ligase are linked via a linker, and some bifunctional compounds have been reported for degrading KRAS proteins (Cell. Chem. Biol., 2020, 27, pp. 19-31; ACS Cent. Sci., 2020, 6, pp. 1367-1375; US2018 / 0015087; WO2019 / 195609; WO2020 / 018788). Summary of the Invention

[0014] It has now surprisingly been found that the combination of compounds of formula (I) as defined herein with certain further anti-cancer agents as defined herein represents a promising strategy for the treatment of cancer.

[0015] Without wishing to be bound by theory, it is believed that the compound of formula (I) defined herein is a bifunctional compound, has the decomposition-inducing effect on G12D mutant KRAS protein and the inhibitory activity of G12D mutant KRAS, and can be used together with anticancer drugs in the treatment of cancer.Specifically, it is believed that the combination of the compound of formula (I) with an anticancer drug selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors and their prodrugs can provide a strong synergistic effect in the treatment of cancer.

[0016] Thus, in a first aspect of the invention there is provided a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g. CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof for use in the treatment of cancer, wherein the compound of formula (I) is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0017] A 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 the treatment of cancer, wherein the treatment of cancer further comprises the administration of an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g. CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof.

[0018] An alternative second aspect of the present invention is an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g. CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof for use in the treatment of cancer, wherein the treatment of cancer further comprises the administration of a compound of Formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0019] A third aspect of the present invention is a pharmaceutical composition comprising a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.

[0020] A fourth aspect of the present invention is a pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.

[0021] A fifth aspect of the present invention is a method of treating cancer, comprising the step of administering to a subject 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 selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor (e.g., a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor) and a prodrug thereof or a pharmaceutically acceptable salt thereof.

[0022] A sixth aspect of the present invention is the use of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of cancer.

[0023] A seventh aspect of the present invention is (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 (B) A pharmaceutical composition comprising an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor (e.g., a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor), and a prodrug thereof or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. 1. A kit of parts for use in the treatment of cancer, comprising: It is a kit of parts in which components (A) and (B) are each provided in a form suitable for administration in conjunction with the other component.

[0024] An eighth aspect of the present invention is use of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors), and prodrugs thereof or pharmaceutically acceptable salts thereof, for the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise defined, 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. Preferences and alternatives for any given aspect, embodiment, feature or parameter of the invention should be considered as disclosed in combination with all preferences and alternatives for all other aspects, features and parameters of the invention, unless the context indicates otherwise.

[0026] Whenever the word "about" is used herein (e.g., in connection with the dose of an active ingredient), it is understood that such variable is approximate and therefore can vary by ±10%, for example ±5%, preferably ±2% (e.g., ±1%) from the number specified herein.

[0027] Those skilled in the art will understand that reference to "treatment" (also "treating") of a particular condition takes its ordinary meaning in the medical arts. Specifically, the term can refer to achieving a decrease in the severity of one or more clinical symptoms associated with the condition or improving the longevity of the treated patient.

[0028] As used herein, reference to a patient refers to a living subject being treated, including a mammalian (e.g., human) patient. Thus, in specific embodiments of related aspects of the invention (e.g., the first, second, fourth, fifth, sixth, and eighth aspects of the invention), the treatment is in a mammal (e.g., a human).

[0029] As used herein, the term "therapeutically effective amount" refers to an amount of a compound that confers a therapeutic effect on a treated patient. The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of and / or feels an effect). For example, in the context of 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 the tumors.

[0030] For the avoidance of doubt, the compounds of formula (I) and anti-cancer agents described herein may exist as solids, and therefore the scope of the present invention includes all their amorphous, crystalline and partially crystalline forms, but the compounds of formula (I) and anti-cancer agents described herein may also exist as oils.When such compounds exist in crystalline and partially crystalline forms, these forms may include hydrates and solvates, which are included in the scope of the present invention.The compounds of the present invention may also exist in dissolved state.

[0031] Compounds for Use As described herein, a first aspect of the invention provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, wherein the compound of formula (I) is: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide A combination is provided in which the combination is selected from the group consisting of:

[0032] In a second aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention for use in the treatment of cancer, wherein the treatment of cancer further comprises the administration of an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof.

[0033] In an alternative second aspect of the present invention, there is provided an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof for use in the treatment of cancer, wherein the treatment of cancer further comprises the administration of a compound of Formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0034] Compounds of formula (I) The compounds of formula (I) referred to herein are: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide The compound is selected from the group consisting of:

[0035] For the avoidance of doubt, the structures of compounds of formula (I) correspond to the structures provided in Examples 1-8. 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0036] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide.

[0037] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide.

[0038] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0039] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

[0040] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0041] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

[0042] 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]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0043] In certain embodiments, the compound of formula (I) is: (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide is selected from the group consisting of:

[0044] In certain embodiments, the compound of formula (I) is: (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide is selected from the group consisting of:

[0045] The compound of formula (I) and the anticancer agent may have tautomers or geometric isomers depending on the type of substituents. In this specification, the compound of formula (I) and the anticancer agent may be described as only one of the isomers, but the present invention includes tautomers or geometric isomers other than those described, and also includes separated isomers or mixtures thereof.

[0046] The compounds of formula (I) may have one or more asymmetric carbon atoms and may therefore exist in particular enantiomeric and diastereomeric forms thereof. The present invention includes separated enantiomers and diastereomers of the compounds of formula (I) or mixtures thereof.

[0047] Enantiomers of chiral compounds having one or more asymmetric carbon atoms may be given the designation "(R)" and "(S)" for each point of chirality based on methods known in the art (e.g., using the Cahn-Ingold-Prelog ranking rules).

[0048] In certain embodiments, reference to a particular stereoisomer of a compound of Formula (I) may refer to the presence of that particular stereoisomer (e.g., the particular enantiomer or diastereoisomer indicated) in the substantial absence of other stereoisomers (i.e., the stereoisomers have different configurations at one or more of the relevant points of chirality).

[0049] In such cases, the compounds of formula (I) in the relevant configuration may optionally be present in an enantiomeric excess (ee) or diastereomeric excess (de) of at least 60% (e.g., at least 70%, 80%, 90%, 95% or 98%, or especially at least 99%, e.g., at least 99.9%).

[0050] Compounds of formula (I) may have axial chirality, which may refer to compounds having one or more axes about which a set of substituents are held in a spatial arrangement that is not superimposable on its mirror image. For the avoidance of doubt, all axial configurations of such compounds are within the scope of the present invention.

[0051] Enantiomers of axially chiral compounds may be given the designation "M" and "P" based on methods known in the art (e.g., using the Cahn-Ingold-Prelog ranking rules, but with the additional rule that two "close" substituents have a higher ranking than two "distant" substituents).

[0052] In certain embodiments, reference to a particular axial stereoisomer of a compound of Formula (I) can mean the presence of that particular stereoisomer (e.g., an isomer having M-axial asymmetry) in the substantial absence of the corresponding opposite stereoisomer (e.g., an isomer having P-axial asymmetry).

[0053] In such cases, in the compound of formula (I), the axial stereoisomer (e.g., the M axial isomer) has a purity of at least 70% (e.g., at least 80%, 90%, 95% or 99%) relative to the other axial stereoisomer (e.g., relative to the P axial chiral isomer).

[0054] For the avoidance of doubt, compounds which are said to have a particular stereochemistry at a defined position (e.g., axial chirality) may also have stereochemistry at one or more other positions and may therefore exist as mixtures of enantiomers or diastereoisomers with respect to the stereochemistry at those positions.

[0055] Furthermore, the present invention includes pharmaceutically acceptable prodrugs (sometimes called precursors) of the compounds represented by formula (I) and anticancer drugs. Pharmaceutically acceptable prodrugs include compounds having a group that can be converted into an amino group, a hydroxy group, a carboxy group, or the like by solvolysis or under physiological conditions. Examples of groups that can be used to form prodrugs include those described in Prog. Med., 1985, 5, pp. 2157-2161, or in "Iyakuhin no Kaihatsu (development of pharmaceuticals)," Vol. 7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, pp. 163-198. Prodrugs include ester derivatives and carbamate derivatives.

[0056] A prodrug may be referred to as a precursor of the active compound (i.e., the compound of formula (I) and the anti-cancer drug), and this precursor may refer to a compound that is metabolized in vivo to form the active compound.

[0057] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be formed by conventional means, for example, by reacting the free acid form or free base form of the compound contained in the formulation of the present invention with one or more equivalents of a suitable acid or base, if necessary, in a solvent or in a medium in which the salt is insoluble, and then removing the solvent or the medium using standard techniques (for example, by rotary evaporation under reduced pressure, by lyophilization or by filtration).Salts can also be prepared by exchanging the counterion of the compound contained in the formulation of the present invention in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0058] Examples of salts include those listed 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 acid addition salts 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 acetylleucine, lysine, and ornithine, and ammonium salts.

