Combination of antibody-drug conjugates and ATR inhibitors

Abstract

The present invention provides improved therapeutic compositions and methods that can enhance the efficacy of existing cancer treatments, improve the duration of the therapeutic response, and / or reduce dose-dependent toxicity. [Solution] A pharmaceutical product is provided for administering an anti-HER2 antibody-drug conjugate represented by the following formula in combination with an ATR inhibitor (where A is the attachment site to the antibody). JPEG2026048860000054.jpg72170

Description

[Technical Field]

[0001] This disclosure relates to an antitumor drug conjugated to an anti-HER2 antibody via a linker structure. A pharmaceutical product for administering a specific antibody-drug conjugate in combination with an ATR inhibitor. Products, as well as specific antibody-drug conjugates and ATR inhibitors in combination, are targeted. Regarding the therapeutic use and methods of administration. [Background technology]

[0002] ATR (ataxia telangiectasia and rad3-related kinase) is serine / threonine It is a protein kinase, specifically a phosphatidylinositol 3 kinase-related kinase (P It is a member of the IKK family. During normal DNA replication, ATR stops replication. The duplicate forks that were mobilized and stopped in the fork remain unrepaired and are double-chained. This can sometimes lead to a break. ATR is damage to single-stranded DNA or a double-strand break during DNA replication. After excision, it is recruited to single-stranded DNA coated with replication protein A (RPA). The mobilization and activation of DNA occurs during the S phase, when DNA is repaired and stalled replication forks are broken down. This causes cellular cycle arrest or nuclear fragmentation and the initiation of programmed cell death (apoptosis).

[0003] As a result, ATR inhibitors can help tumor cells that rely on ATR for DNA repair, such as ATM It is expected to induce growth inhibition in tumor defects. In addition to this monotherapy activity. Therefore, when ATR inhibitors are used in combination, (ATR-dependent DNA repair process) It is also expected that this will enhance the activity of DNA damage induction therapy (through inhibition of ATR inhibitors). An example of this is disclosed, for instance, in International Publication No. 2011 / 154737.

[0004] Inactivation of Schlafen 11 (SLFN11) in cancer cells leads to DNA damage and multiple It has also been shown that it can lead to resistance to anticancer drugs that cause stress. Therefore, S LFN11 is a topoisomerase I inhibitor, but is not limited to other different types. It can serve as a determinant of sensitivity to a class of DNA damaging agents. ppoli et al.,PNAS 2012;109:15030-35;Mura i et al.,Oncotarget 2016;7:76534-50;Mura See i et al., Mol. Cell 2018;69:371-84.

[0005] Antibody-drug conjugates (ADCs), which consist of a cytotoxic drug conjugated to an antibody, This allows for the selective delivery of drugs to cancer cells, and thus prevents drug accumulation within cancer cells. It is expected to kill cancer cells by being applied (Ducry, L., et al., Bio conjugate Chem.(2010)21,5-13;Alley,SC, et al.,Current Opinion in Chemical Biolo gy(2010)14,529-537;Damle NKExpert Opin .Biol.Ther.(2004)4,1445-1452;Senter PD ,et al.,Nature Biotechnology(2012)30,631 -637;Burris HA.,et al.,J.Clin.Oncol.(201 1)29(4):398-405).

[0006] One such antibody-drug conjugate consists of a HER2-targeted antibody and exate Trastuzumab deruxtecan is a derivative of kan (Ogitani Y. et al.). al.,Clinical Cancer Research(2016)22(20) ,5097-5108;Ogitani Y.et al.,Cancer Scien. ce(2016)107,1039-1046).

[0007] Despite the therapeutic potential of antibody-drug conjugates and ATR inhibitors, antibody-drug Test results demonstrating the superior efficacy of using a combination of conjugates and ATR inhibitors. Alternatively, no literature has been published that provides scientific evidence suggesting these test results. Because no test results exist, antibody-drug conjugates and other cancers such as ATR inhibitors Combination administration with therapeutic agents can lead to adverse interactions and / or subadditive therapeutic outcomes. There are combinations, and therefore, the superior or higher effects that can be obtained from these combination therapies It may not be possible to expect this. [Overview of the project] [Problems that the invention aims to solve]

[0008] Therefore, to enhance the efficacy of existing cancer treatments, improve the duration of the therapeutic response, and / or use There is a need for improved therapeutic compositions and methods that can reduce dose-dependent toxicity. It simply exists as it is. [Means for solving the problem]

[0009] The antibody-drug conjugate used in this disclosure (topoisomerase I inhibitor exateca Anti-HER2 antibody-drug conjugates containing derivatives of HER2 are used in specific cancers such as breast cancer and gastric cancer. In cancer treatment, it has been confirmed to show excellent antitumor effects when administered alone. However, enhanced efficacy, improved duration of therapeutic response and / or reduced dose-dependence. To provide drugs and treatments that can achieve higher antitumor effects in cancer treatment, such as those with high toxicity. It is desirable to replicate the antibody-drug conjugate introduced by the antibody-drug conjugate of this disclosure. By inhibiting the DNA damage response to stress and double-strand breaks, ATR inhibitors When administered in combination with an antibody-drug conjugate, it further enhances the antitumor effect. It is possible.

[0010] This disclosure describes the administration of an anti-HER2 antibody-drug conjugate combined with an ATR inhibitor. This provides a pharmaceutical product that can exhibit excellent antitumor effects in cancer treatment. The disclosure states that anti-HER2 antibody-drug conjugates and ATR inhibitors are used in combination to target the target. The therapeutic uses and methods of administering the substance are also provided.

[0011] Specifically, this disclosure relates to the following [1] to

[54] .

[0012] [1] Anti-HER2 antibody-drug conjugates and ATR inhibitors for combined administration A pharmaceutical product containing a harmful agent, the anti-HER2 antibody-drug conjugate, has the following formula: [ka] (In the formula, A represents the attachment site to the antibody.) The drug linker, represented by [the symbol], conjugates to the anti-HER2 antibody via thioether linkage. A pharmaceutical product that is an antibody-drug conjugate.

[0013] [2] The ATR inhibitor is represented by the following formula (I):

Chemical formula

Chemical formula

[0014] [3] In equation (I), R 4 and R 5 They form ring A together with the atoms to which they are bonded. The ring A is formed and contains one heteroatom selected from O and N. 3~6 Shik The pharmaceutical product according to [2], which is a rhalkyl or saturated 4-6 heterocycle.

[0015] [4] In formula (I), ring A is cyclopropyl, tetrahydropyranyl, or piperi A pharmaceutical product according to [2] or [3], which is a dinyl ring.

[0016] [5] In equation (I), R 2A is hydrogen, and R 2B is hydrogen, and R 2C teeth, It is hydrogen, R 2D is hydrogen, and R 2E is hydrogen, and R 2F It is hydrogen. A pharmaceutical product described in any one of [2] to [4].

[0017] [6] In equation (I), R 1 It is 3-methylmorpholine-4-yl, [2]~ A pharmaceutical product as described in any one of [5].

[0018] [7] Compounds of formula (I) are of formula (Ia): [ka] The compound of or a pharmaceutically acceptable salt thereof, as described in any one of [2] to [6]. Pharmaceutical product.

[0019] [8] In equation (Ia), Ring A is a cyclopropyl ring, R 2 teeth, [ka] And, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 And, R 2H It is fluoro, R 3 It is a methyl group, R 6 is hydrogen, and R 7 The pharmaceutical product described in [7] is hydrogen or methyl.

[0020] [9] ATR inhibitors are given by the following formula: [ka] AZD6, also known as ceraracertib or AZ13386215, is represented by [the specified source]. The pharmaceutical product described in [2] is 738 or a pharmaceutically acceptable salt thereof.

[0021]

[10] Anti-HER2 antibodies are CDRs consisting of amino acid sequences represented by SEQ ID NO: 3. H1 (= amino acid residues 26-33 of SEQ ID NO: 1), the amino acid represented by SEQ ID NO: 4 CDRH2 (=amino acid residues 51-58 of SEQ ID NO: 1) and SEQ ID NO: 5 CDRH3 consists of the amino acid sequence represented as shown (= amino acid residues 97-10 of SEQ ID NO: 1) CDRL1 (= 9) consists of a heavy chain including the amino acid sequence represented by SEQ ID NO: 6 The amino acid residues 27-32 of SEQ ID NO: 2 and 1-3 of SEQ ID NO: 7 CDRL2 (= amino acid residues 50-52 of SEQ ID NO 2) and SEQ ID NO 8, which consist of no acid sequences. CDRL3 consists of the amino acid sequence represented by (= amino acid residues 89- of SEQ ID NO: 2) A pharmaceutical product described in any one of [1] to [9], which is an antibody containing a light chain including 97). .

[0022]

[11] Anti-HER2 antibodies are heavy chain antibodies consisting of an amino acid sequence represented by SEQ ID NO: 9 The heavy chain containing the variable region (=amino acid residues 1-120 of SEQ ID NO: 1) and SEQ ID NO: 10 The light chain variable region consisting of the represented amino acid sequence (= amino acid residues 1-107 of SEQ ID NO: 2) A pharmaceutical product described in any one of [1] to [9], which is an antibody containing a light chain containing [a specific substance].

[0023]

[12] Anti-HER2 antibodies consist of a heavy chain and an amino acid sequence represented by Sequence ID No. 1. The antibody contains a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, [1]~[ A pharmaceutical product as described in any one of [9].

[0024]

[13] Anti-HER2 antibodies are represented by the amino acid sequence (=sequence number 11) A heavy chain consisting of 1 amino acid residues (1-449) and an amino acid sequence represented by SEQ ID NO: 2 A pharmaceutical product as described in any one of [1] to [9], which is an antibody containing a series of light chains.

[0025]

[14] The anti-HER2 antibody-drug conjugate is expressed by the following formula: [ka] (In the formula, “antibody” is an antibody conjugated to a drug linker via a thioether bond.) This refers to the HER2 antibody, and n is the number of antibodies per antibody molecule in the antibody-drug conjugate. (This refers to the average number of units of jugated drug linker, where n is in the range of 7-8.) A pharmaceutical product as described in any one of [1] to

[13] , represented by [1].

[0026]

[15] Anti-HER2 antibody-drug conjugates include trastuzumab deruxtecan (D A pharmaceutical product as described in any one of [1] to

[14] , which is S-8201.

[0027]

[16] Contains an anti-HER2 antibody-drug conjugate and an ATR inhibitor for co-administration. A pharmaceutical product according to any one of [1] to

[15] , which is a composition.

[0028]

[17] Anti-HER2 antibody-drug conjugate and ATR inhibitor for sequential or concurrent administration A combination formulation containing harmful agents, the pharmaceutical product described in any one of [1] to

[15] . .

[0029]

[18] For the treatment of cancer, as described in any one of [1]1 to

[17] Pharmaceutical product.

[0030]

[19] Cancers include breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, and esophagogastric junction adenocarcinoma. Biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer gastrointestinal stromal tumors, digestive tract stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatic cell carcinoma Cellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, morphology Select from the group consisting of saccharitoma, myeloma, glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. A pharmaceutical product according to

[18] , which is at least one selected.

[0031]

[20] Cancer is breast cancer,

[19] the pharmaceutical product described.

[0032]

[21] Breast cancer is characterized by an IHC3+ HER2 status score, as described in

[20] . A finished product.

[0033]

[22] Breast cancer is HER2-low expressing breast cancer, as described in

[20] .

[0034]

[23] Breast cancer is characterized by having an IHC2+ HER2 status score, as described in

[20] . A finished product.

[0035]

[24] Breast cancer is characterized by an IHC1+ HER2 status score, as described in

[20] . A finished product.

[0036]

[25] Breast cancer is characterized by an IHC > 0 and a HER2 status score of < 1+, as described in

[20] . A listed pharmaceutical product.

[0037]

[26] Breast cancer is triple-negative breast cancer, as described in

[20] .

[0038]

[27] Cancer is gastric cancer,

[18] the pharmaceutical product described.

[0039]

[28] Cancer is colorectal cancer, the pharmaceutical product described in

[18] .

[0040]

[29] Cancer is lung cancer, the pharmaceutical product described in

[18] .

[0041]

[30] Lung cancer is non-small cell lung cancer, as described in

[29] .

[0042]

[31] Cancer is pancreatic cancer, the pharmaceutical product described in

[18] .

[0043]

[32] Cancer is ovarian cancer, the pharmaceutical product described in

[18] .

[0044]

[33] Cancer is prostate cancer, the pharmaceutical product described in

[18] .

[0045]

[34] Cancer is kidney cancer, the pharmaceutical product described in

[18] .

[0046]

[35] Cancer cells are SLFN11 deficient, as described in

[18] .

[0047]

[36] SLFN11 expression is observed in patients' cancer cells, and in patients' non-cancerous SLFN11 expression. A pharmaceutical product described in

[18] that is lower in proportion to cells.

[0048]

[37] Pharmaceutical preparations for use in the treatment of cancer, as described in any one of [1] to

[17] . thing.

[0049]

[38] Cancer is as described in any one of the following

[19] -

[36] ,

[37] Pharmaceutical products for use as described above.

[0050]

[39] Anti-HER2 antibody-drug conjugates and ATR inhibitors for the treatment of cancer In the manufacture of drugs for administration in combination, anti-HER2 antibody-drug conjugate The use of an anti-HER2 antibody-drug conjugate and an ATR inhibitor, wherein the use of an anti-HER2 antibody-drug conjugate and an ATR inhibitor The harmful agent is used as described in one of [1] to

[15] .

[0051]

[40] Cancer is as described in one of the following

[19] -

[36] ,

[39] Use as described above.

[0052]

[41] The drugs are an anti-HER2 antibody-drug conjugate and an ATR inhibitor for co-administration. The use described in

[39] or

[40] , which is a composition containing harmful agents.

[0053]

[42] The drugs are used in the form of anti-HER2 antibody-drug conjugates and for sequential or simultaneous administration. The use described in

[39] or

[40] , which is a combination formulation containing an ATR inhibitor.

[0054]

[43] Anti-HER2 antibody-drug conjugates and ATR inhibitors are [1]~

[15] As described in one of the following, in combination with ATR inhibitors in the treatment of cancer Anti-HER2 antibody-drug conjugate for use.

[0055]

[44] Cancer is as described in one of the following

[19] -

[36] ,

[43] Anti-HER2 antibody-drug conjugate for use as described above.

[0056]

[45] Use involves sequentially administering an anti-HER2 antibody-drug conjugate and an ATR inhibitor. Anti-HER2 antibody-drug for use as described in

[43] or

[44] , including administering Njugate.

[0057]

[46] Use involves the simultaneous administration of an anti-HER2 antibody-drug conjugate and an ATR inhibitor. Anti-HER2 antibody-drug con for use as described in

[43] or

[44] , including the use of anti-HER2 antibody-drug con Jugate.

[0058]

[47] Anti-HER2 antibody-drug conjugates and ATR inhibitors are [1]~

[15] As described in one of the following, anti-HER2 antibody-drug condyloma in the treatment of cancer An ATR inhibitor for use in combination with a cephalopod.

[0059]

[48] ​​Cancer is as described in one of the following

[19] -

[36] ,

[47] ATR inhibitors for use as described above.

[0060]

[49] Use involves sequentially administering an anti-HER2 antibody-drug conjugate and an ATR inhibitor. An ATR inhibitor for use as described in

[47] or

[48] , including administering.

[0061]

[50] Use involves the simultaneous administration of an anti-HER2 antibody-drug conjugate and an ATR inhibitor. An ATR inhibitor for use as described in

[47] or

[48] , including the act of doing so.

[0062]

[51] A method for treating cancer, the anti-HE method described in any one of [1] to

[15] . In combination, R2 antibody-drug conjugates and ATR inhibitors are used as necessary. A method that includes administering to a target.

[0063]

[52] Cancer is as described in any one of the following

[19] -

[36] ,

[51] Methods used.

