Combination of antibody-drug conjugates with ATM inhibitors

Abstract

The present invention provides improved therapeutic compositions and therapeutic methods that can enhance the efficacy of existing cancer treatment agents, increase the duration of therapeutic response, and / or reduce dose-dependent toxicity. [Solution] A pharmaceutical product is provided for administering an anti-HER2 antibody-drug conjugate in combination with an ATM inhibitor. This anti-HER2 antibody-drug conjugate is an antibody-drug conjugate in which a drug linker represented by the following formula (A represents the attachment site to the antibody) is conjugated to an anti-HER2 antibody via a thioether bond. Also provided are therapeutic use and methods of treatment for administering the antibody-drug conjugate and the ATM inhibitor in combination to a subject. JPEG2026139673000041.jpg50170

Description

[Technical Field]

[0001] This disclosure relates to the linker structure of an anti-HER2 antibody combined with an ATM inhibitor. Pharmaceuticals for the administration of specific antibody-drug conjugates containing an antitumor agent. The product is administered to the target in combination with this specific antibody-drug conjugate and an ATM inhibitor. Regarding the therapeutic use and methods of treatment. [Background technology]

[0002] ATM (Ataxia vasodilator mutation kinase) is a gene mutation that occurs in ataxia vasodilator. It is the first serine / threonine protein kinase identified as a product of this gene. Vasodilated Ataxia is located on human chromosome 11q22-23 and is a large chromosome of approximately 350 kDa. FRAP-AT is a protein that codes for and modulates the activity and function of ATM kinase. Phosphatidylinositol ("PI") adjacent to the M-TRRAP and FATC domains It is characterized by the presence of a 3-kinase-like serine / threonine kinase domain. ATM Kinases have been identified as key players in the DNA damage response induced by double-strand breaks. This is necessary to maintain cellular integrity after DNA damage, and is also important in the S / G2 / M cell cycle transition. It primarily functions in collapsed replication forks and checks the cell cycle. It initiates a point, chromatin modification, HR repair, and pro-survivability signaling cascade. (Lavin,MF;Rev.Mol.Cell Biol.2008,759- 769). ATM kinase is affected by ionizing radiation and topoisomerase-II inhibitors (doxol). Direct double-strand breaks caused by common anticancer treatments such as bicin and etoposide In addition to responding, topoisomers also convert single-strand breaks to double-strand breaks during replication. It also responds to enzyme-I inhibitors (e.g., irinotecan and topotecan). ATMkiner ATM kinase inhibitors can enhance the activity of any of these drugs, and as a result, ATM kinase inhibitors It is expected to be useful in the treatment of cancer. Examples of ATM inhibitors are disclosed, for example, in International Publication No. 2017 / 046216. It is being done.

[0003] Antibody-drug conjugates are composed of cytotoxic preparations conjugated to antibodies. (ADC) can selectively deliver this drug to cancer cells, and therefore, within the cancer cells, It is expected that this will cause the accumulation of these cancer cells and kill them (Ducry, L., e t al.,Bioconjugate Chem.(2010)21,5-13;Al ley,SC,et al.,Current Opinion in Chemi. cal Biology(2010)14,529-537;Damle NKEx pert Opin.Biol.Ther.(2004)4,1445-1452;Se nter PD,et al.,Nature Biotechnology(20 12)30,631-637;Burris HA.,et al.,J.Clin.O ncol. (2011) 29(4): 398-405).

[0004] One such antibody-drug conjugate is trastuzumab deruxtecan. This consists of a HER2-targeting antibody and an exatecan derivative (Ogita ni Y. et al.,Clinical Cancer Research(201 6)22(20),5097-5108;Ogitani Y.et al.,Canc er Science (2016) 107, 1039-1046).

[0005] Despite the therapeutic potential of antibody-drug conjugates and ATM inhibitors, this antibody- This explains the results of a study demonstrating the superior efficacy of combining drug conjugates with ATM inhibitors. No literature has been published that supports this claim, nor any literature explaining the chemical basis for suggesting such test results. It has not been done. Furthermore, if there are no test results, antibody-drug conjugates and ATM inhibitors are used. Concomitant administration with other cancer treatment agents may result in negative interactions and / or additive therapeutic outcomes. There is a possibility that the excellent effects obtained from such combined treatments cannot be expected. There is a possibility. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Therefore, it may enhance the effectiveness of existing cancer treatment agents, increase the duration of therapeutic response, and / or There remains a need for improved therapeutic compositions and methods that can reduce dose-dependent toxicity. It is. [Means for solving the problem]

[0007] The antibody-drug conjugate used in this disclosure (topoisomerase I inhibitor exateca Anti-HER2 antibody-drug conjugates containing derivatives of HER2 are effective when administered alone. It has been confirmed that it shows excellent antitumor effects in the treatment of certain cancers, such as breast cancer and gastric cancer. However, it does not have a superior antitumor effect in cancer treatment (for example, enhanced effectiveness, curative effect). Pharmaceuticals that can improve the duration of therapeutic effect and / or reduce dose-dependent toxicity. It is desirable to provide treatment. By inhibiting the DNA damage response to double-strand breaks, ATM inhibitors work against this antibody- When administered in combination with a drug conjugate, it may further enhance the antitumor effect. .

[0008] This disclosure relates to the administration of an anti-HER2 antibody-drug conjugate combined with an ATM inhibitor. This disclosure also provides pharmaceuticals that can exhibit superior antitumor effects in the treatment of cancer. The patient is administered an anti-HER2 antibody-drug conjugate in combination with an ATM inhibitor. We also provide information on its therapeutic use and treatment methods.

[0009] Specifically, this disclosure relates to the following [1] to

[52] :

[0010] [1] A medical device for concomitant administration comprising an anti-HER2 antibody-drug conjugate and an ATM inhibitor. A pharmaceutical product, wherein the anti-HER2 antibody-drug conjugate has the following formula: [ka] A drug-linker represented by (wherein A represents the site of attachment to the antibody) is linked to a thioether bond. It is an antibody-drug conjugate that is conjugated to an anti-HER2 antibody via a linkage. , pharmaceuticals;

[0011] [2] The ATM inhibitor is defined by the following formula (I): [ka] (In the formula, R 1 It is methyl; R 2 is hydrogen or methyl; or R1 and R 2 , together with the nitrogen atom to which they are bonded form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R 3 is hydrogen or fluoro; R 4 is hydrogen or methyl; R 5 is hydrogen or fluoro), which is a compound represented by, or a pharmaceutically acceptable salt thereof, the pharmaceutical agent according to [1];

[0012] [3] In formula (I), R 1 and R 2 are both methyl; or R 1 and R 2 are , together with the nitrogen atom to which they are bonded, form an azetidinyl ring, a pyrrolidinyl ring, or a piperidiny l ring, the pharmaceutical agent according to [2];

[0013] [4] In formula (I), R 1 and R 2 , together with the nitrogen atom to which they are bonded, form an azetidiny l ring, a pyrrolidinyl ring, or a piperidinyl ring, the pharmaceutical agent according to [2] or [3] ;

[0014] [5] In formula (I), R 3 is hydrogen, the pharmaceutical agent according to any one of [2] to [4] ;

[0015] [6] In formula (I), R 4 is methyl, the pharmaceutical agent according to any one of [2] to [5] ;

[0016] [7] In formula (I), R 5 is fluoro, the pharmaceutical agent according to any one of [2] to [6] ;

[0017] ​ [8] In formula (I), R 1 It is methyl; R 2 is methyl; or R 1 and R 2 These, along with the nitrogen atom to which they bond, It forms a zetidinyl ring, pyrrolidinyl ring, or piperidinyl ring; R 3 is hydrogen or fluorine; R 4 It is methyl; R 5 is hydrogen or fluorine. [2] The pharmaceuticals listed below;

[0018] [9] The ATM inhibitor is given by the following formula: [ka] AZD1390 (also known as AZ13791971), or its pharmaceutical A pharmaceutical product described in [2] that is a generally acceptable salt;

[0019]

[10] The anti-HER2 antibody is the same as the amino acid residues 26-33 of SEQ ID NO: 3 [=SEQ ID NO: 1] CDRH1, consisting of the amino acid sequence represented by ], SEQ ID NO: 4 [= amino acid residue of SEQ ID NO: 1] CDRH2, consisting of the amino acid sequence represented by bases 51-58, and sequence number 5 [=sequence number] Heavy 1 containing CDRH3, which consists of the amino acid sequence represented by amino acid residues 97-109 of No. 1 The chain and the amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 27-32 of SEQ ID NO: 2] Rana CDRL1, amino acid residues 1-3 of SEQ ID NO: 7 [= amino acid residue 50 of SEQ ID NO: 2] CDRL2 consists of an amino acid sequence consisting of ~52, and SEQ ID NO: 8 [= the same as SEQ ID NO: 2] Includes a light chain containing CDRL3, which consists of an amino acid sequence represented by amino acid residues [89-97]. A drug that is an antibody, as described in any one of [1] to [9];

[0020]

[11] The anti-HER2 antibody is the same as the amino acid residues 1-120 of SEQ ID NO: 9 [=SEQ ID NO: 1] A heavy chain containing a heavy chain variable region consisting of the amino acid sequence represented by ], and Sequence ID No. 10 [=sequence number The light chain includes a variable region consisting of the amino acid sequence represented by amino acid residues 1-107 of No. 2. A drug containing a chain, as described in any one of [1] to [9];

[0021]

[12] The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by Sequence ID No. 1, The antibody, which contains a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, is one of the antibodies described in [1] to [9]. Any of the listed medications;

[0022]

[13] The anti-HER2 antibody is the same as the amino acid residues 1-44 of SEQ ID NO: 11 [=SEQ ID NO: 1] A heavy chain consisting of the amino acid sequence represented by [9] and the amino acid sequence represented by Sequence ID No. 2 A drug containing a light chain, as described in any one of [1] to [9];

[0023]

[14] The anti-HER2 antibody-drug conjugate is expressed by the following formula: [ka] (In the formula, “antibody” is conjugated to the drug-linker via a thioether bond) The anti-HER2 antibody is shown, where n is one of the antibody-drug conjugates. This indicates the average number of conjugated drug-linker units per antibody molecule. (where n is in the range of 7 to 8) Medical [1] to

[13] is described in one of the following: Pharmaceuticals;

[0024]

[15] The anti-HER2 antibody-drug conjugate is trastuzumab deruxtec The drug is (DS-8201), as listed in any one of [1] to

[14] ;

[0025]

[16] The product is for simultaneous administration of the anti-HER2 antibody-drug conjugate and the A pharmaceutical product according to any one of [1] to

[15] , comprising an ATM inhibitor;

[0026]

[17] The product is a conjugate of the anti-HER2 antibody-drug for continuous or simultaneous administration. A combination formulation comprising a gate and the ATM inhibitor, one of [1] to

[15] The listed medications;

[0027]

[18] The product is for the treatment of cancer, as described in any one of [1] to

[17] . Pharmaceuticals;

[0028]

[19] The cancers mentioned above include breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, and esophagogastric junction cancer. Adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder Cancer, gastrointestinal stromal tumors, digestive tract stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, Endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, bone A small number of cases selected from the group consisting of myeloma, glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. At least one of the drugs listed in

[18] ;

[0029]

[20] The cancer is breast cancer, as described in

[18] ;

[0030]

[21] The breast cancers described above have a HER2 status score of IHC 3+, as described in

[20] . Listed medicines;

[0031]

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

[20] ;

[0032]

[23] The breast cancers described above have a HER2 status score of IHC 2+, as described in

[20] . Listed medicines;

[0033]

[24] The breast cancers described above have a HER2 status score of IHC 1+, as described in

[20] . Listed medicines;

[0034]

[25] The breast cancers described above have an IHC status score of >0 and <1+. The pharmaceuticals listed in

[20] ;

[0035]

[26] The breast cancer is a tertiary-negative breast cancer, as described in

[20] ;

[0036]

[27] The cancer is gastric cancer, as described in

[18] ;

[0037]

[28] The drug described in

[18] , wherein the cancer is colorectal cancer;

[0038]

[29] The cancer is lung cancer, as described in

[18] ;

[0039]

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

[29] ;

[0040]

[31] The cancer is pancreatic cancer, as described in

[18] ;

[0041]

[32] The cancer is ovarian cancer, as described in

[18] ;

[0042]

[33] The cancer is prostate cancer, as described in

[18] ;

[0043]

[34] The cancer is renal cancer, as described in

[18] ;

[0044]

[35] For use in the treatment of cancer, as defined in any one of [1] to

[17] Pharmaceuticals;

[0045]

[36] The cancers described above are defined in any one of

[19] to

[34] ,

[35] A drug for use as described above;

[0046]

[37] Combining an anti-HER2 antibody-drug conjugate with an ATM inhibitor for the treatment of cancer The anti-HER2 antibody-drug conjugate or in the manufacture of a drug to be administered together This is the use of the ATM inhibitor, wherein the anti-HER2 antibody-drug conjugate and the A TM inhibitors are used as defined in any one of [1] to

[15] ;

[0047]

[38] The cancers described above are defined in any one of

[19] to

[34] , Use as described in

[37] ;

[0048]

[39] The drug is administered simultaneously with the anti-HER2 antibody-drug conjugate and the Use according to

[37] or

[38] , which is a composition comprising an ATM inhibitor;

[0049]

[40] The drug is used for continuous or simultaneous administration of the anti-HER2 antibody-drug conjugate. A combination formulation comprising a gate and the ATM inhibitor, as described in

[37] or

[38] . for;

[0050]

[41] Anti-HER2 antibody for use in combination with ATM inhibitors in cancer treatment A drug conjugate comprising the anti-HER2 antibody-drug conjugate and the ATM inhibitor. A harmful agent is defined as any one of the following [1] to

[15] , an anti-HER2 agent. Body-drug conjugates;

[0051]

[42] The cancer is defined as any one of

[19] to

[34] ,

[41] Anti-HER2 antibody-drug conjugate for use as described above;

[0052]

[43] The use described above involves the anti-HER2 antibody-drug conjugate and the ATM inhibitor Anti-HER2 antibody-drug for use as described in

[41] or

[42] , including continuous administration of the anti-HER2 antibody-drug. Judgment;

[0053]

[44] The use described above involves the anti-HER2 antibody-drug conjugate and the ATM inhibitor Anti-HER2 antibody-drug combination for use as described in

[41] or

[42] , including simultaneous administration of the anti-HER2 antibody-drug combination. Judgment;

[0054]

[45] Use in combination with anti-HER2 antibody-drug conjugates in the treatment of cancer An ATM inhibitor for which the anti-HER2 antibody-drug conjugate and the ATM inhibitor A harmful agent is defined as an ATM inhibitor, as specified in any one of [1] to

[15] . ;

[0055]

[46] The cancers described above are defined in any one of

[19] to

[34] , ATM inhibitors for use as described in

[45] ;

[0056]

[47] The use described above involves the anti-HER2 antibody-drug conjugate and the ATM inhibitor ATM inhibitors for use as described in

[45] or "46", including continuous administration of the following:

[0057]

[48] ​​The use described above involves the anti-HER2 antibody-drug conjugate and the ATM inhibitor ATM inhibitors for use as described in

[45] or "46", including concurrent administration of the following:

[0058]

[49] A method of treating cancer, wherein the subject is one of [1] to

[15] . Combining an anti-HER2 antibody-drug conjugate as defined in the documentation with an ATM inhibitor A method including administration;

[0059]

[50] The cancers described above are defined in any one of

[19] to

[34] , The method described in

[49] ;

[0060]

[51] The method comprises the anti-HER2 antibody-drug conjugate and the ATM inhibitor The method according to

[49] or "50", comprising administering the following continuously; and

[0061]

[52] The method comprises the anti-HER2 antibody-drug conjugate and the ATM inhibitor The method according to

[49] or "50", which includes administering the same at the same time.