[0059] In one embodiment, the pharmaceutically acceptable salt of the compound of Formula (I) and / or the anticancer agent is a hydrochloride (HCl) salt. Furthermore, the present invention also includes various hydrates, solvates, crystalline polymorphs, and amorphous solid forms of the compounds of formula (I) and anticancer agents and their salts. 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.

[0060] anticancer drugs As described herein, the anti-cancer agent is selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors, and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors), and prodrugs thereof.

[0061] The term "CDK4 / 6 inhibitor" refers to cyclin-dependent kinase 4 and 6 inhibitors, including palbociclib, ribociclib, and abemaciclib.

[0062] In one embodiment, the anti-cancer agent is a CDK4 / 6 inhibitor. In a particular embodiment, the CDK4 / 6 agonist is palbociclib. Palbociclib refers to the compound having the name 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one and the following structure:

[0063] [ka]

[0064] The term "SHP2 inhibitors" refers to inhibitors of the protein tyrosine phosphatase SHP2 encoded by PTPN11, and includes TNO155, JAB-3068, RMC-4630 and RLY-1971.

[0065] In one embodiment, the anti-cancer agent is an SHP2 inhibitor. In a particular embodiment, the SHP2 inhibitor is TNO155. TNO155 refers to a compound having the name (3S,4S)-8-[6-amino-5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-pyrazinyl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine and the following structure:

[0066] [ka]

[0067] The term "EGFR inhibitor" refers to an inhibitor of the epidermal growth factor receptor (EGFR), including both tyrosine kinase inhibitors (TKIs) (such as afatinib, erlotinib, or gefitinib) and monoclonal antibodies (such as cetuximab or necitumumab). Tyrosine kinase inhibitors bind to the tyrosine kinase domain of EGFR and inhibit the activity of EGFR; on the other hand, monoclonal antibodies bind to the extracellular component of EGFR and prevent epidermal growth factor from binding to its receptor, thus preventing cell division.

[0068] In one embodiment, the anticancer agent is an EGFR inhibitor. In a specific embodiment, the EGFR inhibitor is a tyrosine kinase inhibitor. In a more specific embodiment, the tyrosine kinase inhibitor is afatinib.

[0069] Afatinib refers to the compound having the name (E)-N-[4-(3-chloro-4-fluoroanilino)-7-[(3S)-oxolan-3-yl]oxyquinazolin-6-yl]-4-(dimethylamino)but-2-enamide and the following structure:

[0070] [ka]

[0071] In certain embodiments, the EGFR inhibitor is cetuximab. The term "mTOR inhibitors" refers to a class of drugs that inhibit the target of rapamycin complex (mTOR), a serine / threonine-specific protein kinase belonging to the phosphatidylinositol-3-kinase (PI3K)-related kinase (PIKK) family. mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The term "mTOR" inhibitors includes everolimus, sirolimus, temsirolimus, ridaforolimus, umirolimus, and zotarolimus.

[0072] In one embodiment, the anticancer agent is an mTOR inhibitor. In a particular embodiment, the mTOR inhibitor is everolimus. Everolimus refers to a compound having the name (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone and the following structure:

[0073] [ka]

[0074] The term "immune checkpoint inhibitor" refers to an inhibitor of immune checkpoint signaling that limits the function of the immune system. Thus, immune checkpoint inhibitors can result in increased T cell activation, proliferation and / or T cell signaling. "Immune checkpoint inhibitors" include anti-PD-1 antibodies (e.g., nivolumab (Opdivo; BMS-936558), pembrolizumab (Keytruda™; MK-3475), pidilizumab (CT-011), cemiplimab (Libtayo, REGN2810), spartalizumab (PDR001), MEDI0680 (AMP-514), dostallimab (TSR-042), cetrelimab (JNJ 63723283), toripalimab (JS001), AMP-224 (GSK-2661380), PF-06801591, tislelizumab (BGB-A317), ABBV-181, BI 754091, or SHR-1210), and anti-PD-L1 antibodies (e.g., Tecentriq; RG7446; MPDL3280A; R05541267), durvalumab (MEDI4736), BMS-936559, avelumab (BAVENCIO), lodapolimab (LY3300054), CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105).

[0075] In one embodiment, the anti-cancer agent is an immune checkpoint inhibitor. In a specific embodiment, the immune checkpoint inhibitor is an anti-PD-1 antibody. In a more specific embodiment, the anti-PD-1 antibody is nivolumab.

[0076] Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to the programmed death 1 (PD-1) receptor and has the following CAS number: 946414-94-4. The term "PI3K inhibitors" refers to a class of drugs that inhibit phosphatidylinositol-3-kinase. PI3K inhibitors include idelalisib, copanlisib, duvelisib, alpelisib, umbralisib, and leniolisib.

[0077] In one embodiment, the anticancer agent is a PI3K inhibitor. In a particular embodiment, the PI3K inhibitor is alpelisib. Alpelisib refers to the compound having the name "(2S)-N1-{4-methyl-5-[2-(1,1,1-trifluoro-2-methyl-2-propanyl)-4-pyridinyl]-1,3-thiazol-2-yl}-1,2-pyrrolidinedicarboxamide" and the following structure:

[0078] [ka]

[0079] The term "SOS1 inhibitor" refers to an inhibitor of the RAS guanine nucleotide exchange factor SOS1. SOS1 inhibitors include BI-3406 and MRTX0902. In one embodiment, the anticancer agent is an SOS1 inhibitor. In a particular embodiment, the SOS1 inhibitor is MRTX0902.

[0080] MRTX0902 refers to a compound having the name "(R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido-[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile," CAS number: 2654743-22-1, and the following structure:

[0081] [ka]

[0082] The term "AURK inhibitor" refers to an inhibitor of Aurora kinase. AUK inhibitors include Aurora kinase A inhibitors and Aurora kinase B inhibitors. AURK inhibitors include alisertib, barasertib, danusertib, AT9283, PF-03814735, and AMG900.

[0083] In one embodiment, the anticancer agent is an AURK inhibitor. In a particular embodiment, the AURK inhibitor is an AURK A inhibitor. In a more particular embodiment, the AURK A inhibitor is alisertib.

[0084] Alisertib refers to the compound with the name "4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid" and the following structure:

[0085] [ka]

[0086] In some embodiments, the anti-cancer agent is selected from the group consisting of a CDK4 / 6 inhibitor, a SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, and a prodrug thereof.

[0087] In some embodiments, the anti-cancer agent is selected from the group consisting of a PI3K inhibitor, an SOS1 inhibitor, an AURK inhibitor, and prodrugs thereof. cancer As used herein, the following terms may be understood to have the meanings indicated.

[0088] The term "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid. "G12D mutant KRAS" refers to KRAS having the above-mentioned "G12D mutation."

[0089] "G12D mutant KRAS-positive cancer" refers to a G12D mutant KRAS-positive cancer, for example, a cancer in which the KRAS G12D mutation has occurred and in which the positive rate of G12D mutant KRAS is high.

[0090] "Pancreatic cancer" refers to a malignant tumor that occurs in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. In one embodiment, the "pancreatic cancer" is pancreatic ductal carcinoma, and in another embodiment, the "pancreatic cancer" is pancreatic ductal adenocarcinoma.

[0091] "Colon cancer" is a malignant tumor that occurs in the large intestine. "Lung cancer" is a malignant tumor that occurs in the lungs. In one embodiment, the cancer is metastatic, locally advanced, recurrent, and / or refractory cancer.

[0092] In certain embodiments, the cancer is a cancer in a patient who has not been previously treated for the associated condition (i.e., has no prior treatment history for previous treatments for that condition), and the patient (or specifically the associated cancer) may be said to be treatment-naive.

[0093] In a further embodiment, the cancer is a cancer in a patient who has received treatment (i.e. a different treatment, that is a treatment other than the treatment defined in the first aspect of the invention) for the relevant condition and who has failed to respond or responded insufficiently to that treatment.

[0094] In one embodiment, the cancer is defined as being refractory to treatment (i.e., a treatment-resistant cancer, a cancer that does not respond or does not respond adequately to other medical treatments, which refers to treatments other than those defined in the first aspect of the invention). A refractory cancer may exhibit resistance to treatment from the start of treatment, or resistance may be acquired by the cancer cells during the course of previous treatments.

[0095] In certain embodiments, the cancer is a cancer that is refractory to therapy with a compound of Formula (I) without the combination defined in the first aspect of the invention (i.e., where the previous therapy included a compound of Formula (I)), but where the cancer treatment did not include treatment with an anti-cancer agent selected from a CDK4 / 6 inhibitor, a SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, a SOS1 inhibitor, and an AURK inhibitor, and prodrugs thereof.

[0096] In one embodiment, the cancer is pancreatic cancer. In a particular embodiment, the pancreatic cancer is pancreatic ductal carcinoma or pancreatic ductal adenocarcinoma. In one embodiment, the cancer is colorectal cancer. In a particular embodiment, the colorectal cancer is colon cancer or rectal cancer.