[0064]

[53] Sequential administration of an anti-HER2 antibody-drug conjugate and an ATR inhibitor The method according to

[51] or

[52] , including the following.

[0065]

[54] Simultaneous administration of an anti-HER2 antibody-drug conjugate and an ATR inhibitor. The method described in

[51] or

[52] , including the method described in

[51] or

[52] . [Effects of the Invention]

[0066] This disclosure relates to an antitumor drug conjugated to an anti-HER2 antibody via a linker structure. The anti-HER2 antibody-drug conjugate is administered in combination with an ATR inhibitor. Pharmaceutical products, as well as specific antibody-drug conjugates and ATR inhibitors in combination, This disclosure provides therapeutic uses and methods for administering to elephants. Therefore, this disclosure is more useful in cancer treatment. We can provide drugs and treatments that can achieve high antitumor efficacy. [Brief explanation of the drawing]

[0067] [Figure 1] This figure shows the amino acid sequence of the heavy chain of the anti-HER2 antibody (SEQ ID NO: 1). [Figure 2] This figure shows the amino acid sequence of the light chain of the anti-HER2 antibody (SEQ ID NO: 2). [Figure 3] This figure shows the amino acid sequence of heavy chain CDRH1 (SEQ ID NO: 3 [= amino acid residues 26-33 of SEQ ID NO: 1]). [Figure 4] This figure shows the amino acid sequence of the heavy chain CDRH2 (SEQ ID NO: 4 [= amino acid residues 51-58 of SEQ ID NO: 1]). [Figure 5] This figure shows the amino acid sequence of the heavy chain CDRH3 (SEQ ID NO: 5 [= amino acid residues 97-109 of SEQ ID NO: 1]). [Figure 6] This figure shows the amino acid sequence of the light chain CDRL1 (SEQ ID NO: 6 [= amino acid residues 27-32 of SEQ ID NO: 2]). [Figure 7] This figure shows the amino acid sequence (SEQ ID NO: 7 [= amino acid residues 50-56 of SEQ ID NO: 2]) containing the amino acid sequence of the light chain CDRL2 (SAS). [Figure 8] This figure shows the amino acid sequence of the light chain CDRL3 (SEQ ID NO: 8 [= amino acid residues 89-97 of SEQ ID NO: 2]). [Figure 9] This figure shows the amino acid sequence of the heavy chain variable region (SEQ ID NO: 9 [= amino acid residues 1-120 of SEQ ID NO: 1]). [Figure 10] This figure shows the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [= amino acid residues 1-107 of SEQ ID NO: 2]). [Figure 11] This figure shows the amino acid sequence of the heavy chain (SEQ ID NO: 11 [= amino acid residues 1-449 of SEQ ID NO: 1]). [Figures 12A-12D] This figure shows the combination matrix obtained from high-throughput screening of DS-8201 and AZD6738 (AZ13386215; ATR inhibitor) in breast cancer cell lines with diverse HER2 expression and a single gastric cell line with high HER2 expression. [Figure 13] This figure shows the synergistic matrix of the combination of DS-8201 and AZD6738 in HER2-high KPL4 cell lines, in terms of (A) relative total cell number as a percentage of the control, and (B) Loewe, Bliss, and HSA scores. [Figure 14] This figure shows the change in total number of cells remaining after treatment compared to zero time for the combination of DS-8201 and AZD6738 in (A) HER2-high KPL4 cell lines and (B) HER2-negative MDA-MB-468 cell lines. [Figure 15] This figure shows the induction of ATM-dependent KAP1 pSer824 signaling, DNA double-strand break (γH2AX) biomarkers, or percentage of cell number (compared to solvent control) for the combination of DS-8201 and AZD6738 in (A) HER2-high KPL4 cell lines or (B) HER2-low MDA-MB-468 cell lines. [Figure 16] This figure shows the changes in tumor volume over time in female nude mice treated with subcutaneously transplanted NCI-N87 tumors, administered twice daily (BID) in combination with DS-8201 at 1 mg / kg or 3 mg / kg and AZD6738 at 25 mg / kg. [Figure 17] This figure shows antibody blot images of DS-8201 or exatecan mesylate combined with AZD6738 in (A) NCI-N87 (gastric cancer) and (B) KPL4 (breast carcinoma) cell lines. [Figures 18A-18B] This figure shows a combination matrix obtained by screen testing of DS-8201 and AZD6738 (ceraracertib) in primary CD34+ bone marrow-derived hematopoietic stem cells and progenitor cells induced to differentiate into erythrocyte, myeloid, or megakaryocyte lineages. [Figure 19] (A) and (B) are figures showing combination matrices obtained by high-throughput screening of DS-8201 and AZD6738 in HER2-low NCI-H522 (lung cancer) cell lines. [Modes for carrying out the invention]

[0068] To make this disclosure easier to understand, we first define certain terms. Additional definitions are provided below. This is described throughout the entire detailed explanation.

[0069] Before describing this disclosure in detail, it should be noted that this disclosure is not limited to any particular composition or method or process, and therefore may vary. It should be understood that further use is possible when used in this specification and the appended claims. Unless explicitly indicated in the context, the singular forms "a", "an", and "That" can refer to multiple things. The terms and the phrases "one or more" and "at least one" are used interchangeably herein. It is possible.

[0070] Furthermore, as used herein, "and / or" does not imply the presence or absence of other features or components. It should be considered a specific disclosure of each of two specific features or components. Therefore, the terms used in phrases such as "A and / or B" in this specification "and / or" includes "A and B", "A or B", "A" (alone) and "B" (alone). It shall be assumed that the term "and / or" is used in phrases such as "A, B and / or C". When used in a phrase, it is intended to encompass each of the following forms: A, B, and C ;A, B or C;A or C;A or B;B or C;A and C;A and B;B and C;A( B (alone); B (alone); and C (alone).

[0071] Unless otherwise defined, all technical and scientific terms used herein refer to the terms relating to this disclosure. It has the same meaning as commonly understood by those skilled in the art in that field. For example, Conci se Dictionary of Biomedicine and Molecule ar Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press;The Dictionary of Cell and Molecule lar Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology,Revised,2000,Oxford Un International Press has compiled a list of many of the terms used in this disclosure from general dictionaries. Provide it to the contractor.

[0072] Units, prefixes, and symbols are expressed in the form recognized by their respective International System of Units (SI). A numerical range includes the number that defines that range.

[0073] When an aspect is described in this specification together with the word “including,” it is always “consisting of and / or similar embodiments are also provided, which are described in terms of "essentially being from" Please understand this.

[0074] The terms “inhibit,” “block,” and “suppress” are used synonymously in this specification. This refers to any statistically significant reduction in biological activity (including complete blockade of activity). For example, "inhibition" is approximately 10%, 20%, 30%, 40%, 50%, 60% of biological activity. may refer to a 70%, 80%, 90% or 100% decrease.

[0075] Cell proliferation is the rate of cell division and / or the proportion of cells in a cell population that undergo cell division and / or the rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation), and can be assayed using techniques recognized in the art.

[0076] The term "subject" refers to any animal (e.g., a mammal) that is a recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in the context of human subjects.

[0077] The term "pharmaceutical product" refers to a formulation that enables the biological activity of an active ingredient in the form of a composition (for co-administration) containing all active ingredients or a combination of individual compositions (combination formulation) each containing at least one, but not all, of the active ingredients (for sequential or co-administration), and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the product is administered. Such a product may be sterile. "Co-administration" means that the active ingredients are administered simultaneously. "Sequential administration" means that the active ingredients are administered one by one, with a time interval between individual administrations, in any order. <了 The time interval can be, for example, less than 24 hours, preferably less than 6 hours, more preferably less than 2 hours. "Treating", or "treatment", or "treat" or "alleviating"

[0078] "treating", or "treatment", or "treat" or "alleviating"​ The terms "or" or "alleviate" mean (1) to cure or slow down the symptoms of a diagnosed condition or disease. (2) Therapeutic measures that cause, reduce, and / or halt the progression of the disease, and (3) Target disease state or prophylactic to prevent and / or slow the onset of disease This refers to both preventative measures and treatment. Those who should be doing so include individuals who already have the disease, those prone to developing the disease, and those who should be taking preventative measures against the disease. Those who are among them. In some aspects, patients may have, for example, a complete or partial or If temporary remission is observed, the cancer in question has been successfully “treated” according to the method of this disclosure. ru.

[0079] The terms "cancer," "tumor," "cancerous," and "malignant" typically refer to conditions characterized by uncontrolled cell growth. It refers to or describes a physiological condition in a mammal characterized by a specific feature. An example of cancer is milk cancer. cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Diseases, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumors, Stromatous endoplasmosis, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial carcinoma , kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, Examples include, but are not limited to, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. i. Cancers include hematological malignancies, such as acute myeloid leukemia, multiple myeloma, and chronic lymphocytosis. Leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and others. These include solid tumors, such as breast cancer, lung cancer, neuroblastoma, and colon cancer.

[0080] As used herein, the term "cytotoxic agent" is broadly defined as an agent that inhibits cellular function. Or prevent and / or cause cell destruction (cell death) and / or antineoplastic / This refers to substances that exert antiproliferative effects. For example, cytotoxic agents inhibit the development and maturation of neoplastic tumor cells. Or, directly or indirectly, prevent diffusion. This term refers only to the cell proliferation inhibitory effect. This includes drugs that do not cause mere cytotoxic effects. This term is defined below. Chemotherapy agents, as well as other HER2 antagonists, anti-angiogenic agents, and tyrosine kinase inhibitors. Agents, protein kinase A inhibitors, members of the cytokine family, radioisotopes and This includes toxins, such as enzymatically active toxins of bacterial, fungal, plant, or animal origin.

[0081] The term "chemotherapeutic agent" is a subset of the term "cytotoxic agent," which includes natural or synthetic compounds. ru.

[0082] By the method or use of the Disclosure herein, administering the compounds disclosed herein to a patient may provide a positive treatment for cancer. It can promote a response. In cancer treatment, the term "positive therapeutic response" refers to the symptoms associated with the disease. This refers to improvement. For example, improvement in a disease can be characterized as a complete response. "Complete remission" means that there is no clinically detectable disease after normalizing any prior test results. This refers to a state of improvement in a disease, even if it is classified as partial remission. "Positive treatment response" refers to a reduction or inhibition of cancer progression and / or duration, a reduction in cancer severity, or This includes improvement and / or improvement of one or more of the symptoms resulting from the administration of the compounds of this disclosure. In specific embodiments, such terms refer to 1, 2 or 2 after administration of the compound of the Disclosure. Refers to three or more results: (1) Stabilization, reduction or elimination of a cancer cell population; (2) Stabilization or reduction of cancer growth; (3) Decrease in cancer formation; (4) Eradication, removal or control of primary, local and / or metastatic cancer; (5) Reduction in mortality; (6) Increase in the duration or proportion of disease - free, recurrence - free, progression - free and / or overall survival; (7) Increase in response rate, response durability or the number of patients responding or achieving remission; (8) Decrease in hospitalization rate; [[ID=__16]](9) Decrease in length of hospitalization; (10) The size of the cancer is maintained and does not increase, or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; and (11) Increase in the number of patients in remission; (12) Decrease in the number of adjuvant therapy drugs (e.g., chemotherapeutic drugs or hormonal therapy drugs) otherwise required for cancer treatment.

[0083] Clinical response can be evaluated using changes detectable by screening techniques such as PET, magnetic resonance imaging (MRI) scans, X - ray imaging, computed tomography (CT) scans, flow cytometry [[ID=__33]] or fluorescence - activated cell sorter (FACS) analysis, histological examination, macroscopic findings and blood chemistry, by, for example, but not limited to, ELISA, RIA, chromatography etc. In addition to these positive treatment responses, subjects undergoing treatment can receive the beneficial effect of improvement in symptoms associated with the disease.

[0084] As used herein, the term "the expression level of SLFN11 is" an amount, for example 0% means that the described amount of cancer cells in the cancer tissue of a patient expresses SLFN11 Note: There seems to be a formatting issue in the original text where line 16 has an underscore in the ID in the English translation. It should be "ID=16" as in the original Japanese text.This means that. Similarly, as used herein, the term "expression of SLFN11" means The level is defined as a certain amount, for example, <10%, which is the amount described in the patient's cancer tissue. This means that the cancer cells express SLFN11. The expression level of SLFN11 is For example, <25%, <20%, <15%, <10%, <9%, <8%, <7%, <6% It could be <5%, <4%, <3%, <2%, <1%, or 0%.

[0085] As used herein, the term "SLFN11 deficiency" refers to a normal gene associated with the gene. It exhibits a phenotype, or, in the case of a protein, is insufficient to demonstrate its physiological function. This refers to the expression level of SLFN11 in related patients, animals, tissues, cells, etc. In the floor model, cells in which the SLFN11 gene has been knocked out (KO) or This animal is an example of "SLFN11 deficiency".

[0086] In this specification, the general term "C" p~q "Alkyl" refers to linear and branched alkyl groups. It includes both. However, references to individual alkyl groups such as "propyl" are linear bars. It is specific only to John (i.e., n-propyl and isopropyl), and "tert References to individual branched alkyl groups such as "-butyl" are specific only to the branched version. Yes, it exists.

[0087] C p~q The prefix C in alkyl and other terms (when p and q are integers) p~ q This indicates the range of carbon atoms present in the base, for example, C 1~4 Alkyl is C1 Cyl(methyl), C2 alkyl(ethyl), C3 alkyl(n-propyl and isopropyl) Propyl as a compound) and C4 alkyl (n-butyl, sec-butyl, isobutyl and Contains tert-butyl.

[0088] C p~q The term alkoxy is -OC p~q Contains alkyl groups.

[0089] C p~q The term alkanoyl includes -C(O) alkyl groups.

[0090] The term "halo" includes fluoro, chloro, bromo, or iodine.

[0091] "Carbocyclyl" contains 3 to 6 ring atoms, where the ring CH2 group can be substituted with a C=O group. It is a monocyclic ring system that is saturated, unsaturated, or partially saturated. "Carbocyclyl" is "Allie "Ru", "C" p~q "Cycloalkyl" and "C p~q Contains "cycloalkenyl".

[0092] "Aryl" is an aromatic monocyclic carbocyrillic ring system.

[0093] "C p~q A "cycloalkenyl" contains at least one C=C bond and a ring CH2 group. It is an unsaturated or partially saturated monocyclic carbocyrillic ring system in which a C=O group can be substituted.

[0094] "C p~q "Cycloalkyl" refers to saturated monocyclic compounds in which the CH2 ring can be substituted with a C=O group. It is a bosicuryl ring system.

[0095] A "heterocyclyl" contains 3 to 6 ring atoms, of which 1, 2, or 3 ring atoms The element is selected from nitrogen, sulfur, or oxygen, and its ring may be linked to carbon or nitrogen, or to a ring of nitrogen or sulfur. Yellow atoms may be oxidized, and the ring CH2 group may be substituted with a C=O group; saturated, unsaturated, or partially saturated. It is a monocyclic ring system. "Heterocyclyl" is also called "heteroaryl" or "cycloheteroaryl". Contains "kill" and "cycloheteralkenyl".

[0096] "Heteroaryl" is a compound that has five or six ring atoms, of which one, two or three A monocyclic aromatic ring in which the ring atom is selected from nitrogen, sulfur, or oxygen, and the ring nitrogen or sulfur can be oxidized. It is a heterocycline.

[0097] "Cycloheteralkenyl" is a compound that has 5 or 6 ring atoms, of which 1 or 2 or It has three ring atoms selected from nitrogen, sulfur, or oxygen, and the ring may be linked to carbon or nitrogen. The ring nitrogen or sulfur atom may be oxidized, and the ring CH2 group may be substituted with a C=O group, unsaturated or partial It is a partially saturated monocyclic heterocycline ring system.