[0062] Favorable effects of disclosure This disclosure describes an antitumor agent conjugated to an anti-HER2 antibody via a linker structure. A pharmaceutical product that involves the combined administration of an anti-HER2 antibody-drug conjugate and an ATM inhibitor, Therapeutic use of combination therapy with specific antibody-drug conjugates and ATM inhibitors This disclosure provides a method for use and treatment of cancer. We can provide the drugs and treatments that can be obtained. [Brief explanation of the drawing]

[0063] [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 (SAS) containing the amino acid sequence of the light chain CDRL2 (SEQ ID NO: 7 [= amino acid residues 50-56 of SEQ ID NO: 2]). [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-12B] This figure shows the combination matrices obtained by high-throughput screening of DS-8201 and AZD1390 (AZ13791971; ATM inhibitor) in three breast cancer cell lines with varying HER2 expression and one gastric cell line with high HER2 expression. [Figure 13] This figure shows the synergistic matrix of the combination of DS-8201 and AZD1390 in HER2-high KPL4 cell lines, in terms of (A) relative total cell number as a control ratio, and (B) Loewe score, Bliss score, and HSA score. [Figure 14]This figure shows the change in total cells remaining after treatment compared to time zero for the combination of DS-8201 and AZD1390 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 damage (γH2AX) biomarkers, or cell number percentages (vs. solvent control) associated with the combination of DS-8201 and AZD1390 in (A) HER2-high KPL4 cell lines or (B) HER2-low MDA-MB-468 cell lines. [Figure 16] This figure shows the time course of tumor volume in female nude mice subcutaneously transplanted with NCI-N87 tumors, treated with DS-8201 alone at 1 mg / kg or 3 mg / kg, or in combination with AZD1390 at 10 mg / kg. [Figure 17] This figure shows antibody blot images of (A) NCI-N87 (gastric cancer) and (B) KPL4 (breast cancer) cell lines, using a combination of DS8201 or exatecan mesylate with ADZ1390. [Figure 18] (A) and (B) are figures showing combination matrices obtained by high-throughput screening of DS-8201 and AZD1390 (ATM inhibitor) in HER2-high NCI-H2170 (lung cancer) cell lines. [Modes for carrying out the invention]

[0064] To make this disclosure easier to understand, certain terms are defined first. Additional definitions will be provided throughout the detailed explanation.

[0065] Before detailing this disclosure, it should be noted that this disclosure is not limited to any particular composition or method, and therefore... It must be understood that this is modifiable. If so, unless the context explicitly indicates otherwise, the singular forms "a," "an," and "the" are used. " includes multiple referents. The term "a" (or "an"), and "one or multiple" The terms "at least one" and "at least one" may be used interchangeably herein.

[0066] Furthermore, as used herein, "and / or" does not imply the presence or absence of other features or components. It must not be considered a specific disclosure of each of two particular features or components. Therefore, the term "and / or" in this specification means "A and / or When used in phrases such as "B", it can mean "A and B", "A or B", "A" (alone), and It is intended to include "B" (alone). Similarly, the term "and / or" is When used in phrases such as "A, B, and / or C," one of the following forms may be used. Intended to include: 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 (alone);B (alone);and C (alone) ).

[0067] Unless otherwise defined, all technical and scientific terms used herein are defined in this disclosure. It has the same meaning as commonly understood by those skilled in the art in the relevant technical field. For example, Concise Dictionary of Biomedicine and Mo Lecular Biology,Juo,Pei-Show,2nd ed.,200 2,CRC Press;The Dictionary of Cell and M Olecular Biology,3rd ed.,1999,Academic P ress; and Oxford Dictionary of Biochemistry And Molecular Biology,Revised,2000,Oxfo Rd University Press states that many of the terms used in this disclosure are to those skilled in the art. Provides a general dictionary.

[0068] Units, prefixes, and symbols are written in the forms recognized by these International System of Units (SI). The numerical range includes the number that defines that range.

[0069] Wherever an aspect is described in this specification 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 the terms "inhibit," "block," and "suppress." These terms are used interchangeably in this specification and refer to any statistically significant decrease in biological activity (e.g., This refers to the complete blocking of this activity. For example, "inhibition" means blocking about 10% of biological activity. , 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% It can refer to a decrease in the rate of cell division and / or the number of cells undergoing cell division within a cell population. Cell populations resulting from proportion and / or terminal differentiation or cell death (e.g., thymidine uptake). Using techniques recognized in the art to measure the rate of cell loss from the group, the cell growth Reproduction can be assayed.

[0070] The term "subject" includes humans, non-human primates, rodents, and related species. However, this does not apply to any animal that may be the recipient of a particular treatment (e.g., mammals It refers to an object. Typically, the terms "subject" and "patient" are used in relation to human subjects. It is used interchangeably in the specification.

[0071] The term "pharmaceutical" refers to a composition containing all active ingredients (for simultaneous administration) or a composition containing all active ingredients. A combination of separate compositions containing at least one of the following but not all of them (compound formulation) (For continuous or simultaneous administration) to allow for the biological activity of the active ingredient. It is in a form that exhibits unacceptable toxicity to the subjects to whom this product is to be administered. This refers to a formulation that does not contain additional ingredients. Such products may be sterile. "Concurrent administration" is This means that the active ingredients are administered simultaneously. "Continuous administration" means that the active ingredients are administered to each individual This means that the drugs are administered one after another in any order at a certain time interval. The interval may be, for example, less than 24 hours, preferably less than 6 hours, and more preferably It could be less than 2 hours.

[0072] "treating" or "treatment" Ku means "to treat" or "to alleviate". Terms such as ")" or "to alleviate" are used when (1) diagnosed To cure, slow down, reduce, and / or halt the progression of symptoms of a pathological condition or disorder. (2) therapeutic measures to prevent and / or reduce the onset of the target pathological condition or disorder. Prophylactic measures to accelerate or preventive e) This refers to both the treatment and the measures taken. Therefore, those who require treatment include those who already have a disability, and those with disabilities. This includes individuals who tend to have [a certain condition] and those who should be protected from [a certain condition]. In certain aspects, [a certain condition] For example, a person may show complete, partial, or transient remission of a particular type of cancer. In this case, the cancer is successfully “treated” in accordance with the method of this disclosure.

[0073] The terms "cancer," "tumor," "cancerous," and "malignant" typically refer to uncontrolled cell proliferation. This refers to or describes a physiological condition in mammals characterized by reproduction. Examples of cancer are listed below. These include, but are not limited to: breast cancer, stomach cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer. Circumstance cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer Cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, digestive tract stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer , liver cancer, hepatocellular carcinoma, uterine body carcinoma, renal cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymph Tumors, plasmacytomas, myelomas, gliomas, glioblastoma multiforme, osteosarcomas, sarcomas, and melanomas. And, hematological malignancies (for example, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, Diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and solid Tumors (e.g., breast cancer, lung cancer, neuroblastoma, and colon cancer) are examples.

[0074] The term "cytotoxic agent" is broadly defined as used herein, and It inhibits or prevents the function of cells and / or causes cell destruction (cell death). This refers to substances that exhibit antineoplastic / antiproliferative effects. For example, cytotoxic agents can cause neoplasms. To directly or indirectly prevent the development, maturation, or spread of tumor cells. This term includes cell proliferation. This also includes drugs that only cause growth inhibition and do not cause mere cytotoxic effects. This term includes the chemotherapeutic agents defined below, as well as other HER2 antagonists. Anti-angiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, cytokines Members of the ammonium group, radioactive isotopes, and toxins (e.g., of bacterial, fungal, plant, or animal origin). It contains enzymatically active toxins. The term "chemotherapeutic agent" is a variant of the term "cytotoxic agent," which includes natural or synthetic compounds. It is a subset.

[0075] By the method or use of the Disclosure herein, administering the compounds disclosed herein to a patient may result in a positive cure for cancer. It may promote therapeutic response. The term "positive therapeutic response" in relation to cancer treatment refers to the symptoms associated with this disease. It refers to an improvement in condition. For example, improvement in a disease may be characterized by a complete response. The term refers to the absence of clinically detectable disease, accompanied by the normalization of any prior test results. Alternatively, improvement in the disease can be classified as a partial response. A "positive therapeutic response" includes cancer Reduction or inhibition of progression and / or duration, reduction or improvement of cancer severity, and / or includes improvement of one or more of the symptoms caused by administration of the compounds of this disclosure. In specific embodiments, such terms may refer to one, two, or more of the compounds of this disclosure after administration. "ku" refers to three or more results: (1) Stabilization, reduction, or elimination of cancer cell populations; (2) Stabilization or reduction of cancer growth; (3) Reduced cancer formation; (4) Eradication, removal, or control of primary, localized, and / or metastatic cancer; (5) Reduction of mortality rate; (6) Increased duration or rate of disease-free, relapse-free, progression-free, and / or overall survival; (7) Increase in response rate, duration of response, or number of patients who respond or go into remission; (8) Reduction in hospitalization rates; (9) Shortening of hospital stay; (10) The size of the tumor is maintained and does not increase or increases by less than 10%, preferably 5 An increase of less than %, preferably less than 4%, preferably less than 2%; and (11) Increase in the number of patients in remission; (12) Adjuvant therapies that would otherwise be necessary for the treatment of cancer (e.g., chemotherapy) A decrease in the number of (pharmaceutical or hormone therapy) agents.

[0076] Clinical response can be evaluated using the following: screening techniques, e.g., PET, magnetic Resonance imaging (MRI) scan, X-ray imaging, computed tomography ( CT scan, flow cytometry, or fluorescence-activated cell sorting (FACS) Analysis, histological examination, macroscopic findings, and blood chemistry tests, for example, but not limited to ELIS Changes detectable by A, RIA, chromatography, and similar methods. These positive changes In addition to therapeutic response, those receiving treatment also benefit from the improvement of symptoms associated with the disease. obtain.

[0077] As used herein, the term "effective dose" means the symptoms and / or conditions to be treated. Compounds that are sufficient to significantly and positively alter (e.g., provide a positive clinical response) Or it means the amount of the composition. The effective amount of the active ingredient used in pharmaceuticals is the amount of the treatment being performed. The condition, the severity of this condition, the duration of treatment, the nature of the concomitant therapy, and the specific effective ingredients being used. The specific pharmaceutically acceptable excipients / carriers used, as well as the knowledge and expertise of the attending physician. Similar factors within the phylogenetic field will cause variations. Specifically, antibody-drug conjugates The effective amount of the compound of formula (I) used in combination with the treatment of cancer is when this combination is To alleviate symptoms in warm-blooded animals (e.g., humans), to alleviate cancer symptoms, cancer To slow progression, or to reduce the risk of worsening in patients with cancer symptoms. It is a sufficient amount.

[0078] When the term "arbitrarily" is used, there may be other characteristics that follow it. It is intended that it does not need to exist. Therefore, the use of the term "optionally" This includes cases where this feature exists, as well as cases where this feature does not exist. For example, as a group that is "optionally substituted with one methoxy group", methoxy substitution Examples include groups having a methoxy substituent and groups without a methoxy substituent.

[0079] The term "substituted" means that any atom supporting a substituent maintains its acceptable valency. Under the condition that one or more hydrogen atoms on the specified base (for example, one or two water atoms) A single element (or one hydrogen atom) is a substituent (for example, one or two substituents, or This means that it is replaced by one substituent. The combination of substituents is stable. This includes only compounds and stable synthetic intermediates. "Stable" refers to the compound or intermediate in question. A drug that is sufficiently robust to be isolated and is a synthetic intermediate or has potential therapeutic utility. It means that it has usefulness as one of the agents. A certain group is "substituted" or "as is". If it is not explained that it is "selectively substituted", then it is not substituted (i.e., explicitly stated It must be assumed that none of the hydrogen atoms on the base have been replaced.

[0080] The term "pharmaceutically acceptable" means that a substance (e.g., a salt, dosage form, or excipient) is pharmaceutically acceptable. Used to indicate that it is suitable for use in patients. Pharmacologically acceptable. For a list of examples of salt, see Handbook of Pharmaceutical Sa lts:Properties,Selection and Use,PHSta hl and CGWermuth, editors, Weinheim / Zuer It can be found in ich:Wiley-VCH / VHCA, 2002. Formula (I) or (I A suitable pharmaceutically acceptable salt of compound I) is, for example, an acid addition salt. Formula (I) or ( II) The acid addition salt of the compound is obtained by adding this compound to a suitable inorganic acid or an acid known to those skilled in the art under conditions known to those skilled in the art. It can be formed by contact with an acid. The acid addition salt can be, for example, hydrochloric acid, hydrobromic acid, or sulfuric acid. It can be formed using an inorganic acid selected from the group consisting of , and phosphoric acid. In addition, an acid addition salt can be formed Trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid Acids, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, and It can also be formed using an organic acid selected from the group consisting of bi-p-toluenesulfonic acid.

[0081] Therefore, an embodiment of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. In terms of form, this pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, phosphate, and Lifluoroacetate, citrate, maleate, oxalate, acetate, formate, benzoic acid Salt, fumarate, succinate, tartrate, lactate, pyruvate, methanesulfonate, It is a benzenesulfonate or p-toluenesulfonate. Formula (I) or (I In another embodiment of the compound of I), or a pharmaceutically acceptable salt thereof, this pharmaceutically acceptable The salt is a methanesulfonate. Compounds of formula (I) or (II), or their pharmaceuticals. In another embodiment of the pharmaceutically acceptable salt, this pharmaceutically acceptable salt is monomethane. It is a sulfonate, that is, a compound of formula (I) or (II) versus a compound of methanesulfonic acid. The stoichiometry is 1:1.

[0082] The compounds and salts described herein may exist in solvated and non-solvated forms. For example, the solvated form can be the hydrated form, such as a hemihydrate, monohydrate, or dihydrate. This disclosure may be a trihydrate or an alternative amount thereof. All solvated and non-solvated forms, in particular, such forms of ATM kinase It is included insofar as it possesses inhibitory activity.

[0083] The atoms of the compounds and salts described herein may exist as their isotopes. This disclosure relates to all compounds of formula (I) or (II) in which an atom is one of its isotopes. A compound in which one or more carbon atoms are replaced (for example, one or more carbon atoms are replaced) 11 C or 13 It is a carbon isotope, or one or more hydrogen atoms, 2 H young or 3 A compound of formula (I) or (II) that is an H isotope, or one or more fluoride compounds Elementary atoms, 18 It includes compounds of formula (I) or (II) that are 15F isotopes.

[0084] The compounds and salts described herein may exist as mixtures of tautomers. "Tautomers" are structural isomers that exist in equilibrium, resulting from the movement of hydrogen atoms. This disclosure describes all tautomers of compounds of formula (I) or (II), in particular such as The tautomer is included insofar as it possesses ATM kinase inhibitory activity.

[0085] The compounds and salts described herein are due to one or more chiral carbon atoms, It may exist in an optically active form or a racemic form. This disclosure relates to a substance having ATM kinase inhibitory activity. , including all optically active or racemic forms of compounds of formula (I) or (II). The synthesis of the sex morphology can be carried out by standard techniques of organic chemistry known in the art, for example, This can be carried out by synthesis using optically active materials, or by racemic division. ru.

[0086] Therefore, an embodiment of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof. Morphologically, this compound has an enantiomeric excess (%ee) of ≥95%, ≥98%, or ≥99%. It is a single optical isomer. In another embodiment, this single optical isomer is a mirror with ≥99% accuracy. It exists with an image surplus ratio (%ee).

[0087] The compounds and salts described herein may be crystalline and may contain one or more types of crystals. It may exhibit a crystalline form. This disclosure relates to a compound of formula (I) or (I) having ATM kinase inhibitory activity. I) Any crystalline or amorphous form of the compound, or a mixture thereof Includes.

[0088] Description of the Embodiment The following describes preferred modes for implementing this disclosure. The forms shown are merely to illustrate an example of a typical embodiment of the present disclosure. It is not intended to limit the scope of the indication.

[0089] 1. Antibody-drug conjugates The antibody-drug conjugate used in this disclosure is given by the following formula: [ka] A drug-linker represented by (wherein A represents the attachment site to the antibody) Antibody-drug conjugates are conjugated to anti-HER2 antibodies via thioether linkage. It is a gate.

[0090] In this disclosure, the substructure consisting of a linker and a drug in an antibody-drug conjugate is defined as follows: This is called a "drug-linker." This drug-linker is located at the interchain disulfide bond site in the antibody. The chains are formed at two locations (between the heavy chains and between the heavy and light chains). It is connected to an ol group (in other words, the sulfur atom of a cysteine ​​residue).