[0097] In one embodiment, the cancer is lung cancer. In a particular embodiment, the lung cancer is small cell lung cancer or non-small cell lung cancer. In one embodiment, the cancer is a G12D mutant KRAS positive cancer.

[0098] In certain embodiments, the G12D mutant KRAS positive cancer is G12D mutant KRAS positive pancreatic cancer.In alternative embodiments, the G12D mutant KRAS positive cancer is G12D mutant KRAS positive colon cancer.In alternative embodiments, the G12D mutant KRAS positive cancer is G12D mutant KRAS positive lung cancer.

[0099] According to a second aspect of the present invention is an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof for use in the treatment of cancer, wherein the treatment of cancer further comprises the administration of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof.

[0100] For the avoidance of doubt, the second aspect of the invention may have any of the particular features and embodiments described herein for the first aspect of the invention, including all combinations thereof.

[0101] Pharmaceutical Composition According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, an anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.

[0102] For the avoidance of doubt, the pharmaceutical composition of the third aspect of the invention may have any of the particular features and embodiments described herein for the other (e.g. first and second) aspects of the invention, including all combinations thereof.

[0103] Suitable pharmaceutical compositions may be commercially available or, alternatively, are described in literature such as Remington, The Science and Practice of Pharmacy, 19th Edition, Mack Printing Company, Easton, Pennsylvania (1995), and Martindale-The Complete Drug Reference (35th Edition), and documents referenced therein, the relevant disclosures of all of which are incorporated herein by reference in their entireties. Alternatively, the preparation of suitable compositions, particularly combination formulations comprising both a compound of Formula (I) and an anticancer agent or a pharmaceutically acceptable salt thereof, can be carried out by one skilled in the art using routine techniques.

[0104] Reference to a pharmaceutically acceptable excipient may be understood to include pharmaceutically acceptable diluents, carriers and / or adjuvants, as known to those skilled in the art. In certain embodiments, the pharmaceutical composition may be suitable for administration according to one or more of the methods of administration described herein.

[0105] For the avoidance of doubt, the pharmaceutical compositions described herein may comprise one or more doses of the compounds of formula (I) and / or anti-cancer agents described herein, or may comprise partial doses of such components (in which case multiple such compositions may be administered in a course of treatment as described herein).

[0106] For the avoidance of doubt, the pharmaceutical compositions described herein may also be referred to as pharmaceutical formulations. According to a fourth aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.

[0107] For the avoidance of doubt, the pharmaceutical composition of the fourth aspect of the invention may have any of the particular features and embodiments described herein for the other (e.g. first to third) aspects of the invention, including all combinations thereof.

[0108] Administration As used herein, by referring to methods and treatments involving a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent or a pharmaceutically acceptable salt thereof (both as defined in the first aspect of the invention), we include the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent or a pharmaceutically acceptable salt thereof (including pharmaceutical compositions comprising each component) sequentially, separately or simultaneously as part of a medical intervention directed to the treatment of the relevant disease or disorder.

[0109] Thus, in certain embodiments, two active ingredients (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent or a pharmaceutically acceptable salt thereof) are administered together or sufficiently closely in time (repeatedly as necessary) to allow a greater beneficial effect to the patient over the course of treatment of the relevant condition than if either the formulation comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the formulation comprising the anti-cancer agent (defined in the first aspect of the invention) or a pharmaceutically acceptable salt thereof, were administered alone (repeatedly as necessary) in the absence of the other agent over the same course of treatment. The determination of whether a combination results in a greater beneficial effect with respect to, and over the course of, the treatment of a particular cancer can be made routinely by one of ordinary skill in the art.

[0110] In further embodiments, the two compounds or compositions are administered (repeatedly as necessary) before, after, and / or contemporaneously with the administration of the other component. When used in this context, the terms "administered simultaneously" and "administered contemporaneously" include administration of individual doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an anti-cancer agent (as defined in the first aspect of the invention) or a pharmaceutically acceptable salt thereof, within 2 hours (e.g., within 60 minutes, 45 minutes, 30 minutes, 20 minutes, or 10 minutes) of each other.

[0111] In certain embodiments, the two compounds or compositions are administered sequentially (repeatedly as needed). As used in this context, the term "administered sequentially" includes administration of individual doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent (as defined in the first aspect of the present invention) or a pharmaceutically acceptable salt thereof, with a time interval 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) between each other.

[0112] For the avoidance of doubt, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same) may be administered prior to the administration of the anti-cancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same). Alternatively, the anti-cancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same) may be administered prior to the formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same).

[0113] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing it) and a formulation containing an anticancer drug or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing it) are administered sequentially, for example, the second drug is administered after confirming 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.

[0114] Those skilled in the art will appreciate that the compounds and pharmaceutical formulations defined herein can be administered either orally using tablets, pills, capsules, granules, powders, liquids or other agents, or parenterally using intra-articular, intravenous, intramuscular or other injectable, transmucosal or inhalant agents.

[0115] The solid composition for oral administration can be tablets, powders, granules or other medicines.In such solid compositions, one or more active ingredients are mixed with at least one inert excipient.Compositions can contain inert additives such as lubricants, disintegrants, stabilizers, and dissolution aids according to conventional methods.Tablets or pills can be coated with sugar coating or gastric or enteric film as needed.

[0116] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and contain commonly used inert diluents, such as purified water or EtOH (ethanol). In addition to the inert diluent, the liquid composition may contain auxiliary agents such as solubilizers, wetting agents, or suspending agents, sweeteners, flavors, aromatics, or preservatives.

[0117] Injectables for parenteral administration include sterile 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 include alcohols such as EtOH. Such compositions may further contain isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These may be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. In addition, such compositions may be prepared as sterile solid compositions, which are dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0118] Transmucosal agents such as inhalants or nasal agents can be used in solid, liquid, or semisolid form and can be prepared according to conventionally known methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., can be added as appropriate. Administration can be carried out by using a suitable device for inhalation or insufflation. For example, the drug can be administered using a known device such as a metered dose inhaler or nebulizer, either as a compound alone, as a powder of a formulated mixture, or as a solution or suspension combined with a pharmaceutically acceptable carrier. Dry powder inhalers and the like can be used for single or multiple doses, and dry powder or powder-containing capsules can be used. Alternatively, they can be used in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.

[0119] In one embodiment, the compounds and compositions described herein are administered orally, intraarticularly, intravenously, intramuscularly, transmucosally, or by inhalation. In certain embodiments, the compounds and compositions described herein are administered intravenously.

[0120] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally or by inhalation, for example, intravenously.

[0121] In one embodiment, the anti-cancer agent or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising same) is administered orally, intraarticularly, intravenously, intramuscularly, transmucosally or by inhalation, e.g., orally or intravenously (as determined by the anti-cancer agent used).

[0122] 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 (e.g., intravenously).

[0123] In an alternative embodiment, the compound of formula (I) or its pharmaceutically acceptable salt and the anticancer agent or its pharmaceutically acceptable salt are administered sequentially via different administration routes. For example, the compound of formula (I) or its pharmaceutically acceptable salt may be administered intravenously, and the anticancer agent or its pharmaceutically acceptable salt may be administered orally.

[0124] Dosage Those skilled in the art will be able to determine appropriate (i.e., therapeutically effective) doses of the compounds of formula (I) and anti-cancer agents described herein using routine techniques and by reference to relevant literature on those techniques, such as relevant marketing authorizations and / or adopted formularies.

[0125] For the avoidance of doubt, references herein to uses, compounds for use, methods, combinations, compositions and kits of parts are intended to include references to the agents used therein being in their therapeutically effective amounts.

[0126] Exemplary doses of the compounds of formula (I) and anti-cancer agents described herein are as follows: In the case of oral administration, the daily dose of the compound of formula (I) and / or the anticancer agent may be approximately 0.001 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, and more preferably 0.1 to 10 mg / kg body weight, and this dose may be given once a day or divided into 2 to 4 doses (e.g., 2, 3, or 4 times a day).

[0127] For intravenous administration, the daily dose of the compound of formula (I) and / or the anticancer agent may be about 0.0001 to 10 mg / kg body weight, given once a day or in two to four divided doses (e.g., two, three, or four times a day).

[0128] Additionally, the daily dose of the transmucosal agent is about 0.001 to 100 mg / kg body weight, given once a day or divided into multiple doses (eg, two, three, or four times a day). Those skilled in the art will understand that the dosage to be used will be determined appropriately for each individual case, taking into consideration the symptoms, age, sex, etc. of the patient.

[0129] Treatment methods According to a fifth aspect of the present invention is a method of treating cancer, the method comprising the step of administering to a subject in need of treatment a therapeutically effective amount of a 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 anti-cancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors, and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof.