[0098] "Cycloheteroalkyl" is a compound having 5 or 6 ring atoms, of which 1, 2 or Three ring atoms are selected from nitrogen, sulfur, or oxygen, and the ring may be linked to carbon or nitrogen. A saturated monocyclic complex in which a nitrogen or sulfur atom can be oxidized and the ring CH2 group can be substituted with a C=O group. It is a ring system.

[0099] This specification may use synthetic terminology to describe groups containing two or more functionalities. Unless otherwise specified herein, these terms shall be understood as they are understood in the art. It is interpreted as such. For example, carbocyclyl C p~q Alkyl is added to carbocyclyl Therefore, C is substituted. p~qContains alkyl and heterocycline C p~q Alkyl is hetero C substituted by cyclyl p~q Contains alkyl and bis(C p~q Alkyl)amino These are two Cs that may be the same or different. p~q amino acids substituted with alkyl groups include.

[0100] Hello C p~q Alkyl is a compound with one or more halo substituents, particularly one, two, or three halo substituents. Therefore, C is substituted. p~q It is an alkyl group. Similarly, halo C p~q Alkoxy and other halves Other general terms including "ro" encompass one or more halo substituents, particularly one, two, or three halo substituents. It may include.

[0101] Hydroxy C p~q Alkyl is defined as having one or more hydroxyl substituents, particularly one, two, or three C substituted with a hydroxy substituent p~q It is an alkyl group. Similarly, hydroxy C p~q Other general terms containing hydroxy, such as alkoxy, include one or more, especially 1, 2 or It may contain three hydroxyl substituents.

[0102] C p~q Alkoxy C p~q Alkyl is composed of one or more C p~q Alkoxy substituents, in particular 1, 2, or 3 C p~q C substituted with alkoxy substituents p~q Alkyl Similarly, C p~q Alkoxy C p~q C such as alkoxy p~q Others containing alkoxy The general term is one or more C p~q Alkoxy substituents, particularly 1, 2, or 3 C substituents p~qa It may include lucoxy substituents.

[0103] The optional substituents are "one or two", "one, two or three", or "one, two, three or four". When selected from the group or substituent of ", this definition means that all substituents are one of the specific group To be selected (i.e., all substituents are the same) or to have two or more substituents on a particular group Please understand that this includes selection from the top down (i.e., the substituents are not the same).

[0104] The compounds disclosed herein are computer software (ACD / Name version 10). Named using 06).

[0105] Preferred values ​​for any R group or any part or substituent of such group are: The following are some examples: C 1~3 For alkyl groups: methyl, ethyl, propyl, and isopropyl; C 1~6 In the case of alkyl: C 1~3 Alkyl, butyl, 2-methylpropyl, tert- Butyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl, and hexyl; C 3~6 For cycloalkyl groups: cyclopropyl, cyclobutyl, cyclopentyl and cyclopropyl Chlohexyl; C 3~6 Cycloalkyl C 1~3 For alkyl groups: cyclopropylmethyl, cyclopropyl ethyl cyclobutylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl; In the case of aryls: phenyl; Aryl C 1~3 For alkyl groups: benzyl and phenethyl; In the case of carbocylyl: aryl, cyclohexenyl and C3 ~6 Cycloalkyl; In the case of halo: fluoro, chloro, bromo and iodo; C 1~3 In the case of alkoxy: methoxy, ethoxy, propoxy and isopropoxy; C 1~6 In the case of alkoxy: C 1~3 Alkoxy, butoxy, tert-butoxy, pen Tyloxy, 1-ethylpropoxy and hexyloxy; C 1~3 In the case of alkanoyl: acetyl and propanoyl; C 1~6 In the case of alkanoyl: acetyl, propanoyl and 2-methylpropanoyl; In the case of heteroaryl: pyridinyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl , furanyl, pyridazinyl and pyrazinyl; Heteroaryl C 1~3 Alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl Le, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, fra Nilethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, Pyrazinylmethyl, pyrazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyr Midiniylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, 1,3,4-triazolylpropyl and oxazolylmethyl; In the case of heterocyclyl: heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, Azetidinyl, morpholinyl, dihydro-2H-pyranyl, tetrahydropyridine and te Tetrahydrofuranyl; In the case of saturated heterocyclyl: oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl , azetidinil, morpholinil, tetrahydropyranil, and tetrahydrofuranil.

[0106] The examples given for terms used in the detailed description are not limiting. This should be noted.

[0107] As used herein, the term "effective dose" means a significant amount of the symptoms and / or conditions to be treated. A compound or combination that is sufficient to cause a positive change (e.g., to provide a positive clinical response). This refers to the quantity of the product. The effective amount of active ingredient used in a pharmaceutical product depends on the knowledge and expertise of the attending physician. Within the technology, the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, and the benefits The specific active ingredients used, the specific pharmaceutically acceptable excipients / carriers utilized, and The results will vary depending on the same factors. Specifically, the combination with antibody-drug conjugates Therefore, the effective amount of the compound of formula (I) used in cancer treatment is the combination of which is used in humans, etc. To alleviate cancer symptoms, slow cancer progression, or treat cancer symptoms in warm-blooded animals This is a sufficient amount to reduce the risk of exacerbation in patients.

[0108] As used herein, the term "pharmaceutically acceptable" means a reasonable benefit / risk ratio and Consistent with human and animal studies, without excessive toxicity, irritation, allergic reactions, or other problems or complications. Compounds and materials that are suitable for use in contact with the tissues of objects and are within the bounds of reasonable medical judgment. This refers to compositions and / or dosage forms.

[0109] Certain compounds of formula (I) can exist as stereoisomers. This disclosure relates to formula ( I) All geometric and optical isomers of the compounds, as well as mixtures thereof including racemic mixtures. It will be understood that this includes tautomers and mixtures thereof. ru.

[0110] Solvates and mixtures thereof also form embodiments of the present disclosure. For example, preferred compounds of formula (I) Solvates include, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, trihydrates, or solvates. It could be an alternative quantity.

[0111] A compound of formula (I) defined above contains one or more asymmetric carbon atoms or sulfur atoms. To the extent that an atom may exist in an optically active or racemic form, this disclosure is defined as follows: Please understand that this includes all such optically active or racemic forms that possess the activity described above. This disclosure encompasses all such stereoisomers having the activity defined herein. Furthermore, the names of chiral compounds (R,S) are arbitrary scalemic mixtures. It was also understood that (R) and (S) represent a substance or racemic mixture, and that (R) and (S) represent an enantiomer. i. If the name does not contain (R,S), (R), or (S), the name is any Scaremi. This refers to a racemic mixture or a racemic mixture, where the racemic mixture is R and S enantio The racemic mixture contains R and S enantiomers in any relative proportion, in a 50:5 ratio. It should be understood that it is contained in a ratio of 0. The synthesis of the optically active form is well known in the art. Standard techniques in organic chemistry, such as synthesis from optically active starting materials or resolution of racemic forms This can be done. The racemic mixture can be separated into individual enantiomers using known procedures. It can be separated (for example, Advanced Organic Chemistry See 3rd Edition, author J March, pp. 104-107. Desired). Suitable procedures include the formation of diastereomeric conductors by reaction of a racemic material with a chiral auxiliary, followed by separation of this diastereomer, for example by chromatography, and then cleavage of this auxiliary molecular species. Similarly, the activities described above can be evaluated using standard laboratory techniques. It will be understood that the compounds of formula (I) may include compounds containing one or more isotope substitutions. For example, H can be in any isotopic form including H, H (D) and

[0112] H (T), C can be in any isotopic form including C, 1 C and 2 C, and O can be in any isotopic form including 3 O and 18 12 O, etc. 13 14 16

[0113] <00011९6>[[ID=3५]] The present disclosure may use the compounds of formula (I) and salts thereof as defined herein. The salts for use in pharmaceutical products are pharmaceutically acceptable salts, but other salts may also be useful in the production of the compounds of formula (I) and their pharmaceutically acceptable salts. Examples of the pharmaceutically acceptable salts of the present disclosure may include acid addition salts of the compounds of formula (I) as defined herein that are sufficiently basic to form such salts. Such acid addition salts may include, but are not limited to, fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate salt and maleate salts and salts formed with phosphoric acid and sulfuric acid. Further, when the compound of formula (I) is sufficiently acidic, the salt is a base salt, and examples include alkali metal salts such as sodium or potassium, alkaline earth metal salts such as

[0115] calcium or magnesium, ammonium salts and organic amine salts such as For example, calcium or magnesium or organic amine salts, such as triethylamine, ethanol Nolamine, diethanolamine, triethanolamine, morpholine, N-methyl methyl Peridine, N-ethylpiperidine, dibenzylamine, or amino acids, such as lysine These are some examples, but are not limited to them.

[0115] The compound of formula (I) can also be provided as an in vivo hydrolyzable ester. In vivo hydrolyzable esters of compounds of formula (I) containing a boxy or hydroxyl group are For example, pharmaceutically acceptable substances that are cleaved in the human or animal body to produce hydrophilic acids or alcohols. It is an ester. Such esters can be tested, for example, by administering the compound intravenously to test animals. It can be identified by administering the substance and then testing the body fluids of the test animals.

[0116] Suitable pharmaceutically acceptable esters for carboxy include C 1~6 Alkoxymethyl Esters, for example, methoxymethyl, C 1~6 Alkanoyloxymethyl esters, for example Pivaloyloxymethyl, phthalidyl ester, C 3~8 Cycloalk Carbonyl Oxygen (cycloalkcarbonyloxy)C 1~6 Alkyl esters, for example, 1-C Chlohexylcarbonyloxyethyl, (1,3-dioxolenn-2-one)ylmethyl Esters, for example, (5-methyl-1,3-dioxolenn-2-one)ylmethyl and C1 ~6 Alkoxycarbonyloxyethyl esters, for example, 1-methoxycarbonyloxy Ethyl is an example, and can be formed at any carboxyl group in the compounds of this disclosure. ru.

[0117] Suitable pharmaceutically acceptable esters for hydroxyl include inorganic esters, such as phosphorus. Acid esters (including phosphoramidite cyclic esters) and α-acyloxyalkyl esters The reaction that generates a hydroxyl group as a result of in vivo hydrolysis of ester and ester decomposition Examples of linked compounds include α-acyloxyalkyl ethers. Examples include hydroxy and 2,2-dimethylpropionyloxymethoxy. As for the in vivo hydrolyzable ester-forming group, C 1~10 Alkanoyl, example For example, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl, C 1~10 Alkoxycarbonyl (to produce alkyl carbonate esters), for example, Toxiccarbonyl, di-C 1~4 Alkylcarbamoyl and N-(di-C) 1~4 Alkyl (Aminoethyl)-NC 1~4 Alkylcarbamoyl (to produce carbamates) , G-C 1~4 Examples include alkylaminoacetyl and carboxyacetyl. Phenyle Examples of ring substituents on acetyl and benzoyl include aminomethyl, C 1~4 Alkyl Minomethyl and di-(C) 1~4 Alkyl)aminomethyl and the 3 or 4 position of the benzoyl ring Examples include morpholino or piperazine, which are bonded to a ring nitrogen atom via a methylene bond group. Other interesting in vivo hydrolyzable esters include, for example, R A C(O)O C 1~6 alkyl-CO-(wherein R in the formula) A For example, benzyl oxy-C 1~4 Alkyl Examples include (or phenyl). Suitable substitutions on the phenyl group in such esters. For example, 4-C 1~4 Alkylpiperazino-C 1~4 Alkyl, piperazino -C 1~4 Alkyl and morpholino-C 1~4 Alkyl compounds are examples.

[0118] The compound of formula (I) is broken down in the body of a human or animal to produce the compound of formula (I). It can also be administered in the form of a prodrug. Various forms of prodrugs are known in the art. Yes, there are. For examples of such prodrug derivatives, see below: a) Design of Prodrugs, edited by H.Bundgaa rd, (Elsevier, 1985) and Methods in Enzymolog y,Vol.42,p.309-396,edited by K.Widder,et al. (Academic Press, 1985); b)A Textbook of Drug Design and Development ent,edited by Krogsgaard-Larsen and H.Bundg aard,Chapter 5“Design and Application of Prodrugs”, by H.Bundgaard p.113~191(1991 ); c) H. Bundgaard, Advanced Drug Delivery Rev. iews, 8, 1-38 (1992); d)H.Bundgaard,et al.,Journal of Pharmace Utical Sciences, 77, 285 (1988); and e) N.Kakeya, et al.,Chem Pharm Bull,32,69 2 (1984).

[0119] The following describes preferred forms for implementing this disclosure. The descriptions are provided solely to illustrate an example of a typical embodiment of the present disclosure. This is not intended to limit the scope.

[0120] 1. Antibody-drug conjugates The antibody-drug conjugate used in this disclosure is given by the following formula: [ka] (In the formula, A represents the attachment site to the antibody.) The drug linker thus represents a conjugate to the anti-HER2 antibody via a thioether bond. It is an antibody-drug conjugate.

[0121] In this disclosure, the substructure consisting of a linker and a drug in an antibody-drug conjugate is defined as follows: It is called a "drug linker." A drug linker is an interchain disulfide bond site (heavy chain) in an antibody. Thiol groups formed at the two sites in between and the two sites between the heavy chain and the light chain (in other words) It connects to the sulfur atom of the cysteine ​​residue.

[0122] The drug linker of this disclosure contains, as an ingredient, exatecan, a topoisomerase I inhibitor. (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3 ,9,12,15-Hexahydro-9-hydroxy-4-methyl-10H,13H-ben Zo[de]pirano[3',4':6,7]indrizino[1,2-b]quinoline-10,1 3-Dione (Chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3 -Dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3', 4':6,7]Indrizino[1,2-b]Quinoline-10,13(9H,15H)-Di It includes (also represented as ON). Exatecan is an antitumor represented by the following formula. It is an effective camptothecin derivative. [ka]

[0123] The anti-HER2 antibody-drug conjugate used in this disclosure can also be represented by the following formula. It is possible. [ka]

[0124] In this specification, the drug linker is an anti-HER2 antibody ("antibody-") via thioether linkage. It is conjugated to ( ). The meaning of n is the average number of conjugated drug molecules (D This is the same meaning as what is called AR (drug-antibody ratio), and it refers to the amount of conjugation per antibody molecule. This refers to the average number of units of the drug linker used.

[0125] After being transferred into cancer cells, the anti-HER2 antibody-drug conjugate used in this disclosure It is cleaved at the linker portion, releasing a compound represented by the following formula. [ka]

[0126] This compound is the source of the antitumor activity of the antibody-drug conjugate used in this disclosure. It is presumed that it has a topoisomerase I inhibitory effect, and it has been confirmed to have this effect. Ogitani Y. et al.,Clinical Cancer Resear ch,2016,Oct 15;22(20):5097-5108,Epub 201 (6 Mar 29).

[0127] The anti-HER2 antibody-drug conjugate used in this disclosure has a bystander effect. It is known that (Ogitani Y. et al., Cancer Science) nce(2016)107,1039-1046). The bystander effect is thus The antibody-drug conjugate used in this disclosure is internalized within cancer cells expressing the target. Subsequently, the released compound also affects cancer cells present in the surrounding area that do not express the target. The antitumor effect is exerted throughout the entire process. The bystander effect is fully realized. According to the instructions, anti-HER2 antibody-drug conjugates are used in combination with ATR inhibitors. Even in such cases, it exhibits excellent antitumor effects.

[0128] 2. Antibodies in antibody-drug conjugates The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is derived from any species. This can be derived, preferably from humans, rats, mice, or rabbits, as an anti-HE agent. It is an R2 antibody. When the antibody is induced from a species other than human, this is preferably well known. It is chimeric or humanized using this technology. Anti-HER2 antibodies are polyclonal antibodies or It may be a monoclonal antibody, and is preferably a monoclonal antibody.

[0129] The antibodies in the antibody-drug conjugates used in this disclosure preferably target cancer cells. An anti-HER2 antibody having properties that allow it to be converted, preferably one that recognizes, for example, cancer cells. The property of binding to cancer cells, the property of internalizing within cancer cells, and / or the property of binding to cancer cells. This is an antibody that possesses cell-destroying activity.