[0091] The drug-linker of this disclosure has as a component the topoisomerase I inhibitor exa Thecane (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1, 2,3,9,12,15-Hexahydro-9-hydroxy-4-methyl-10H,13H -Benzo[de]pirano[3',4':6,7]indridino[1,2-b]quinoline-1 0,13-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) It contains (also represented as )-zion). Exatecan has antitumor effects. It is a thecin derivative, and its formula is as follows: [ka] is represented by.

[0092] The anti-HER2 antibody-drug conjugate used in the present disclosure has the following formula:

Chemical

[0093] Accordingly, the drug-linker is conjugated to an anti-HER2 antibody ("antibody- ) via a thioether bond. The meaning of n is the same as that of the average number of so-called conjugated drug molecules (DAR: drug to conjugate ratio), which represents the average number of conjugated drug-linker units per antibody molecule.

[0094] After migrating into cancer cells, the anti-HER2 antibody-drug conjugate used in the present disclosure is cleaved at the linker moiety, and a compound represented by the following formula:

Chemical

[0095] This compound is presumed to be the origin of the antitumor activity of the antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogita ni Y.et al., Clinical Cancer Research, 201 6, Oct 15;22(20):5097-5108, Epub 2016 Mar 29).

[0096] The anti-HER2 antibody-drug conjugate used in the present disclosure is known to have a bystander effect (Ogitani Y.et al., Cancer Scie nce) ​​​(nce(2016)107,1039-1046). This bystander effect is described in this disclosure. The antibody-drug conjugate used in this study migrates internally into cancer cells expressing the target. Next, the released compound acts against cancer cells present in the surrounding area that do not express the target. Even if it does not exert an antitumor effect, it does so through a process that produces an antitumor effect. This bystander effect is The anti-HER2 antibody-drug conjugate is used in combination with the ATM inhibitor relating to this disclosure. Even if this occurs, it will still exhibit excellent antitumor effects.

[0097] 2. Antibodies in antibody-drug conjugates The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is of any species The antibody may be, preferably, derived from a human, rat, horse, or rabbit. If this antibody is derived from a species other than human, preferably using known techniques It is either chimeric or humanized. This anti-HER2 antibody is polyclonal It may be an antibody, or it may be a monoclonal antibody, preferably a monoclonal antibody It is the body.

[0098] The antibodies in the antibody-drug conjugates used in this disclosure possess properties that may target cancer cells. Preferably an anti-HER2 antibody having, for example, the property of recognizing cancer cells. , properties of binding to cancer cells, properties of internal migration into cancer cells, and / or cells against cancer cells It is an antibody that possesses destructive activity.

[0099] The binding activity of anti-HER2 antibodies against cancer cells was confirmed using flow cytometry. The internal transfer of antibodies to cancer cells can be confirmed using the following: (1) to therapeutic antibodies Using binding of a secondary antibody (which is fluorescently labeled), the antibody taken up into cells under a fluorescence microscope is an assay for visualization (Cell Death and Differentia tion (2008) 15, 751-761), (2) an assay for measuring fluorescence intensity of antibodies taken up into cells by using binding of a fluorescently labeled secondary antibody to a therapeutic antibody (M olecular Biology of the Cell, Vol. 15, 5268 -5282, December 2004), or (3) the Mab-ZAP assay using binding of an immunotoxin to a therapeutic antibody, wherein said toxin is released upon uptake into cells and inhibits cell proliferation (Bio Techniques 28 : 162-165, January 2000). As the immunotoxin, a recombinant fusion protein of the catalytic domain of diphtheria toxin and protein G may be used.

[0100] The antitumor activity of the present anti-HER2 antibody can be confirmed in vitro by determining its inhibitory activity against cell proliferation. For example, a cancer cell line that overexpresses HER2 as the target protein of this antibody is cultured, the antibody is added to this culture system at various concentrations, and the inhibitory activity against focus formation, colony formation, and spheroid growth is determined. Antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse transplanted with a cancer cell line that highly expresses the target protein, and determining changes in said cancer cells .

[0101] Since the conjugated compound in the anti-HER2 antibody-drug conjugate exerts an antitumor effect, it is preferable that the anti-HER2 antibody itself will also have an antitumor effect ​​​​​​​ However, it is not essential. Specifically and selectively increasing the cytotoxic activity of antitumor compounds against cancer cells. For the purpose of exerting its effects, anti-HER2 antibodies have the property of internalizing and migrating into cancer cells. It is important, and equally preferable, that it would have this feature.

[0102] The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is used in the art. It can be obtained by known procedures. For example, the antibodies of this disclosure can be obtained by commonly performed procedures in the art. It can be obtained using a method which involves immunizing animals with antigen polypeptides. This includes, and recovering and purifying the antibodies produced in vivo. The origin of this antigen. This is not limited to humans, but can also refer to animals derived from non-human animals such as mice, rats, and similar species. Immunization can be performed with the antigen. In this case, the antibody that binds to the obtained heterologous antigen and the human antigen Cross-reactivity with other antibodies can be tested to screen for antibodies applicable to human diseases.

[0103] Alternatively, antibody-producing cells that produce antibodies against an antigen may be produced by methods known in the art (e.g., For example, Kohler and Milstein, Nature (1975) 256, p .495-497; and Kennet, R.ed., Monoclonal Antib. odies, p.365-367, Plenum Press, NY (1980)) According to the instructions, myeloma cells were fused to establish a hybridoma, and then this hybrid... Monoclonal antibodies can be obtained from this material.

[0104] By genetically modifying host cells to produce genes that code for antigen proteins, This allows us to obtain the antigen. Specifically, we prepare a vector that enables the expression of the antigen gene. The antigen expressed in this way is prepared, introduced into host cells, and expressed. , can be purified. Genetically modified antigen-expressing cells as described above, or cells expressing this antigen This antibody can also be obtained by immunizing animals using cell lines.

[0105] The anti-HER2 antibody in the antibody-drug conjugate used in this disclosure is preferably a Artificial modification for the purpose of reducing heterogenous antigenicity against humans, such as melanin antibodies or humanized antibodies. The recombinant antibody obtained by, or preferably, a human-derived antibody (i.e., a human antibody) These antibodies contain only the gene sequence of ). These antibodies are manufactured using known methods. obtain.

[0106] Chimeric antibodies are antibodies in which the variable region and constant region of the antibody originate from different species (for example, The variable region of an antibody derived from a mouse or rat is connected to the constant region of a human antibody. Chimeric antibodies can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6 851-6855, (1984).

[0107] As a humanized antibody, only the complementarity-determining region (CDR) of a heterologous antibody is incorporated into a human-derived antibody. Antibodies obtained by [doing something] (Nature (1986) 321, pp. 522-525) , and by the CDR transplantation method, some of the amino acid residues of the heterologous antibody framework are transferred to human antibodies. The antibody obtained by transplanting the CDR sequence of this heterologous antibody (International Publication No. 90 / 0 (Pamphlet No. 7861), and humanized antibodies using gene transformation mutagenesis strategies ( U.S. Patent No. 5,821,337 may be cited as an example.

[0108] As a human antibody, it is a human having a human chromosome fragment containing the genes for the heavy and light chains of the human antibody. Antibodies produced using antibody-producing mice (Tomizuka, K. et a l.,Nature Genetics(1997)16,p.133-143;Kur oiwa, Y. et.al., Nucl. Acids Res. (1998) 26, p. 3447-3448;Yoshida,H.et.al.,Animal Cell T echnology:Basic and Applied Aspects vol. 10, p.69-73 (Kitagawa, Y., Matsuda, T. and Iij ima, S. eds.), Kluwer Academic Publishers, 1 999;Tomizuka,K.et.al.,Proc.Natl.Acad.Sci See, for example, .USA(2000)97, pp.722-727. Alternatives These include antibodies obtained by phage display and selected from human antibody libraries. Antibodies(Wormstone,IMet.al,Investigative Oph thalmology&Visual Science.(2002)43(7),p. 2301-2308;Carmen,S.et.al.,Briefings in F unctional Genomics and Proteomics(2002), 1(2), p.189-203;Siriwardena,D.et.al.,Opht (See halmology (2002) 109(3), pp. 427-431, etc.) This can be used as an example.

[0109] This disclosure describes the anti-HER2 antibody in the antibody-drug conjugate used in this disclosure. Modified variants are also included. These modified variants involve chemically modifying the antibody relating to this disclosure or This refers to variants obtained through biological modification. Examples of chemically modified variants. Examples include: variants involving the linkage of chemical sites to the amino acid backbone, N-chain variants. Variants including the linkage of chemical sites to reductive or O-linked carbohydrate chains. Biological modifications. Examples of variants include: post-translation modifications (e.g., N-linked or O-linked). Glycosylation of the receptacle, treatment of the N-terminus or C-terminus, deamidation, isomerization of aspartic acid Variants obtained by (modification or oxidation of methionine), and expressed in prokaryotic host cells. A variant in which a methionine residue is added to the N-terminus. Furthermore, relating to this disclosure Antibodies labeled to enable the detection or isolation of antibodies or antigens (e.g., enzyme-labeled antibodies) Modified variants (including the body, fluorescently labeled antibodies, and affinity-labeled antibodies) are also included in the meaning of modified variants. Such modified variants of antibodies related to this process improve the stability and retention of the antibody in the bloodstream, and their antimicrobial properties. It is useful for reducing genicity, detecting or isolating antibodies or antigens, and similar applications.

[0110] Furthermore, modifications (glycosylation, defucusitization) of the glycan linked to the antibody relating to this disclosure. By regulating the antibody's glycan (e.g., glycation), antibody-dependent cytotoxic activity can be enhanced. As a technique for adjusting modifications, see International Publication No. 99 / 54342, and the same No. 00 / Pamphlet No. 61739, Pamphlet No. 02 / 31140, Pamphlet No. 2007 / 13 This information was disclosed in pamphlet No. 3855, pamphlet No. 2013 / 120066, etc. Such technologies are known. However, this technology is not limited to these. Among anti-HER2 antibodies, some have modified glycans that have been regulated.

[0111] Lysine residues at the carboxyl terminus of the heavy chain of antibodies produced in cultured mammalian cells It is known that it is missing, (Journal of Chromatograph y A,705:129-134(1995)), and produced in cultured mammalian cells. Two amino acid residues (glycine and lysine) are missing from the carboxyl terminus of the heavy chain of the antibody. It is missing, and a proline residue newly located at this carboxyl terminus is amidated. It is also known that (Analytical Biochemistry, 360:75- 83 (2007). However, such deletions and modifications of the heavy chain affect the antigenicity of this antibody. It affects affinity and effector function (complement activation, antibody-dependent cytotoxicity, etc.). No. Therefore, the anti-HER2 antibody relating to this disclosure does not include antibodies that have been subjected to such modification, and This antibody also includes a functional fragment in which one or two amino acids are missing from the carboxyl terminus of the heavy chain. The missing deletion variant, the variant obtained by amidation of the deletion variant (for example) This also includes heavy chains in which the proline residue at the carboxyl terminus is amidated, and similar types. A deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody relating to this disclosure. The types of ants are as long as their antigen-binding affinity and effector function are preserved, as described above. Not limited to riant. The two heavy chains constituting the antibody relating to this disclosure are a full-length heavy chain and It may be one selected from the group consisting of the deletion variants described above. , or any combination of two selected from these. The ratio of the amounts of each deletion variant is, The types of cultured mammalian cells that produce anti-HER2 antibodies as disclosed herein, and the culture conditions thereof. Although it may be affected by this, both heavy chains of the antibody relating to this disclosure are carbo An antibody lacking one amino acid residue at the xyl terminus is exemplified as a preferred example. obtain.

[0112] Examples of isotypes of anti-HER2 antibodies relating to this disclosure include IgG(IgG1, Ig Examples include IgG2, IgG3, and IgG4, with IgG1 or IgG2 being preferred. This can be used as an example.

[0113] In this disclosure, the term "anti-HER2 antibody" refers to HER2 (human epidermal growth factor receptor 2). It specifically binds to type ErbB-2, and preferably, by binding to HER2, it triggers HER2 emission This refers to antibodies that have the activity to interlocate into existing cells.

[0114] Examples of anti-HER2 antibodies include trastuzumab (U.S. Patent No. 5821337) and Pertuzumab (International Publication No. 01 / 00245) is mentioned, and trusz Mab can be cited as a preferred example.

[0115] 3. Manufacturing of antibody-drug conjugates Drug-phosphorus for use in the manufacture of anti-HER2 antibody-drug conjugates relating to this disclosure The Kerr intermediate is given by the following formula: [ka] It is represented as follows.

[0116] This drug-linker intermediate has the chemical name N-[6-(2,5-dioxo-2,5-dihydr [H-pyrrole-1-yl)hexanoyl]glycylglycyl-L-phenylalanine Lu-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4 -methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H ,12H-benzo[de]pirano[3',4':6,7]indridino[1,2-b]quino It can be represented as phosphate-1-yl]amino}2-oxoethoxy)methyl]glycinamide. , and also refer to International Publication No. 2014 / 057687 and No. 2015 / 098099 Pamphlet No. 2015 / 115091, Pamphlet No. 2015 / 1559 Please refer to the explanations in pamphlet No. 98, pamphlet No. 2019 / 044947, etc. It can be manufactured.

[0117] The anti-HER2 antibody-drug conjugate used in this disclosure is the drug described above. The product-linker intermediate and the anti-HERE compound having a thiol group (also called a sulfhydryl group) It can be produced by reacting it with two antibodies.

[0118] An anti-HER2 antibody having a sulfhydryl group can be obtained by a method 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 per interchain disulfide in an antibody. Using the base agent (e.g., tris(2-carboxyethyl)phosphine hydrochloride (TCEP)) Then, in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), this antibody By reacting with this antibody, the interchain disulfides within the antibody are partially or completely reduced. This allows us to obtain an anti-HER2 antibody that has a sulfhydryl group.

[0119] Furthermore, 2 to 20 molar equivalents of the drug per anti-HER2 antibody containing a sulfhydryl group. By using a mono-linker intermediate, 2 to 8 drug molecules can be added per antibody molecule. It is possible to manufacture conjugated anti-HER2 antibody-drug conjugates.

[0120] The amount of conjugate per anti-HER2 antibody molecule in the manufactured antibody-drug conjugate The average number of drug molecules that were filtered was measured by an antibody at two wavelengths, for example, 280 nm and 370 nm. -Calculation based on the measurement of UV absorbance of drug conjugates and their conjugation precursors. It can be determined by the extraction method (UV method), or by treating the antibody-drug conjugate with a reducing agent. The calculation method (HPLC method) is based on the quantification of the fragments obtained by HPLC measurement. It can be more definitively determined.

[0121] Conjugation between anti-HER2 antibody and drug-linker intermediate, and antibody-drug Calculate the average number of conjugated drug molecules per antibody molecule in a conjugate. International publication pamphlet No. 2014 / 057687, and International publication pamphlet No. 2015 / 098099. Brochure, Pamphlet No. 2015 / 115091, Pamphlet No. 2015 / 155998 Pamphlet No. 2017 / 002776, Pamphlet No. 2018 / 2121 This can be done by referring to the explanation in section 36, etc.

[0122] In this disclosure, the term “anti-HER2 antibody-drug conjugate” refers to the anti-HER2 antibody-drug conjugate as used in this disclosure. Antibody-drug conjugates in which the antibody in the body-drug conjugate is an anti-HER2 antibody It refers to the word "to".

[0123] This anti-HER2 antibody preferably consists of amino acid residues 26-33 of SEQ ID NO: 1. CDRH1 consists of an anoacid sequence, and amino acid sequences consisting of amino acid residues 51-58 of SEQ ID NO: 1 CDRH2 consisting of a row, and amino acid residues 97-109 of SEQ ID NO: 1 A heavy chain containing CDRH3 in a row, and an amino acid residue consisting of amino acid residues 27-32 of SEQ ID NO: 2 CDRL1 consists of an anoacid sequence, and the amino acid sequence consists of amino acid residues 50-52 of SEQ ID NO 2. CDRL2 consisting of a column, and the amino acid sequence consisting of amino acid residues 89-97 of SEQ ID NO: 2 An antibody comprising a light chain containing CDRL3, more preferably the amine of SEQ ID NO: 1. A heavy chain containing a heavy chain variable region consisting of an amino acid sequence of no acid residues 1 to 120, and the sequence number A light chain containing a light chain variable region consisting of an amino acid sequence of 2 amino acid residues 1 to 107 The antibody contains, and more preferably, the amino acid sequence represented by SEQ ID NO: 1. An antibody comprising a chain and a light chain consisting of the amino acid sequence represented by Sequence ID No. 2, or a sequence The heavy chain consists of amino acid residues 1-449 of sequence number 1, and all amino acid residues 1- of sequence number 2. This antibody contains a light chain consisting of a sequence of 214 amino acids.