[0130] For the avoidance of doubt, the method of the fifth aspect of the invention may have any of the particular features and embodiments described above for the other (e.g. first to fourth) aspects of the invention, including all combinations thereof.

[0131] Use in the manufacture of medicines A sixth aspect of the present invention is the use of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors) and prodrugs thereof or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of cancer.

[0132] For the avoidance of doubt, use of the sixth aspect of the invention may have any of the specific features and embodiments described above for the other (e.g. first to fifth) aspects of the invention, including all combinations thereof.

[0133] parts kit According to a seventh aspect of the present invention, (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 (B) A pharmaceutical composition comprising an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor (e.g., a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor), and a prodrug thereof or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. 1. A kit of parts for use in the treatment of cancer, comprising: A kit of parts is provided in which components (A) and (B) are each provided in a form suitable for administration in conjunction with the other component.

[0134] As used herein, by referring to multiple compounds being administered in conjunction with one another, we include that such components are administered sequentially, separately or simultaneously as part of a medical intervention directed to the treatment of the relevant disease or disorder, as described herein.

[0135] In an alternative seventh aspect of the present invention, (I) one of components (A) or (B) according to the seventh aspect of the present invention, and (II) Instructions for using the component in conjunction with one of the two components. A kit of parts for use in treating cancer is provided, comprising:

[0136] For the avoidance of doubt, the kit of parts of the seventh aspect of the present invention may have any of the specific features and embodiments described above for the other (e.g. first to sixth) aspects of the present invention, including all combinations thereof.

[0137] Therapeutic Use In an eighth aspect of the present invention, there is provided use of a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and an anticancer agent selected from the group consisting of CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PI3K inhibitors, SOS1 inhibitors and AURK inhibitors (e.g., CDK4 / 6 inhibitors, SHP2 inhibitors, EGFR inhibitors, mTOR inhibitors, immune checkpoint inhibitors), and prodrugs thereof or pharmaceutically acceptable salts thereof, for the treatment of cancer.

[0138] For the avoidance of doubt, use of the eighth aspect of the invention may have any of the specific features and embodiments described above for the other (e.g. first to seventh) aspects of the invention, including all combinations thereof.

[0139] Preparation of Compounds / Compositions The pharmaceutical compositions, combination products and kits described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice.

[0140] Thus, in a further aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition as described herein, which process comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent, both as described herein, with one or more pharmaceutically acceptable excipients.

[0141] In a further aspect of the present invention, there is provided a process for the preparation of a combination product or kit-of-parts as hereinbefore defined, which process comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anti-cancer agent, both as described herein.

[0142] As used herein, reference to mixing means that the two components are suitable for administration together. Thus, in relation to the method for the preparation of the kit of parts defined above, by "mixing" two components with each other, we mean that the two components of the kit of parts are: (i) may be provided as separate formulations (i.e., independently of each other), which formulations are then combined for use in conjunction with each other in combination therapy; or (ii) may be packaged and presented together as a "combination pack" of separate components for use in conjunction with each other in combination therapy; Include.

[0143] The compounds described herein, including the compounds of formula (I) and pharmaceutically acceptable salts thereof and anti-cancer 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 published literature relating to each such compound.

[0144] Certain compounds described herein, such as the anti-cancer agents described herein, and pharmaceutical compositions containing same, may be commercially available from sources known to those of skill in the art. The compound of formula (I) and its salts can be produced by applying various known synthetic methods using characteristics based on its basic structure or the type of substituents. Depending on the type of functional group, replacing the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) during the process from the raw material to the intermediate is often an effective production technique. Examples of protecting groups include those listed in P.G.M.Wuts and T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 5th Edition, John Wiley & Sons Inc., 2014, and a group appropriately selected from the above protecting groups is used depending on the reaction conditions. In such a method, a reaction is carried out with a protecting group introduced, and then the protecting group is removed as necessary, thereby obtaining the desired compound.

[0145] In addition, prodrugs of the compound of formula (I) can be prepared by introducing the same special protecting group as the above in the process from the raw material to the intermediate, or by further carrying out a reaction using the obtained compound of formula (I). This reaction can be carried out by applying a method known to those skilled in the art, such as conventional esterification, amidation, or dehydration.

[0146] Isolation and purification are carried out by applying conventional chemical procedures, such as extraction, fractional crystallization or various types of fractional chromatography. Various isomers may be prepared by selecting appropriate starting compounds, or may be separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., fractional crystallization of racemates with optically active bases or acids to give diastereomeric salts, chromatography using chiral columns, etc.), and can be similarly prepared from optically active appropriate starting compounds.

[0147] In addition, the compound of formula (I) or an intermediate thereof often has axial chirality and is obtained as a mixture of axial stereoisomers, but each axial stereoisomer can be isolated by a conventional separation procedure, for example, separation using octadecylsilyl (ODS) column chromatography or silica gel column chromatography.

[0148] Effect of the invention The treatments described herein may have the advantage that they may be more effective, less toxic, longer acting, more potent, cause fewer side effects, and / or have a better therapeutic profile than treatments for the same conditions known in the prior art.

[0149] Without wishing to be bound by theory, it is believed that the compound of formula (I) has a degradation-inducing effect on G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and that the compound of formula (I) can act synergistically in the treatment of cancer, particularly G12D mutant KRAS-positive cancer, when used together with an anticancer drug selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, an AURK inhibitor, and prodrugs thereof. [Example]

[0150] The preparation method of the compound of formula (I) will be explained in more detail below based on examples. Please note that the present invention is not limited to the compounds described in the following examples. In addition, the preparation methods of the starting compounds are shown in the preparation examples. The preparation method of the compound of formula (I) is not limited to the preparation methods of the specific examples below, and the compound of formula (I) can also be prepared by a combination of these preparation methods or methods that are obvious to those skilled in the art.

[0151] In the event of a discrepancy between the nomenclature and the visually depicted structure of a compound, the latter takes precedence (unless contradicted by any experimental details that may be given and / or clear from the context).

[0152] For convenience, the concentration in mol / L is indicated as M. For example, 1M aqueous sodium hydroxide solution means a 1 mol / L aqueous sodium hydroxide solution. Abbreviation The following abbreviations may be used in this document: DMF: N,N-dimethylformamide DMAc: N,N-dimethylacetamide THF: tetrahydrofuran MeCN: acetonitrile MeOH: Methanol EtOH: ethanol DOX: 1,4-dioxane DMSO: dimethyl sulfoxide TEA: Triethylamine DIPEA: N,N-diisopropylethylamine tBuOK: potassium tert-butoxide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DABCO: 1,4-diazabicyclo[2.2.2]octane PdCl2(dppf)·CH2Cl2:[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct Pd / C: Palladium on carbon Manufacturing example Manufacturing Example 1 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was cooled in an ice bath, and then DIPEA (240 mL) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) were added, 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 aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total volume of the solution was approximately 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 give 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.

[0153] Manufacturing Example 2 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) under an argon atmosphere with stirring at room temperature, and the mixture was stirred overnight at room temperature. Approximately 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was 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.

[0154] Manufacturing Example 3 Under an argon atmosphere, tBuOK (2.54 g) was added to a mixture of tert-butyl (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.9 g), benzyl alcohol (2.37 g), and THF (40 mL) under ice bath cooling. The mixture was stirred at the same temperature for 1.5 hours. Ice water and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixture of hexane / ethyl acetate (6 / 1) was added to the resulting 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.

[0155] Manufacturing Example 4 Under an argon atmosphere, a mixture of 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 (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropyl borate (1.27 g), potassium phosphate tribasic (5.67 g), and PdCl(dppf) CHCl (600 mg) was stirred at 100 °C for 3 h. After cooling to room temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium chloride solution was added to the resulting residue, and the mixture was extracted with CHCl. ​​The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to 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.

[0156] Manufacturing Example 5 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 (3.15 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) A mixture of 2-dicyclohexylphosphino-2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl (2-methyl- ... The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give fractions containing (1) a less polar diastereomeric mixture (Peak-1 and Peak-2; Peak-1 and Peak-2 had the same axial chirality) and (2) a more polar diastereomeric mixture (Peak-3 and Peak-4; Peak-3 and Peak-4 had the same axial chirality). Among these fractions, fractions containing the less polar diastereomeric mixture (peak-1 and peak-2, identical axial asymmetry) were pooled to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.42 g) as a foamy solid.Additionally, fractions containing the more polar diastereomeric mixture (peaks 3 and 4, identical axial asymmetry) were pooled to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.37 g) as a foamy solid. The less polar diastereomeric mixture was used in the subsequent reaction.

[0157] Manufacturing Example 6 To a solution of tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (10 g), a mixture of less polar diastereomers obtained in Preparation 11, in MeOH (200 mL) was added 10% Pd / C (50% water, 2 g), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The resulting reaction mixture was filtered through a Celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (8.11 g) as a foamy solid.

