TW202410899A - Anti cancer combinations comprising chemotherapy - Google Patents

Abstract

There is provided herein a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-cancer agent for use in the treatment of cancer, wherein the compound of formula (I) and the anti-cancer agent are as described in the description.

Description

Chemotherapy of anticancer combination

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

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

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

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

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

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

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

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

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

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

In recent years, bifunctional compounds collectively called PROTAC (Proteolysis Targeting Chimera) or SNIPER (Specific and Non-Genetic IAP-Dependent Protein Clearer) have been discovered as a technology for inducing the degradation of target proteins and are expected to be a novel drug development model technology (Drug. Discov. Today Technol., 2019, 31, pp. 15-27). Such bifunctional compounds promote the formation of a complex of target protein and E3 ligase in cells, and the degradation of target protein is induced by using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases identify proteins to be degraded to convert proteins into ubiquitin, thereby promoting degradation by proteasomes.

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

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

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

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

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

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

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

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

The third category of the present invention is a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first category of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

The fourth category of the present invention is a pharmaceutical composition for treating cancer, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first category of the present invention and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

The fifth category of the present invention is a method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

The sixth category of the present invention is the use of the compound of formula (I) or its pharmaceutically acceptable salt and anticancer agent or its pharmaceutically acceptable salt according to the first category of the present invention for the manufacture of a drug for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

The seventh category of the present invention is a kit-of-parts, which includes:

(A) A pharmaceutical composition comprising: a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected as appropriate, and

(B) A pharmaceutical composition comprising: an anticancer agent or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable formulations as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof,

Each of the components (A) and (B) is provided in a form suitable for administration in combination with the other component,

This kit is used to treat cancer.

The eighth category of the present invention is the use of the compound of formula (I) or its pharmaceutically acceptable salt and anticancer agent or its pharmaceutically acceptable salt according to the first category of the present invention for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the field to which the present invention relates.

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

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

Those skilled in the art will understand that references to "treatment" (and similarly "treating") of a particular condition adopt their standard meanings in the medical art. Specifically, such terms may refer to achieving a reduction in the severity of one or more clinical symptoms associated with the condition or prolonging the life of the patient being treated.

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

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

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

Compounds for use

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

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

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

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

Compound of formula (I)

The compound of formula (I) mentioned herein is a compound selected from the group consisting of:

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide,

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide,

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

(4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

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

In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide.

唑啶-3-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

[0134] Oxydridine-3-yl)phenyl]ethyl}-L-prolinamide.

In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide.

In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide.

唑-5-基)苯基]乙基}-L-脯胺醯胺。 In one embodiment, the compound of formula (I) is (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

In a specific embodiment, the compound of formula (I) is selected from the group consisting of:

(4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

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

(4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide,

唑啶-3-基)苯基]乙基}-L-脯胺醯胺， (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and

唑-5-基)苯基]乙基}-L-脯胺醯胺。 (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide.

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

The compound of formula (I) may have one or more asymmetric carbon atoms and may therefore exist in the form of its specific mirror image isomers and non-mirror image isomers. The present invention includes separated mirror image isomers and non-mirror image isomers of the compound of formula (I) or mixtures thereof.

Mirror isomers of chiral compounds having one or more asymmetric carbon atoms can be given with "(R)" and "(S)" labels relative to each chiral point based on methods known in the art (e.g., using the Cahn-Ingold-Prelog priority rule).

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., a particular mirror image isomer or non-mirror image isomer indicated) in the substantial absence of other stereoisomers (i.e., the stereoisomers have different configurations at one or more relevant chiral points).

In such cases, the compound in the relevant configuration may be present in an excess of at least 60% (e.g. at least 70%, 80%, 90%, 95% or 98%, or in particular at least 99%, for example at least 99.9%) of the mirror image isomer or the non-mirror image isomer (d.e.) as desired.

Compounds of formula (I) may have axial chirality, which may refer to compounds having one or more axes around which the substituents are arranged in a spatial arrangement that does not overlap with their mirror images. For the avoidance of doubt, all axial arrangements of such compounds are within the scope of the present invention.

Mirror isomers of axially chiral compounds can be given with "M" and "P" labels based on methods known in the art (e.g., using the Cahn-Ingold-Prelog priority rules with the additional rule that two "proximal" substituents have higher priority than distal substituents).

In certain embodiments, reference to a specific stereoisomer of a compound of formula (I) may refer to the presence of a specific stereoisomer (e.g., an isomer having M-chirality) in the substantial absence of the corresponding opposite stereoisomer (e.g., an isomer having P-chirality).

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

For the avoidance of doubt, a compound having 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 a mixture of mirror image isomers or non-mirror image isomers with respect to the stereochemistry at those positions.

In addition, the present invention includes pharmaceutically acceptable prodrugs (which may be referred to as prodrivers) of compounds represented by formula (I) and anticancer agents. Pharmaceutically acceptable prodrugs will include compounds having groups that can be decomposed by solvents or converted into amine, hydroxyl, carboxyl or similar groups 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 "Iyakuhin no Kaihatsu (development of pharmaceuticals)", Vol. 7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, pp. 163-198. Prodrugs include ester and carbamate derivatives or derivatives such as conjugates (e.g., conjugates of albumin-bound paclitaxel).

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

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

Exemplary 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, citric acid, lactic acid, apple acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid, Tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamine; salts of inorganic metals, such as sodium, potassium, magnesium, calcium or aluminum; salts of organic bases, such as methylamine, ethylamine or ethanolamine; salts of various amino acids and amino acid derivatives, such as acetylleucine, lysine and ornithine; and ammonium salts.