[0124] In this anti-HER2 antibody-drug conjugate, the conjugate per antibody molecule The average number of drug-linker units is preferably 2 to 8, more preferably 3 to 8. Yes, more preferably 7 to 8, and even more preferably 7.5 to 8, More preferably, it is about 8.

[0125] The anti-HER2 antibody-drug conjugate used in this disclosure is described in International Publication No. 2015 / 1 It can be manufactured by referring to the instructions in pamphlet No. 15091, etc.

[0126] In a preferred embodiment, the anti-HER2 antibody-drug conjugate is trastuzumab It's a Luxtecan (DS-8201).

[0127] 4. ATM inhibitors In this disclosure, the term "ATM inhibitor" refers to ATM (Ataxia vasodilator mutation kinase). This refers to drugs that inhibit ). ATM inhibitors in this disclosure selectively inhibit kinase ATM. It is possible to obtain or to non-selectively inhibit ATM and also inhibit other kinases. In other words, the ATM inhibitors in this disclosure selectively inhibit ATM. The inhibitor is not particularly limited insofar as it is a drug having the described properties, and its preference A good example is the one disclosed below: International Publication No. 2017 / 04 Pamphlet No. 6216, Pamphlet No. 2015 / 170081, Pamphlet No. 2018 / Pamphlet No. 167203, Pamphlet No. 2017 / 153578, Pamphlet No. 201 Pamphlet No. 7 / 162611, Pamphlet No. 2017 / 162605, and No. 2 Pamphlet No. 017 / 174446, Pamphlet No. 2017 / 076895, and the same Pamphlet No. 2017 / 076898, and Pamphlet No. 2017 / 194632. , same No. 2019 / 057757.

[0128] In other embodiments of the ATM inhibitor used in this disclosure, the ATM inhibitor is as follows: The selected compound is: AZD1390: 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl) [ropoxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one (International Publication No. 2) Brochure No. 017 / 046216; Example 2), and its deuterated form: 4,6-Dijutero-7-fluoro-1-isopropyl-3-methyl-8-[6-[3 -(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline- 2-on, and 4-Dutero-7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1 [-Piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-o hmm; AZD0156 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (Oxane-4-yl)imidazo[5,4-c]quinoline-2-one (International Publication No. 201) Pamphlet No. 5 / 170081: Example 1); M4076 8-(1,3-dimethyl-1H-pyrazole-4-yl)-1-(3-fluoro-5-methyl) Toxypyridine-4-yl)-7-methoxy-3-methyl-1,3-dihydroimidazo [4,5-c]Quinoline-2-one (International Publication No. 2016 / 155884 pamphlet) ); M3541 3-Fluoro-4-[7-Methoxy-3-methyl-8-(1-methyl-1H-pyrazole] -4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline -1-yl]benzonitrile (International Publication No. 2012 / 028233); KU-55933 2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one(C AS number 587871-26-9; International Publication No. 2003070726A1 pamphlet ); KU-60019: 2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-N-{5-[6-(4 -Molfolinyl)-4-oxo-4H-pyran-2-yl]-9H-thioxanthene-2 -yl acetamide (CAS number 925701-49-1); KU-59403 3-(4-methyl-1-piperazinyl)-N-{6-[6-(4-morpholinyl)-4- Oxo-4H-pyran-2-yl]-2-thianthrenyl}propanamide (International Publication No. Pamphlet No. 2005016919; CP466722 2-(6,7-dimethoxyquinazoline-4-yl)-5-(2-pyridyl)-1,2,4 -Triazole-3-amine (CAS number 1080622-86-1); NVP-BEZ235 2-methyl-2-[4-[3-methyl-2-oxo-8-(3-quinolyl)imidazo[4 ,5-c]Quinoline-1-yl]phenyl]propannitrile(ductic;CAS No. Issue No. 915019-65-7; International Publication No. 2006 / 122806 pamphlet); 6-[6-(methoxymethyl)-3-pyridyl]-4-[[(1S)-1-tetrahydro Pyran-4-ylethyl]amino]quinoline-3-carboxamide (Degorce et al,J Med chem,2016,59,6281); 7-Fluoro-6-[6-(methoxymethyl)-3-pyridyl]-4-[[(1S)-1 -(1-methylpyrazole-3-yl)ethyl]amino]quinoline-3-carboxamide (Degorce et al,J Med chem,2016,59,6281); 6-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-N-methyl-4- [[(1S)-1-tetrahydropyran-4-ylethyl]amino]sinnoline-3-ca Ruboxamide (Barlaam et al, Med Chem Lett, 2018, 9,809-814); N-methyl-4-(6-phenylimidazo[1,2-a]pyrazine-3-yl)benzamide de(Valerie et al,Mol Can Ther,2018,1637); 1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3 -pyridyl]imidazo[4,5-c]sinnoline-2-one (International Publication No. 2019 / 05) Pamphlet No. 7757); and 2-(7-methoxy-9H-thioxanthene-4-yl)-6-morpholinopyran-4 -On (J.Med.Chem, 2019, 62, 2988).

[0129] According to preferred embodiments of the ATM inhibitor used in this disclosure, the ATM inhibitor is as follows: Equation (I): [ka] (In the formula, R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 These are the nitrogen atoms to which they bond. Together with it, it forms an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 (It is hydrogen or fluorine.) The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0130] "R 1 and R 2 These, along with the nitrogen atom to which they are bonded, form an azetidinyl ring, pyrrolidinyl When it is mentioned that it "forms a R ring or a piperidinyl ring", this means that 1 Base and R 2 The groups are linked by carbon-carbon covalent bonds, suitable for forming the corresponding ring. This means that it forms an unsubstituted alkylene chain of the specified length. For example, R 1 and R 2 but When these form a pyrrolidinyl ring together with the nitrogen atom to which they are bonded, R 1 and R 2 Together they form an unsubstituted butylene chain, and this unsubstituted butylene chain has two terminal carbons. , it is attached to the relevant nitrogen atom in formula (I).

[0131] Some of the values ​​of the variable groups in formula (I) are as follows. Such values ​​are specified herein. Used in combination with any of the definitions, claims, or defined embodiments. Further embodiments of the compound of formula (I) below may be provided: a)R 1 It is methyl. b)R 2 It is methyl. c)R 2 It is hydrogen. d)R 1 It is methyl, and R 2 It is either hydrogen or methyl. e)R 1 and R 2 Both are methyl. f)R 1 and R 2 Both are methyl; or R 1 and R 2 These combine Together with the nitrogen atom, it forms an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring. ru. g)R 1 and R 2 Both are methyl; or R 1 and R 2 These combine It forms an azetidinyl ring together with the nitrogen atom. h)R 1 and R 2 Both are methyl; or R 1 and R 2 These combine It forms a pyrrolidinyl ring together with the nitrogen atom. i)R 1 and R 2 Both are methyl; or R 1 and R 2 These combine It forms a piperidinyl ring together with the nitrogen atom. j)R 1 and R 2 Both are methyl. k)R 1 and R 2 These, along with the nitrogen atom to which they are bonded, form an azetidinyl ring, pyrrolidinyl It forms a 1x ring or a piperidinyl ring. l)R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form an azetidinyl ring. ru. m)R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a pyrrolidinyl ring. ru. n)R 1 and R 2 These, together with the nitrogen atom to which they are bonded, form a piperidinyl ring. ru. o)R 3 and R 5 Both are H. p)R 3 and R5 both are fluoro. q) R 3 is hydrogen. r) R 3 is fluoro. s) R 4 is hydrogen. t) R 4 is methyl. u) R 5 is hydrogen. v) R 5 is fluoro.

[0132] In one embodiment, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein in the formula , R 1 is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 , together with the nitrogen atom to which they are bonded , form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R 3 is hydrogen or fluoro; R 4 is hydrogen or methyl; R 5 is hydrogen or fluoro.

[0133] In another embodiment, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein in the formula , R 1 is methyl; R 2 is hydrogen or methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 5 is hydrogen.

[0134] In another embodiment, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, which The compound is selected from the group consisting of the following: 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -Isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl) [ropoxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one; 7-fluoro-1-isopropyl-3-methyl-8-[6-(3-pyrrolidine-1-yl) [propoxy)-3-pyridyl]imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]-3-pyridyl]-7-fluor Ro-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3 -pyridyl]imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-isopropyl -3-methylimidazo[4,5-c]quinoline-2-one; 1-Isopropyl-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)- 3-pyridyl]imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]-3-pyridyl]-1-isopropyl Ropyru-3-methylimidazo[4,5-c]quinoline-2-one; 8-[2-fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1 -Isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -Isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7 -Fluoro-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-o hmm; 8-[2-fluoro-6-(3-pyrrolidine-1-ylpropoxy)-3-pyridyl]- 1-Isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 7-Fluoro-8-[2-Fluoro-6-(3-pyrrolidine-1-ylpropoxy)-3 -pyridyl]-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2- on; 7-Fluoro-8-[2-Fluoro-6-[3-(1-piperidyl)propoxy]-3- Pyridyl]-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-o hmm; 8-[6-[3-(azetidine-1-yl)propoxy]-2-fluoro-3-pyridyl ]-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]-2-fluoro-3-pyridyl ]-7-fluoro-1-isopropyl-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -Isopropyl-3H-imidazo[4,5-c]quinoline-2-one; and 7-Fluoro-1-isopropyl-8-[6-[3-(1-piperidyl)propoxy]- 3-pyridyl]-3H-imidazo[4,5-c]quinoline-2-one.

[0135] In another embodiment, the compound represented by formula (I) is 7-fluoro-1-isopropyl- 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imida Zo[4,5-c]quinoline-2-one, or a pharmaceutically acceptable salt thereof.

[0136] In another embodiment, the compound represented by formula (I) is 7-fluoro-1-isopropyl- 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imida It is zo[4,5-c]quinoline-2-one.

[0137] In another embodiment, the compound according to formula (I) is 7-fluoro-1-isopropyl-3- Methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[ It is a pharmaceutically acceptable salt of [4,5-c]quinoline-2-one.

[0138] In another embodiment, the compound represented by formula (I) is 8-[6-[3-(azetidine-1 -yl)propoxy]-3-pyridyl]-1-isopropyl-3-methylimidazo[4 [5-c]Quinoline-2-one, or a pharmaceutically acceptable salt thereof.

[0139] In another embodiment, the compound represented by formula (I) is 8-[6-[3-(azetidine-1 -yl)propoxy]-3-pyridyl]-1-isopropyl-3-methylimidazo[4 [5-c]Quinoline-2-one.

[0140] In another embodiment, the compound represented by formula (I) is 8-[6-[3-(azetidine-1 -yl)propoxy]-3-pyridyl]-1-isopropyl-3-methylimidazo[4 It is a pharmaceutically acceptable salt of [5-c]quinoline-2-one.

[0141] In another embodiment, the compound according to formula (I) is 8-[6-[3-(dimethylamino)p [ropoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methylimidazo [4,5-c]quinoline-2-one, or a pharmaceutically acceptable salt thereof.

[0142] In another embodiment, the compound represented by formula (I) is 8-[6-[3-(dimethylamino )Propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methylimi It is dazo[4,5-c]quinoline-2-one.

[0143] In another embodiment, the compound represented by formula (I) is 8-[6-[3-(dimethylamino )Propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methylimi It is a pharmaceutically acceptable salt of dazo[4,5-c]quinoline-2-one.

[0144] In another embodiment, the compound according to formula (I) is 7-fluoro-1-isopropyl-3- Methyl-8-[6-[3-(1-oxidepiperidine-1-ium-1-yl)propoxy [C]-3-pyridyl]imidazo[4,5-c]quinoline-2-one, or its pharmaceutically permitted It is a tolerable salt.

[0145] In another embodiment, the compound represented by formula (I) is 7-fluoro-1-isopropyl- 3-methyl-8-[6-[3-(1-oxidepiperidine-1-ium-1-yl)pro It is [poxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one.

[0146] In another embodiment, the compound according to formula (I) is 7-fluoro-1-isopropyl-3- Methyl-8-[6-[3-(1-oxidepiperidine-1-ium-1-yl)propoxy The pharmaceutically acceptable [C]-3-pyridyl]imidazo[4,5-c]quinoline-2-one It is salt.

[0147] According to other preferred embodiments of the ATM inhibitor used in this disclosure, this ATM inhibitor This is expressed by the following equation (II): [ka] (In the formula, Q is a cyclobutyl ring or a cyclopentyl ring, each of which is a Hydro It is optionally substituted with a xy group or a methoxy group, or Q is an oxetanyl ring. , a tetrahydrofuranyl ring, or an oxanyl ring, each of which is one It is optionally substituted with a methyl group; R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 Together, the azetidinyl ring, pi It forms a loridinyl ring or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 (It is hydrogen or fluorine.) The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0148] The terms "cyclobutyl ring" and "cyclopentyl ring" refer to carbon that does not contain heteroatoms. Refers to an elementary ring. 1-methoxycyclobuta-3-yl group, and 3-methoxycyclobuta-1- The yl group has the same structure as shown below. [ka]

[0149] The cis-1-methoxycyclobuta-3-yl group is cis-3-methoxycyclobuta- It is equivalent to 1-IL and has the following structure. [ka]

[0150] The same rule applies to other cyclobutyl groups, for example, 1-hydroxycyclobutyl This also applies to the ta-3-yl group and the 3-hydroxycyclobuta-1-yl group.

[0151] Similarly, the 1-methoxycyclopenta-3-yl group and the 3-methoxycyclopenta-1- The yl group has the same structure as shown below. [ka]

[0152] The term "oxetanyl ring" refers to the oxetan-2-yl group and the oxetan-3-yl group. It includes the group, and these structures are shown below. [ka]

[0153] The term "tetrahydrofuranyl ring" refers to the tetrahydrofuran-2-yl group and tetra It contains a lahydrofuran-3-yl group, and these structures are shown below. [ka]

[0154] The term "oxanyl ring" refers to the oxan-2-yl group, the oxan-3-yl group, and It contains an oxan-4-yl group, and its structure is shown below. [ka] In the structure shown above, the dashed lines indicate the bonding positions of the relevant groups.

[0155] The oxanyl ring can also be called the tetrahydropyranyl ring. Similarly, oxane-4 -The yl ring may be called the tetrahydropyran-4-yl ring; the oxan-3-yl ring is te It can be called a trahydropyran-3-yl ring, and the oxan-2-yl ring is tetrahydropyran It can be called an 1-2-yl ring.

[0156] "R 1 and R 2 Together, they form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring. When it is mentioned that it is "achieving," this means that R 1 Base and R 2 The basis is carbon-carbon sharing. They are linked by bonds, forming unsubstituted alkylene chains of a length appropriate for the corresponding ring. It means that.