[0158] Manufacturing Example 7 To a mixture of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (7.48 g), DMF (70 mL), and 1-(chloromethyl)-4-ethynylbenzene (1.9 g) was added cesium carbonate (6.2 g) while stirring at room temperature, and the mixture was stirred at 60 °C under an argon atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and ice water and saturated aqueous ammonium chloride were added. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble materials were then removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate), and the resulting solid was filtered to obtain 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 (8.12 g) as a foamy solid.

[0159] Manufacturing Example 8 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-methyl To a mixture of [butanoyl]-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) was added anhydrous copper(II) sulfate (389 mg) at room temperature, 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 saturated aqueous sodium chloride 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 tert-butyl(1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl 1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.62 g) was obtained as a solid.

[0160] Manufacturing Example 12 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 hours. After the mixture was cooled to room temperature, hydrochloric acid (1 M, 60 mL) was added and the mixture was extracted with CHCl3 / 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]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (3.26 g) as a solid.

[0161] Manufacturing Example 13 (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1 To a mixture of [H-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) was added HATU (70 mg) under ice bath cooling, and the mixture was stirred for 1 hour under ice bath cooling. Water, saturated aqueous sodium chloride, and ethyl acetate were added to the mixture, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium 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 tert-butyl(1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(2-oxo -1,3-oxazolidin-3-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (173 mg) was obtained as a solid.

[0162] Manufacturing Example 14 To a solution of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (5.01 g) in DMAc (80 mL) were added 4-methyl-1,3-thiazole (2.88 mL) and potassium acetate (3.11 g) at room temperature. The mixture was degassed and backfilled 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 the insoluble material 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 saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The insoluble material 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 obtain tert-butyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.66 g) as a solid.

[0163] Manufacturing Example 15 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 PdCl(dppf) CHCl (1.14 g) under an argon atmosphere, and the mixture was stirred at 100 °C for 16 h. After cooling 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 obtain tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.74 g) as a solid.

[0164] Manufacturing Example 17 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 CHCl (50 mL) and MeOH (50 mL), hydrogen chloride (4 M DOX solution, 20 mL) was added 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 hydrochloride (2.12 g) as a solid. The filtrate was concentrated under reduced pressure and dried to give (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.01 g) as a solid.

[0165] Manufacturing Example 18 To a solution of tert-butyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.34 g) in CHCl (25 mL) and MeOH (25 mL) was added hydrogen chloride (4 M DOX solution, 25.6 mL) at −20 to −10° C. The mixture was stirred at room temperature for 5 h. 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.

[0166] Manufacturing Example 20 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 bath cooling, followed by the addition of HATU (3.02 g) in small portions to maintain the internal temperature below 5 °C. The mixture was stirred under ice bath cooling for 1 hour and then at room temperature for 1 hour. Under ice bath cooling, water (120 mL), 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 three times with ethyl acetate / isopropyl alcohol (9 / 1). The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium 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 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.

[0167] Manufacturing Example 21 To a mixture of (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol 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 bath cooling, followed by the addition of HATU (4.5 g) in small portions under ice bath cooling. The mixture was stirred under ice bath cooling for 1 hour and then at room temperature for 1 hour. Water, saturated aqueous sodium chloride, and ethyl acetate were added under ice bath cooling, and the aqueous layer was extracted with ethyl acetate and then with ethyl acetate / isopropyl alcohol (9 / 1). The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium 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 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.

[0168] Manufacturing Example 23 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 CHCl (18 mL) and MeOH (18 mL) was added hydrogen chloride (4 M DOX solution, 17 mL) under ice bath cooling, and the mixture was stirred for 1 hour under ice bath cooling and at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and dried to give (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (2.92 g) as a solid.

[0169] Manufacturing Example 24 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 CHCl (35 mL) and MeOH (30 mL) was added hydrogen chloride (4 M DOX solution, 28 mL) at -20 to -10 °C, and the mixture was stirred at room temperature for 5 h. 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 hydrochloride (4.71 g) as a solid.

[0170] Manufacturing Example 26 To a mixture of (4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide hydrochloride (3.81 g), N-(tert-butoxycarbonyl)-L-valine (2.16 g), and DMF (45 mL) was added DIPEA (6.2 mL), followed by the addition of HATU (3.61 g) in small portions under ice bath cooling. The mixture was stirred under ice bath cooling for 1 hour and at room temperature for 1 hour. Water, saturated aqueous sodium chloride, and ethyl acetate were added under ice bath cooling, and the aqueous layer was extracted with ethyl acetate and then with ethyl acetate / isopropyl alcohol (9 / 1). The combined organic layers were washed with saturated aqueous sodium chloride 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 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.

[0171] Manufacturing Example 29 To a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (4.43 g) in CHCl (35 mL) and MeOH (35 mL) was added hydrogen chloride (4 M DOX solution, 20 mL) at -20 to -15 °C, and the mixture was stirred at room temperature for 6 h. 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 hydrochloride (4.21 g) as a solid.

[0172] Manufacturing Example 33 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 hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), and MeCN (20 mL) was added a solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (1.06 g) in MeCN (5 mL) dropwise over 10 minutes under ice-bath cooling. The mixture was stirred for 5 hours under ice-bath cooling. Water, saturated aqueous sodium chloride, 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 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-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.

[0173] Manufacturing Example 37 A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL), and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred at 100 °C overnight under an argon atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and the mixture was filtered through a Celite pad. The filtrate was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g) as an oil.

[0174] Manufacturing Example 38 Palladium(II) acetate (200 mg) was added to a mixture of tert-butyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g), 5-bromo-1,3-thiazole-4-carboxylic acid methyl ester (2.6 g), tripotassium phosphate (3.8 g), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (730 mg), DOX (30 mL), and water (6 mL) under an argon atmosphere. The mixture was stirred at room temperature for 3 hours at 100 °C. After cooling to room temperature, ethyl acetate was added, and the mixture was washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.48 g) as a solid.

[0175] Manufacturing Example 39 Under a nitrogen atmosphere, diisobutylaluminum hydride (1 M toluene solution, 11 mL) was added dropwise to a solution of methyl 5-(4-{(1R)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}phenyl)-1,3-thiazole-4-carboxylate (1.01 g) in CHCl (20 mL) under ice bath cooling, and the mixture was stirred under ice bath cooling for 1 hour. The reaction was quenched with MeOH under ice bath cooling, 10% aqueous sodium potassium tartrate (60 mL) and CHCl were added, and the mixture was stirred overnight. The mixture was separated into layers, the aqueous layer was extracted with CHCl, and the 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 dissolved in MeOH (10 mL), and sodium borohydride (350 mg) was added under ice bath cooling. The mixture was stirred under ice bath cooling for 1 hour. Water was added, and the mixture was extracted with CHCl. ​​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 purified by silica gel column chromatography (CHCl / 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.

[0176] Manufacturing Example 41 To a mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g), 2,2-dimethoxypropane (3.3 mL), and acetone (15 mL), boron trifluoride-diethyl ether complex (26 μL) was added, and the mixture was stirred at room temperature for 1 hour. TEA (66 μL) was added, 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 give tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.09 g) as a solid.

[0177] Manufacturing Example 42 To a solution of tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (300 mg) and 1,3-oxazolidin-2-one (183 mg) in DOX (1.69 mL) was added copper(I) iodide (32 mg), racemic-(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 Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,3-oxazolidin-3-carboxylate (120 mg) as a solid.

[0178] Manufacturing Example 48 To a mixture of tert-butyl (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-carboxylate (350 mg) and CHCl (7 mL) was added m-chloroperbenzoic acid (approximately 30% water content, 100 mg) with stirring under ice bath cooling. The reaction mixture was stirred under ice bath cooling for 1.5 hours, diluted with CHCl, and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate. The organic layer was dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to give the sulfoxide. The resulting sulfoxide was mixed with (S)-2-methoxypropanol (45 mg) and THF (4 mL). KOtBu (80 mg) was added to the mixture under ice-methanol cooling, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. 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 aqueous sodium chloride 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 tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-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-carboxylate (280 mg) as a foamy solid.

[0179] Manufacturing Example 51 To tert-butyl (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-carboxylate (211 mg) was added MeOH (3 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added while stirring at room temperature. The mixture was then stirred at room temperature under an argon atmosphere for 1 hour. Ice and saturated aqueous sodium bicarbonate 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 and dried over anhydrous magnesium sulfate. Insoluble materials were 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 less polar diastereomer tert-butyl (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-carboxylate (single axial stereoisomer, 87 mg) as a solid, and the more polar diastereomer, tert-butyl (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-carboxylate (single axial stereoisomer, 59 mg) as a solid. The less polar diastereomer was used in the subsequent reaction.