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

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

Anticancer agent

As described herein, the anticancer agent is selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, camptothecin analogs and fluoropyrimidine compounds, and prodrugs thereof.

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

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

Paclitaxel refers to a compound having the name benzoic acid [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-diethyloxy-15-[(2R,3S)-3-benzylamino-2-hydroxy-3-phenylpropionyl]oxy-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxotetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl] ester and the following structure:

In a specific embodiment, the taxane is docetaxel.

Docetaxel refers to a compound with the name of benzoic acid [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1,9,12-trihydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylprop-2-yl)oxycarbonylamino]-3-phenylpropionyl]oxy-10,14,17,17-tetramethyl-11-oxotetracyclo[11.3.1.03,10.04,7]heptadeca-13-en-2-yl] ester and the following structure:

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

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

In one embodiment, the anticancer agent is a fluorinated nucleoside. In a particular embodiment, the fluorinated nucleoside contains at least one fluorine substituent on the sugar unit of the nucleoside.

In certain embodiments, the fluorinated nucleoside is gemcitabine.

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

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

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

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

Camptosine analogs are compounds that are structurally related to camptosine, such as irinotecan, aminocamptosine, 9-nitrocamptosine (rubitecan), gimatecan, topotecan, silatecan, cositecan, exatecan, lurtotecan, and belotecan. The term "camptosine analog" may include compounds that contain the following substructures:

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

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

"Fluoropyrimidine" compounds refer to pyrimidines substituted with at least one fluorine substituent and include capecitabine, floxuridine and fluorouracil (5-FU). Those skilled in the art will understand that capecitabine is a prodrug of 5-FU.

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

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

cancer

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

"G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is changed from glycine to aspartic acid.

"G12D mutant KRAS" means KRAS with "G12D mutation".

"G12D mutant KRAS-positive cancer" is a G12D mutant KRAS-positive cancer, and is, for example, a cancer in which the KRAS G12D mutation occurs and a cancer with a high positive rate for the G12D mutant KRAS.

"Pancreatic cancer" is a malignant tumor that develops in the pancreas. Examples include pancreatic duct carcinoma and pancreatic duct adenocarcinoma. In one embodiment, "pancreatic cancer" is pancreatic duct carcinoma, and in one embodiment, "pancreatic cancer" is pancreatic duct adenocarcinoma.

"Colonectal cancer" is a malignant tumor that develops in the large intestine.

"Lung cancer" is a malignant tumor that develops in the lungs.

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

In one embodiment, the cancer is in a patient who has not been previously treated for the relevant condition (i.e., has no history of prior treatment for the condition), and the patient (or specifically, the relevant cancer) may be referred to as treatment-naive.

In another embodiment, the cancer is in a patient who has been treated for a related condition (i.e., a different treatment, other than the treatment defined in the first category of the invention) and has not responded or has not responded adequately to that treatment.

In one embodiment, cancer is defined as difficult to treat (i.e., a treatment-resistant cancer is a cancer that does not respond or responds inadequately to other medical treatments, which other medical treatments would refer to medical treatments other than those defined in the first category of the present invention). Refractory cancers may exhibit resistance to treatment from the start of medical treatment, or cancer cells may acquire resistance during a course of previous medical treatment.

In a particular embodiment, the cancer is refractory to treatment with a compound of formula (I) in the absence of a combination as defined in the first category of the invention (i.e., wherein the prior treatment included a compound of formula (I), but wherein the treatment did not include treatment with an anticancer agent selected from the group consisting of taxane compounds, fluorinated nucleosides, platinum compounds, campestrol analogs, and fluoropyrimidine compounds).

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

In one embodiment, the cancer is colorectal cancer. In a specific embodiment, the colorectal cancer is colorectal cancer or rectal cancer.

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

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

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

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

For the avoidance of doubt, the second aspect of the present invention may have any of the specific features and embodiments described herein with respect to the first aspect of the present invention, including all combinations thereof.

Pharmaceutical composition

According to the third aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

For the avoidance of doubt, the pharmaceutical composition of the third category of the present invention may have any of the specific features and embodiments described herein with respect to other (e.g., first and second) categories of the present invention, including all combinations thereof.

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

References to pharmaceutically acceptable formulations are 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 administered according to one or more of the modes of administration as described herein.

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

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

According to the fourth aspect of the present invention, a pharmaceutical composition for treating cancer is provided, which comprises a compound of formula (I) according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof.

For the avoidance of doubt, the pharmaceutical composition of the fourth category of the present invention may have any of the specific features and embodiments described herein with respect to other (e.g., first to third) categories of the present invention, including all combinations thereof.

Invest

As used herein, references to methods and treatments involving compounds of formula (I) or their pharmaceutically acceptable salts and anticancer agents or their pharmaceutically acceptable salts (both as defined in the first category of the invention) include sequential, separate or simultaneous administration of compounds of formula (I) or their pharmaceutically acceptable salts and anticancer agents or their pharmaceutically acceptable salts (including pharmaceutical compositions comprising the respective components) as part of a medical intervention for the treatment of the relevant disease or condition.