[0157] The values ​​of some of the variable groups in formula (II) are as follows. Such values ​​are used herein. Use in combination with any of the definitions, claims, or defined embodiments. This may provide further embodiments of the compound of formula (II) below: a) Q is a cyclobutyl ring or a cyclopentyl ring, each of which is one It is substituted with a hydroxyl group or a methoxy group, or Q is an oxetanyl ring, tetra A lahydrofuranyl ring or an oxanyl ring, each of which has one methyl group It is optionally substituted in the base. b) Q is a cyclobutyl ring substituted with one hydroxyl group or methoxy group. Q is either an oxetanyl ring or an oxanyl ring, and each of these is It is optionally substituted with one methyl group. c) Q is a cyclobutyl ring substituted with one hydroxyl or methoxy group. Q is either present or is an oxetanyl ring or an oxanyl ring. d) Q is cyclobutyl, 1-methoxy-cyclobuta-3-yl, 1-hydroxy- Clobuta-3-yl, 3-methoxycyclopenta-1-yl, oxetane-3-yl, te Trahydrofuran-3-yl, oxan-3-yl, oxan-4-yl, or 4-methyl It is ruoxan-4-yl. e) Q is 1-methoxycyclobuta-3-yl, 1-hydroxy-cyclobuta-3- Il, 3-methoxycyclopenta-1-yl, oxetane-3-yl, oxan-3-yl It is either yl, oxan-4-yl, or 4-methyloxan-4-yl. f) Q is 1-methoxycyclobuta-3-yl, 1-hydroxy-cyclobuta-3- It is yl, or oxan-4-yl. g) Q is cis-1-methoxycyclobuta-3-yl or oxan-4-yl. . h) Q is a cyclobutyl ring or a cyclopentyl ring, each of which is one It is optionally substituted with a hydroxyl group or a methoxy group. i) Q is a cyclobutyl ring or a cyclopentyl ring, each of which is one It is optionally substituted with a methoxy group. j)Q is a cyclobutyl ring substituted with one hydroxyl or methoxy group. . k)Q is cyclobutyl, 1-hydroxycyclobuta-3-yl, or 1-methoxy It is cyclobuta-3-yl. l) Q is cyclobutyl. m)Q is a cyclopentyl ring substituted with one hydroxyl or methoxy group. ru. n)Q is a cyclopentyl ring substituted with one methoxy group. o) Q is 3-methoxycyclopental-1-yl. p)Q is 1-hydroxy-cyclobuta-3-yl or 1-methoxy-cyclobuta-3 -It is q) Q is cis-1-hydroxy-cyclobuta-3-yl or cis-1-methoxy-cy It is blackbuta-3-yl. r)Q is cis-1-methoxycyclobuta-3-yl. s)Q is an oxetanyl ring, a tetrahydrofuranyl ring, or an oxanyl ring, and this Each of these is optionally substituted with a single methyl group. t) Q is an oxetanyl ring or an oxanyl ring, each of which has one methyl group It is optionally substituted with a ru group. u)Q is an oxetanyl ring or a tetrahydrofuranyl ring. v) Q is an oxetanyl ring. w)Q is oxetane-3-yl. x)Q is a tetrahydrofuranyl ring. y)Q is tetrahydrofuran-3-yl. z)Q is an oxanyl ring that is optionally substituted with one methyl group. aa) Q is an oxanyl ring. bb)Q is oxan-4-yl. cc)R 1 It is methyl. dd)R 2 It is methyl. ee)R2 It is hydrogen. ff)R 1 It is methyl, and R 2 It is either hydrogen or methyl. gg)R 1 and R 2 Both are methyl; or R 1 and R 2 Together, Pyroligi It forms a nil ring. hh)R 1 and R 2 Both are methyl. ii)R 1 and R 2 Together, they form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring. It is forming. jj)R 1 and R 2 Together, they form an azetidinyl ring. kk)R 1 and R 2 Together, they form a pyrrolidinyl ring. ll)R 1 and R 2 Together, they form a piperidinyl ring. mm)R 3 and R 5 Both are hydrogen. nn)R 3 It is hydrogen. oo)R 3 It is fluoro. pp)R 4 It is hydrogen. qq)R 4 It is methyl. rr)R 5 It is hydrogen. ss)R 5 It is fluoro.

[0158] In one embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, Inside, Q is cyclobutyl, 1-methoxy-cyclobuta-3-yl, 1-hydroxy-cyclobuta Ta-3-yl, 3-methoxycyclopenta-1-yl, oxetan-3-yl, tetrahydroxy Drofuran-3-yl, oxan-3-yl, oxan-4-yl, or 4-methyl ox It is San-4-Ill; R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 Together, the azetidinyl ring, pi It forms a loridinyl ring or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 It is hydrogen or fluorocarbon.

[0159] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, During the ceremony, Q is 1-methoxycyclobuta-3-yl, 1-hydroxycyclobuta-3-yl, 3-Methoxycyclopenta-1-yl, oxetane-3-yl, oxan-3-yl, o It is xan-4-yl or 4-methyloxan-4-yl; R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 Together, the azetidinyl ring, pi It forms a loridinyl ring or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 It is hydrogen or fluorocarbon.

[0160] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, During the ceremony, Q is 1-methoxycyclobuta-3-yl, 1-hydroxycyclobuta-3-yl, or 3-methoxycyclopental-1-yl; R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 Together, the azetidinyl ring, pi It forms a loridinyl ring or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 It is hydrogen or fluorocarbon.

[0161] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, During the ceremony, Q is oxetan-3-yl, oxan-3-yl, oxan-4-yl, or 4-methyl It is luoxan-4-yl; R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 Together, the azetidinyl ring, pi It forms a loridinyl ring or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 It is hydrogen or fluorocarbon.

[0162] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, During the ceremony, Q is cis-1-methoxycyclobuta-3-yl or oxan-4-yl; R 1 It is methyl; R 2 is methyl or hydrogen; R 3 is hydrogen; R 4 is methyl or hydrogen; R 5 It is hydrogen.

[0163] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, This compound is selected from the group consisting of the following: 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxetane-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(oxan- 4-yl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( (cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2 -on; 1-(3-cis-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine) -1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3S)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-7 -Fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 7-Fluoro-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)-3- Pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 7-Fluoro-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)-3- Pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1R,3 R)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1S,3 S)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3 -pyrroridine-1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quino Lyn-2-on; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chill-1-[(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-o hmm; 1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidine-1-ylpro) [Poxy)pyridine-3-yl]-3H-imidazo[4,5-c]quinoline-2-one; 1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpropoxy)pyri [Jin-3-il]-3H-imidazo[4,5-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2- on; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chil-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-( Oxane-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-[ (3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2-one; and 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylamino [Propoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one; 3-methyl l-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1- [(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl] -3-methylimidazo[4,5-c]quinoline-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pi [Lysyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]ki Norin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7 -fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[ 4,5-c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c] Norin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c] Norin-2-one; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro- 3-Pyridyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinoline-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pi [Lysyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinoline-2- on; 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1- [(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1- [(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)pro [Poxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one; 1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3 -pyridyl]imidazo[4,5-c]quinoline-2-one; 1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)- 3-pyridyl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[6-(3-pyrroridine-1-ylpropoxy)-3-pyridyl]-1 -[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2- on; 8-[6-[3-(azetidine-1-yl)propoxy]-3-pyridyl]-3-methyl -1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline- 2-on; 8-[2-fluoro-6-(3-pyrrolidine-1-ylpropoxy)-3-pyridyl]- 3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]quinoline-2 -on; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]quinoline-2 -on; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3- Pyrrolidine-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinoline- 2-on; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3- Pyrrolidine-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinoline- 2-on; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1R,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c)Quinoline-2-one; and 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1S,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one.

[0164] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, This compound is selected from the group consisting of the following: 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxetane-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(oxan- 4-yl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( (cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2 -on; 1-(3-cis-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine) -1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3S)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-7 -Fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1R,3 R)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1S,3 S)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3 -pyrroridine-1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quino Lyn-2-on; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chill-1-[(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-o hmm; 1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidine-1-ylpro) [Poxy)pyridine-3-yl]-3H-imidazo[4,5-c]quinoline-2-one; 1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpropoxy)pyri [Jin-3-il]-3H-imidazo[4,5-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2- on; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chil-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-( Oxane-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-[ (3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2-one; and 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylamino [Propoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one.

[0165] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, This compound is selected from the group consisting of the following: 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (oxetane-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- (4-methyloxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-(oxetan-3-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-7-fluoro-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(cis-3- Methoxycyclobutyl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-(oxan- 4-yl)-3H-imidazo[4,5-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( (cis-3-hydroxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2 -on; 1-(3-cis-hydroxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine) -1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-3-methyl-1- [(3S)-oxane-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-7 -Fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 8-[6-(3-dimethylaminopropoxy)-2-fluoropyridine-3-yl]-3 -methyl-1-[(3R)-oxan-3-yl]imidazo[5,4-c]quinoline-2 -on; 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-pyrrolidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3 -pyrroridine-1-ylpropoxy)pyridine-3-yl]imidazo[4,5-c]quino Lyn-2-on; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-pyrrolidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-pyrrolidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-pyrrolidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3S)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 3-methyl-1-[(3R)-oxan-3-yl]-8-[6-(3-piperidine-1 -ylpropoxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-piperidine- 1-Ilpropoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one ; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chill-1-[(3R)-oxane-3-yl]imidazo[5,4-c]quinoline-2-o hmm; 1-(cis-3-methoxycyclobutyl)-8-[6-(3-pyrrolidine-1-ylpro) [Poxy)pyridine-3-yl]-3H-imidazo[4,5-c]quinoline-2-one; 1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpropoxy)pyri [Jin-3-il]-3H-imidazo[4,5-c]quinoline-2-one; 3-methyl-1-(oxan-4-yl)-8-[6-(3-piperidine-1-ylpro [Poxy)pyridine-3-yl]imidazo[5,4-c]quinoline-2-one; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-1-( cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2- on; 8-[6-[3-(azetidine-1-yl)propoxy]pyridine-3-yl]-3-methyl Chil-1-(oxan-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-( Oxane-4-yl)imidazo[5,4-c]quinoline-2-one; 3-methyl-8-[6-(3-methylaminopropoxy)pyridine-3-yl]-1-[ (3S)-oxan-3-yl]imidazo[5,4-c]quinoline-2-one; and 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-(3-methylamino [Propoxy)pyridine-3-yl]imidazo[4,5-c]quinoline-2-one.

[0166] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, This compound is selected from the group consisting of the following: 7-Fluoro-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)-3- Pyridyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 7-Fluoro-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)-3- Pyridyl]-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 3-methyl-8-[6-[3-(methylamino)propoxy]-3-pyridyl]-1-[ (3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one ; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl] -3-methylimidazo[4,5-c]quinoline-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pi [Lysyl]-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]ki Norin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7 -fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[ 4,5-c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c] Norin-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c] Norin-2-one; 1-Cyclobutyl-8-[6-[3-(dimethylamino)propoxy]-2-fluoro- 3-Pyridyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-3 -methyl-1-(oxetan-3-yl)imidazo[4,5-c]quinoline-2-one; 7-Fluoro-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pi [Lysyl]-1-tetrahydropyran-4-yl-imidazo[4,5-c]quinoline-2- on; 13-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1 -[(3R)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2- on; 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1- [(3S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-ol hmm; 3-Methyl-1-(oxetan-3-yl)-8-[6-[3-(1-piperidyl)pro [Poxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one; 1-Cyclobutyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3 -pyridyl]imidazo[4,5-c]quinoline-2-one; 1-Cyclobutyl-3-methyl-8-[6-(3-pyrrolidine-1-ylpropoxy)- 3-pyridyl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[6-(3-pyrroridine-1-ylpropoxy)-3-pyridyl]-1 -[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2- on; 8-[6-[3-(azetidine-1-yl)propoxy]-3-pyridyl]-3-methyl -1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline- 2-on; 8-[2-fluoro-6-(3-pyrrolidine-1-ylpropoxy)-3-pyridyl]- 3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c] Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]quinoline-2 -on; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]quinoline-2 -on; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-(3- Pyrrolidine-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinoline- 2-on; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-(3- Pyrrolidine-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinoline- 2-on; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -[(1R,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -[(1S,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1R,3S)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c)Quinoline-2-one; and 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -[(1S,3R)-3-methoxycyclopentyl]-3-methylimidazo[4,5- c]Quinoline-2-one.

[0167] In another embodiment, the compound is represented by formula (II) or a pharmaceutically acceptable salt thereof, This compound is selected from the group consisting of the following: 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1R,3 R)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; and 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-1-[(1S,3 S)-3-Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on.

[0168] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl] -1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinori N-2-one or a pharmaceutically acceptable salt thereof is provided.

[0169] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl] -1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinori N-2-on is provided.

[0170] In one embodiment, 8-[6-(3-dimethylaminopropoxy)pyridine-3-yl] -1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]quinori A pharmaceutically acceptable salt of n-2-one is provided.

[0171] In another embodiment, the compound represented by formula (II) is 8-[6-(3-dimethylamino [Propoxy)pyridine-3-yl]-3-methyl-1-(oxan-4-yl)imidazo [5,4-c]Quinoline-2-one or a pharmaceutically acceptable salt thereof.

[0172] In another embodiment, the compound represented by formula (II) is 8-[6-(3-dimethylamino [Propoxy)pyridine-3-yl]-3-methyl-1-(oxan-4-yl)imidazo [5,4-c]quinoline-2-one.

[0173] In another embodiment, the compound according to formula (II) is 8-[6-(3-dimethylaminopro [poxy)pyridine-3-yl]-3-methyl-1-(oxan-4-yl)imidazo[5 It is a pharmaceutically acceptable salt of [4-c]quinoline-2-one.

[0174] In another embodiment, the compound represented by formula (II) is 1-(cis-3-methoxycyclo Butyl)-3-methyl-8-{6-[3-(pyrrolidine-1-yl)propoxy]pyridin ∇-3-yl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one or a pharmaceutically acceptable salt thereof.

[0175] In another embodiment, the compound represented by formula (II) is 1-(cis-3-methoxycyclo Butyl)-3-methyl-8-{6-[3-(pyrrolidine-1-yl)propoxy]pyridin ∇-3-yl-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one That is the case.

[0176] In another embodiment, the compound according to formula (II) is 1-(cis-3-methoxycyclobutyrate). (Lu)-3-methyl-8-{6-[3-(pyrrolidin-1-yl)propoxy]pyridine- 3-yl}-1,3-dihydro-2H-imidazo[4,5-c]quinoline-2-one medicine It is a scientifically acceptable salt.

[0177] In preferred embodiments, the ATM inhibitor used in this disclosure is a compound of formula (I). This compound has the following formula: [ka] AZD1390, represented by [formula], or a pharmaceutically acceptable salt thereof.

[0178] In another preferred embodiment, the ATM inhibitor used in this disclosure is a compound of formula (II). The compound is represented by the following formula: [ka] AZD0156, represented by [formula], or a pharmaceutically acceptable salt thereof.

[0179] ATM inhibitors such as compounds of formula (I) and formula (II) are obtained by methods known in the art. It can be prepared, for example, in International Publication No. 2017 / 046216 and the same No. 201 It can be prepared by the method disclosed in pamphlet No. 5 / 170081.

[0180] Compounds of formula (I) or (II), and other ATM inhibitors mentioned herein, It will be understood that this may include compounds having one or more isotopic substitutions. For example. H can be any isotopic form, for example, 1 H, 2 H(D), and 3 H(T) C can be any isotopic form, for example, 12 C, 13 C, and 14 It could be C; O can be any isotopic form, for example, 16 O and 18 It can be O; etc.

[0181] Specifically, as explained in International Publication No. 2018 / 167203 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl) )propoxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one(AZD1 390) has a chemical structure [ka] 4,6-dijutero-7-fluoro-1-isopropyl-3-methyl-8-[6 -[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quino It can exist as phosphorus-2-one.

[0182] Alternatively, it is explained in the same way in International Publication No. 2018 / 167203. Uni, AZD1390 has a chemical structure [ka] 4-Dutero-7-Fluor-1-Isopropyl-3-methyl-8-[6-[3 -(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline- It can exist as a 2-on.