[0130] The binding activity of anti-HER2 antibodies against cancer cells is confirmed using flow cytometry. This is possible. The internalization of antibodies into cancer cells is achieved by (1) a secondary antibody that binds to the therapeutic antibody (fluorescent A fluorescence microscopy assay (Ce) for visualizing antibodies incorporated into cells using labeling. ll Death and Differentiation(2008)15,751 -761), (2) Using a secondary antibody (fluorescently labeled) that binds to the therapeutic antibody, incorporated into the cell Assay to measure the intensity of the fluorescence (Molecular Biology of t he Cell, Vol. 15, 5268-5282, December 2004), Or (3) When incorporated into cells, it releases toxins that inhibit cell growth, or binds to therapeutic antibodies. Mab-ZAP assay using immunotoxins (Bio Techniques 28: This can be confirmed using (162-165, January 2000). Immunotoxin For example, a recombinant complex protein of the diphtheria toxin catalytic domain and protein G is used. It is possible.

[0131] The antitumor activity of anti-HER2 antibodies is measured by their inhibitory activity against cell growth. This can be confirmed in vitro. For example, using an antibody with an excess of HER2 as a target protein. Cancer cell lines expressing the virus are cultured, and antibodies are added to the culture system at various concentrations to induce lesion formation and colony formation. The inhibitory activity against formation and globular proliferation is measured. For example, by increasing the expression of the target protein. By administering antibodies to nude mice transplanted with cancer cell lines and measuring changes in the cancer cells, Furthermore, antitumor activity can be confirmed in vivo.

[0132] Anti-HER2 antibody-drug conjugates are conjugated with compounds that exert antitumor effects. Therefore, while it is desirable for anti-HER2 antibodies themselves to have antitumor effects, it is not essential. In order to specifically and selectively exert the cytotoxicity of antitumor compounds against cancer cells, It is important that the HER2 antibody has the property of being internalized and migrated into tumor cells, and is also favorable. It seems so.

[0133] The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is already known in the art. It can be obtained by known procedures. For example, the antibodies of this disclosure are obtained by moving antigenic polypeptides. This technology involves immunizing a substance, recovering the antibodies produced in vivo, and purifying them. It can be obtained using methods that are normally performed. The origin of the antigen is not limited to humans, but also Mau It is also possible to confine animals to immunity using antigens derived from non-human animals such as rats. In this case, the cross-reactivity between the obtained antibody that binds to the heterologous antigen and the human antigen is tested to determine the human disease. It is possible to screen for antibodies that are applicable to [the subject].

[0134] Instead, antibody-producing cells that produce antibodies against an antigen according to methods known in the art. To fuse with myeloma cells (for example, Kohler and Milstein, Natu re(1975)256, p.495-497; and Kennet, R.ed., Mon. oclonal antibodies,p.365-367,Plenum Pres. s,NY (1980), established the hybridoma, and subsequently monoclonal Antibodies can be obtained.

[0135] Antigens are used to genetically modify host cells to produce genes that code for antigen proteins. This can be obtained by doing so. Specifically, it allows the antigen gene to be expressed. A vector is prepared and introduced into host cells to express this gene. The antigen can be purified. The antibody is produced by the genetically modified antigen-expressing cells or by the antigen-expressing cells described above. It can also be obtained by immunizing animals with a cell line.

[0136] The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is preferably a HER2 antibody. Antibodies such as melanin antibodies or humanized antibodies are used to reduce heterologous antigenicity against humans. Recombinant antibodies obtained by artificial modification, or preferably antibodies derived from humans. In other words, these are antibodies that possess only the gene sequence of human antibodies. These antibodies are known to be able to perform the following methods It can be produced using this method.

[0137] Chimeric antibodies are antibodies derived from species with different variable and constant regions, for example. As an example, a chimeric antibody in which the variable region of a mouse or rat-derived antibody is conjugated to a constant region derived from a human. It can be listed (Proc.Natl.Acad.Sci.USA,81,6851) -6855, (1984).

[0138] For humanized antibodies, only the complementarity-determining region (CDR) of a heterologous antibody is incorporated into a human-derived antibody. Antibodies obtained by mixing (Nature (1986) 321, pp. 522~52) 5) and, by the CDR transplantation method, some of the amino acid residues of the heterologous antibody framework and heterologous Antibodies obtained by transplanting the CDR sequence of an antibody into a human antibody (International Publication 90 / 07) Pamphlet No. 861) and gene conversion mutagenesis Mutagenesis) strategy used to humanize antibodies (U.S. Patent No. 5821) Examples include Specification No. 337.

[0139] As for human antibodies, human chromosome fragments containing the genes for the heavy and light chains of human antibodies are used. Antibodies produced using human antibody-producing mice (Tomizuka, K .et al.,Nature Genetics(1997)16,p.133-14 3;Kuroiwa,Y.et.al., Nucl.Acids Res.(1998) 26,p.3447-3448;Yoshida,H.et.al.,Animal Cell Technology:Basic and Applied Aspect s vol.10, p.69-73 (Kitagawa, Y., Matsuda, Ta nd Iijima, S. eds.), Kluwer Academic Publishing. hers,1999;Tomizuka,K.et.al.,Proc.Natl.Ac See, for example, ad.Sci.USA (2000) 97, pp. 722-727. This can be shown. Alternatively, antibodies obtained by phage display (human antibodies) can be shown. Antibodies selected from the somatic library (Wormstone, IMet.al, Inv estimative Ophthalmology&Visual Science. (2002)43(7),p.2301-2308;Carmen,S.et.al., Briefings in Functional Genomics and Pro teomics(2002),1(2),p.189-203;Siriwardena ,D.et.al.,Ophthalmology(2002)109(3),p.42 Examples include (see 7-431, etc.).

[0140] This disclosure includes modifications of the anti-HER2 antibody in the antibody-drug conjugate used herein. This also includes variants. Modified variants are those which are subjected to chemical or biological modification of the antibody of this disclosure. This refers to mutants obtained by modifying the amino acid skeleton. An example of a chemically modified mutant is one obtained by modifying the amino acid skeleton. Mutants containing the bonding of the chemical moiety, bonding of the chemical moiety to an N-linked or O-linked carbohydrate chain Examples include mutants containing [specific modifications]. Examples of biologically modified mutants include post-translational modifications (for example...). N-bond or O-bond glycosylation, N-terminus or C-terminus treatment, deamidation, Mutants obtained by isomerization of spartic acid or oxidation of methionine, and prokaryotic hosts. One example is a mutant in which a methionine residue is added to the N-terminus when expressed in cells. Furthermore, antibodies labeled to enable detection or isolation of the antibodies or antigens of this disclosure, For example, enzyme-labeled, fluorescently labeled, and affinity-labeled variants are also included in the definition of modified variants. These modified variants of the antibodies described herein improve the stability and blood retention of the antibodies, and their antigens It is useful for reducing sex, detecting or isolating antibodies or antigens, etc.

[0141] Furthermore, the modification of the glycan bound to the antibody of this disclosure (glycosylation, deglycosylation) can be controlled. Antibody-dependent cytotoxic activity can be enhanced by methods such as fucosylation. As a technique for regulating the modification of glycans, see International Publication No. 99 / 54342 pamphlet. Lett, and its pamphlet No. 00 / 61739, and its pamphlet No. 02 / 31140, Pamphlet No. 2007 / 133855, Pamphlet No. 2013 / 120066 The technologies disclosed in this disclosure are known. However, the technologies are not limited to these. Anti-HER2 antibodies also include antibodies in which glycan modification has been regulated.

[0142] Lysine at the carboxyl terminus of the heavy chain of antibodies produced in cultured mammalian cells It is known that residues are deleted (Journal of Chromatogra phy A,705:129-134(1995)), produced in cultured mammalian cells. The two amino acid residues at the carboxyl terminus of the heavy chain of the antibody (glycine and lysine) ) is deleted, and a new proline residue located at the carboxyl terminus is amidated. (Analytical Biochemistry, 360:75-83) (2007)). However, such deletions and modifications of heavy chain sequences are the antigen-binding parent of antibodies. It affects compatibility and effector function (activation of complementary antibody-dependent cytotoxicity, etc.). No. Therefore, the anti-HER2 antibodies of this disclosure do not include antibodies that have undergone such modifications or the function of the antibody. It also includes fragments, and one or two amino acids are missing from the carboxyl terminus of the heavy chain. Lost deletion mutants, mutants obtained by amidation of deletion mutants (e.g., carboxy This also includes heavy chains with amidated proline residues at the terminal end. Antigen binding affinity and eph As long as the receptor function is preserved, the carboxyl terminus of the heavy chain of the anti-HER2 antibody of this disclosure The types of deletion mutants having a deletion are not limited to the above-mentioned mutants. The two heavy chains are selected from a group consisting of a full-length heavy chain and the deletion mutants mentioned above. It could be a type, and from this, it could be a combination of two types selected. The amount of each deletion mutant The ratio is determined by the type of cultured mammalian cells and culture conditions that produce the anti-HER2 antibody of this disclosure. Although it may be affected by, both heavy chains in the antibody of this disclosure have carboxyl terminals An antibody in which one amino acid residue is deleted can be cited as a preferred example.

[0143] Examples of isotypes of the anti-HER2 antibody disclosed herein include IgG(IgG1, IgG2) Examples include IgG3 and IgG4, with IgG1 or IgG2 being preferred. It is possible.

[0144] In this disclosure, the term "anti-HER2 antibody" refers to HER2 (human epidermal growth factor receptor type 2). ;Specifically binds to ErbB-2), and preferably binds to HER2, thereby HER 2. This refers to antibodies that have the activity to be internalized in cells that express them.

[0145] An example of an anti-HER2 antibody is trastuzumab (U.S. Patent No. 5821337). And pertuzumab (International Publication No. 01 / 00245) is mentioned, and Trust Zumab can be cited as a preferred example.

[0146] 3. Production of antibody-drug conjugates Drug linker intermediate used in the production of the anti-HER2 antibody-drug conjugate of this disclosure It can be expressed by the following formula: [ka]

[0147] The drug linker intermediate has the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1 H-pyrrole-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N -[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl Lu-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12 H-benzo[de]pirano[3',4':6,7]indridino[1,2-b]quinoline- It can be represented as 1-yl]amino}-2-oxoethoxy)methyl]glycinamide International publication pamphlet No. 2014 / 057687, and International publication No. 2015 / 098099. Brochure, brochure No. 2015 / 115091, brochure No. 2015 / 15599 Refer to the descriptions in Pamphlet No. 8, Pamphlet No. 2019 / 044947, etc. It can be produced in this way.

[0148] The anti-HER2 antibody-drug conjugate used in this disclosure is the drug linker intermediate described above. The body is reacted with an anti-HER2 antibody that has a thiol group (also known as a sulfhydryl group). It can be produced by [method].

[0149] Anti-HER2 antibodies containing sulfhydryl groups can be obtained by methods well known in the art. (Hermanson, GT, Bioconjugate Techniq) ues,pp.56-136,pp.456-493,Academic Press( 1996)). For example, 0.3 to 3 molar equivalents of Tris per interchain disulfide in an antibody ( Using a reducing agent such as 2-carboxyethyl)phosphine hydrochloride (TCEP), The antibody reacts with a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA). By doing so, the antibody contains partially or completely reduced interchain disulfides. This allows us to obtain anti-HER2 antibodies that have hydryl groups.

[0150] Furthermore, 2 to 20 molar equivalents of drug linker per anti-HER2 antibody containing a sulfhydryl group - By using an intermediate, 2 to 8 drug molecules are conjugated per antibody molecule. This can lead to the production of anti-HER2 antibody-drug conjugates.

[0151] The amount of conjugate per anti-HER2 antibody molecule of the produced antibody-drug conjugate The average number of drug molecules detected is, for example, the antibody at two wavelengths, 280 nm and 370 nm. - Measuring the UV absorbance of drug conjugates and their conjugation precursors The calculation method is based on (UV method) or by treating the antibody-drug conjugate with a reducing agent. A method of calculation based on the quantification of the obtained fragments by HPLC measurement. This can be determined by the HPLC method.

[0152] Conjugation of anti-HER2 antibodies with drug linker intermediates and antibody-drug conjugation The calculation of the average number of conjugated drug molecules per antibody molecule in the gate is based on the International Publicly Released (IPO) Pamphlet No. 2014 / 057687, and Pamphlet No. 2015 / 098099. Pamphlet No. 2015 / 115091, Pamphlet No. 2015 / 155998 T, and the same brochure No. 2017 / 002776 and the same bread No. 2018 / 212136. This can be done by referring to markings such as frets.

[0153] In this disclosure, the term "anti-HER2 antibody-drug conjugate" means the antibody- An antibody-drug conjugate in which the antibody in the drug conjugate is an anti-HER2 antibody To point.

[0154] The anti-HER2 antibody is preferably an amino acid consisting of amino acid residues 26-33 of SEQ ID NO: 1. CDRH1 consisting of an acid sequence, amino acid sequence consisting of amino acid residues 51-58 of SEQ ID NO: 1 CDRH2 consists of amino acid residues 97-109 of SEQ ID NO: 1 The heavy chain containing CDRH3 and the amino acids consisting of amino acid residues 27-32 of SEQ ID NO: 2 CDRL1 consists of an acid sequence, and the amino acid sequence consists of amino acid residues 50-52 of SEQ ID NO: 2. From CDRL2 and the amino acid sequence consisting of amino acid residues 89-97 of SEQ ID NO: 2 An antibody containing a light chain containing CDRL3, more preferably amino acid residues 1-1 of SEQ ID NO: 1 Heavy chain containing a heavy chain variable region consisting of a sequence of 20 amino acids and amino acid residue of SEQ ID NO: 2 An antibody containing a light chain that includes a light chain variable region consisting of an amino acid sequence of groups 1 to 107, and furthermore Preferably, a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and SEQ ID NO: 2 An antibody containing a light chain consisting of the amino acid sequence represented as shown, or amino acid residues 1-4 of SEQ ID NO: 1 From the heavy chain consisting of 49 and the amino acid sequence consisting of all amino acid residues 1-214 of SEQ ID NO: 2 It is an antibody that contains a light chain.

[0155] Drug conjugated to each antibody molecule in an anti-HER2 antibody-drug conjugate The average number of linker units is preferably 2 to 8, more preferably 3 to 8, and even more preferably More preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0156] The anti-HER2 antibody-drug conjugate used in this disclosure is from International Publication No. 2015 / 1 It can be produced by referring to pamphlet No. 15091, etc.

[0157] In a preferred embodiment, the anti-HER2 antibody-drug conjugate is trastuzumabdel It's a Kustecan (DS-8201).

[0158] 4. ATR inhibitors In this disclosure, the term "ATR inhibitor" refers to ATR (ataxia telangiectasia and rad). This refers to agents that inhibit kinase ATR. The ATR inhibitors of this disclosure selectively inhibit kinase ATR. It may selectively inhibit ATR, or it may non-selectively inhibit ATR, thereby inhibiting kinases other than ATR. The ATR inhibitors of this disclosure are not particularly limited insofar as they are agents having the properties described. A good example of this is disclosed in International Publication No. 2011 / 154737. Examples of things that can be done include:

[0159] Other examples of ATR inhibitors that may be used in accordance with this disclosure include BAY-1895344, ET These are P-46464 and VE-821.

[0160] Preferably, the ATR inhibitors of this disclosure selectively inhibit ATR.