Thus, in certain embodiments, the two active ingredients (i.e., the compound of formula (I) or its pharmaceutically acceptable salt and the anticancer agent or its pharmaceutically acceptable salt) are administered together or sufficiently close in time (as appropriate) to achieve a greater beneficial effect for the patient in the course of treatment of the relevant condition, compared to when a formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or a formulation comprising an anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt is administered alone (as appropriate) in the absence of other components in the same course of treatment. Determining whether a combination provides a greater beneficial effect for the patient in the treatment of a particular cancer and in the course of treatment can be routinely achieved by those skilled in the art.

In other embodiments, the two compounds or compositions are administered before, after and/or simultaneously (or repeatedly as appropriate) with the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time as" include individual doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt thereof being administered within 2 hours (e.g., within 60 minutes, 45 minutes, 30 minutes, 20 minutes or 10 minutes) of each other.

In certain embodiments, the two compounds or compositions are administered sequentially (or repeatedly, if appropriate). When used in this context, the term "sequential administration" includes that the individual doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the anticancer agent (as defined in the first category of the present invention) or a pharmaceutically acceptable salt thereof are administered at intervals of between 2 hours and 7 days (e.g., 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days or 6 days) from each other.

For the avoidance of doubt, the compound of formula (I) or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) may be administered before the anticancer agent or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same). Alternatively, the anticancer agent or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same) may be administered before the compound of formula (I) or its pharmaceutically acceptable salt (or pharmaceutical composition comprising the same).

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

Those skilled in the art will appreciate that the compounds and pharmaceutical formulations as defined herein may be administered orally with tablets, pills, capsules, granules, powders, liquids or other dosage forms or parenterally with intraarticular, intravenous, intramuscular or other injections, transmucosal dosage forms or inhalants.

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

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

Injections 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 are alcohols, such as EtOH. Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. Such compositions are sterilized, for example, by filtering through a bacteria-retaining filter, incorporating a microbicide or irradiating. In addition, such compositions can be produced in the form of sterile solid compositions, which are dissolved or suspended in sterile water or a sterile solvent for injection before use.

Transmucosal dosage forms, such as inhalants or nasal dosage forms, are used in solid, liquid or semisolid form and can be produced according to conventional known methods. For example, known excipients and additional pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. Administration may be performed by using a suitable device for inhalation or insufflation. For example, the dosage form may be administered in the form of a powder of a single compound or a formulated mixture, or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier using known devices, such as a metered and administered inhalation device, or a nebulizer. A dry powder inhaler or the like can be used for single or multiple administrations, and a dry powder or a capsule containing the powder can be used. Alternatively, the reagent can be used in the form of a pressurized aerosol spray or the like using a suitable propellant, for example, a suitable gas such as chlorofluorocarbon or carbon dioxide.

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

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

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

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 administration route (e.g., intravenously).

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

Dosage

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

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

Exemplary dosages of the compounds of formula (I) and anticancer agents as 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 appropriately about 0.001 to 100 mg/kg body weight, preferably 0.1 to 30 mg/kg body weight, more preferably 0.1 to 10 mg/kg body weight, and the dose may be given once or divided into two to four times a day (e.g., twice, three times or four times a day).

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

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

Those skilled in the art will understand that dosage is determined on an individual basis, taking into account the patient's symptoms, age, sex, and the like.

Treatment methods

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

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

Use in the preparation of pharmaceutical preparations

The sixth category of the present invention is the use of the compound of formula (I) or its pharmaceutically acceptable salt and anticancer agent or its pharmaceutically acceptable salt according to the first category of the present invention for the manufacture of a drug for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof.

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

Component Kit

According to the seventh aspect of the present invention, a component kit is provided, which comprises:

(A) A pharmaceutical composition comprising: a compound of formula (I) according to the first category of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected as appropriate, and

(B) A pharmaceutical composition comprising: an anticancer agent or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable formulations as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof,

Each of the components (A) and (B) is provided in a form suitable for administration in combination with the other component,

This kit is used to treat cancer.

As used herein, referring to components administered in conjunction with one another, we include such components being administered sequentially, separately or simultaneously as part of a medical intervention directed to treating the relevant disease or condition as described herein.

In an alternative seventh aspect of the present invention, a component kit is provided, which comprises:

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

(II) instructions for use of the component in combination with the other of the two components,

This kit is used to treat cancer.

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

For therapeutic use

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

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

Preparation of compounds/compositions

The pharmaceutical compositions, combination products and kits described herein may be prepared in accordance with standard and/or generally accepted medical practice.

Therefore, in another aspect of the present invention, a process for preparing a pharmaceutical composition as described herein is provided, which comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent as described herein with one or more pharmaceutically acceptable excipients.

In other aspects of the present invention, a process for preparing a combination product or a kit of parts as defined above is provided. The process comprises combining a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and an anticancer agent.

As used herein, reference to combining will mean making the two components suitable for administration together with each other.

Therefore, with respect to the method of preparing a kit of parts as defined above, by "combining" the two components with each other, we include that the two components of the kit of parts may:

(i) provided as separate formulations (i.e., separate from each other) which are subsequently combined together for use in combination with each other in combination therapy; or

(ii) The individual components are packaged and presented together as a "combination pack" for use in conjunction with each other in combination therapy.

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

Certain compounds as described herein, such as anticancer agents as described herein, and pharmaceutical compositions containing the same can be purchased from sources known to those skilled in the art.

The compound of formula (I) and its salt can be produced by applying various known synthesis methods using characteristics based on its basic structure or substituent type. Here, depending on the type of functional group, as a production technology, it is sometimes effective to replace the functional group with an appropriate protective group (a group that can be easily converted into a functional group) during the process from the raw material to the intermediate. Examples of protective groups include the protective groups described in P.G.M.Wuts and T.W.Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014, and the group appropriately selected from these protective groups is used depending on the reaction conditions. In this type of method, the reaction is carried out with the introduction of the protective group, and the protective group is then removed as necessary, thereby obtaining the desired compound.