[0183] Other examples of ATM inhibitors that may be used in accordance with this disclosure are listed below: 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-isopropyl-3- Methyl-imidazo[4,5-c]quinoline-2-one; 1-Isopropyl-3-methyl-8-[4-[3-(pyrrolidine-1-ylpropoxy) [phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(azetidine-1-yl)propoxy]phenyl]-1-isopropyl -3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(azetidine-1-yl)propoxy]phenyl]-7-fluoro-1 -Isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-1-isopropyl-3-methyl Chil-imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(1S,3S)- [3-Methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline-2-o hmm; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(1R,3R)- [3-Methoxycyclopentyl]-3-methyl-imidazo[4,5-c]quinoline-2-o hmm; 8-[4-[3-(dimethylamino)propoxy]phenyl]-3-methyl-1-[(3 R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-3-methyl-1-[(3 S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-3-methyl Ru-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline -2-on; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(cis-3-methyl (Cicyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-1-(syl (S-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]quinoline-2- on; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-1-[ [Lance-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline -2-on; 3-methyl-8-[4-(3-pyrrolidine-1-ylpropoxy)phenyl]-1-[( 3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[4-(3-pyrrolidine-1-ylpropoxy)phenyl]-1-[( 3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[4-[3-(1-piperidyl)propoxy]phenyl]-1-[(3 S)-tetrahydrofuran-3-yl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[4-[3-(1-piperidyl)propoxy]phenyl]-1-tetra Hydropyran-4-ylimidazo[4,5-c]quinoline-2-one; 1-[trans-3-methoxycyclopentyl]-3-methyl-8-[4-[3-(pyro Lysine-1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(trans-3-methylamino) Toxycyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 1-(trans-4-methoxycyclohexyl)-3-methyl-8-[4-[3-(pyro Lysine-1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(azetidine-1-yl)propoxy]phenyl]-7-fluoro-1 -[trans-3-methoxycyclopentyl]-3-methylimidazo[4,5-c] Norin-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(cis-4-methyl (Cicyclohexyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(cis-4-methyl (Cicyclohexyl)-3-methylimidazo[4,5-c]quinoline-2-one; 1-(cis-4-methoxycyclohexyl)-3-methyl-8-[4-(3-(pyrrolidi (n-1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[trans-3-phenyl] Toxycyclohexyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[trans-3-phenyl] Toxycyclohexyl]-3-methylimidazo[4,5-c]quinoline-2-one; 1-[trans-3-methoxycyclohexyl]-3-methyl-8-[4-(3-(pyro Lysine-1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[cis-3-methyl [Cicyclohexyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[cis-3-methyl [Cicyclohexyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[cis-3-methyl [Cicyclopentyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-1-[Syl [S-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 1-[cis-3-methoxycyclohexyl]-3-methyl-8-[4-(3-pyrrolidine] -1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2one; 1-[cis-3-methoxycyclohexyl]-3-methyl-8-[4-(3-pyrrolidine] -1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2one; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[4-[3- (1-Piperidyl)propoxy]phenyl]imidazo[4,5-c]quinoline-2-one ; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[4-(3-pyrrolidine- 1-Ilpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 1-(trans-3-methoxycyclobutyl)-3-methyl-8-[4-(3-(Helicobacter pylori) Zin-1-ylpropoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[4-[3-(1-piperyl) [zyl]propoxy]phenyl]imidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-3-methyl-1-tetra Hydropyran-4-ylimidazo[4,5-c]quinoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-3-methyl Ru-1-tetrahydropyran-4-ylimidazo[4,5-c]quinoline-2-one; 7-Fluoro-3-methyl-8-[4-(3-pyrrolidine-1-ylpropoxy)phen [4,5-c]quinoline-2-one ; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-1-[(3S )-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-1-[(3R )-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 1-(3-(cis)methoxycyclobutyl)-3-methyl-8-[4-[(2-pyrrolidine n-1-ylethoxy)phenyl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[4-[2-(pyrrolidine-1-ylethoxy)phenyl]-1-[( 3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 3-methyl-8-[4-[2-(pyrrolidine-1-ylethoxy)phenyl]-1-[( 3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-1-[(1S,3S)-3 -Methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline-2-one ; 1-Cyclobutyl-8-[4-[2-(dimethylamino)ethoxy]phenyl]-3-Me Chil-imidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-3-methyl-1-tetraphenyl Dropyran-4-yl-imidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-1-(3-(cis)methyl (Cicyclobutyl)-3-methylimidazo[4,5-c]quinoline-2-one; 8-[4-[2-(dimethylamino)ethoxy]phenyl]-7-fluoro-3-methyl -1-tetrahydropyran-4-ylimidazo[4,5-c]quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-7-fluor Ro-1-isopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-1-yl Sopropyl-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4 ,5-c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[ 4,5-c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3S)-tetrahydrofuran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c] Norin-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-(trans-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-(trans-4-methoxycyclohexyl)-3-methyl-imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-tetrahydropyran-4-ylimidazo[4,5-c]quinoline -2-on; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imi Dazo[4,5-c]quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imi Dazo[4,5-c]quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c] Norin-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imi Dazo[4,5-c]quinoline-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imi Dazo[4,5-c]quinoline-2-one; 8-[6-[(3S)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[ 4,5-c]Quinoline-2-one; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-1-[ [trans-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinori n-2-on; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-3-methyl Chil-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinori n-2-on; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-1-( (Trans-4-methoxycyclohexyl)-3-methylimidazo[4,5-c]quinori n-2-on; 1-Cyclobutyl-8-[6-[3-(dimethylamino)azetidine-1-yl]-3- [Pyridyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-3-methyl Chill-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinori n-2-on; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-3-methyl Chil-1-tetrahydropyran-4-ylimidazo[4,5-c]quinoline-2-one ; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-7-fu Luoro-1-[trans-3-methoxycyclopentyl]-3-methylimidazo[4, 5-c]Quinoline-2-one; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-7-fu Luoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c Quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-[tra [3-methoxycyclopentyl]-3-methylimidazo[4,5-c]quinoline- 2-on; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-3-methyl -1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline- 2-on; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-3-methyl -1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline- 2-on; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-(cis -3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]quinoline-2-o hmm; 1-Cyclobutyl-8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyri [zyl]-3-methylimidazo[4,5-c]quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-3-methyl -1-(oxetane-3-yl)imidazo[4,5-c]quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-3-methyl -1-tetrahydropyran-4-ylimidazo[4,5-c]quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-7-fluor Ro-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-7-fluor Ro-3-methyl-1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5- c]Quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-7-fluor Ro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c] Norin-2-one; 8-[6-[(3R)-3-(dimethylamino)-1-piperidyl]-3-pyridyl]- 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methylimidazo[4, 5-c]Quinoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-(cis-4-methoxycyclohexyl)-3-methyl-imidazo[4,5-c] Quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-[(S [S-3-methoxycyclohexyl]-3-methylimidazo[4,5-c]quinoline-2 -on; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[cis-3-methoxycyclohexyl]-3-methyl-imidazo[4,5-c] Quinoline-2-one; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-1-[ [cis-3-methoxycyclohexyl]-3-methyl-imidazo[4,5-c]quinoline- 2-on; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[trans-3-methoxycyclohexyl]-3-methyl-imidazo[4,5- c]Quinoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-[tra [3-methoxycyclohexyl]-3-methyl-imidazo[4,5-c]quinoline- 2-on; 8-[6-[3-(dimethylamino)azetidine-1-yl]-3-pyridyl]-1-[ [trans-3-methoxycyclohexyl]-3-methylimidazo[4,5-c]quinori n-2-on; 7-Fluoro-1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-[4 -(methylamino)-1-piperidyl]-3-pyridyl]imidazo[4,5-c]quinori n-2-on; 3-methyl-8-[6-[4-(methylamino)-1-piperidyl]-3-pyridyl]- 1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2 -on; 3-methyl-8-[6-[4-(methylamino)-1-piperidyl]-3-pyridyl]- 1-[(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]quinoline-2 -on; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-[4-(methylamide) [(n)-1-piperidyl]-3-pyridyl]imidazo[4,5-c]quinoline-2-one; and 3-methyl-8-[6-[4-(methylamino)-1-piperidyl]-3-pyridyl]- 1-Tetrahydropyran-4-ylimidazo[4,5-c]quinoline-2-one. (R)-8-(6-(methoxymethyl)pyridine-3-yl)-3-methyl-1-(teto (Lahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]quinoline-2(3 H)-on; (S)-8-(6-(methoxymethyl)pyridine-3-yl)-3-methyl-1-(teto (Lahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]quinoline-2(3 H)-on; (S)-7-fluoro-8-(6-(methoxymethyl)pyridine-3-yl)-3-methyl Ru-1-(tetrahydro-2H-pyran-3-yl)-1,3-dihydro-2H-imida Zo[4,5-c]quinoline-2-one; (R)-7-fluoro-8-(2-fluoro-6-(methoxymethyl)pyridine-3-I (Lu)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[ 4,5-c]Quinoline-2(3H)-one; (S)-7-fluoro-8-(2-fluoro-6-(methoxymethyl)pyridine-3-I (Lu)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[ 4,5-c]Quinoline-2(3H)-one; (R)-8-(2-fluoro-6-(methoxymethyl)pyridine-3-yl)-3-methyl Ru-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]ki Norin-2(3H)-one; (S)-8-(2-fluoro-6-(methoxymethyl)pyridine-3-yl)-3-methyl Ru-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]ki Norin-2(3H)-one; (R)-7-fluoro-8-(6-(methoxymethyl)pyridine-3-yl)-3-methyl Lu-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-c]ki Norin-2(3H)-one; rac-1-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-8-(6- (Methoxymethyl)pyridine-3-yl)-3-methyl-1,3-dihydro-2H-imi Dazo[4,5-c]quinoline-2-one; (R)-1-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-8-(6- (Methoxymethyl)pyridine-3-yl)-3-methyl-1,3-dihydro-2H-imi Dazo[4,5-c]quinoline-2-one; (S)-1-(3,3-dimethyltetrahydro-2H-pyran-4-yl)-8-(6- (Methoxymethyl)pyridine-3-yl)-3-methyl-1,3-dihydro-2H-imi Dazo[4,5-c]quinoline-2-one; (S)-8-(6-(methoxymethyl)pyridine-3-yl)-1-(tetrahydro-2 H-pyran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinoline- 2-on; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1S) -1-(1-methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-ca Ruboxamide; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1R) -1-(1-methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-ca Ruboxamide; 7-Fluoro-6-[2-Fluoro-6-(methoxymethyl)pyridine-3-yl]-4 -{[(1S)-1-(1-methyl-1H-pyrazole-3-yl)ethyl]amino} Norin-3-carboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] MINO-7-Fluoro-6-[2-Fluoro-6-(methoxymethyl)pyridine-3-I [Lu]Quinoline-3-carboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] MINO-7-Fluoro-6-[2-Fluoro-6-(Hydroxymethyl)pyridine-3- Ilquinoline-3-carboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-7-fluoro-6-[6-(methoxymethyl)pyridine-3-yl]quinoline- 3-Carboxamide; 4-{[(1R)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-7-fluoro-6-[6-(methoxymethyl)pyridine-3-yl]quinoline- 3-Carboxamide; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1S) -1-(1H-pyrazole-3-yl)ethyl]amino}quinoline-3-carboxamide ; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1R) -1-(1H-pyrazole-3-yl)ethyl]amino}quinoline-3-carboxamide ; 7-Fluoro-4-{[(1S)-1-(4-Fluoro-1-methyl-1H-pyrazole [-3-yl)ethyl]amino}-6-[6-(methoxymethyl)pyridine-3-yl]k Norin-3-carboxamide; 7-Fluoro-4-{[(1R)-1-(4-Fluoro-1-methyl-1H-pyrazole [-3-yl)ethyl]amino}-6-[6-(methoxymethyl)pyridine-3-yl]k Norin-3-carboxamide; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1S) -1-(4-methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-ca Ruboxamide; 7-Fluoro-6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1R) -1-(4-methyl l-1H-pyrazole-3-yl)ethyl]amino}quinoline-3- Carboxamide; 7-Fluoro-6-[6-(hydroxymethyl)pyridine-3-yl]-4-{[(1S )-1-(1-methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3- Carboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-7-fluoro-6-[6-(hydroxymethyl)pyridine-3-yl]quinoline -3-carboxamide; 4-{[(1R)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-7-fluoro-6-[6-(hydroxymethyl)pyridine-3-yl]quinoline -3-carboxamide; 6-[2-fluoro-6-(methoxymethyl)pyridine-3-yl]-4-{[(1S) -1-(1-methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-ca Ruboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[2-fluoro-6-(methoxymethyl)pyridine-3-yl]quinoline- 3-Carboxamide; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[6-(methoxymethyl)pyridine-3-yl]quinoline-3-carboxa Mido; 4-{[(1R)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[6-(methoxymethyl)pyridine-3-yl]quinoline-3-carboxa Mido; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[2-fluoro-6-(hydroxymethyl)pyridine-3-yl]quinoline -3-carboxamide; 6-[6-(hydroxymethyl)pyridine-3-yl]-4-{[(1S)-1-(1- Methyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-carboxamide ; 4-{[(1S)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[6-(hydroxymethyl)pyridine-3-yl]quinoline-3-carboc Samido; 4-{[(1R)-1-(1,4-dimethyl-1H-pyrazole-3-yl)ethyl] Mino-6-[6-(hydroxymethyl)pyridine-3-yl]quinoline-3-carboc Samido; 4-{[(1S)-1-(4-fluoro-1-methyl-1H-pyrazole-3-yl)e [Tyl]amino}-6-[6-(methoxymethyl)pyridine-3-yl]quinoline-3-ca Ruboxamide; 6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1S)-1-(1-methyl Tyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-carboxamide; 6-[6-(methoxymethyl)pyridine-3-yl]-4-{[(1R)-1-(1-methyl Tyl-1H-pyrazole-3-yl)ethyl]amino}quinoline-3-carboxamide; 6-[2-fluoro-6-(methoxymethyl)-3-pyridyl]-4-[[(1S)-1 -(4-fluoro-1-methylpyrazole-3-yl)ethyl]amino]quinoline-3 -Carboxamide; 6-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-N-methyl-4- [[(1S)-1-(oxan-4-yl)ethyl]amino]sinnoline-3-carb Samido; 6-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-4-[[(1S) -1-(oxan-4-yl)ethyl]amino]sinnoline-3-carboxamide; 4-[[(1S)-1-(oxan-4-yl)ethyl]amino]-6-[6-(3-p Roridine-1-ylpropoxy)pyridine-3-yl]sinnoline-3-carboxamide ; 6-[6-(3-methylaminopropoxy)pyridine-3-yl]-4-[[(1S)- 1-(oxan-4-yl)ethyl]amino]sinnoline-3-carboxamide; N-methyl-6-[6-(3-methylaminopropoxy)pyridine-3-yl]-4-[ [(1S)-1-(oxan-4-yl)ethyl]amino]sinnoline-3-carboxa Mido; 6-[6-(3-dimethylaminopropoxy)pyridine-3-yl]-N-methyl-4- [[(1R)-1-(oxan-4-yl)ethyl]amino]sinnoline-3-carb Samido; N,N-dimethyl-3-[[5-(3-methyl-2-oxo-1-tetrahydropyran- 4-Il-imidazo[4,5-c]quinoline-8-yl)-2-pyridyl]oxy]pro Pan-1-amine oxide; 8-(6-(3-(4-fluoropiperidine-1-yl)propoxy)pyridine-3-yl (Lu)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c Quinoline-2-one; (S)-8-(6-(3-(3-fluoropyrrolidine-1-yl)propoxy)pyridine -3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4 ,5-c]Quinoline-2-one; (R)-8-(6-(3-(3-fluoropyrrolidine-1-yl)propoxy)pyridine -3-yl)-1-isopropyl-3-methyl-1,3-dihydro-2H-imidazo[4 ,5-c]Quinoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- Tetrahydropyran-4-ylimidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-(cis-3- Methoxycyclobutyl)-3-methylimidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3S)-tetrahydropyran-3-yl]imidazo[4,5-c]sinnoline-2- on; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-3-methyl-1- [(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]sinnoline-2- on; 3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1- Tetrahydropyran-4-ylimidazo[4,5-c]sinnoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-isopropyl-3- Methyl-imidazo[4,5-c]sinnoline-2-one; 1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3 -pyridyl]imidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-isopropyl -3-methylimidazo[4,5-c]sinnoline-2-one; 1-Isopropyl-3-methyl-8-[4-[3-(pyrrolidine-1-ylpropoxy) [phenyl]imidazo[4,5-c]sinnolin-2-one; 1-Isopropyl-3-methyl-8-(4-(3-(piperidine-1-yl)propoxy )phenyl)-1,3-dihydro-2H-imidazo[4,5-c]sinnolin-2-one ; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-(trans- 3-Methoxycyclobutyl)-3-methyl-imidazo[4,5-c]sinnoline-2-o hmm; 8-[6-[3-[4-fluoro-1-piperidyl)propoxy]-3-pyridyl]-1 -Isopropyl-3-methyl-imidazo[4,5-c]sinnoline-2-one; 8-[6-[3-[(3R)-3-fluoropyrrolidine-1-yl]propoxy]-3- Pyridyl]-1-isopropyl-3-methylimidazo[4,5-c]sinnoline-2- on; 1-Isopropyl-3-methyl-8-[2-methyl-6-[3-(1-piperidyl)pro [poxy]-3-pyridyl]imidazo[4,5-c]sinnoline-2-one; 1-(trans-3-methoxycyclobutyl)-3-methyl-8-[4-[3-(1-p [Peridyl)propoxy]phenyl]imidazo[4,5-c]sinnolin-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(trans-3-methylamino) Toxycyclobutyl)-3-methylimidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(4-fluoro-1-piperidyl)propoxy]-3-pyridyl]-1 -(trans-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]sine Norin-2-one; 8-[6-[3-(4-fluoro-1-piperidyl)propoxy]-3-pyridyl]-1 -(cis-3-methoxycyclobutyl)-3-methylimidazo[4,5-c]sinnoli n-2-on; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[4-[3-(1-piperyl) [zyl)propoxy]phenyl]imidazo[4,5-c]sinnolin-2-one; 8-[6-[3-[(3R)-3-fluoropyrrolidine-1-yl]propoxy]-3- Pyridyl]-1-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5 -c] Synnoline-2-on; 8-[4-[3-(dimethylamino)propoxy]phenyl]-3-methyl-1-[(3 R)-tetrahydropyran-3-yl]imidazo[4,5-c]synnoline-2-one; 3-methyl-8-[4-[3-(1-piperidyl)propoxy]phenyl]-1-[(3 R)-tetrahydropyran-3-yl]imidazo[4,5-c]synnoline-2-one; 8-[6-[3-(4-fluoro-1-piperidyl)propoxy]-3-pyridyl]-3 -methyl-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]cy Nnorin-2-on; 8-[4-[3-(dimethylamino)propoxy]phenyl]-3-methyl-1-(1- Methylcyclopropyl)imidazo[4,5-c]sinnoline-2-one; 3-methyl-1-(1-methylcyclopropyl)-8-[4-[3-(1-piperidyl) [propoxy]phenyl]imidazo[4,5-c]synnolin-2one; 8-[6-[3-(4-fluoro-1-piperidyl)propoxy]-3-pyridyl]-3 -methyl-1-(1-methylcyclopropyl)imidazo[4,5-c]sinnoline-2- on; 3-methyl-1-(1-methylcyclopropyl)-8-[6-[3-(1-piperidyl) [propoxy]-3-pyridyl]imidazo[4,5-c]sinnoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(1R,3R)- 3-Methoxycyclopentyl]-3-methyl-imidazo[4,5-c]sinnoline-2- on; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[4-[3- (1-piperidyl)propoxy]phenyl]imidazo[4,5-c]sinnoline-2-o hmm; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(1S,3S)- 3-Methoxycyclopentyl]-3-methyl-imidazo[4,5-c]sinnoline-2- on; 1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]Synnoline- 2-on; 8-[6-[3-[(3S)-3-fluoropyrrolidine-1-yl]propoxy]-3- Pyridyl]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methylimi Dazo[4,5-c]sinnoline-2-one; 1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-8-[6-[3- (1-Piperidyl)propoxy]-3-Pyridyl]imidazo[4,5-c]Synnoline- 2-on; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-(cis-3-methyl (Cicyclobutyl)-3-methylimidazo[4,5-c]sinnoline-2-one; 1-(cis-3-methoxycyclobutyl)-3-methyl-8-[6-[3-(1-piper [Dyl)propoxy]-3-pyridyl]imidazo[4,5-c]sinnoline-2-one; 8-[6-[3-[(3S)-3-fluoropyrrolidine-1-yl]propoxy]-3- Pyridyl]-1-(trans-3-methoxycyclobutyl)-3-methylimidazo[4 ,5-c]Synnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-[(4S)- 3,3-dimethyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c Synnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-[(4R)- 3,3-dimethyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c ]Synnorin-2-on 1-[3,3-dimethyltetrahydropyran-4-yl]-3-methyl-8-{4-[3 -(1-piperidinyl)propoxy]phenyl}-1,3-dihydro-2H-imidazo[ 4,5-c]Synnoline-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(4S)-3,3 -dimethyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c]sine Norin-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-[(4R)-3,3 -dimethyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c]sine Norin-2-one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-1-iso Propyl-3-methylimidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1 -Isopropyl-3-methyl-imidazo[4,5-c]sinnoline-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl) [ropoxy]-3-pyridyl]imidazo[4,5-c]sinnoline-2-one; 7-Fluoro-1-isopropyl-3-methyl-8-[4-[3-(1-piperidyl) [ropoxy]phenyl]imidazo[4,5-c]sinnolin-2one; 8-[4-[3-(dimethylamino)propoxy]phenyl]-1-isopropyl-3. 7-Methylimidazo[4,5-c]sinnoline-2-one; 1-Isopropyl-3,7-dimethyl-8-[6-[3-(1-piperidyl)propoxy ]-3-pyridyl]imidazo[4,5-c]sinnoline-2-one; 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-isopropyl -3,7-dimethylimidazo[4,5-c]sinnoline-2one; 1-Isopropyl-3,7-dimethyl-8-[4-[3-(1-piperidyl)propoxy ]phenyl]imidazo[4,5-c]sinnolin-2-one; 3-(difluoromethyl)-8-[6-[3-(dimethylamino)propoxy]-3-p Lysyl-1-isopropyl-imidazo[4,5-c]synnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-isopropyl-3-methylimidazo[4,5-c]sinnoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-isopropyl Ropyru-3-methylimidazo[4,5-c]sinnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-3-methyl-1-[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c] Synnoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-[3, [3-dimethyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c]s Nnorin-2-on 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[3,3-dimethyltetrahydropyran-4-yl]-3-methylimidazo[ 4,5-c]Synnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[trans-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c Synnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c] cy Nnorin-2-on; 8-[6-[3-(dimethylamino)pyrroridine-1-yl]-3-pyridyl]-3-methyl Chil-1-tetrahydropyran-4-yl-imidazo[4,5-c]sinnoline-2-o hmm; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[(1R,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4 ,5-c]Synnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-[(1S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4 ,5-c]Synnoline-2-one; 8-[6-[4-(dimethylamino)-1-piperidyl]-3-pyridyl]-1-(cis -3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]sinnoline-2- on; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-1-isopropyl -3-methylimidazo[4,5-c]sinnoline-2-one; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-1-[3,3-di [methyltetrahydropyran-4-yl]-3-methylimidazo[4,5-c]sinnoli n-2-on; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-1-[(1R,3 R)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]sinnoline -2-on; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-1-[(1S,3 S)-3-methoxycyclopentyl]-3-methylimidazo[4,5-c]sinnoline -2-on; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-3-methyl-1- [(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]sinnoline-2- on; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-7-fluoro-1-isopropyl-3-methylimidazo[4,5-c]sinnoline -2-on; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-7-fluoro-1 -Isopropyl-3-methyl-imidazo[4,5-c]sinnoline-2-one; 8-[6-[(3R)-3-(dimethylamino)pyrrolidine-1-yl]-3-pyridyl ]-1-isopropyl-3,7-dimethylimidazo[4,5-c]sinnoline-2-o hmm; 8-[4-[4-(dimethylamino)-1-piperidyl]phenyl]-1-isopropyl -3,7-dimethylimidazo[4,5-c]cinnoline-2one; and 8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1 -Isopropyl-3-methyl-imidazo[4,5-c]sinnoline-2-one.