[0161] According to preferred embodiments of the ATR inhibitor used in this disclosure, the ATR inhibitor is as follows: Equation (I): [ka] (In the formula, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, R 2 teeth, [ka] And, n is either 0 or 1. R 2A , R 2C , R 2E and R 2F These are, independently, hydrogen or methyl, R 2B and R 2D These are, independently, hydrogen or methyl, R 2G -NHR 7 and -NHCOR 8 Selected from, R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 Each is independently either hydrogen or methyl, or R 4 and R 5 That Together with the atoms to which they are bonded, they form ring A. Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl or It is a saturated 4-6 membered heterocycle, R 6 It is hydrogen, R 7 is hydrogen or methyl, and R 8 (It is methyl.) It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0162] In a preferred embodiment, the ATR inhibitor is a compound represented by formula (I), R 1 It is 3-methylmorpholine-4-yl, R 2 teeth, [ka] And, n is either 0 or 1. R 2A , R 2C , R 2E and R 2F These are, independently, hydrogen or methyl, R 2B and R 2D These are, independently, hydrogen or methyl, R 2G The -NH2, -NHMe, and -NHCOMe options are selected. R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 Each is independently either hydrogen or methyl, or R 4 and R 5 That Together with the atoms to which they are bonded, they form ring A. Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl or It is a saturated 4-6 membered heterocycle, R 6 is hydrogen, a compound, or a pharmaceutically acceptable salt thereof.

[0163] An additional embodiment of the ATR inhibitor is ring A, n, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 Reach biR 8 This refers to the compound of formula (I) and its pharmaceutically acceptable salts, as defined below. Certain substituents, such as those defined herein, in the definitions, claims, or embodiments. It can be used appropriately even in cases of misalignment.

[0164] n In one embodiment, n is 0.

[0165] In another embodiment, n is 1.

[0166] R 1 In one embodiment, R 1 These are morpholine-4-yl and 3-methylmorpholine-4-yl Selected from.

[0167] In further embodiments, R 1 It is 3-methylmorpholine-4-yl.

[0168] In further embodiments, R 1 teeth, [ka] That is the case.

[0169] In further embodiments, R 1 teeth, [ka] That is the case.

[0170] R 2 In one embodiment, R 2 teeth, [ka] That is the case.

[0171] In another embodiment, R 2 teeth, [ka] That is the case.

[0172] In another embodiment, R 2 teeth, [ka] That is the case.

[0173] In another embodiment, R 2 teeth, [ka] That is the case.

[0174] R 2A In one embodiment, R 2A It is hydrogen.

[0175] R 2B In one embodiment, R 2B It is hydrogen.

[0176] R 2C In one embodiment, R 2C It is hydrogen.

[0177] R 2D In one embodiment, R 2D It is hydrogen.

[0178] R 2E In one embodiment, R 2E It is hydrogen.

[0179] R 2F In one embodiment, R 2F It is hydrogen.

[0180] R 2G In one embodiment, R 2G -NHR 7 and -NHCOR 8 Selected from.

[0181] In another embodiment, R 2G -NHR7 That is the case.

[0182] In another embodiment, R 2G is -NHCOR 8 That is the case.

[0183] In another embodiment, R 2G The -NH2, -NHMe, and -NHCOMe options are selected. ru.

[0184] In another embodiment of this disclosure, R 2G It is -NH2.

[0185] In another embodiment, R 2G It is -NHMe.

[0186] In another embodiment, R 2G It is -NHCOMe.

[0187] R 4 and R 5 In one embodiment, R 4 and R 5 It is hydrogen.

[0188] In another embodiment, R 4 and R 5 It is methyl.

[0189] In another embodiment, R 4 and R 5 These, together with the atoms to which they are bonded, form ring A. ru.

[0190] Ring A In one embodiment, ring A contains a C heteroatom selected from O and N. 3~ It is a 6-cycloalkyl or saturated 4-6 heterocycle.

[0191] In another embodiment, ring A is cyclopropyl, cyclobutyl, cyclopentyl, oxal Tanyl, tetrahydrofuryl, tetrahydropyranil, azetidinil, pyrrolidinil or It is a piperidinyl ring.

[0192] In another embodiment, ring A is cyclopropyl, cyclobutyl, cyclopentyl, tetra It is a hydropyranyl or piperidinyl ring.

[0193] In another embodiment, ring A is cyclopropyl, cyclopentyl, tetrahydropyranyl Alternatively, it is a piperidinyl ring.

[0194] In another embodiment, ring A is cyclopropyl, tetrahydropyranyl, or piperidinyl It is a ring.

[0195] In another embodiment, ring A is a cyclopropyl or tetrahydropyranyl ring.

[0196] In another embodiment, ring A is a piperidinyl ring.

[0197] In another embodiment, ring A is a tetrahydropyranyl ring.

[0198] In another embodiment, ring A is a cyclopropyl ring.

[0199] R 6 In one embodiment, R 6 It is hydrogen.

[0200] R 7 In one embodiment, R 7 It is either hydrogen or methyl.

[0201] In another embodiment, R 7 It is methyl.

[0202] In another embodiment, R 7 It is hydrogen.

[0203] R 8 In one embodiment, R 12 It is methyl.

[0204] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 and -NHCOR 8 Selected from, R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 They form ring A together with the atoms to which they are bonded, Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl or It is a saturated 4-6 heterocycle, R 6 It is hydrogen, R 7 is hydrogen or methyl, and R 8 It is methyl.

[0205] In another embodiment, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G The -NH2, -NHMe, and -NHCOMe options are selected. R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 They form ring A together with the atoms to which they are bonded, Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl or It is a saturated 4-6 heterocycle, R 6 It is hydrogen.

[0206] In another embodiment, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 and -NHCOR 8 Selected from, R 2H It is fluoro, R3 It is methyl, R 4 and R 5 They form ring A together with the atoms to which they are bonded, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro The rings are furyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl rings. , R 6 It is hydrogen, R 7 is hydrogen or methyl, and R 8 It is methyl.

[0207] In another embodiment, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G The -NH2, -NHMe, and -NHCOMe options are selected. R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 They form ring A together with the atoms to which they are bonded, Ring A is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydro The rings are furyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl rings. , and R6 It is hydrogen.

[0208] In another embodiment, the compound of formula (I) is formula (Ia): [ka] (In the formula, Ring A is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. R 2 teeth, [ka] And, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 and -NHCOR 8 Selected from, R 2H It is fluoro, R 3 It is a methyl group, R 6 It is hydrogen, R 7 is hydrogen or methyl, and R 8 (It is methyl.) It is a compound of or a pharmaceutically acceptable salt thereof.

[0209] In another embodiment, the compound of formula (I) is the compound of formula (Ia) or the pharmaceutically acceptable compound thereof. It is a salt, and in the formula, Ring A is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. R 2 teeth, [ka] And, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G The -NH2, -NHMe, and -NHCOMe options are selected. R 2H It is fluoro, R 3 is a methyl group, and R 6 It is hydrogen.

[0210] In another embodiment, the compound of formula (I) is the compound of formula (Ia) or the pharmaceutically acceptable compound thereof. It is a salt, and in the formula, Ring A is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. R 2 teeth, [ka] And, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2EIt is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 And, R 2H It is fluoro, R 3 It is a methyl group, R 6 is hydrogen, and R 7 It is hydrogen.

[0211] In another embodiment, the compound of formula (I) is the compound of formula (Ia) or the pharmaceutically acceptable compound thereof. It is a salt, and in the formula, Ring A is a cyclopropyl ring, R 2 teeth, [ka] And, n is 0, R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 And, R 2H It is fluoro, R 3 It is a methyl group, R 6 is hydrogen, and R 7 It is methyl.

[0212] In other embodiments, the ATR inhibitor used in this disclosure is a compound selected from the following: 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[((R)-S-methylmorpholine-4-yl]-((R)-S-methylmorpholine-4-yl) [Sulfonimidoyl)methyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b] Pyridine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[ [2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[ [2,3-b]pyridine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-( (R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1 H-benzimidazole-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-( (S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1 H-benzimidazole-2-amine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indo Lu; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indo Lu; 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzyl Midazole-2-amine; 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzyl Midazole-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl-1H-benzimidazole-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl-1H-benzimidazole-2-amine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-(-S-methyl Sulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3 -c] pyridine; N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl) Ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl} -1H-benzimidazole-2-amine; N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl) Ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl} -1H-benzimidazole-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-( (S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyri Midine-2-yl}-1H-benzimidazole-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-( (R)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyri Midine-2-yl}-1H-benzimidazole-2-amine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((S)-S- Methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2- Il-1H-indole; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfon [(3R)-3-methylmorpholin-4-yl]pyrimidyl]ethyl-6-[(3R)-3-methylmorpholin-4-yl]pyrimidyl 1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl-1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl-1H-benzimidazole-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl-1H-benzimidazole-2-amine; 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl] -6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine- 2-yl}-1H-benzimidazole-2-amine; and It is a pharmaceutically acceptable salt.

[0213] In other embodiments, the ATR inhibitor used in this disclosure is a compound selected from the following: 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[(R)-(S-methylmorpholine-4-yl]-6-[(R)-(S-methylmorpholine-4-yl] [Sulfonimidoyl)methyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b] Pyridine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[ [2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S- Methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[ [2,3-b]pyridine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-( R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H -Benzimidazole-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-( S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H -Benzimidazole-2-amine; and It is a pharmaceutically acceptable salt.

[0214] In preferred embodiments, the ATR inhibitor used in this disclosure has the following formula: [ka] The compound AZD6738, represented by 4-{4-[(3R)-3-methylmorpholine} -4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl] Pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine or its pharmaceutically acceptable form It is a salt.

[0215] ATR inhibitors, such as compounds of formula (I) including AZD6738, are listed in International Publication No. 2011 / As disclosed in pamphlet No. 154737, and by methods known in the art, It can be manufactured.

[0216] 5. Combination of antibody-drug conjugates with ATR inhibitors In a first combined embodiment of this disclosure, an anti-HER2 inhibitor is combined with an ATR inhibitor. The body-drug conjugate is given by the following formula: [ka] (In the formula, A represents the attachment site to the antibody.) The drug linker, represented by [the symbol], conjugates to the anti-HER2 antibody via thioether linkage. It is an antibody-drug conjugate.

[0217] In another combination embodiment, the resistance defined above with respect to the first combination embodiment is The HER2 antibody-drug conjugate is given by the following formula (I): [ka] (In the formula, R 1 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, R 2 teeth, [ka] And, n is either 0 or 1. R 2A , R 2C , R 2E and R 2F These are, independently, hydrogen or methyl, R 2B and R 2D These are, independently, hydrogen or methyl, R 2G -NHR 7 and -NHCOR 8 Selected from, R 2H It is fluoro, R 3 It is methyl, R 4 and R 5 Each is independently either hydrogen or methyl, or R 4 and R 5 That Together with the atoms to which they are bonded, they form ring A. Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl or It is a saturated 4-6 membered heterocycle, R 6 It is hydrogen, R 7 is hydrogen or methyl, R 8 (It is methyl.) ATR inhibitors, which are compounds represented by or pharmaceutically acceptable salts thereof, are used in combination with It can be done.

[0218] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with an ATR inhibitor, which is a compound represented by formula (I) defined above. In equation (I), R 4 and R 5 They form ring A together with the atoms to which they are bonded, and Ring A contains one heteroatom selected from O and N. 3~6 Cycloalkyl Alternatively, it is a saturated 4-6 heterocycle.

[0219] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, in formula (I), R 4 and R 5 That These atoms, together with the bonded atoms, form ring A, and ring A is composed of cyclopropyl and tetrahydrogen It is a ropyranil or piperidinil ring.

[0220] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, in formula (I), R 2A It is hydrogen. , R 2B is hydrogen, and R 2C is hydrogen, and R 2D is hydrogen, and R 2E is water It is prime, and R 2F It is hydrogen.

[0221] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, in formula (I), R 1 3-methylmethyl It is rufoline-4-yl.

[0222] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, and the compound of formula (I) is of formula (Ia): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0223] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, and the compound of formula (I) is of formula (Ia) It is a compound, and in formula (Ia), Ring A is a cyclopropyl ring, R 2 teeth, [ka] And, n is either 0 or 1. R 2A It is hydrogen, R 2B It is hydrogen, R 2C It is hydrogen, R 2D It is hydrogen, R 2E It is hydrogen, R 2F It is hydrogen, R 2G -NHR 7 And, R 2H It is fluoro, R 3 It is a methyl group, R 6 is hydrogen, and R 7 It is either hydrogen or methyl.

[0224] In another combined embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATR inhibitor defined above, and the ATR inhibitor is given by the following formula: [ka] AZD6738 represented by or a pharmaceutically acceptable salt thereof.

[0225] In each of the above combined embodiments, the anti-HER2 antibody is SEQ ID NO: 3 CDRH1 consists of an amino acid sequence represented by , and amino acid represented by SEQ ID NO: 4 CDRH2 consists of an acid sequence, and CDR consists of an amino acid sequence represented by SEQ ID NO: 5. CDRL1 consists of a heavy chain containing H3 and an amino acid sequence represented by SEQ ID NO: 6. CDRL2 and SEQ ID NO: 8 consist of amino acid sequences consisting of amino acid residues 1-3 in sequence number 7. It contains a light chain containing CDRL3, which consists of an amino acid sequence represented by the above combination. In each other embodiment of the embodiment, the anti-HER2 antibody is represented by SEQ ID NO: 9 A heavy chain containing a heavy chain variable region consisting of the amino acid sequence and the amino acid represented by SEQ ID NO: 10 The light chain includes a light chain variable region consisting of an acid sequence. Each of the above combination embodiments In another embodiment, the anti-HER2 antibody is derived from the amino acid sequence represented by SEQ ID NO: 1. It includes a heavy chain and a light chain consisting of the amino acid sequence represented by Sequence ID No. 2. In each of the other embodiments of the combined embodiment, the anti-HER2 antibody is by SEQ ID NO: 11 A heavy chain consisting of the amino acid sequence represented by and the amino acid sequence represented by Sequence ID No. 2 It contains a light chain.

[0226] In a particularly preferred combination embodiment of the present disclosure, an anti-HER2 antibody-drug conjugate This is trastuzumab deruxtecan (DS-8201), and ATR inhibitors are as follows: formula: [ka] This is a compound represented by [formula], which is also identified as AZD6738.

[0227] 6. Therapeutic combination use and methods The anti-HER2 antibody-drug conjugate and ATR inhibitor described herein are administered in combination. The pharmaceutical products, their therapeutic uses, and methods are described below.

[0228] The pharmaceutical products, therapeutic uses, and methods described herein are anti-HER2 antibody-drug conjugates. The and ATR inhibitors are contained separately as active ingredients in different formulations, simultaneously or separately. In some cases, the administration is characterized by being performed at a specific time, and antibody-drug conjugates and ATR inhibitors are also used. In some cases, the harmful agent is administered as the active ingredient in a single formulation.

[0229] In the pharmaceutical products and therapeutic methods of this disclosure, a single ATR inhibitor used in this disclosure is It may also be administered in combination with an anti-HER2 antibody-drug conjugate, or two or more types. Different ATR inhibitors may also be administered in combination with antibody-drug conjugates. .

[0230] The pharmaceutical products and therapeutic methods of this disclosure can be used to treat cancer, and preferably This includes breast cancer (including triple-negative breast cancer and luminal breast cancer), gastric cancer (also known as gastric adenocarcinoma), Colorectal cancer (also known as colon and rectal cancer, and including colon cancer and rectal cancer), lung cancer (small cell lung cancer) Cancer (including cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), esophageal and gastric cancer Junctional adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urinary tract Epithelial cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer Cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant phosphorus This includes peritoneum, plasmacytoma, myeloma, glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. It can be used to treat at least one type of cancer selected from the group, and more preferably This includes breast cancer, stomach cancer, colorectal cancer, lung cancer (preferably non-small cell lung cancer), pancreatic cancer, ovarian cancer, and prostate cancer. To be used to treat at least one type of cancer selected from the group consisting of cancer and kidney cancer. It is possible.

[0231] The presence or absence of the HER2 tumor marker can be determined, for example, by taking tumor tissue from a cancer patient and sterilizing it in formalin. Prepare fixed paraffin-embedded (FFPE) specimens, and then perform immunohistochemistry (IH) on the specimens. C) Gene product (tan) using the flow cytometer or Western blot method. Tests related to proteins, or, for example, in situ hybridization (ISH) methods, Tests related to gene transcription using q-PCR or microarray analysis By subjecting it to, or by collecting cell-free circulating tumor DNA (ctDNA) from cancer patients, c By subjecting tDNA to tests using methods such as next-generation sequencing (NGS), It is possible to determine this.