[0180] Manufacturing Example 52 tert-Butyl (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-carboxylate (80 mg) in t-BuOH (0.7 mL), THF (0.7 mL) To a solution of (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (53 mg), sodium ascorbate (33 mg), and CuI (12 mg) were added at room temperature, and the mixture was stirred at 50 °C for 3 h. After cooling to room temperature, an aqueous solution of EDTA disodium salt was added. The mixture was extracted three times with CHCl, 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 tert-butyl(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-carboxylate (102 mg) was obtained as a foamy solid.

[0181] Manufacturing Example 57 To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL), and CHCl (1880 mL) was added 1,1′,1″-(chloromethanetriyl)tribenzene (335 g) 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 and aqueous layers were separated. The aqueous layer was extracted three times with CHCl (400 mL). The combined organic layers were dried over anhydrous sodium sulfate. The insoluble matter was then removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue for trituration (0° C., 2 hours), and 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) was then collected by filtration and dried under reduced pressure to give a solid.

[0182] Manufacturing Example 58 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. Methyl iodide (26.68 mL) was added at -78 °C, and the mixture was stirred at 25 °C for 2.5 hours. Water (2000 mL) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layer was dried over anhydrous sodium sulfate. Insoluble materials were then removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 mL) / petroleum ether (50 mL) was added to the resulting 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.

[0183] Manufacturing Example 59 Palladium acetate (4.52 g) was added to a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was degassed and backfilled with nitrogen three times, and then stirred at 100 °C for 12 hours under a nitrogen atmosphere. 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 material was removed by filtration. Activated carbon (50 g) was added to the resulting solution, which was stirred at 20° C. for 1 hour and filtered, washing with ethyl acetate (50 mL) three times. The filtrate was concentrated. Methanol (200 mL) was added to the resulting residue for trituration, and the resulting solid was filtered and dried under reduced pressure to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0184] Manufacturing Example 60 Under 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), tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg), and DMF (2.5 mL). The mixture was stirred at 170 °C for 30 minutes under microwave irradiation. The mixture was cooled to room temperature, then diluted with ethyl acetate, and insoluble matter was removed by filtration through a Celite pad. The filtrate was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to afford 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.

[0185] In the tables below, "PEx" stands for "Preparation Example" and "PSyn" indicates that other Preparation Examples were similarly prepared using the same method as the "PEx" in the same row of the table (i.e., "PEx" was prepared using the same method as that used to prepare the Preparation Example number indicated in the "PSyn" column).

[0186] Structure: Chemical structural formula (compounds with "*" in the chemical structural formula indicate that the compound is a single axial stereoisomer). nHCl: nhydrochloride ("nHCl" indicates that the compound is a monohydrochloride to trihydrochloride salt). Data: physicochemical data. ESI+: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [M+H]). + ), ESI-: m / z value in mass spectrometry (ionization method ESI, unless otherwise specified [M−H] - ), NMR: in DMSO-d 1 δ value (ppm) of peaks in H-NMR (500 MHz), NMR (100 °C): in DMSO-d6 at 100 °C1 δ value (ppm) of peak in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad (spectrum) (e.g., brs).

[0187] [Table 1-1]

[0188] [Table 1-2]

[0189] [Table 1-3]

[0190] [Table 1-4]

[0191] [Table 1-5]

[0192] [Table 1-6]

[0193] [Table 1-7]

[0194] [Table 1-8]

[0195] [Table 1-9]

[0196]

Table 1-10

[0197]

Table 1-11

[0198]

Table 1-12

[0199]

Table 1-13

[0200]

Table 1-14

[0201]

Table 1-15

[0202]

Table 1-16

[0203]

Table 1-17

[0204]

Table 1-18

[0205]

Table 1-19

[0206] [Table 1-20]

[0207] Example Below are examples of compounds of formula (I) and their characteristics. In the examples below, an asterisk indicates that the compound is a single axial stereoisomer.

[0208] Example 1: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

[0209] [ka]

[0210] 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 To a mixture of {{(1-oxobutan-2-yl)}-1H-1,2,3-triazol-4-yl)phenyl}-methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5.61 g) and CHCl (60 mL), trifluoroacetic acid (27 mL) was added under ice-bath cooling, and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted three times with CHCl / MeOH (5 / 1), and the combined organic layers were then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by ODS column chromatography (MeCN / 0.1% formic acid). Saturated aqueous sodium bicarbonate solution was added to the fractions containing the target compound, and the mixture was extracted three times with CHCl / MeOH (5 / 1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain the product. Isopropyl acetate (70 mL) was added to the obtained product, and the mixture was stirred at 80°C for 10 minutes and then at room temperature overnight. Hexane (70 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was then filtered, washed with isopropyl acetate / hexane (1 / 1), and dried under reduced pressure at 40°C overnight to obtain the title compound (3.01 g) as a solid. ESI+:1117.3; 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). Example 2: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide trihydrochloride

[0211] [ka]

[0212] Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H To a mixture of [(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), DIPEA (50 μL) and HATU (35 mg) were added sequentially under ice bath cooling, and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give the amide product (59 mg). The resulting compound was then dissolved in CHCl (0.5 mL) and MeOH (0.5 mL), and hydrogen chloride (4 M DOX solution, 0.5 mL) was added under ice bath cooling. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitated solid was filtered, washed with diethyl ether, and dried under reduced pressure to give the title compound (43 mg) as a solid. ESI+:1133.3. Example 3: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide

[0213] [ka]

[0214] 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)pyrrolidine To a mixture of {(oxan-1-yl)-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl}-methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg), CHCl (2 mL), and MeOH (2 mL) was added hydrogen chloride (4 M DOX solution, 0.988 mL) under ice-bath cooling, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and CHCl and saturated aqueous sodium bicarbonate were added, and the mixture was stirred for a while. The aqueous layer was then extracted with CHCl / MeOH (5 / 1), and the combined 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 purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) and then by ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). The fractions containing the target compound were combined, made basic with saturated aqueous sodium bicarbonate, and then extracted twice with CHCl3 / 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 resulting solid was washed with diethyl ether and dried under reduced pressure to give the title compound (74 mg) as a solid. ESI+:1105.7. Example 4: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide

[0215] [ka]

[0216] This compound was prepared using a method similar to that provided in Example 5 below. ESI+:1100.4; 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, br d), 8.01 (1H, br d), 8.43 (1H, s), 12.75 (1H, br s). Example 5: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide

[0217] [ka]

[0218] 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]meth To a solution of {{(c1,2,3-dimethyl-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) in CHCl (55 mL), trifluoroacetic acid (27 mL) was added dropwise over 20 minutes under ice-bath cooling, and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate and CHCl / MeOH (9 / 1) were added to the residue. The mixture was extracted three times with CHCl / MeOH (9 / 1), and the combined organic layers were then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by ODS column chromatography (MeCN / 0.1% formic acid). Saturated aqueous sodium bicarbonate was added to the fractions containing the target compound, and the mixture was extracted three times with CHCl3 / MeOH (9 / 1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain the product. EtOH was added to the obtained 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 obtain a solid (2.98 g). ESI+:1114.5; 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, br s). Example 6: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

[0219] [ka]

[0220] tert-Butyl(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-oxobutane-2- To a mixture of {(2S)-2-methoxypropoxy)quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (98 mg) and CHCl (3 mL) was added trifluoroacetic acid (1 mL) under ice-methanol bath cooling, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The resulting reaction mixture was concentrated under reduced pressure, and ice, saturated aqueous sodium bicarbonate, and CHCl / MeOH (10 / 1) were added to the residue. The mixture was stirred for 10 minutes, then extracted with CHCl / MeOH (10 / 1), and the combined organic layers were dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting product was dissolved in MeOH, concentrated, and dried under reduced pressure to give the title compound (73 mg) as a solid. ESI+:1105.7; 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, br d), 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). Example 7: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(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

[0221] [ka]

[0222] This compound was prepared using a method similar to that provided in Example 6 above. ESI+:1102.8; 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). Example 8: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1-1H-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

[0223] [ka]

[0224] This compound was prepared using a method similar to that provided in Example 6 above. ESI+:1089.9. Biological Examples Example A1: In vivo combination therapy with molecular targeted agents in xenograft mice derived from human KRAS G12D mutation-positive KP-4 pancreatic cancer cell line KP-4 cells (Japanese Collection of Research Bioresources Cell Bank, National Institutes of Biomedical Innovation, Health and Nutrition, Cat# JCRB0182) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. Six to eight-week-old female nude mice (BALB / c nude mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were inoculated with KP-4 cells (1 × 10) in 0.2 mL of DPBS (containing 50% BD Matrigel (Corning Incorporated)) for tumor development. 7 The animals were randomized and the mean tumor size was approximately 200 mm 3Treatment began 8 days after tumor inoculation, when tumor volume reached 100 μg / mL. Animals were assigned to groups using Excel-based randomization software, which performed stratified randomization based on tumor volume. Each group consisted of five mice. Test substances were administered as shown in Table 2. Solvent A was prepared by mixing 4% (v / v) ethanol in a 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) polyoxyethylene hydrogenated castor oil (HCO-40). The compound from Example 1 was dissolved in this solvent. Palbociclib (CDK4 / 6 inhibitor) and TNO155 (SHP2 inhibitor) were dissolved in a 0.5% methylcellulose (MC) / 0.5% Tween 80 solution (solvent B). Tumor size and body weight were measured two to three times weekly. Tumor volume was calculated using the following formula:

[0225] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The tumor growth inhibition (TGI) rate (%) by the test compound was calculated for each group using the formula: TGI (%) = [1 - (Ti - T1) / (Vi - V1)] x 100; Ti is the mean tumor volume of the treatment group on a given day, T1 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the vehicle control group on the same day as Ti, and V1 is the mean tumor volume of the vehicle group on the first day of treatment.