[0184] 5. Combinations of antibody-drug conjugates and ATM inhibitors In a first combination embodiment of the present disclosure, an anti-HERI agent is combined with an ATM inhibitor. The two-antibody-drug conjugate is expressed by the following formula: [ka] A drug-linker represented by (wherein A represents the site of attachment to the antibody) is linked to a thioether bond. It is an antibody-drug conjugate that is conjugated to an anti-HER2 antibody via a linkage. .

[0185] In another combination embodiment, the resistance defined above with respect to the first combination embodiment is The HER2 antibody-drug conjugate is expressed by the following formula (I): [ka] (In the formula, R 1 It is methyl; R 2 is hydrogen or methyl; or R 1 and R 2 These are the nitrogen atoms to which they bond. Together with it, it forms an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R 3 is hydrogen or fluorine; R 4 is hydrogen or methyl; R 5 (It is hydrogen or fluorine.) A compound represented by, or a pharmaceutically acceptable salt thereof, in combination with an ATM inhibitor. Yes, they are.

[0186] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with an ATM inhibitor, which is a compound represented by formula (I) defined above. In equation (I), R 1 and R 2 Both are methyl; or R 1 and R 2 This is Together with the nitrogen atom to which they are bonded, they form an azetidinyl ring, a pyrrolidinyl ring, or piperidinyl ring. It forms a ring.

[0187] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, in formula (I), R 1 and R 2 teeth These, along with the nitrogen atom to which they are bonded, form an azetidinyl ring, a pyrrolidinyl ring, or pipette. It forms a lysinyl ring.

[0188] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, in formula (I), R 3 is with hydrogen be.

[0189] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, in formula (I), R 4 is methyl That is the case.

[0190] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, in formula (I), R 5 , Fluoro It is Ro.

[0191] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, in formula (I), R 1 It is methyl; R 2 is methyl; or R 1 and R 2 These, along with the nitrogen atom to which they bond, It forms a zetidinyl ring, pyrrolidinyl ring, or piperidinyl ring; R 3 is hydrogen or fluorine; R 4 It is methyl; R 5 It is hydrogen or fluorocarbon.

[0192] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined above This is combined with the ATM inhibitor defined above, and this ATM inhibitor is defined by the following formula : [ka] AZD1390, represented by [formula], or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment of each of the combination embodiments described above, anti-HER2 The antibody consists of the amino acid sequence represented by SEQ ID NO: 3, CDRH1, and SEQ ID NO: 4. CDRH2, which consists of an amino acid sequence, and CDRH2, which consists of an amino acid sequence represented by Sequence ID No. 5. CDRL1 consists of a heavy chain containing RH3 and the amino acid sequence represented by SEQ ID NO: 6. CDRL2 consists of an amino acid sequence of amino acid residues 1-3, and is represented by Sequence ID No. 8. It contains a light chain containing CDRL3, which consists of the amino acid sequence described above. In each of the other embodiments of the combined embodiment, the anti-HER2 antibody is represented by SEQ ID NO: 9. A heavy chain containing a heavy chain variable region consisting of an amino acid sequence, and an amino acid sequence represented by SEQ ID NO: 10 Includes a light chain containing a light chain variable region consisting of columns. Combination embodiment as described above. In each of these different embodiments, the anti-HER2 antibody is an amino acid sequence represented by SEQ ID NO: 1. It consists of a heavy chain made up of the amino acid sequence represented by SEQ ID NO: 2 and a light chain made up of the amino acid sequence represented by SEQ ID NO: 2. In each of the different embodiments of the combination being described, the anti-HER2 antibody is sequence A heavy chain consisting of the amino acid sequence represented by number 11, and the amino acid sequence represented by sequence number 2 It includes a light chain.

[0194] In particularly preferred combination embodiments of this disclosure, an anti-HER2 antibody-drug conjugate It is trastuzumab deruxtecan (DS-8201), and ATM inhibitors are AZ Also identified as D1390, the following formula: [ka] It is a compound represented by [formula].

[0195] 6. Combination therapy and treatment methods The following describes the anti-HER2 antibody-drug conjugate and ATM inhibitor related to this disclosure. This refers to pharmaceuticals administered in combination with other agents, as well as their therapeutic use and treatment methods.

[0196] The pharmaceuticals disclosed herein, as well as their therapeutic uses and methods of treatment, are anti-HER2 antibody-drug condyloma. The agonist and ATM inhibitor are separately included as active ingredients in separate formulations and administered simultaneously. This antibody-drug combination may be characterized by being administered at the same time or at different times. The administration of a single formulation containing jugate and an ATM inhibitor as active ingredients. It could also be considered a characteristic.

[0197] The pharmaceuticals and therapeutic methods disclosed herein use a single ATM inhibitor as an anti-H It can be administered in combination with an ER2 antibody-drug conjugate, or with two or more different A TM inhibitors can be administered in combination with this antibody-drug conjugate.

[0198] The pharmaceuticals and therapeutic methods of this disclosure may be used to treat cancer, preferably breast cancer (for example, 3 (Cell-negative breast cancer and tubular breast cancer), gastric cancer (also called gastric adenocarcinoma), colorectal cancer (colon and rectum) Also known as cancer, it includes colorectal cancer and rectal cancer), lung cancer (for example, small cell lung cancer and non-small cell lung cancer), Alveolar lung cancer, esophageal cancer, head and neck cancer (e.g., salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, bile duct cancer Cariological cancers (e.g., bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer Adenocarcinoma, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine body Carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, At least one of the following groups is selected: glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. It can also be used to treat one other type of cancer, more preferably breast cancer, gastric cancer, colorectal cancer, lung cancer (preferably A small number of cancers are selected from the group consisting of (or non-small cell lung cancer), pancreatic cancer, ovarian cancer, prostate cancer, and kidney cancer. It can be used to treat at least one type of cancer.

[0199] 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 a fixed paraffin-embedded (FFPE) specimen, and then perform immunohistochemistry (I) on this specimen, for example. Gene product (T) obtained by HC method, flow cytometry, or Western blotting. It may be subjected to testing related to protein, or, for example, in situ hybridization. Genetic analysis by (ISH) method, quantitative PCR (q-PCRR), or microarray analysis. It can be determined by subjecting the patient to a transduction testing, or by obtaining acellular circulating tumor D from a cancer patient. NA (ctDNA) is collected, and this ctDNA is subjected to next-generation sequencing (NGS) or other methods. This can be determined by subjecting it to testing.

[0200] The pharmaceuticals and treatment methods disclosed herein may be used for cancer, which is HER2-overexpressing cancer (high-grade cancer). It may be moderate, or it may be HER2-low expression cancer.

[0201] In this disclosure, the term "HER2-overexpressing cancer" is used by those skilled in the art to describe HER2-overexpressing cancer. It is not particularly limited insofar as it is recognized as such. A preferred example of HER2-overexpressing cancer is, The following are possible: In the IHC procedure, a score of 3+ was assigned to HER2 expression. Cancers that have been diagnosed and have been assigned a 2+ score for HER2 expression in IHC Furthermore, regarding HER2 expression in in situ hybridization (ISH) Cancer determined to be positive. The in situ hybridization method of this disclosure is fluorescence In situ hybridization (FISH), and dual-color in situ Hybridization (DISH) is one example.

[0202] In this disclosure, the term "HER2-low expression cancer" is defined as a cancer recognized by those skilled in the art as a HER2-low expression cancer. It is not particularly limited to the extent that it is known. Preferred examples of HER2-low expression cancers are as follows: Possible examples: In the IHC method, a score of 2+ was assigned to HER2 expression. Furthermore, in situ hybridization determined that the HER2 expression was negative. Cancers that have been diagnosed and those that have been assigned a score of 1+ for HER2 expression in IHC Cancer.

[0203] A method for scoring the degree of HER2 expression using the IHC method, or an in situ hybrida A method for determining whether a person is positive or negative for HER2 expression by an ionization method is a method for those skilled in the art. It is not particularly limited insofar as it is recognized by the method. As an example of this method, HER2 testing Guidelines for Breast Cancer, 4th Edition (Japanese Pathology Committee for the Optimal Use of HER2 in Breast Cancer) (Developed by the Japanese Pathology Board) The methods being used can be listed as follows.

[0204] Cancer (especially cancers related to the treatment of breast cancer) is HER2-overexpressing (high or moderate) breast cancer or This may be low-expression breast cancer or triple-negative breast cancer, and / or IHC 3+, IHC 2+, They may have an IHC 1+ or an IHC > 0 and < 1+ HER2 status score.

[0205] The pharmaceuticals and therapeutic methods of this disclosure may preferably be used in mammals, but more preferably For use on humans.

[0206] The antitumor effects of the pharmaceuticals and therapeutic methods disclosed herein were investigated by transplanting cancer cells into test animals as a model. To manufacture and measure the reduction in tumor volume or the life-extending effect of applying the pharmaceuticals and therapeutic methods disclosed herein. This can be confirmed by the antibody-drug conjugate and ATM inhibitor used in this disclosure. The effects of combination therapy with harmful agents are compared to the effects of monotherapy with the antibody-drug conjugate used in this disclosure. By comparing the antitumor effect with the antitumor effect of administering this ATM inhibitor alone, It is permissible.