[0232] The pharmaceutical products and therapeutic methods of this disclosure are for HER2-overexpressing cancers (high or moderate). It can be used in HER2-expressing cancers, which may also be HER2-low expressing cancers.

[0233] In this disclosure, the term "HER2-overexpressing cancer" means that it is a cancer that is overexpressed by those skilled in the art. It is not particularly limited as long as it is recognized as cancer. Preferred examples of HER2-overexpressing cancer include Cancers that obtained a 3+ score for HER2 expression in the IHC method and cancers that obtained a 3+ score for HER2 expression in the IHC method A score of 2+ was obtained for ER2 expression, and the in situ hybridization method (ISH) was used. This refers to cancers that have been determined to be positive for HER2 expression in this study. As an example of in situ hybridization, fluorescent in situ hybridization is used. The fish-in-situ hybridization method (FISH) and the two-color in-situ hybridization method (DISH) are It can be listed.

[0234] In this disclosure, the term "HER2-low expression cancer" means that it is a HER2-low expression cancer as determined by those skilled in the art. It is not particularly limited as long as it is recognized as present. A preferred example of HER2-low-expressing cancer is IH In the C method, a score of 2+ was obtained for HER2 expression, and in situ hybridises Cancers that were determined to be negative for HER2 expression by the hysterectomy method and cancers that were determined to be H by the IHC method We can list cancers that received a score of 1+ regarding ER2 expression.

[0235] A method for scoring the degree of HER2 expression by IHC or in situ hybrid The method for determining whether HER2 expression is positive or negative by dilation is as follows: The law is not particularly limited as long as it is known to those skilled in the art. An example of the method is the 4th edition. tion of the guidelines for HER2 testing, breast cancer(Japanese Pathology Board f or Optimal Use of HER2 for Breast Cancer The methods described in the (ed.) are examples.

[0236] In particular, regarding the treatment of breast cancer, cancer is characterized by HER2 overexpression (high or moderate) or low expression. It may be breast cancer or triple-negative breast cancer, and / or IHC3+, IHC2 They may have an HER2 status score of +, IHC1+, or IHC>0 and <1+.

[0237] The pharmaceutical products and therapeutic methods of this disclosure may preferably be used in mammals, but more Preferably used on humans.

[0238] The antitumor effects of the pharmaceutical products and therapeutic methods of this disclosure are obtained by transplanting cancer cells into test animals. Reduced tumor volume by preparing a model and applying the pharmaceutical products and therapeutic methods of this disclosure. This can be confirmed by measuring the effect of reducing or extending the lifespan. Subsequently, the method used in this disclosure The effects of using antibody-drug conjugates in combination with ATR inhibitors are described in this disclosure. Antitumor effects of monotherapy with antibody-drug conjugates and monotherapy with ATR inhibitors This can be confirmed by comparing it with the previous statement.

[0239] The antitumor effects of the pharmaceutical products and therapeutic methods disclosed herein are evaluated by Response Evaluator. tion Criteria in Solid Tumors (RECIST), WH One of the following evaluation methods is used: the O evaluation method, the Macdonald evaluation method, or methods such as weight measurement. This can be confirmed in clinical trials, and results include complete response (CR), partial response (PR), and progression. Disease progression (PD), objective response rate (ORR), duration of response (DR), progression-free survival (PFS). ), and other indicators such as overall survival (OS) can be used as criteria for determination.

[0240] By using the above method, existing pharmaceutical products and therapeutic methods related to cancer treatment can be used. It is possible to confirm the superior antitumor effect of the pharmaceutical products and therapeutic methods of this disclosure. ru.

[0241] The pharmaceutical products and therapeutic methods of this disclosure delay the growth of cancer cells and inhibit their proliferation. Furthermore, it is possible to kill cancer cells. These effects mean that cancer patients are affected by cancer. To enable relief from the symptoms caused, or to improve the quality of life (QOL) of cancer patients. This can improve the condition and lead to therapeutic effects by prolonging the lives of cancer patients. Even if the disclosed pharmaceutical products and therapeutic methods do not achieve the killing of cancer cells, they are still effective against cancer cells. By inhibiting or controlling cell proliferation, longer survival can be achieved, and cancer patients This can further improve their quality of life.

[0242] The pharmaceutical products of this disclosure, when applied to patients as systemic therapy, also affect cancer tissue. When applied locally, it is expected to exert a therapeutic effect.

[0243] The pharmaceutical product of this disclosure is administered containing at least one pharmaceutically suitable component. This is possible. Pharmacopoecitable components include the antibody-drug conjugate used in this disclosure and Depending on the dose and concentration of the ATR inhibitor, a formulation additive commonly used in this field may be used. Additives and other components can be suitably selected and applied. Anti-HER2 used in this disclosure Antibody-drug conjugates include buffers such as histidine buffer, sucrose, and Contains vehicles such as trehalose and surfactants such as polysorbate 80 and 20. It can be administered as a pharmaceutical product. The antibody-drug conjugate used in this disclosure Pharmaceutical products containing can preferably be used as injectable preparations, and more preferably with water. It can be used as a liquid injectable or lyophilized injectable, and more preferably as a lyophilized injectable. It can be used.

[0244] The pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in this disclosure is aqueous. If it is an injectable preparation, the aqueous injectable preparation is preferably diluted with a suitable diluent and then administered intravenously. It can be given as an injectable agent. Examples of diluents include dextrose solution and physiological saline. Examples can be given, preferably a dextrose solution, and more preferably A 5% dextrose solution can be used as an example.

[0245] If the pharmaceutical product of this disclosure is a lyophilized injectable preparation, it must be pre-dissolved in water for injection. A required amount of lyophilized injectable preparation is preferably diluted with a suitable diluent, and then administered with an intravenous injectable preparation. It can be given as follows. Examples of diluents include dextrose solution and physiological saline. This can be done, preferably a dextrose solution, more preferably a 5% dextrose solution. A kistrose solution can be given as an example.

[0246] Examples of applicable routes of administration for the pharmaceutical products of this disclosure include intravenous routes and intradermal routes. Subcutaneous, intramuscular, and intraperitoneal routes can be cited, with intravenous routes being preferred.

[0247] The anti-HER2 antibody-drug conjugate used in this disclosure is used in humans for 1 to 180 days. It can be administered at intervals, preferably at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks. It can be administered at intervals of three weeks, more preferably. The anti-HER2 antibody-drug conjugate is administered at a dose of approximately 0.001-100 mg / It can be administered in doses of kg, preferably about 0.8 to 12.4 mg / kJ per dose. It can be administered in doses of 0 g. For example, an anti-HER2 antibody-drug conjugate is 0 .8mg / kg, 1.6mg / kg, 3.2mg / kg, 5.4mg / kg, 6.4mg It can be administered once every three weeks at doses of 7.4 mg / kg or 8 mg / kg. Preferably, it should be administered once every three weeks at a dose of 5.4 mg / kg or 6.4 mg / kg. can.

[0248] For example, formulations of ATR inhibitor compounds of formula (I) intended for oral administration to humans are generally For example, it contains 1 mg to 1000 mg of the active ingredient, which is about 5 to 98 times the weight of the total composition. It is formulated with an appropriate and convenient amount of excipients, which may vary in quantity percentage. Administration route and administration rate Further information on Dimen can be found in Comprehensive Medicinal Ch emistry(Corwin Hansch;Chairman of Editor ial Board), Pergamon Press 1990, Volume 5, You can refer to Chapter 25.3.

[0249] The size of the dose required for therapeutic treatment of a specific medical condition depends on the patient being treated, the route of administration, and the treatment itself. The ATR inevitably changes depending on the severity of the target disease. The range is 0.1 to 50 mg / kg. A daily dose of the inhibitor can be used. For example, the ATR inhibitor used in this disclosure is If the compound AZD6738 or a pharmaceutically acceptable salt thereof is used, the ATR inhibitor is preferred. The dosage is 20 mg, 40 mg, 60 mg, 80 mg, or 120 mg per dose, twice a day. It can be administered orally in doses of 160 mg, 200 mg, or 240 mg.

[0250] The pharmaceutical products and therapeutic methods described herein are adjuvant chemotherapy in combination with surgical procedures. It can be used as a law. The pharmaceutical product of this disclosure reduces tumor size before surgery. It may be administered for the purpose of (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy) (or it may be administered after surgery to prevent tumor recurrence (postoperative adjuvant) (Also known as chemotherapy or adjuvant therapy). [Examples]

[0251] This disclosure will be described in detail with reference to the embodiments shown below. However, this disclosure This is not limited to these examples. Furthermore, this should never be interpreted restrictively.

[0252] Example 1: Production of antibody-drug conjugates In accordance with the production method described in International Publication No. 2015 / 115091, Anti-HER2 antibody (amino acid sequence represented by SEQ ID NO: 11 (amino acid residue of SEQ ID NO: 1) A heavy chain consisting of groups 1-449 and all amino acid residues 1-214 of Sequence ID No. 2 Using an antibody (containing a light chain made up of an acid sequence), the following formula: [ka] (In the formula, A represents the attachment site to the antibody.) The drug linker, represented by [the symbol], conjugates to the anti-HER2 antibody via thioether linkage. The anti-HER2 antibody-drug conjugate (DS-8201) has been produced. Rustuzumab deruxtecan). The DAR of the antibody-drug conjugate is 7.7 or 7.8. That is the case.

[0253] Example 2: Production of ATR inhibitors According to the production method described in International Publication No. 2011 / 154737, formula ( I) Prepare the ATR inhibitor. Specifically, 4-{4-[(3R)-3-methylmorpho Phosphate-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl [Lu]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine; [ka] Prepare according to Example 2.02 of International Publication No. 2011 / 154737. It is possible.

[0254] Example 3: Antitumor test (1) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATR inhibitor Harmful agent AZD6738(4-{4-[(3R)-3-methylmorpholine-4-yl]-6- [1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-I Combination with {-1H-pyrrolo[2,3-b]pyridine) method: A high-throughput combination screen was conducted, using DS-8201 and AZD Using a combination with 6738 (ATR inhibitor), various HER2-expressing breast cancer cell lines and We treated one gastric cell line with high HER2 expression (Table 1).

[0255] [Table 1]

[0256] The values ​​displayed on the screen were performed as a 6x6 dose-response matrix for each combination. This was a 7-day cell titer-glo cell viability assay (using DS-8201). (For the first case, a 5-point logarithmic continuous dilution; for the second case, a semi-logarithmic continuous dilution.)

[0257] Furthermore, trastuzumab and exatecan (DNA topoisomerase I inhibitors) are also available at AZD. Screening was performed in parallel with 6738.

[0258] The combined activity was evaluated based on the combination of ΔEmax and HSA synergy score. Ta.

[0259] result: The results are shown in Figures 12A to 12D and Table 2.

[0260] Figures 12A and 12B show the matrix of measured cell viability signals. The X-axis is The Y-axis represents drug A (DS-8201), and the Y-axis represents drug B (AZD6738). The values ​​within the box are... This represents the ratio of cells treated with drugs A+B compared to the DMSO control on day 7. All values ​​are normalized to the cell viability value on day 0. Values ​​between 0 and 100 are increased. This represents the percentage of growth inhibition, and values ​​above 100 indicate cell death.

[0261] Figures 12C and 12D show the HSA excess matrix. The values ​​within the box represent the HSA (highest unit This represents the excess value calculated by the agent model.

[0262] Table 2 below shows the HSA synergistic effect and Loewe adductority score.

[0263] [Table 2]

[0264] Loewe dose additiveity is the principle that two compounds act on the same molecular target through the same mechanism. In this case, the expected response is predicted. This is based on the estimation of zero interactions between compounds. Additive properties are calculated independently of the dose-response correlation.

[0265] HSA (best monotherapy) [Berenbaum 1989] at its corresponding concentration Quantify the higher effect of the two single compounds. Quantify the combined effect of the combination. The effects of each single agent at the concentrations used in the procedure are compared. Excess exceeding the maximum single agent effect is considered a violation of the guidelines. It exhibits the same effect. HSA does not require the compound to act on the same target.

[0266] Excess matrix: For each well of the concentration matrix, the measured or adapted value for each concentration Compare the predicted non-synchronized values ​​of the degree pairs. The predicted values ​​are determined by the selected model. The difference between the predicted value and the observed value may indicate a synergistic or antagonistic effect, and this difference may be exceeded. The excess matrix is ​​shown. The excess matrix values ​​are combined to form a score for excess volume and synergistic effect. Summarize by core.

[0267] As can be seen from Figures 12A-12D and Table 2, AZD6738 (AZ13386215) It interacts synergistically with DS-8201, and also with AZD6738 at Emax (3 μM). And 10 μg / ml (0.064 μM) DS-8201) HER2+ cell line NCI- It increased cell death of N87, KPL4, and HCC1954, even at low concentrations where monotherapy activity was low. Combination activity was observed. The combination of AZD6738 and DS-8201 was H It was also active in ER2-low HCC1937, HCC38, and MDA-MB-468 cell lines. The benefits of the combination were also observed in Emax in the HER2 low ER+ cell line T47D. Ta.

[0268] The results showed that AZD6738 was used in both high and low HER2-expressing cell lines in vitro. ATR inhibition enhances the antitumor efficacy of DS-8201. AZD673 Compound 8 exhibited synergistic combination activity, increasing cell death in HER2-enhanced cell lines. Beneficial combination activity was also observed in HER2-low cancer cell lines.

[0269] Example 4: Antitumor test (2) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATR inhibitor Harmful agent AZD6738(4-{4-[(3R)-3-methylmorpholine-4-yl]-6- [1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-I Combination with {-1H-pyrrolo[2,3-b]pyridine) DS-8201 or exatecan mesylate in cancer cell lines with varying HER2 expression levels It was tested both alone and in combination with AZD6738.

[0270] method: Cells grown under their respective conditions were seeded at the optimal density in a 96-well plate. Then, over the duration of the assay (4-8 days: the treatment period depends on the growth rate of each cell line), the line The cells were propagated. Immediately after seeding, the specified compound was administered to the cells in a total volume of 200 μL / well. The samples were then placed in an incubator. A 6x8 concentration-response matrix was provided for each combination. The combination was performed as follows: At the endpoint, cells were immersed in 2% PFA at room temperature for 20 minutes. Fixed. To obtain the cell count at the start of treatment, one additional plate was used in each experiment. The cells were then fixed behind the joined cells. Subsequently, the cells were treated with 0.5% Triton- in PBS. The cells were permeabilized in X100 for 10 minutes. After washing with PBS, the cells were treated with 5% FB in PBS in RT. Blocked in S for 1 hour, then overnight in 5% FBS + 0.05% triton at 4°C, primary antimicrobial agent. The cells were incubated with the body. After washing three times in PBS, the cells were left at room temperature in Hoech's PBS. t33258 was incubated with a secondary antibody in 5% FBS + 0.05% Triton for 1 hour. Incubated. After washing three times in PBS, the 10x objective lens and 9 field / w were used. Cells were scanned using a Cellinsight instrument equipped with a pharmacokinetic system. Images were then transferred to Columbus. Based on nuclear Hoechst staining and nuclear intensity of other biomarkers investigated, cells Numerical analysis was performed. The relative values ​​of each well were compared to the solvent control using the total cell count / well. Target growth was calculated. The Combinefit software was used to calculate the synergy score. Growth inhibition data was analyzed using (Di Veroli GY et al., Bio Informatics 2016, 32(18)2866-8). IF biomarkers The average of the total nuclear intensity per well was also expressed in comparison to the solvent control.

[0271] result: The results are shown in Figures 13-15 and Tables 3 and 4.