In addition, the prodrug of the compound of formula (I) can be produced by introducing a specific group in the process of converting the raw material into an intermediate with respect to the above protective group or by further reacting the obtained compound of formula (I). This reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation or dehydration.

Separation and purification are carried out by applying common chemical procedures such as extraction, fractional crystallization or various types of elution chromatography.

Various types of isomers can be produced by selecting appropriate raw material compounds or can be separated using differences in the physiochemical properties between isomers. For example, optical isomers can be obtained by general optical separation methods for racemates (e.g., fractional crystallization for inducing racemates into non-image-bearing isomer salts with optically active bases or acids, chromatography using a chiral column or the like, or the like) and can also be produced from appropriate optically active raw material compounds.

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

Advantages of the present invention

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

Without theoretical constraints, it is believed that the compound of formula (I) has an inducing degradation effect on G12D mutant KRAS protein and G12D mutant KRAS inhibitory activity, and can be used together with anticancer agents to act synergistically in the treatment of cancer, and specifically G12D mutant KRAS positive cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and their prodrugs.

Examples

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

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

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

Abbreviation

The following abbreviations may be used in this article.

DMF: N,N-dimethylformamide

DMAc: N,N-dimethylacetamide

THF: Tetrahydrofuran

MeCN: acetonitrile

MeOH: methanol

EtOH: ethanol

烷 DOX: 1,4-dimethoxy

alkyl

DMSO: dimethyl sulfoxide

TEA: triethylamine

DIPEA: N,N-diisopropylethylamine

tBuOK: Potassium tertiary butoxide

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

DABCO: 1,4-diazabicyclo[2.2.2]octane

PdCl ₂ (dppf)．CH ₂ Cl ₂ ：[1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct

Pd/C: Palladium/Carbon

Preparation Example

Preparation 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 with an ice bath, followed by the addition of DIPEA (240 mL) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (48 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total volume of the solution became about 400 mL. A mixed solvent (hexane/ethyl acetate = 4/1, 1000 mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered to obtain (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (123 g) as a solid.

Preparation Example 2

To a mixture of (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (30 g), tetrahydro-2H-pyran-4-ol (15.0 mL), DMF (150 mL), THF (100 mL) and DABCO (1.15 g) was added cesium carbonate (50.3 g) with stirring at room temperature under an argon atmosphere, and the mixture was stirred at room temperature overnight. About 1 kg of ice water was added to the reaction mixture, and the mixture was stirred at room temperature for 6 hours. The precipitated solid was filtered, washed with water and dried under reduced pressure overnight to obtain (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (32.8 g) as a solid.

Preparation Example 3

To a mixture of (1S,4S)-5-{7-bromo-8-fluoro-6-iodo-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (11.9 g), benzyl alcohol (2.37 g) and THF (40 mL) was added tBuOK (2.54 g) under an argon stream with ice-bath cooling, and the mixture was stirred at the same temperature for 1.5 hours. Ice water and a saturated aqueous ammonium chloride solution were added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and a mixed solvent of hexane/ethyl acetate (6/1) was added to the resulting residue. The mixture was stirred for a while, and the precipitated solid was filtered and dried to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (11.8 g) as a solid.

Preparation Example 4

Under an argon atmosphere, a mixture of (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-iodo-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.47 g), MeCN (88 mL), DOX (10 mL), water (22 mL), cyclopropylboronic acid (1.27 g), tripotassium phosphate (5.67 g) and PdCl ₂ (dppf) ． CH ₂ Cl ₂ (600 mg) was stirred at 100° C. for 3 hours. After the reaction mixture was cooled to room temperature, the solution was concentrated under reduced pressure. A saturated aqueous sodium chloride solution was added to the obtained residue, and the mixture was extracted with CHCl _3. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.8 g) as a foamy solid.

Preparation Example 5

(1S,4S)-5-{8-(Benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.15 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentyl)-1H-indazole (1.92 g), tripotassium phosphate (4. A mixture of 2-(4-(2-(2-(2-amino-1,1'-biphenyl)-4-yl)-2-nitropropoxy)-1,2-dicyclohexylphosphine (0.1 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (0.12 g), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (II) (0.2 g), DOX (40 mL) and water (8 mL) was degassed and replaced with hydrogen at room temperature with stirring, and then the mixture was stirred at 100° C. under an atmosphere of hydrogen for 2.5 hours. Water (about 150 mL) was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, insoluble 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), and fractions containing (1) a low-polarity non-mirror isomeric mixture (peak-1 and peak-2; peak-1 and peak-2 have the same axial chirality) and (2) a high-polarity non-mirror isomeric mixture (peak-3 and peak-4; peak-3 and peak-4 have the same axial chirality) were obtained. Among these fractions, the fraction containing a low-polarity non-mirror image-forming isomeric mixture (peak-1 and peak-2, same axial chirality) was collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (1.42 g) as a foamy solid. In addition, the fraction containing the highly polar non-mirror isomer mixture (peak-3 and peak-4, same axial chirality) was collected to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (1.37 g) as a foamy solid. The low polar non-mirror isomer mixture was used for the subsequent reaction.