[0226] [Table 2]

[0227] As shown in the test results in Table 2, the compound of Example 1, in combination with palbociclib or TNO155, exhibited antitumor activity in mice bearing human pancreatic cancer cells with a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to palbociclib or TNO155 monotherapy for the treatment of G12D-mutated KRAS-positive pancreatic cancer.

[0228] Example A2: In vivo combination therapy with molecular targeted agents in xenograft mice derived from human KRAS G12D mutation-positive KP-4 pancreatic cancer cell line KP-4 cells (JCRB Cell Bank, National Institutes of Biomedical Innovation, Health and Nutrition, Cat# JCRB0182) were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. Seven to eight-week-old female nude mice (BALB / c nude mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were inoculated with KP-4 cells (1 × 10) in 0.2 mL of DPBS (containing 50% BD Matrigel (Corning Incorporated)) for tumor development. 7 The animals were randomized and the mean tumor size was approximately 150-180 mm. 3 Treatment began 6 days after tumor inoculation, when tumor volume reached 100 μg / mL. Animals were assigned to groups using Excel-based randomization software, which performed stratified randomization based on tumor volume. Each group consisted of five mice. Test substances were administered as shown in Table 3. Solvent A was prepared by mixing 4% (v / v) ethanol in 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) HCO-40. The compound of Example 1 was dissolved in this solvent. Alpelisib (a PI3Kα inhibitor) was dissolved in 0.5% MC / 0.5% Tween 80 (solvent B). MRTX0902 (an SOS1 inhibitor) was dissolved in 10% DMSO / 90% (20% SBE-β-CD in saline) (solvent C). Alisertib (an Aurora A inhibitor) was dissolved in 10% 2-hydroxypropyl-β-cyclodextrin / 1% sodium bicarbonate (solvent D). Tumor size and body weight were measured 2-3 times a week. Tumor volume was calculated using the following formula:

[0229] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The TGI rate (%) due to the test compound was calculated for each group using the formula: TGI (%) = [1 - (Ti - T1) / (Vi - V1)] x 100; Ti is the mean tumor volume of the treatment group on a given day, T1 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the vehicle control group on the same day as Ti, and V1 is the mean tumor volume of the vehicle group on the first day of treatment.

[0230] [Table 3]

[0231] As shown in the test results set forth in Table 3, the compound of Example 1, in combination with alpelisib, MRTX0902, or alisertib, exhibited antitumor activity in mice bearing human pancreatic cancer cells harboring a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to the monotherapy of alpelisib, MRTX0902, or alisertib for the treatment of G12D-mutated KRAS-positive pancreatic cancer.

[0232] Example B: In vivo combination therapy with molecular targeted agents in xenograft mice derived from human KRAS G12D mutation-positive AsPC-1 pancreatic cancer cell line AsPC-1 cells (American Type Culture Collection, Cat# CRL-1682) were cultured in RPMI-1640 medium supplemented with 10% FBS at 37°C in an atmosphere of 5% CO2 in air. Six to eight-week-old female nude mice (BALB / c nude mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were inoculated with AsPC-1 cells (1 × 10 cells) in 0.2 mL of DPBS (containing 50% BD Matrigel (Corning Incorporated)) for tumor development. 6 The animals were randomized and the mean tumor size was approximately 200 mm 3Treatment began 17 days after tumor inoculation, when tumor volume reached 1000 mcg. Animals were assigned to groups using Excel-based randomization software, which performed stratified randomization based on tumor volume. Each group consisted of five mice. Test articles were administered as shown in Table 4. Solvent A was prepared by mixing 4% (v / v) ethanol in 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) HCO-40. The compound from Example 1 was dissolved in this solvent. Afatinib (an EGFR inhibitor) was dissolved in a 0.5% MC / 0.5% Tween 80 solution (solvent B). Everolimus (an mTOR inhibitor) was dissolved in a 5% Tween 80 / propylene glycol solution. Tumor size and body weight were measured two to three times weekly. Tumor volume was calculated using the following formula:

[0233] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The TGI rate (%) due to the test compound was calculated for each group using the formula: TGI (%) = [1 - (Ti - T1) / (Vi - V1)] x 100; Ti is the mean tumor volume of the treatment group on a given day, T1 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the vehicle control group on the same day as Ti, and V1 is the mean tumor volume of the vehicle group on the first day of treatment.

[0234] [Table 4]

[0235] As shown in the test results in Table 4, the compound of Example 1, in combination with afatinib or everolimus, exhibited antitumor activity in mice bearing human pancreatic cancer cells with a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to afatinib or everolimus monotherapy for the treatment of G12D-mutated KRAS-positive pancreatic cancer.

[0236] Example C: In vivo combination therapy with immune checkpoint inhibitors in a mixed xenograft model derived from human KRAS G12D mutation-positive HPAC pancreatic cancer cell lines and human CD3-positive T cells HPAC cells (ATCC, Cat# CRL-2119) were cultured in RPMI-1640 medium supplemented with 10% FBS at 37°C in an atmosphere of 5% CO2 in air. CD3+ T cells were obtained from peripheral blood mononuclear cells using the CD3 MACS isolation procedure according to the manufacturer's instructions (Miltenyi Biotec, Bergisch Gladbach, Germany). CD3+ T cells were expanded in RPMI-1640 supplemented with FBS and IL-2 (final 10 ng / mL) by co-culture with mitomycin C (final 25 μg / mL)-treated HPAC cells for a total of 10 days. Six-week-old male NOD-scid mice (NOD / ShiJic-scid mice, CLEA Japan, Inc.) were inoculated with HPAC cells (5 × 10 ng / mL) for tumor development. 6 cells) and CD3-positive T cells (1 × 10) previously co-cultured with mitomycin C-treated HPAC cells. 5 The animals were randomized and the mean tumor size was approximately 50 mm. 3 Treatment began 7 days after tumor inoculation, when the tumor reached a volume of 1000 μg. Each group consisted of 13 mice. Test articles were administered as shown in Table 5. Solvent A was prepared by mixing 4% (v / v) ethanol in 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) HCO-40. The compound of Example 1 was dissolved in this solvent. Nivolumab (anti-programmed death-1 [PD-1]) was dissolved in DPBS. Tumor size and body weight were measured three times a week. Tumor volume was calculated using the following formula:

[0237] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The TGI rate (%) due to the test compound was calculated for each group using the formula: TGI (%) = [1 - (Ti - T1) / (Vi - V1)] x 100; Ti is the mean tumor volume of the treatment group on a given day, T1 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the vehicle control group on the same day as Ti, and V1 is the mean tumor volume of the vehicle group on the first day of treatment.

[0238] [Table 5]

[0239] As shown in the test results in Table 5, the compound of Example 1, in combination with nivolumab, exhibited antitumor activity in mice bearing human pancreatic cancer cells with a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to nivolumab monotherapy for the treatment of G12D-mutated KRAS-positive pancreatic cancer.

[0240] Example D: In vivo combination therapy with molecular targeted agents in xenograft mice derived from human KRAS G12D mutation-positive GP5d colon cancer cell line GP5d cells (ECACC, Cat# 95090715) were cultured in DMEM medium supplemented with 2 mM glutamine and 10% fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. 7-8 week-old female nude mice (BALB / c nude mice, Beijing Vital River Laboratory Animal Technology Co., Ltd.) were inoculated with GP5d cells (3 × 10 cells) in 0.2 mL of DPBS (containing 50% BD Matrigel (Corning Incorporated)) for tumor development. 6 The animals were randomized and the mean tumor size was approximately 150-180 mm. 3Treatment began 10 days after tumor inoculation, when tumor volume reached 100 μg. Animals were assigned to groups using Excel-based randomization software, which performed stratified randomization based on tumor volume. Each group consisted of five mice. Test substances were administered as shown in Table 6. Solvent A was prepared by mixing 4% (v / v) ethanol in 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) HCO-40. The compound of Example 1 was dissolved in this solvent. Alpelisib (a PI3K alpha inhibitor) was dissolved in 0.5% MC / 0.5% Tween 80 (solvent B). MRTX0902 (an SOS1 inhibitor) was dissolved in 10% DMSO / 90% (20% SBE-β-CD in saline) (solvent C). Alisertib (an Aurora A inhibitor) was dissolved in 10% 2-hydroxypropyl-β-cyclodextrin / 1% sodium bicarbonate (solvent D). Tumor size and body weight were measured 2-3 times a week. Tumor volume was calculated using the following formula:

[0241] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The TGI rate (%) due to the test compound was calculated for each group using the formula: TGI (%) = [1 - (Ti - T1) / (Vi - V1)] x 100; Ti is the mean tumor volume of the treatment group on a given day, T1 is the mean tumor volume of the treatment group on the first day of treatment, Vi is the mean tumor volume of the vehicle control group on the same day as Ti, and V1 is the mean tumor volume of the vehicle group on the first day of treatment.