[0272] Table 3 below shows the results for DS-8201 and exaten cell lines used in in vitro studies. The study demonstrated monotherapy activity of Kan and AZD6738ATR.

[0273] [Table 3]

[0274] Figure 13 shows DS-8201 and AZD6738(A) in HER2-high KPL4 cell lines. This shows the synergistic effect matrix when combined with TR inhibitors.

[0275] In Figure 13, (A) is the relative total as a percentage of the DMSO vehicle control. The cell (nucleus) count is shown (control = 100%, no remaining cells = 0%; dark areas indicate a very low total cell count). (A small area), (B) is the synergistic effect of Loewe, Bliss and HSA scores. This shows the rix (higher = more synergistic effect; dark areas are regions with high combined synergistic effect). (It is a region.)

[0276] Table 4 below shows the synergistic effect score (Lo) of the DS-8201 in combination with the AZD6738. This shows the total sum of ewe, Bliss, and HSA.

[0277] [Table 4]

[0278] Figure 14 shows (A) HER2-positive KPL4 cell lines and (B) HER2-negative MDA-MB- Regarding the combination of DS-8201 and AZD6738 in 468 cell lines, at zero time This shows the multiplicative change in the total number of cells remaining 4-8 days after treatment compared to the period. A positive value indicates growth. (Multiplier increase) A zero value indicates arrest of cell division, and a negative value indicates net cell loss and cell death. This represents a surrogate. The enclosed area shows the cell division arrest or combination compared to monotherapy. This indicates the area of ​​cell loss.

[0279] Figure 15 shows (A) HER2-high KPL4 cell lines or (B) HER2-low MDA-MB-46 cell lines. Regarding the combination of DS-8201 and AZD6738 in 8 cell lines, ATM-dependent Induction of KAP1 pSer824 signaling, DNA double-strand break (γH2AX) The biomarker or percentage of cell count (relative to the solvent control) is shown. A. Compared to monotherapy, the combination therapy induces a DNA damage response, DNA damage, or cell loss. This shows the region where conductivity has increased.

[0280] According to the results above, in a high HER2 KPL4 breast cancer cell line model, ATR inhibitors Clinically significant concentrations of DS-8201 (and E) in combination with AZD6738 Synergistic activity and cell death were observed with Satecan. Furthermore, DS-8201 (and Exa Tecan, ATM (KAP1 pSer824) activation and DNA strand breakage (γH2AX) This induces a concentration-dependent biomarker, which in combination with AZD6738 further Enhanced. In the HER2-negative MDA-MB-468 breast cancer cell line, combined DS- In 8201, weak combinatorial activity and low activation of the DNA damage response pathway were observed. On the other hand, exatecan supports the HER2 and tumor targeting dependence of DS-8201. It still showed activity, but did not show free exatecan. These data indicate that This is dependent on tumor HER2 expression and therefore increased compared to free topoisomerase I inhibitors. DS-8201 when combined with the ATR inhibitor AZD6738, which may provide a therapeutic index. It exhibits a strong enhancing effect on activity.

[0281] Example 5: Antitumor test (3) - In vivo Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATR inhibitor Harmful agent AZD6738(4-{4-[(3R)-3-methylmorpholine-4-yl]-6- [1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-I Combination with {-1H-pyrrolo[2,3-b]pyridine) method: We used 5-8 week old female nude mice (Charles River) before the start of the study. The subjects underwent a 7-day acclimatization period. 1 × 10 7 Individual NCI-N87 tumor cells (in Matrigel at a ratio of 1:1 The tumor was subcutaneously transplanted into the flank of a female nude mouse. The tumor was approximately 150 mm. 3 Once it reaches that point, go to Table 5. As shown, tumors of similar size were randomly assigned to the treatment group.

[0282] [Table 5]

[0283] The dosage of the compound for each animal was calculated based on the individual body weight on the day of administration. BID(1 day) The medication was administered twice at 8-hour intervals. DS-8201 and AZD6738 were administered on the same day. DS-8201 was administered approximately one hour after the AM PO administration of AZD6738. Any animal receiving treatment with ZD6738 should be kept moist from 24 hours before administration until the end of the treatment period. They were given moistened feed. Unless otherwise specified, the medication period was 28 days (1 cycle). .

[0284] DS-8201 is formulated at 3 mg / kg and 1 mg / kg. Prepare the DS-8201 medication solution by diluting the undiluted DS-8201 solution (20.1 mg / ml) to 25 mM. Dilute the histidine buffer in 9% sucrose (pH 5.5) to a concentration of 0.6 mg / ml. By doing so, the medication solutions are prepared on the day of administration, and the dosages are 3 mg / kg and 1 mg / kg, respectively. In this case, the dosage was set to 0.2 mg / ml. After thoroughly mixing each medication solution with a pipette, IV The drug was administered via injection at a dose of 5 ml / kg.

[0285] Formulated with AZD6738 at 25 mg / kg To prepare a 25 mg / kg dosage solution, use AZD6738 at a concentration of 2.5 mg / ml. Prepared a solution and obtained a dosage volume of 10 ml / kg for PO administration. DMSO (total vehicle volume) 10% of the compound was added and thoroughly mixed with a pellet mortar and pestle. The compound was completely dissolved. To do this, sonication for about 5 minutes was required. After that, propylene glycol (total Add 40% of the vehicle volume and mix thoroughly with an electromagnetic stirrer. Add 10 ml of sterile water. The chemicals are added to a glass Wheaton vial, and the chemicals remaining in the vial are removed. Rinse off all the mixture and then transfer it to a glass bottle. Use up all of the remaining sterile water (final vehicle) 50% of the volume was added to a glass bottle and thoroughly mixed with an electromagnetic stirrer. The drug solution was administered up to 7 The mixture was continuously mixed for several days, protected from light, and kept at room temperature. 25 mg / kg of AZD The final medication matrix of 6738 was a clear solution with a slightly yellowish hue.

[0286] measurement Tumor growth inhibition (TGI) from the start of the study to the day of tumor measurement was used to compare tumor volume in the control and treatment groups. This was evaluated by comparing the geometric mean changes. Tumor regression was assessed by comparing baseline (cured It was calculated as the percentage reduction in tumor volume from the pre-treatment value. Regression%=(1-RTV)*100% In the formula, RTV = geometric mean relative tumor volume.

[0287] On the final measurement day, statistical significance compared to the vehicle control was calculated using (log(relative tumor volume)). The evaluation was performed using a one-tailed t-test of the formula =log(final volume / initial volume).

[0288] result: The tumor volume after treatment with DS-8201 and / or AZD6738 is shown in Figure 16. The data shows the change in tumor volume over time in the treatment group. The dotted line in Figure 16 indicates the end of the medication period. The values ​​shown are as follows. For complete dosage and schedule information, please refer to Table 5 above. The mean was ±SEM; the mice treated with the vehicle were initially n=10, and all others The treatment group consisted of n=8.

[0289] In NCI-N87 xenografts, DS-8201 or AZD6738 monotherapy or The best TGI response after treatment with DS-8201 in combination with AZD6738 (maximum TG) Table 6 shows the I / regression.

[0290] [Table 6]

[0291] Monotherapy with DS-8201 at 3 mg / kg resulted in an 84% reduction in maximum tumor size at 33 days post-treatment. It showed long-term inhibition (TGI). DS-8201 at 1 mg / kg showed a 22% reduction at 37 days post-treatment. It showed a maximum TGI of 62% with AZD6738 monotherapy. The level reached I. Combination therapy with DS-8201 at 1 mg / kg was administered with a vehicle. Compared to control mice, this resulted in a significant reduction in NCI-N87 tumor volume at 1 mg / kg. With DS-8201+AZD6738, a significant effect of 75% maximum TGI was observed at 30 days post-treatment. This was observed.

[0292] Combination therapy using higher doses of DS-8201 and AZD6738 (3 mg / kg) The method achieved a maximum tumor regression of 120% at 33 days post-treatment, and in all corresponding cases... It showed a better response than drug therapy.

[0293] All treatment groups showed tolerance, and one average body weight was observed between the vehicle, monotherapy, or combination therapy groups. No significant differences were observed.

[0294] Example 6: Inhibition of ATR signaling Combination of DS-8201 and ATR inhibitor AZD6738 method RPM supplemented with 10% FCS in a humidified incubator at 37°C containing 5% CO2. Gastric cancer NCI-N87 and breast cancer KPL4 cell lines were cultured in I1640. The cells were then... To allow for linear propagation over the incubation period, seeds were sown at the optimal density in 6-well plates. Two days later, the cells were treated with the specified compound (AZD6738 monotherapy or DS-8201 or E The patient was administered (in combination with xatecan mesylate) and returned to the incubator. Protea 50 mM Tris-HCl pH 7.5 containing phosphatase and phosphatase inhibitors. By lysing cells in %SDS, whole cell extraction can be performed 7, 24, or 48 hours after administration. The exudate was obtained. The dissolved material was boiled at 95°C for 5 minutes. Nanodrop was used at 240 nm. The protein concentration was measured, and 50 μg of the lysate was added to a 4-12% Bis Tris gel. The protein was transferred using iBlot2. The primary antibody (see Table 7) was placed at 4°C. 3% milk TBS-tween 0.05% incubated overnight, HRP conjugate The prepared secondary antibody was incubated at room temperature for 1 hour. Blotting was performed using a G-box. It was converted into an image.

[0295] [Table 7]

[0296] result: The results were obtained in (A) NCI-N87 (gastric cancer) and (B) KPL4 (breast cancer) cell lines. AZD6738 monotherapy or combination therapy with DS-8201 (or exatecan mesylate). The morphology of the antibody blot image obtained using the combination method is shown in Figure 17.

[0297] In both HER2-high NCI-N87 and KPL4, DS-8201 at 30 μg / mL or Exposure to the warhead (exatecan mesylate) is due to pATR-T1989 and pChk1- Activation of the ATR pathway and cell cycle arrest (pCdc2-) are indicated by an increase in S345. Y15) was induced. The combination with 1 μM AZD6738 showed pATR and pChk It inhibits the activation of pKap1 and cell cycle arrest, while also exacerbating DNA damage (pKap1, g H2AX), ultimately led to increased cell death (cCasp3). Therefore, AZD67 Compound 38 is shown to inhibit DS-8201-induced ATR signaling.

[0298] Example 7 Antibody-drug conjugate DS-820 in vitro in hematopoietic stem cells and progenitor cells. Combination therapy of 1 (trastuzumab deruxtecan) and the ATR inhibitor AZD6738 method Cryopreserved human bone marrow CD34 + Thaw the progenitor cells (Lonza) and add 3 units containing 5% CO2. Maintenance medium in a 7°C humidified incubator (25 ng / ml SCF, 50 ng / ml TPO and 50 ng / ml of Flt3-L human recombinant protein (all Peprote StemSpan SFEM II (Stem Cell Techn) containing ch During the course of the drug, recovery was allowed to continue overnight. The following day, in the presence of the drug, differentiation of red blood cells was performed. Preferred Cell Systems (SEC-BFU1-40H), Myeloid Cell differentiation (Preferred Cell Systems, SEC-GM1-40H) ) or differentiation of megakaryocyte cells (Stem Cell Technologies, 09707) In a culture medium suitable for ) , a concentration of 5000 cells / ml for erythrocytes and myeloid cells. For 15000 cells / ml in the case of megakaryocytes, the cells were resuspended. DS-8 201(0.667, 0.222, 0.074, 0.025, 0.008 and 0 μM; so (Equivalent to 100, 33.3, 11.1, 3.7, 1.23, and 0 μg / ml respectively) A TR inhibitor AZD6738 / ceralaseltib (1.11, 0.37, 0.123, 0.0 Adding the combined solution (41, 0.014, 0 μM) to the cells (100 μl) in triple layers. 6× in a 96-well tissue culture plate (Corning) with white walls and a transparent bottom. Seeds were seeded in a matrix pattern of 6. Cells were then heated in humidified ink containing 5% CO2 at 37°C. The cells were cultured in a vibrator for 5 days.

[0299] Survival rate is measured using CellTiter-Glo 2.0 (10 μl / U) from Promega. The luminescence was measured using an optimized capacitance (of the Envision platelet), and the Envision platelet was used for measurement. The detection was performed using a Perkin Elmer. The relative emission signal was generated. In the ata Screener software (Genedata), control wells (either type) The compound was normalized to the percentage of 0 μM (the control was equal to 0, and the maximum cell death was (Equivalent to 100). Synergistic effect analysis was conducted by Loewe, Bliss, and the best monotherapy (HSA) The evaluation was performed using Dell, and the synergy score and excess matrix were calculated for each combination dose pair. Based on non-synergistic interactions, the difference between observed survival and predicted survival is compared. This was determined by [the following criteria].

[0300] result: Figures 18A and 18B show induction to differentiate into erythrocyte, myelocyte, or megakaryocyte lineages. Primary CD34 +DS-8201 and AZD in bone marrow-derived hematopoietic stem cells and progenitor cells The combination matrix obtained from combination therapy with 6738 (ceraracertib) is shown. Figure 18A shows the measured cell viability signal, with the X-axis representing drug A (DS-82). The graph shows the concentration of drug 01), and the Y-axis shows the concentration of drug B (AZD6738). The values ​​within the box represent the drug This represents the percentage of growth inhibition in cells treated with A+B, which is normalized to a control value equal to 0. Large cell death is equal to 100. Figure 18B shows HSA and Loewe hypermatrix. The values ​​within the box are the excess values ​​calculated by the HSA and Loewe adductor models, respectively. represent.

[0301] Table 8 shows the HSA adductor and Loewe synergistic effect scores.

[0302] [Table 8]

[0303] Primary CD34 separated into arbitrary series + DS-8201 and AZD in bone marrow cells No synergistic toxicity was observed with concurrent treatment of 6738, and cell death in the combination was observed compared to monotherapy. At the active dose of the method, the interaction occurred according to the predicted Loewe synergistic interaction.

[0304] Therefore, AZD6738 differentiates into erythrocyte lineage, myelocyte lineage, or megakaryocyte lineage. Induced primary CD34 + In bone marrow-derived hematopoietic stem cells and progenitor cells, DS-8201 and They do not interact synergistically, and this combination is associated with a favorable safety profile. It suggests obtaining something.

[0305] Example 8: Antitumor test (4) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATR inhibitor Harmful agent AZD6738(4-{4-[(3R)-3-methylmorpholine-4-yl]-6- [1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-I Combination with {-1H-pyrrolo[2,3-b]pyridine) method: We conducted a high-throughput combination screen, and here we found lung cancer with low HER2 expression. The cell line NCI-H522 (Table 9) was combined with DS-8201 and AZD6738. I was treated there.

[0306] [Table 9]

[0307] The values ​​displayed on the screen were performed as a 6x6 dose-response matrix for each combination. This was a 7-day cell titer-glo cell viability assay (DS-8201). Both AZD6738 and AZD6738 were used in semi-logarithmic serial dilutions.

[0308] The combined activity was evaluated based on the combination of ΔEmax and HSA synergy score. Ta.

[0309] result: The results are shown in Figures 19A and 19B and Table 10.

[0310] Figure 19A shows the matrix of measured cell viability signals. The X-axis represents drug A(D The graph represents S-8201), and the Y-axis represents drug B (AZD6738). The values ​​within the box are from day 7. This represents the ratio of cells treated with drug A + B compared to the DMSO control. All values This is normalized to the cell viability value on day 0. Values ​​between 0 and 100 indicate the growth inhibition level. - Represents cents, and values ​​above 100 indicate cell death.

[0311] Figure 19B shows the HSA excess matrix. The values ​​in the box represent the HSA (highest monotherapy) model. This represents the excess value calculated by [the relevant method].

[0312] Table 10 below shows the HSA adductor and Loewe synergistic effect scores.

[0313] [Table 10]

[0314] As can be seen from Figures 19A and 19B and Table 10, AZD6738 is DS-8201 It interacted synergistically with the other cells and also increased cell death in HER2-low lung cell lines.