Preparation Example 6

To a MeOH (200 mL) solution of the low-polarity non-mirror isomeric mixture (1S, 4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (10 g) obtained in Preparation Example 11 was added 10% Pd/C (50% wet, 2 g), and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The obtained reaction mixture was filtered through a diatomaceous earth 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 obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (8.11 g) as a foamy solid.

Preparation Example 7

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

Preparation Example 8

At room temperature, (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (4.24 g), (4R)-1-[(2S)-2-azido To a mixture of 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), 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 layers were washed with a saturated aqueous sodium chloride solution 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 (CHCl ₃ /MeOH) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-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}aminoformyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.62 g).

Preparation Example 12

To a solution of (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (3.97 g) in 1,2-dichloroethane (60 mL) was added at room temperature. To the solution was added trimethyltin(IV) hydroxide (3.35 g), 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 CHCl ₃ /MeOH (9/1). The organic layer was washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-L-proline (3.26 g) as a solid.

Preparation Example 13

唑啶-2-酮單鹽酸鹽(60mg)、DIPEA(70μL)及DMF(3mL)之混合物中添加HATU(70mg)，且將混合物在冰浴冷卻下攪拌1小時。將水、飽和氯化鈉水溶液及乙酸乙酯添加至混合物中，且分離水層。水層用乙酸乙酯萃取，且合併之有機層用水及飽和氯化鈉水溶液洗滌，且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)純化，得到呈固體狀之(1S,4S)-5-{6-環丙基-7-[6-氟-5-甲基-1-(氧雜環己-2-基)-1H-吲唑-4-基]-8-{[4-(1-{(2S)-1-[(2S,4R)-4-羥基-2-({(1R)-2-羥基-1-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-三唑-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1] 庚烷-2-甲酸三級丁酯(173mg)。 Under ice cooling, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-L-proline (150 mg), 3-{4-[(1R)-1-amino-2-hydroxyethyl]phenyl}-1,3-

To a mixture of oxazolidin-2-one monohydrochloride (60 mg), DIPEA (70 μL) and DMF (3 mL) was added HATU (70 mg), and the mixture was stirred for 1 hour under ice-bath cooling. Water, a saturated aqueous sodium chloride solution 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 layer was washed with water and a saturated aqueous sodium chloride solution, 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 (CHCl ₃ /MeOH) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-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-

[0147] The mixture was mixed with 1,2-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (173 mg).

Preparation Example 14

To a solution of tributyl 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, and the mixture was degassed and filled with hydrogen three times. Potassium acetate (356 mg) was added at room temperature and the mixture was stirred at 100° C. for 16 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added, and insoluble materials were removed by filtering through a diatomaceous earth pad. Water was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble 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, 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.

Preparation Example 15

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

Preparation Example 17

To a solution of tributyl {(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.41 g) in CH ₂ Cl ₂ (50 mL) and MeOH (50 mL) was added hydrochloric acid (4M DOX solution, 20 mL) dropwise under ice-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 concentrated filtrate was dried under reduced pressure to obtain (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol hydrochloride (2.01 g) as a solid.

Preparation Example 18

To a solution of tributyl {(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}carbamate (3.34 g) in CH ₂ Cl ₂ (25 mL) and MeOH (25 mL) was added hydrochloric acid (4M DOX solution, 25.6 mL) at -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R)-2-amino-2-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]ethan-1-ol hydrochloride (3.06 g) as a solid.

Preparation 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-butyloxycarbonyl)-4-hydroxy-L-proline (1.76 g) and DMF (22 mL) was added DIPEA (4.7 mL) under ice-bath cooling, and then HATU (3.02 g) was added dropwise under ice-bath cooling to maintain the internal temperature below 5° C. The mixture was stirred under ice-bath cooling for 1 hour and at room temperature for 1 hour. Under ice-cooling, water (120 mL), a saturated aqueous sodium chloride solution (50 ml) and ethyl acetate were added, and the aqueous layer was extracted three times with ethyl acetate and then three times with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give tributyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidine-1-carboxylate (3.09 g) as an oily substance.

Preparation 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-butyloxycarbonyl)-4-hydroxy-L-proline (2.81 g) and DMF (40 mL) was added DIPEA (7.8 mL) under ice-bath cooling, and then HATU (4.5 g) was added dropwise under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling and at room temperature for 1 hour. Under ice-bath cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, and then extracted with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tributyl ester (5.01 g) as an oily substance.

Preparation Example 23

To a solution of tributyl (2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidine-1-carboxylate (3.09 g) in _CH2Cl2 ( ₁₈ mL) and MeOH (18 mL) was added hydrochloric acid (4 M DOX solution, 17 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 5 hours. The reaction mixture was concentrated and dried under reduced pressure to 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.

Preparation Example 24

To a solution of (2S,4R)-2-({(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}aminocarbonyl)-4-hydroxypyrrolidine-1-carboxylic acid tributyl ester (5.01 g) in CH ₂ Cl ₂ (35 mL) and MeOH (30 mL) was added hydrochloric acid (4M DOX solution, 28 mL) at -20 to -10°C, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R)-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide hydrochloride (4.71 g) as a solid.

Preparation 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-butyloxycarbonyl)-L-valeric acid (2.16 g) and DMF (45 mL) was added DIPEA (6.2 mL), followed by dropwise addition of HATU (3.61 g) under ice-bath cooling. The mixture was stirred for 1 hour under ice-bath cooling and at room temperature for 1 hour. Under ice-bath cooling, water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate, followed by extraction with ethyl acetate/isopropanol (9/1). The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give N-(tert-butyloxycarbonyl)-L-prolinamide-(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.