[0242] [Table 6]

[0243] As shown in the test results set forth in Table 6, the compound of Example 1, in combination with alpelisib, MRTX0902, or alisertib, exhibited antitumor activity in mice bearing human colon cancer cells harboring a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to the monotherapy of alpelisib, MRTX0902, or alisertib for the treatment of G12D-mutated KRAS-positive colon cancer.

[0244] Example E: In vivo combination therapy with cetuximab in mice xenografted with human KRAS G12D mutation-positive GP5d colon cancer cell line GP5d cells (ECACC, Cat# 95090715) were cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin solution in an atmosphere of 5% CO2 in air at 37°C. Five-week-old male nude mice (BALB / c nude mice, Charles River Laboratories Japan, Inc.) were inoculated with GP5d cells (2.6 × 10 cells) contained in 0.1 mL of DPBS (containing 50% Cultrex Basement Membrane Extract (R&D Systems)) for tumor development. 6 The animals were randomized and the mean tumor size was approximately 50-100 mm. 3 Treatment began 10 days after tumor inoculation, when the tumor volume reached 100 μg. Animals were assigned to groups using Excel-based randomization software, which performed stratified randomization based on their tumor volume. Each group consisted of eight mice. Test articles were administered as shown in Table 7. Solvent A was prepared by mixing 4% (v / v) ethanol in 5% glucose solution, 1% (v / v) 50% (2-hydroxypropyl)-β-cyclodextrin, and 9% (v / v) HCO-40. The compound of Example 1 was dissolved therein. Cetuximab (anti-EGFR antibody, ERBITUX Injection (Merck Biopharma Co., Ltd.)) was administered undiluted. Tumor size and body weight were measured twice weekly. Tumor volume was calculated using the following formula:

[0245] [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] × [Tumor short diameter (mm)] 2 ×0.5 The TGI rate was calculated using the following formula: TGI (%) = 100 × (1 − [mean tumor volume on day 21 − mean tumor volume on day 0] for each group / [mean tumor volume on day 21 − mean tumor volume on day 0] for the vehicle control group).

[0246] [Table 7]

[0247] As shown in the test results in Table 7, the compound of Example 1, in combination with cetuximab, exhibited antitumor activity in mice bearing human colon cancer cells with a KRAS G12D mutation, suggesting that the combination with the compound of Example 1 is superior to cetuximab monotherapy for the treatment of G12D-mutated KRAS-positive colon cancer. [Industrial Applicability]

[0248] The present invention has excellent antitumor activity and can be used to treat G12D mutant KRAS-positive cancers, particularly G12D mutant KRAS-positive pancreatic cancer, colon cancer, and / or lung cancer, etc.

Claims

1. 1. A combination for use in the treatment of cancer, comprising: (a) Below: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, and pharmaceutically acceptable salts thereof; or a pharmaceutically acceptable salt thereof; and (b) an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, a SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor, and a prodrug thereof or a pharmaceutically acceptable salt thereof; The above combinations.

2. A pharmaceutical composition comprising the compound according to claim 1 (a) or a pharmaceutically acceptable salt thereof, an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor, and prodrugs thereof or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.

3. The pharmaceutical composition of claim 2 for use in the treatment of cancer.

4. A pharmaceutical composition for use in treating cancer, comprising the compound of claim 1 (a) or a pharmaceutically acceptable salt thereof, The pharmaceutical composition for use in combination with an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, a SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor, as well as prodrugs thereof or pharmaceutically acceptable salts thereof.

5. The pharmaceutical composition according to claim 4 , which is administered sequentially, separately or simultaneously with the anticancer drug.

6. Use of the compound according to (a) of claim 1 or a pharmaceutically acceptable salt thereof together with an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor, and a prodrug thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

7. (A) a pharmaceutical composition comprising the compound of claim 1(a) or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; and (B) A pharmaceutical composition comprising an anticancer agent selected from the group consisting of a CDK4 / 6 inhibitor, an SHP2 inhibitor, an EGFR inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, a PI3K inhibitor, an SOS1 inhibitor, and an AURK inhibitor, and a prodrug thereof or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; 1. A kit of parts for use in the treatment of cancer, comprising: A kit of parts in which components (A) and (B) are each provided in a form suitable for administration in conjunction with the other component.

8. (a) or a pharmaceutically acceptable salt thereof, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, and pharmaceutically acceptable salts thereof; The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, selected from the group consisting of:

9. (a) or a pharmaceutically acceptable salt thereof, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, and pharmaceutically acceptable salts thereof; The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, selected from the group consisting of:

10. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is a CDK4 / 6 inhibitor.

11. 11. The combination, pharmaceutical composition or kit-of-parts according to claim 10, wherein the CDK4 / 6 inhibitor is palbociclib.

12. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is an SHP2 inhibitor.

13. 13. A combination, pharmaceutical composition or kit-of-parts according to claim 12, wherein the SHP2 inhibitor is TNO155.

14. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is an EGFR inhibitor.

15. 15. The combination, pharmaceutical composition or kit-of-parts according to claim 14, wherein the EGFR inhibitor is afatinib.

16. 15. A combination, pharmaceutical composition or kit-of-parts according to claim 14, wherein the EGFR inhibitor is cetuximab.

17. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer drug is an mTOR inhibitor.

18. 18. The combination, pharmaceutical composition or kit-of-parts of claim 17, wherein the mTOR inhibitor is everolimus.

19. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is an immune checkpoint inhibitor.

20. 20. The combination, pharmaceutical composition or kit-of-parts according to claim 19, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

21. 21. The combination, pharmaceutical composition or kit-of-parts of claim 20, wherein the anti-PD-1 antibody is nivolumab.

22. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is a PI3K inhibitor.

23. 23. A combination, pharmaceutical composition or kit-of-parts according to claim 22, wherein the PI3K inhibitor is alpelisib.

24. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anticancer drug is an SOS1 inhibitor.

25. 25. The combination, pharmaceutical composition or kit-of-parts according to claim 24, wherein the SOS1 inhibitor is MRTX0902.

26. The combination according to claim 1, the pharmaceutical composition according to any one of claims 2 to 5, or the kit of parts according to claim 7, wherein the anti-cancer agent is an AURK inhibitor.

27. 27. The combination, pharmaceutical composition or kit-of-parts of claim 26, wherein the AURK inhibitor is alisertib.

28. The combination according to claim 1, the pharmaceutical composition according to any one of claims 3 to 5, or the kit of parts according to claim 7, wherein the cancer is pancreatic cancer, colon cancer, or lung cancer.

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

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

31. The use described in claim 6, wherein the anticancer agent is a CDK4 / 6 inhibitor.

32. The use described in claim 31, wherein the CDK4 / 6 inhibitor is palbociclib.

33. The use described in claim 6, wherein the anticancer agent is an SHP2 inhibitor.

34. The use described in claim 33, wherein the SHP2 inhibitor is TNO155.

35. The use described in claim 6, wherein the anticancer agent is an EGFR inhibitor.

36. The use described in claim 35, wherein the EGFR inhibitor is afatinib.

37. The use of claim 35, wherein the EGFR inhibitor is cetuximab.

38. The use described in claim 6, wherein the anticancer agent is an mTOR inhibitor.

39. The use described in claim 38, wherein the mTOR inhibitor is everolimus.

40. The use described in claim 6, wherein the anticancer agent is an immune checkpoint inhibitor.

41. The use described in claim 40, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

42. The use described in claim 41, wherein the anti-PD-1 antibody is nivolumab.

43. The use described in claim 6, wherein the anticancer agent is a PI3K inhibitor.

44. The use described in claim 43, wherein the PI3K inhibitor is alpelisib.

45. The use described in claim 6, wherein the anticancer agent is an SOS1 inhibitor.

46. The use described in claim 45, wherein the SOS1 inhibitor is MRTX0902.

47. The use described in claim 6, wherein the anticancer agent is an AURK inhibitor.

48. The use described in claim 47, wherein the AURK inhibitor is alisertib.

49. The use described in claim 6, wherein the cancer is pancreatic cancer, colon cancer or lung cancer.

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