[0315] The foregoing specification is considered sufficient to enable those skilled in the art to carry out the embodiments. The above description and examples illustrate specific embodiments in detail, and the inventors Describe the intended best-case scenario. However, how detailed the above description may be in writing. Regardless of what is described, the embodiments can be carried out in many ways, and the claims Please understand that the enclosure includes any equivalent object.

[0316] Free text for sequence listings SEQ ID NO: 1 - Amino acid sequence of the heavy chain of the anti-HER2 antibody Sequence ID 2 - Amino acid sequence of the light chain of the anti-HER2 antibody SEQ ID NO: 3 - Amino acids of heavy chain CDRH1 (= amino acid residues 26-33 of SEQ ID NO: 1) array SEQ ID NO: 4 - Amino acids of heavy chain CDRH2 (= amino acid residues 51-58 of SEQ ID NO: 1) array SEQ ID NO: 5 - Heavy chain CDRH3 (= amino acid residues 97-109 of SEQ ID NO: 1) Acid sequence Sequence ID 6 - Amino acids of light chain CDRL1 (= amino acid residues 27-32 of Sequence ID 2) array Sequence ID 7 - Light chain CDRL2 (SAS) (= amino acid residues 50-56 of Sequence ID 2) Amino acid sequence containing the amino acid sequence Sequence ID 8 - Amino acids of light chain CDRL3 (= amino acid residues 89-97 of Sequence ID 2) array SEQ ID NO: 9 - Amino acid distribution of the heavy chain variable region (=amino acid residues 1-120 of SEQ ID NO: 1) column SEQ ID NO: 10 - Amino acids in the light chain variable region (= amino acid residues 1-107 of SEQ ID NO: 2) array SEQ ID NO: 11 - Amino acid sequence of the heavy chain (= amino acid residues 1-449 of SEQ ID NO: 1)

Claims

1. Anti-HER2 antibody-drug conjugates and ATR inhibitors for combined administration A pharmaceutical product comprising the anti-HER2 antibody-drug conjugate having the following formula: 【Chemistry 1】 (In the formula, A represents the attachment site to the antibody.) The drug linker represented by conjugates to the anti-HER2 antibody via thioether linkage. A pharmaceutical product that is an antibody-drug conjugate.

2. The ATR inhibitor is given by the following formula (I): 【Chemistry 2】 (In the formula, R １ It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, R ２ teeth, 【Transformation 3】 And, n is either 0 or 1, R ２Ａ , R ２Ｃ , R ２Ｅ and R ２Ｆ These are, independently, hydrogen or methyl, R ２Ｂ and R ２Ｄ These are, independently, hydrogen or methyl, R ２Ｇ is selected from -NHR ７ and -NHCOR ８ and R ２Ｈ It is fluoro, R ３ It is methyl, R ４ and R ５ Each is independently either hydrogen or methyl, or R ４ and R ５ That Together with the atoms to which they are bonded, they form ring A. Ring A contains one heteroatom selected from O and N. ３～６ Cycloalkyl or It is a saturated 4-6 membered heterocycle, R ６ It is hydrogen, R ７ is hydrogen or methyl, R ８ (It is methyl.) The pharmaceutical product according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof. A finished product.

3. In equation (I), R ４ and R ５ These, together with the atoms to which they are bonded, form ring A. , and ring A contains one heteroatom selected from O and N. ３～６ Cycloal The pharmaceutical product according to claim 2, wherein it is a quill or a saturated 4-6 heterocycle.

4. In formula (I), ring A is cyclopropyl, tetrahydropyranyl, or piperidinyl. A pharmacokinetic product according to claim 2 or 3, which is a ring.

5. In equation (I), R ２Ａ is hydrogen, and R ２Ｂ is hydrogen, and R ２Ｃ is with hydrogen Yes, R ２Ｄ is hydrogen, and R ２Ｅ is hydrogen, and R ２Ｆ It is hydrogen, claim A pharmaceutical product as described in any one of items 2 to 4.

6. In equation (I), R １ The is 3-methylmorpholine-4-yl, according to claims 2 to 5. A pharmaceutical product as described in any one of the items.

7. The compound of formula (I) is of formula (Ia): 【Chemistry 4】 A compound or a pharmaceutically acceptable salt thereof, as described in any one of claims 2 to 6. Drug-derived product.

8. In equation (Ia), Ring A is a cyclopropyl ring, R ２ teeth, 【Transformation 5】 And, n is either 0 or 1, R ２Ａ It is hydrogen, R ２Ｂ It is hydrogen, R ２Ｃ It is hydrogen, R ２Ｄ It is hydrogen, R ２Ｅ It is hydrogen, R ２Ｆ It is hydrogen, R ２Ｇ -NHR ７ And, R ２Ｈ It is fluoro, R ３ It is a methyl group, R ６ is hydrogen, and R ７ The pharmaceutical product according to claim 7, wherein is hydrogen or methyl.

9. The aforementioned ATR inhibitor is given by the following formula: 【Transformation 6】 Claim 2 describes AZD6738 represented by or a pharmaceutically acceptable salt thereof. A pharmaceutical product.

10. The aforementioned anti-HER2 antibody consists of the amino acid sequence represented by SEQ ID NO:

3. CDRH2, consisting of the amino acid sequence represented by Sequence ID No. 4, and Sequence ID No. 5 The heavy chain containing CDRH3, which consists of the amino acid sequence represented, and the sequence represented by SEQ ID NO: 6 CDRL1 consists of an amino acid sequence, and amino acid residues 1-3 of SEQ ID NO: 7 CDRL2 consists of a series and CDRL3 consists of an amino acid sequence represented by Sequence ID No.

8. A pharmaceutical product according to any one of claims 1 to 9, wherein the antibody contains a light chain containing the above.

11. The anti-HER2 antibody has a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO:

9. It includes a heavy chain containing a region and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO:

10. A pharmaceutical product according to any one of claims 1 to 9, wherein the antibody contains a light chain.

12. The anti-HER2 antibody consists of a heavy chain and a compound amino acid sequence represented by SEQ ID NO:

1. The antibody comprising a light chain consisting of an amino acid sequence represented by column number 2, according to claims 1 to 9. A pharmaceutical product as described in any one of the items.

13. The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 and Claims 1 to 9 are antibodies comprising a light chain consisting of the amino acid sequence represented by Sequence ID No.

2. A pharmaceutical product as described in any one of the items.

14. The anti-HER2 antibody-drug conjugate is given by the following formula: 【Transformation 7】 (In the formula, the "antibody" is conjugated to the drug linker via a thioether bond) This refers to the anti-HER2 antibody, and n is one antibody molecule in the antibody-drug conjugate. n refers to the average number of units of the drug linker conjugated around, where n is 7 to 8. (This is the range.) A pharmaceutical product according to any one of claims 1 to 13, as represented by [the specified method].

15. The aforementioned anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS- The pharmaceutical product according to any one of claims 1 to 14, which is 8201).

16. For simultaneous administration, the anti-HER2 antibody-drug conjugate and the ATR inhibitor are included. A pharmaceutical product according to any one of claims 1 to 15, which is a composition.

17. For sequential or simultaneous administration, the anti-HER2 antibody-drug conjugate and the ATR inhibitor are used. A pharmaceutical product according to any one of claims 1 to 15, which is a combination formulation containing a harmful agent.

18. A pharmaceutical product according to any one of claims 1 to 17, for the treatment of cancer.

19. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and bile duct cancer. Urothelial cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach cancer Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma , uterine body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, phenotypic cancer Selected from the group consisting of cystic tumors, myelomas, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. The pharmaceutical product according to claim 18, wherein at least one of the above is present.

20. The pharmaceutical product according to claim 18, wherein the cancer is breast cancer.

21. The breast cancer has an IHC3+ HER2 status score, according to claim 20. thing.

22. The pharmaceutical product according to claim 20, wherein the breast cancer is a HER2-low expressing breast cancer.

23. The breast cancer has an IHC2+ HER2 status score, according to claim 20. thing.

24. The breast cancer has an IHC1+ HER2 status score, according to claim 20. thing.

25. The breast cancer described in claim 20 has an IHC > 0 and < 1+ HER2 status score. A pharmaceutical product.

26. The pharmaceutical product according to claim 20, wherein the breast cancer is triple-negative breast cancer.

27. The pharmaceutical product according to claim 18, wherein the cancer is gastric cancer.

28. The pharmaceutical product according to claim 18, wherein the cancer is colorectal cancer.

29. The pharmaceutical product according to claim 18, wherein the cancer is lung cancer.

30. The pharmaceutical product according to claim 29, wherein the lung cancer is non-small cell lung cancer.

31. The pharmaceutical product according to claim 18, wherein the cancer is pancreatic cancer.

32. The pharmaceutical product according to claim 18, wherein the cancer is ovarian cancer.

33. The pharmaceutical product according to claim 18, wherein the cancer is prostate cancer.

34. The pharmaceutical product according to claim 18, wherein the cancer is kidney cancer.

35. The pharmaceutical product according to claim 18, wherein the cancer cells of the aforementioned cancer are SLFN11 deficient.

36. SLFN11 expression is observed in the patient's cancer cells, and in the patient's SLFN11-expressing non-cancerous cells. The pharmaceutical product according to claim 18, which is lower in comparison to the above.

37. A pharmaceutical product according to any one of claims 1 to 17, for use in the treatment of cancer.

38. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and bile duct cancer. Urothelial cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach cancer Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma , uterine body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, phenotypic cancer Selected from the group consisting of cystic tumors, myelomas, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. A pharmaceutical product for use according to claim 37, which is at least one of the following.

39. The aforementioned cancer is breast cancer, the pharmaceutical product for use according to claim 37.

40. The breast cancer has an IHC3+ HER2 status score, and is used according to claim 39. A pharmaceutical product for the eyes.

41. The breast cancer is HER2-low expressing breast cancer, the pharmaceutical product for use according to claim 39. 。

42. The breast cancer has an IHC2+ HER2 status score, and is used according to claim 39. A pharmaceutical product for the eyes.

43. The breast cancer has an IHC1+ HER2 status score, and is used according to claim 39. A pharmaceutical product for the eyes.

44. The breast cancer described in claim 39 has an IHC > 0 and < 1+ HER2 status score. A pharmaceutical product for use.

45. The breast cancer is triple-negative breast cancer, according to the pharmaceutical product for use described in claim 39. A finished product.

46. The aforementioned cancer is gastric cancer, the pharmaceutical product for use according to claim 37.

47. The pharmaceutical product for use according to claim 37, wherein the cancer is colorectal cancer.

48. The pharmacopoeia for use according to claim 37, wherein the cancer is lung cancer.

49. The pharmaceutical product for use according to claim 48, wherein the lung cancer is non-small cell lung cancer.

50. The pharmaceutical product for use according to claim 37, wherein the cancer is pancreatic cancer.

51. The pharmaceutical product for use according to claim 37, wherein the cancer is ovarian cancer.

52. The pharmaceutical product for use according to claim 37, wherein the cancer is prostate cancer.

53. The pharmaceutical product for use according to claim 37, wherein the cancer is renal cancer.

54. The cancer cells of the aforementioned cancer are SLFN11 deficient, according to claim 37 for use A finished product.

55. SLFN11 expression is observed in the patient's cancer cells, and in the patient's SLFN11-expressing non-cancerous cells. A pharmaceutical product for use according to claim 37, which is lower in comparison to the pharmaceutical product for use according to claim 37.

56. To treat cancer, a combination of anti-HER2 antibody-drug conjugates and ATR inhibitors is used. In the manufacture of a drug for administration in combination, the anti-HER2 antibody-drug conjugate or This is the use of the ATR inhibitor, the anti-HER2 antibody-drug conjugate and the The ATR inhibitor is used as described in any one of claims 1 to 15.

57. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and bile duct cancer. Urothelial cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach cancer Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma , uterine body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, phenotypic cancer Selected from the group consisting of cystic tumors, myelomas, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. The use according to claim 56, which is at least one of the following.

58. The use according to claim 56, wherein the cancer is breast cancer.

59. The use according to claim 58, wherein the breast cancer has an IHC3+ HER2 status score.

60. The use according to claim 58, wherein the breast cancer is a HER2-low expressing breast cancer.

61. The use according to claim 58, wherein the breast cancer has an IHC2+ HER2 status score.

62. The use according to claim 58, wherein the breast cancer has an IHC1+ HER2 status score.

63. The breast cancer described in claim 58 has an IHC > 0 and < 1+ HER2 status score. Use.

64. The use according to claim 58, wherein the breast cancer is triple-negative breast cancer.

65. The use according to claim 56, wherein the cancer is gastric cancer.

66. The use according to claim 56, wherein the cancer is colorectal cancer.

67. The use according to claim 56, wherein the cancer is lung cancer.

68. The use according to claim 67, wherein the lung cancer is non-small cell lung cancer.

69. The use according to claim 56, wherein the cancer is pancreatic cancer.

70. The use according to claim 56, wherein the cancer is ovarian cancer.

71. The use according to claim 56, wherein the cancer is prostate cancer.

72. The use according to claim 56, wherein the cancer is kidney cancer.

73. The use according to claim 56, wherein the cancer cells of the aforementioned cancer are SLFN11 deficient.

74. SLFN11 expression is observed in the patient's cancer cells, and in the patient's SLFN11-expressing non-cancerous cells. The use described in claim 56, which is lower compared to the use described in claim 56.

75. The aforementioned drug is administered simultaneously with the anti-HER2 antibody-drug conjugate and the AT. The use according to any one of claims 56 to 74, wherein the composition contains an R inhibitor.

76. The aforementioned drugs are administered sequentially or concurrently with the anti-HER2 antibody-drug conjugate and The combination formulation comprising the aforementioned ATR inhibitor, as described in any one of claims 56 to 74. Use.

77. A method for treating cancer, comprising an anti-HER2 antibody according to any one of claims 1 to 15. Drug conjugates and ATR inhibitors, in combination, are used for the target population that requires them. A method that includes administering the substance.

78. The aforementioned cancers include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, and bile duct cancer. Urothelial cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, stomach cancer Intestinal stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma , uterine body cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, phenotypic cancer Selected from the group consisting of cystic tumors, myelomas, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. The method according to claim 77, wherein at least one of the following is achieved.

79. The method according to claim 77, wherein the cancer is breast cancer.

80. The method according to claim 79, wherein the breast cancer has an IHC3+ HER2 status score.

81. The method according to claim 79, wherein the breast cancer is a HER2-low-expressing breast cancer.

82. The method according to claim 79, wherein the breast cancer has an IHC2+ HER2 status score.

83. The method according to claim 79, wherein the breast cancer has an IHC1+ HER2 status score.

84. The breast cancer described in claim 79 has an IHC > 0 and < 1+ HER2 status score. The method.

85. The method according to claim 79, wherein the breast cancer is triple-negative breast cancer.

86. The method according to claim 77, wherein the cancer is gastric cancer.

87. The method according to claim 77, wherein the cancer is colorectal cancer.

88. The method according to claim 77, wherein the cancer is lung cancer.

89. The method according to claim 88, wherein the lung cancer is non-small cell lung cancer.

90. The method according to claim 77, wherein the cancer is pancreatic cancer.

91. The method according to claim 77, wherein the cancer is ovarian cancer.

92. The method according to claim 77, wherein the cancer is prostate cancer.

93. The method according to claim 77, wherein the cancer is kidney cancer.

94. The method according to claim 77, wherein the cancer cells of the aforementioned cancer are SLFN11 deficient.

95. SLFN11 expression is observed in the patient's cancer cells, and in the patient's SLFN11-expressing non-cancerous cells. The method according to claim 77, which is lower compared to the method according to claim 77.

96. The anti-HER2 antibody-drug conjugate and the ATR inhibitor are administered sequentially. The method according to any one of claims 77 to 95, including the following.

97. The anti-HER2 antibody-drug conjugate and the ATR inhibitor are administered simultaneously. The method according to any one of claims 77 to 95, including the method described in any one of claims 77 to 95.

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