Preparation Example 29

To a solution of N-(tert-butyloxycarbonyl)-L-prolinamide-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (4.43 g) in _CH2Cl2 ( ₃₅ mL) and MeOH (35 mL) was added hydrochloric acid (4M DOX solution, 20 mL) at -20 to -15°C, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give L-prolinamide-(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.

Preparation Example 33

To a mixture of L-hydroxy-(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 dropwise a solution of 2-azido-1,3-dimethylimidazolium hexafluorophosphate (1.06 g) in MeCN (5 mL) over 10 minutes or longer under ice-cooling, and the mixture was stirred under ice-cooling for 5 hours. Water, a saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give (4R)-1-[(2S)-2-azido-3-methylbutyryl]-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.

Preparation Example 37

A mixture of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (2.04 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-1,3,2-dioxaborolane (2.05 g), potassium acetate (1.91 g), DOX (40 mL) and bis(triphenylphosphine)palladium(II) dichloride (460 mg) was stirred at 100° C. overnight under an atmosphere of hydrogen. The reaction solution cooled to room temperature was diluted with ethyl acetate, and the mixture was filtered through a diatomaceous earth pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution, 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 obtain tributyl {(1R)-2-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (3.21 g) as an oily substance.

Preparation Example 38

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

Preparation Example 39

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

Preparation Example 41

唑啶-3-甲酸三級丁酯(1.09g)。 To a mixture of tributyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (1 g), 2,2-dimethoxypropane (3.3 mL) and acetone (15 mL) was added boron trifluoride-diethyl ether complex (26 μL), and the mixture was stirred at room temperature for 1 hour. TEA (66 μL) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

Tributyl oxazolidinone-3-carboxylate (1.09 g).

Preparation Example 42

唑啶-3-甲酸三級丁酯(300mg)及1,3-

唑啶-2-酮(183mg)之DOX(1.69mL)溶液中添加碘化銅(I)(32mg)、外消旋-(1R,2R)-環己烷-1,2-二胺(20μL)及碳酸鉀(290mg)。在微波照射下，將混合物在140℃攪拌2小時且在150℃攪拌1小時。添加乙酸乙酯及水，且經由矽藻土墊過濾混合物。在減壓下濃縮濾液，且殘餘物藉由矽膠管柱層析(己烷/乙酸乙酯)純化，得到呈固體狀之(4R)-2,2-二甲基-4-[4-(2-側氧基-1,3-

唑啶-3-基)苯基]-1,3-

唑啶-3-甲酸三級丁酯(120mg)。 At room temperature, (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

Azolidin-3-carboxylic acid tributyl ester (300 mg) and 1,3-

To a solution of oxazolidin-2-one (183 mg) in DOX (1.69 mL) were added copper (I) iodide (32 mg), racemic-(1R,2R)-cyclohexane-1,2-diamine (20 μL) and potassium carbonate (290 mg). Under microwave irradiation, the mixture was stirred at 140° C. for 2 hours and at 150° C. for 1 hour. Ethyl acetate and water were added, and the mixture was filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain (4R)-2,2-dimethyl-4-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]-1,3-

Tributyl oxazolidinone-3-carboxylate (120 mg).

Preparation Example 48

To a mixture of (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(ethylthio)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (350 mg) and CH ₂ Cl ₂ (7 mL) was added m-chloroperbenzoic acid (about 30% water content, 100 mg) with stirring under ice-cooling. The reaction mixture was stirred under ice-cooling for 1.5 hours, and diluted with CH ₂ Cl ₂ , washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain sulfoxide. The obtained sulfoxide was mixed with (S)-2-methoxypropanol (45 mg) and THF (4 mL). KOtBu (80 mg) was added to the mixture under ice-methanol bath cooling, and the mixture was stirred at room temperature under an argon atmosphere for 1 hour. Ice water and an aqueous solution of ammonium chloride were added to the reaction mixture, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica, hexane/ethyl acetate) to give (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-carboxylic acid tributyl ester (280 mg) as a foamy solid.

Preparation Example 51

MeOH (3 mL) was added to (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (211 mg) and 4-methylbenzene-1-sulfonic acid monohydrate (48 mg) was added at room temperature with stirring. Subsequently, the mixture was stirred at room temperature under an atmosphere of hydrogen for 1 hour. Ice and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution 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 obtain the low-polarity non-mirror image isomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl butyl as a solid. Ester (single axial stereoisomer, 87 mg) and the highly polar non-mirror image isomer (1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (single axial stereoisomer, 59 mg) in the form of a solid. The low polar non-mirror image isomer was used for the subsequent reaction.

Preparation Example 52

(1S,4S)-5-{6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (80 mg) was dissolved in t-BuOH (0.7 mL) at room temperature. To a solution of (4R)-1-[(2S)-2-azido-3-methylbutyryl]-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) in 4% paraformaldehyde (0.7 mL), THF (0.7 mL) and water (0.7 mL) was added, and the mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, a solution of EDTA disodium salt in water was added. The mixture was extracted three times with CH ₂ Cl ₂ , and the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (basic silica gel, CHCl ₃ /MeOH) to give (1S,4S)-5-{6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (102 mg) as a foamy solid.

Preparation Example 57

To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL) and CH ₂ Cl ₂ (1880 mL) was added 1,1',1"-(chloromethanetriyl)triphenyl (335 g) at room temperature. 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. CH ₂ Cl ₂ The aqueous layer was extracted three times with 400 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. Subsequently, insoluble matter was 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 then collected by filtration and dried under reduced pressure to obtain 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.

Preparation Example 58

To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) and 2-methyltetrahydrofuran (1000 mL) was added lithium diisopropylamine (2M THF solution, 214.28 mL) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2.5 hours. Iodomethane (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to quench the reactant, and the mixture was extracted twice with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate. Subsequently, insoluble materials were 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.

Preparation Example 59

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

Preparation Example 60

唑-5-甲酸(178mg)、氯化四正丁銨(195mg)、(4R)-4-(4-溴苯基)-2,2-二甲基-1,3-

唑啶-3-甲酸三級丁酯(250mg)、碳酸銫(344mg)及DMF(2.5mL)之混合物中，且將混合物在170℃在微波照射下攪拌30分鐘。將混合物冷卻至室溫且隨後用乙酸乙酯稀釋，且藉由經由矽藻土墊進行過濾移除不可溶物質。濾液用水及飽和氯化鈉水溶液洗滌且經無水硫酸鎂乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。所得殘餘物藉由矽膠管柱層析(CHCl₃/MeOH)來純化，得到呈固體狀之(4R)- 2,2-二甲基-4-[4-(4-甲基-1,3-

唑-5-基)苯基]-1,3-

唑啶-3-甲酸三級丁酯(215mg)。 Under an argon atmosphere, bis(tri-butylphosphine)palladium(0) (18 mg) was added to 4-methyl-1,3-

Oxazole-5-carboxylic acid (178 mg), tetrabutylammonium chloride (195 mg), (4R)-4-(4-bromophenyl)-2,2-dimethyl-1,3-

In a mixture of tributyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL), the mixture was stirred at 170° C. under microwave irradiation for 30 minutes. The mixture was cooled to room temperature and then diluted with ethyl acetate, and the insoluble matter was removed by filtration through a diatomaceous earth pad. The filtrate was washed with water and a saturated aqueous sodium chloride solution 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 (CHCl ₃ /MeOH) to give (4R)- 2,2-dimethyl-4-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]-1,3-

Tributyl oxazolidinone-3-carboxylate (215 mg).

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

Structure: Chemical formula (the compound with "*" in the chemical formula indicates that the compound is a single axial stereoisomer). n HCl: n hydrochloride ("n HCl" indicates that the compound is a monohydrochloride to a trihydrochloride), Data: Physiological and chemical 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, [MH] ^- ), NMR: ^{δ 1H} -NMR (500MHz) peak value (ppm) in DMSO-d ₆ , NMR (100℃): δ ^1H- NMR (500MHz) peak value (ppm) in DMSO-d ₆ at 100℃ Peak value (ppm) in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: doublet of doublets (spectrum), t: triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum) (Example: br s).

Examples

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

In the following examples, the asterisk indicates that the compound is a single axial stereoisomer.

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

Under ice-cooling, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-2-yl)-1H- To a mixture of 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}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxacyclohexan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (5.61 g) and CH ₂ Cl ₂ (60 mL) was added trifluoroacetic acid (27 mL), and then the mixture was stirred at room temperature for 2 hrs. The obtained reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted three times with CHCl ₃ /MeOH (5/1), and the combined organic layers were then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the obtained crude product was purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). A saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl ₃ /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, CHCl ₃ /MeOH) to give the product. Isopropyl acetate (70 mL) was added to the obtained product, and the mixture was stirred at 80° C. for 10 minutes and at room temperature overnight. Hexane (70 mL) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, the obtained solid was filtered, washed with isopropyl acetate/hexane (1/1), and dried at 40° C. under reduced pressure overnight to give the title compound (3.01 g) as a solid.

ESI+: 1117.3;

NMR (100°C): 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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide trihydrochloride

Under a nitrogen atmosphere, (4R)-1-[(2S)-2-(4-{4-[({4-[(1S,4S)-5-(tributyloxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexan-2-yl)-1H-indazol-4-yl]-2-[(oxacyclohexan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzene was added to the mixture. To a mixture of (2R)-2-amino-2-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethan-1-ol dihydrochloride (25 mg) and DMF (1 mL) were added DIPEA (50 μL) and HATU (35 mg) in that order, 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 a 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 obtained residue was purified by silica gel column chromatography (CHCl ₃ /MeOH) to give an amide product (59 mg). Subsequently, the obtained compound was dissolved in CH ₂ Cl ₂ (0.5 mL) and MeOH (0.5 mL), and hydrochloric acid (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 obtained 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.

唑啶-3-基)苯基]乙基}-L-脯胺醯胺 Example 3: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide

唑啶-3-基)苯基]乙基}胺甲醯基)吡咯啶-1-基]-3-甲基-1-側氧基丁-2-基}-1H-1,2,3-三唑-4-基)苯基]甲氧基}-2-[(氧雜環己-4-基)氧基]喹唑啉-4-基}-2,5-二氮雜二環[2.2.1]庚烷-2-甲酸三級丁酯(170mg)、CH₂Cl₂(2mL)及MeOH(2mL)之混合物中添加鹽酸(4M DOX溶液，0.988mL)，且將混合物在室溫下攪拌3小時。將混合物在減壓下濃縮，添加CHCl₃及飽和碳酸氫鈉水溶液，且將混合物攪拌片刻。隨後，用CHCl₃/MeOH(5/1)萃取水層，且合併之有機層經無水硫酸鈉乾燥。藉由過濾移除不可溶物質，且在減壓下濃縮濾液。殘餘物藉由矽膠管柱層析(鹼性矽膠，CHCl₃/MeOH)純化，且隨後藉由ODS管柱層析(MeCN/0.1%甲酸水溶液溶液)純化。合併含有目標化合物之溶離份，用飽和碳酸氫鈉水溶液鹼化，且隨後用CHCl₃/MeOH(5/1)萃取兩次。合併之有機層經無水硫酸鈉乾燥。藉由過濾 移除不可溶物質，且在減壓下濃縮濾液。所得固體用二乙醚洗滌，且在減壓下乾燥，得到呈固體狀之標題化合物(74mg)。 Under ice-cooling, (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexyl-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-

To a mixture _of tributyl ₂ - _[ ( ... Subsequently, the aqueous layer was extracted with CHCl ₃ /MeOH (5/1), 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 (basic silica gel, CHCl ₃ /MeOH), and then purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). The fractions containing the target compound were combined, alkalized with saturated sodium bicarbonate aqueous solution, and then extracted twice with CHCl ₃ /MeOH (5/1). 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 obtained 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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide

This compound was prepared using a method similar to that provided in Example 5 below.

ESI+: 1100.4;

NMR (100 ° C): 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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide

The mixture was added to (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-oxobutyl To a solution _{of tributyl 2} -[( ... The mixture was extracted three times with CHCl ₃ /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 aqueous solution). A saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was extracted three times with CHCl ₃ /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, CHCl ₃ /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 obtained precipitate was filtered, washed with diethyl ether, and dried under reduced pressure to a solid state (2.98 g).

ESI+: 1114.5;

NMR (100°C): 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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide

Under cooling in an ice-methanol bath, (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}aminocarbonyl)pyrrolidin-1-yl]-3-methyl-1-oxobutyl-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester (98 mg) and CH ₂ Cl ₂ were added. To a mixture of 4-(2-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ _[ [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ _[ [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[

ESI+: 1105.7;

NMR (100 ° C): 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]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide

This compound was prepared using a method similar to that provided in Example 6 above.

ESI+: 1102.8;

NMR (100 ° C): 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).

唑-5-基)苯基]乙基}-L-脯胺醯胺 Example 8: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide

This compound was prepared using a method similar to that provided in Example 6 above.

ESI+: 1089.9.

Biological examples

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

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

[Tumor volume (mm ³ )] = [Long diameter of tumor (mm)] × [Short diameter of tumor (mm)] ² × 0.5

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

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

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

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

[Tumor volume (mm ³ )] = [Long diameter of tumor (mm)] × [Short diameter of tumor (mm)] ² × 0.5

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

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

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

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

[Tumor volume (mm ³ )] = [Long diameter of tumor (mm)] × [Short diameter of tumor (mm)] ² × 0.5

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

The following results were obtained (Table 4).

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

Industry Availability

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

Claims (22)

A combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof, for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof, wherein the compound of formula (I) is selected from the group consisting of: (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-{4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}ethyl]-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(2-oxo-1,3-

oxazolidin-3-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]- 7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxacyclohexyl-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-N-{(1R)-1-[4-(1-ethyl-1H-pyrazol-5-yl)phenyl]-2-hydroxyethyl}-4-hydroxy-L-prolinamide, and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutyryl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-

oxazol-5-yl)phenyl]ethyl}-L-prolinamide. The compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 is used for treating cancer, wherein the treatment further comprises administering an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 and an anticancer agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable formulations selected as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorine-containing nucleosides, platinum compounds, camptothecin analogs, fluoropyrimidine compounds and prodrugs thereof. The pharmaceutical composition as described in claim 3 is used for treating cancer. A method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anticancer agent or a pharmaceutically acceptable salt thereof, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrol analogs, fluoropyrimidine compounds and prodrugs thereof. A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as described in claim 1 for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and prodrugs thereof. A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an anticancer agent or a pharmaceutically acceptable salt thereof as described in claim 1, for the manufacture of a medicament for treating cancer, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, alkaloid analogs, fluoropyrimidine compounds and prodrugs thereof. A kit-of-parts comprising: (A) A pharmaceutical composition comprising: a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients selected as appropriate, and (B) A pharmaceutical composition comprising: an anticancer agent or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable formulations as appropriate, wherein the anticancer agent is selected from the group consisting of: taxane compounds, fluorinated nucleosides, platinum compounds, dendrite analogs, fluoropyrimidine compounds and prodrugs thereof, Each of the components (A) and (B) is provided in a form suitable for administration in combination with the other component, This kit is used to treat cancer. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a taxane compound. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 9, wherein the taxane compound is paclitaxel. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 9, wherein the taxane compound is docetaxel. A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a fluorinated nucleoside. The compound for use, pharmaceutical composition, pharmaceutical composition for use, method, use or kit of parts for use as described in claim 12, wherein the fluorinated nucleoside is gemcitabine. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a platinum compound. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 14, wherein the platinum compound is oxaliplatin. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a catecholamine analog. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 16, wherein the campestrin analog is irinotecan. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 8, wherein the anticancer agent is a fluoropyrimidine compound. A compound for use, a pharmaceutical composition, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in claim 18, wherein the fluoropyrimidine compound is 5-FU. A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is pancreatic cancer. A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is colorectal cancer. A compound for use, a pharmaceutical composition for use, a pharmaceutical composition for use, a method, a use or a kit of parts for use as described in any one of claims 1 to 19, wherein the cancer is lung cancer.