[0207] The antitumor effects of the pharmaceuticals and treatment methods disclosed herein are based on the Solid Tumor Response Evaluation Criteria (RECIST). ), WHO assessment method, Macdonald assessment method, weight measurement, and other approaches This can be confirmed in clinical trials using one of the evaluation methods, and complete response (CR), partial response (PR); Progressive disease (PD), Objective response rate (ORR), Duration of response (DoR), Progression-free survival This can be determined based on progression-free survival (PFS), overall survival (OS), and similar indicators.

[0208] By using the above method, this disclosure relates to existing pharmaceuticals and treatment methods for cancer. The superiority of the antitumor effect of the pharmaceuticals and treatment methods can be confirmed.

[0209] The pharmaceuticals and therapeutic methods disclosed herein may delay the development of cancer cells and inhibit their proliferation. Furthermore, it can kill cancer cells. These effects mean that cancer patients can be affected by cancer. The symptoms may disappear, or the quality of life (QOL) of cancer patients may be improved, Therapeutic effects can be achieved by maintaining the quality of life of cancer patients. The pharmaceuticals and treatments disclosed herein. Even if the method fails to achieve the death of cancer cells, it may inhibit or control the proliferation of cancer cells. By managing this, it is possible to achieve long-term survival while simultaneously improving the quality of life (QOL) of cancer patients.

[0210] The pharmaceuticals disclosed herein can be used for systemic treatment of patients, as well as for topical application to cancer tissue. Therefore, it can be expected to exert therapeutic effects.

[0211] A medicinal product of this disclosure containing at least one pharmaceutically suitable ingredient may be administered. Suitable components are the dosage of antibody-drug conjugates and ATM inhibitors used in this disclosure. Depending on the dosage concentration, or similar, pharmaceutical additives commonly used in the art or the same Anti-HER2 antibodies used in this disclosure may be suitably selected and applied from the same category. - Drug conjugates, for example, buffers such as histidine buffer, sucrose and trehalose Pharmaceuticals containing vehicles such as rose, and surfactants such as polysorbate 80 and 20. It may be administered as follows. The pharmaceutical product containing the antibody-drug conjugate used in this disclosure is preferred It can be used as an injectable preparation, and more preferably as an aqueous injectable preparation or a lyophilized injectable preparation. It can be used, and more preferably, as a lyophilized injectable preparation.

[0212] The pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in this disclosure is available in aqueous injection form. In some cases, this aqueous injection is preferably diluted with a suitable diluent and then administered intravenously. It can be administered as an injection. Examples of diluents include dextrose solution and physiological saline. A dextrose solution may be exemplified, preferably a 5% dextrose solution. A liquid can be used as an example.

[0213] If the pharmaceutical product disclosed herein is a lyophilized injectable preparation, the lyophilization process involves pre-dissolving it in sterile water for injection. Preferably, the required amount of the injectable drug is diluted with a suitable diluent and then administered by intravenous infusion. Obtain. Examples of diluents include dextrose solution and physiological saline, preferably A dextrose solution may be exemplified, more preferably a 5% dextrose solution. ru.

[0214] Examples of applicable routes of administration for the drugs described herein include intravenous, intradermal, and subcutaneous routes. Possible routes include intramuscular and intraperitoneal routes, with intravenous routes being preferred.

[0215] The anti-HER2 antibody-drug conjugate used in this disclosure is used in a 1-180 day interval. It can be administered to the body, preferably at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks. Preferably, it may be administered at intervals of 3 weeks. Anti-HER2 antibody-drug condyloma used in this disclosure The drug can be administered in doses of approximately 0.001 to 100 mg / kg per single dose, and is preferred. Alternatively, it can be administered in doses of 0.8 to 12.4 mg / kg per single dose. For example, The anti-HER2 antibody-drug conjugate was administered at 0.8 mg / kg, 1.6 mg / kg, and 3. 2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / It can be administered once every three weeks at a dose of kg, preferably 5.4 mg / kg or 6.4 mg / kg. It can be administered once every three weeks at a dose of kg.

[0216] Compounds of formula (I) or (II) are typically administered at concentrations of 2.5 to 5000 mg / m². 2 (Animal body area) ) or administered to warm-blooded animals at a unit dose in the range of approximately 0.05 to 100 mg / kg. This usually provides a therapeutically effective dose. The dosage form typically contains, for example, 0.1 to 250 mg of the active ingredient. The daily dose is: The host being treated, the specific route of administration, any concurrent treatments, and the disease being treated. It will inevitably fluctuate depending on the severity of the condition. Therefore, a general practitioner treating any particular patient will The optimal dosage can be determined.

[0217] This medicine is available in a form suitable for oral use (e.g., tablets, lozenges, hard or soft tablets). Capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, Or a form suitable as an elixir), a form suitable for topical use (e.g., cream, ointment, Administration by inhalation (in a form suitable as a gel, or as an aqueous or oily liquid or suspension). Suitable forms (for example, finely pulverized powder or liquid aerosol), blow A form suitable for administration by mail (for example, a form suitable as a finely powdered substance), or parenteral administration. Suitable form for administration (e.g., intravenous, subcutaneous, intramuscular, or sterile for intramuscular administration) Suitable in an aqueous or oily solution form, or as a suppository for rectal administration. It may take any form. This composition can be obtained by a conventional procedure known in the art. Compositions intended for oral use may contain additional components, for example, one or more. It may contain several colorants, sweeteners, flavorings, and / or preservatives.

[0218] The size of the dose required for the therapeutic treatment of a particular medical condition depends on the patient being treated, the route of administration, and the treatment It will always fluctuate depending on the severity of the disease being treated. Compounds of formula (I) or (II) are generally Constant, 2.5~5000mg / m 2 (Animal body area) or approximately 0.05-100 mg / kg It is administered to warm-blooded animals in a unit dose within the specified range, and this is usually therapeutically effective. A suitable dosage is provided. The unit dosage form, such as tablets or capsules, is usually, for example, 0.1 to 250. It will contain mg of the active ingredient.

[0219] The pharmaceuticals and treatment methods disclosed herein are used as adjuvant chemotherapy in combination with surgical procedures. It may be used. The pharmaceuticals of this disclosure may be administered for the purpose of reducing tumor size before surgery. (This is called preoperative adjuvant chemotherapy or neoadjuvant therapy), and after surgery. It may be administered to prevent tumor recurrence (postoperative adjuvant chemotherapy or adjuvant chemotherapy). (This is called endotherapy.) [Examples]

[0220] This disclosure will be described in detail with reference to the embodiments shown below. However, this disclosure is, These are not the only examples. Furthermore, they should never be interpreted restrictively.

[0221] Example 1: Production of antibody-drug conjugates According to the manufacturing method described in International Publication No. 2015 / 115091, Furthermore, an 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 1-449 and amino acids consisting of all amino acid residues 1-214 of SEQ ID NO: 2 Using an antibody (containing a light chain consisting of a sequence), the following formula: [ka] (In the formula, A represents the attachment site to the antibody.) The drug-linker represented by this symbol is conjugated to the anti-HER2 antibody via thioether linkage. We have manufactured an anti-HER2 antibody-drug conjugate (DS-8201: Truss Tuzumab (deruxtecan). The DAR of this antibody-drug conjugate is 7.7 or 7. It was 0.8.

[0222] Example 2: Production of ATM inhibitors According to the manufacturing method described in International Publication No. 2017 / 046216 Prepare an ATM inhibitor of formula (I). Specifically, see International Publication No. 2017 / 046216 According to Example 2 of the pamphlet, 7-fluoro-1-isopropyl-3-methyl-8 -[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c Quinoline-2-on: [ka] It can be prepared.

[0223] Example 3: Antitumor test (1) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and AT M inhibitor AZD1390 (7-fluoro-1-isopropyl-3-methyl-8-[6-[ 3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline -2-on) combination

[0224] method: High-throughput combination screening is performed, and in this screening, HER Table 1 shows three breast cancer cell lines with varying HER2 expression levels, and one gastric cell line with high HER2 expression. This was treated with a combination of DS-8201 and AZD1390 (ATM inhibitor).

[0225] [Table 1]

[0226] This screening reads a 7-day cell titer-global cell viability assay. This is cell titer-glo cell viability beef. This was performed as a 6x6 dose-response matrix for each combination (regarding DS-8201). (For the first part, a 5-point logarithmic continuous dilution, and for the second part, a semi-logarithmic continuous dilution). In addition, AZD1 In parallel with 390, trastuzumab and exatecan (DNA topoisomerase I inhibitor) ) were also screened. Combined activity was evaluated based on the combination of ΔEmax and HSA synergy scores. I evaluated it based on that.

[0227] result: The results are shown in Figures 12A and 12B, and Table 2.

[0228] Figure 12A shows the matrix of measured cell viability signals. The X-axis represents drug A(D The Y-axis represents drug B (AZD1390), and the Y-axis represents drug B (AZD1390). The values ​​in the box are: This represents the ratio of cells treated with drugs A+B compared to DMSO control on day 7. All values ​​are normalized to the cell viability value on day 0. Values ​​from 0 to 100 are: This represents the percentage of growth inhibition, and values ​​above 100 indicate cell death. Figure 12B shows HSA excess matrix This shows the values ​​in the box. The values ​​in the box are HSA (Highest Single Drug). This represents the excess value calculated by the (e)Agent) model.

[0229] Table 2 below shows the HSA synergistic score and the Loewe additive score.

[0230] [Table 2]

[0231] Loewe dose additiveity is the phenomenon where two compounds act on the same molecular target through the same mechanism. This predicts the reaction expected in combination. This Loewe dose-additive property is that the interaction between compounds is zero Additiveness is calculated based on the assumption that it is true, and is independent of the properties of the dose-response relationship.

[0232] HSA (Highest Single Drug) [Berenbaum 1989] refers to two types at corresponding concentrations. The effect of the single compound with the higher efficacy is quantified. The combined effect is determined by the concentrations used in this combination. The effects of each individual drug are compared. Exceeding the maximum single-drug effect indicates synergy. HSA is It is not necessary for the compounds to affect the same target.

[0233] Excess matrix: For each well in the concentration matrix, the measured or fitted value is each This is compared to the predicted non-synchronized value for the concentration pair. This predicted value is used in the selected model. This is determined by the difference between the predicted and actual values, which may show synergistic or antagonistic effects, and excess maturity This is shown in Rix. The excess matrix value is a combination of the excess amount and the synergistic score. It is summarized in section A.

[0234] As shown in Figures 12A and 12B, and Table 2, the AZ is combined with the DS-8201. D1390 (AZ13791971) is EMAX (0.3μM AZD1390 and 1 HER2+ cell line KPL4 and In NCI-N87, it showed synergistic activity and increased cell death. At lower concentrations, in combination... Activity was also observed. The single drug AZD1390 was not active within the selected concentration range. In addition, AZD1390 and DS-8201 are HER2 low cell lineage MDA-MB- In 468 and T47D, co-administrative activity was observed with DS-8201 Emax.

[0235] The results show that ATM inhibition using AZD1390 allows for in vitro high-HER2 injections. The antitumor efficacy of DS-8201 was observed in both the present cell lineage and the low-HER2-expressing cell lineage. It has been demonstrated that it enhances the HER2 hypercell lineage. AZD1390 is a phase enhancer in HER2 hypercell lineages. It showed a synergistic combination activity and increased cell death. Beneficial combination activity was also observed in HER2-low cancer cell lines. We observed the activity of the substance.

[0236] Example 4: Antitumor test (2) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATM Inhibitor AZD1390 (7-fluoro-1-isopropyl-3-methyl-8-[6-[3 -(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline- Combination with 2-on)

[0237] DS-8201 or exatecan mesylate is used in cancer cell lines with different HER2 expression levels. The device was tested both independently and in combination with the AZD1390.

[0238] method: Cells grown under each condition were subjected to an assay period (4-8 days; the treatment period was the same for each cell). (Depending on the growth rate of the line) 96 wells per well at the optimal density for linear propagation. Seeds were sown in the container. Immediately after sowing, the cells were given 200 μL / well of the indicated compound. The drug was administered and placed in an incubator. The combinations were analyzed using a 6x8 concentration response for each combination. The process was performed as a matrix. At the endpoint, the cells were fertilized in 2% PFA for 20 minutes at room temperature. Fixed. To obtain the cell count at the start of treatment, one additional plate was used for each experiment. The cells were fixed after being attached. Then, the cells were soaked in 0.5% PBS for 10 minutes. The cells were permeabilized with Triton-X100. After washing with PBS, the cells were refrigerated in PBS for 1 hour. Block with 5% PBS and incubate overnight at 4°C, then inoculate with 5% FBS + 0.05% triton The cells were incubated with the primary antibody in a suitable environment. After three washes with PBS, the cells were left at room temperature. For one hour, 5% FBS + 0.05% tr containing Hoechst33258 was administered. The cells were incubated with a secondary antibody in iton. After three washes with PBS, the cells were removed. The images were scanned using a Cellinsight instrument with a 10x objective lens and 9 fields of view / wells. The images were analyzed to determine the number of cells based on nuclear Hoechst staining, and other biomarkers examined. Nuclear intensity was analyzed using Columbus. Total cell count / well was used. Then, relative growth in each well was calculated compared to the solvent control. A synergistic score was calculated. To do this, growth inhibition data was analyzed using Combenefit software. Di Veroli GY et al.,Bioinformatics 2016, 32(18),2866-8). The mean / well of the sum of nuclear intensities of IF biomarkers is also This is shown in comparison to the solvent control.

[0239] result: The results are shown in Figures 13-15 and Tables 3 and 4.

[0240] Table 3 below shows the results for DS-8201 and Exaten in the cell lines used in the in vitro study. The study demonstrates monotherapy activity of Kan and AZD1390.

[0241] [Table 3]

[0242] Figure 13 shows DS-8201 and AZD1390 in HER2-high KPL4 cell lines. This shows a synergistic matrix of combinations with [the specified element].

[0243] In Figure 13, (A) is the relative total cells as the proportion of the DMSO vehicle control. (Nuclei) number is shown (control = 100%, no remaining cells = 0%; dark areas indicate total number of cells) (B) is a region with a very small number of cells, and the Loewe score, Bliss score, and The calculated synergistic matrix for HSA scores is shown (higher = greater synergy). Effects; dark areas indicate regions with high synergistic effects.

[0244] Table 4 below shows the synergistic scores for DS-8201 in combination with AZD1390. This shows the total for Loewe, Bliss, and HSA.

[0245] [Table 4]

[0246] Figure 14 shows (A) HER2-high KPL4 cell lineage and (B) HER2-negative MDA- Regarding the combination of DS-8201 and AZD1390 in the MB-468 cell lineage. This shows the multiplicative change in the total number of cells remaining after 4-8 days of treatment compared to time zero. Positive values ​​indicate an increase. This indicates proliferation (multiplication), a value of zero indicates cell division arrest, and a negative value indicates net This represents the loss of cells and serves as a substitute for cell death. The area enclosed by the box represents monotherapy. This shows the regions of cell division arrest or cell loss for each combination compared to the others.

[0247] Figure 15 shows (A) HER2-high KPL4 cell lines, or (B) HER2-low MDA-M Regarding the combination of DS-8201 and AZD1390 in the B-468 cell line A Induction of TM-dependent KAP1 pSer824 signaling, DNA double-strand break damage (γH 2AX) Shows biomarkers or cell number percentages (vs. solvent control). Enclosed in a box. The region involved induction of a DNA damage response in combination with monotherapy, DNA damage, or cell damage. This shows an area of ​​increasing loss.

[0248] According to the results above, ATM inhibition in a high HER2 KPL4 breast cancer cell lineage model Clinically appropriate use of DS-8201 (and exatecan) in combination with the agent AZD1390. Synergistic activity and cell death were observed at various concentrations. In addition, DS-8201 (and exatecan This involves the activation of the ATM biomarker (KAP1 pSer824) and DNA strand breakage. (γH2AX) is induced in a concentration-dependent manner, and this induction is further enhanced when combined with AZD1390. It was enhanced. In the HER2-negative MDA-MB-468 breast cancer cell lineage, DS-8201 In this combination, weak combination activity and poor activation of the DNA damage response pathway were observed. However, exatecan still exhibits combination activity, and HE of DS-8201 This supported R2 and tumor targeting dependence, but not with free exatecan. The data were obtained in combination with the tumor HER2 expression-dependent ATM inhibitor AZD1390. In that case, a strong enhancement of activity by DS-8201 was observed, and therefore, free topoiso It may increase the therapeutic index compared to melanase-I inhibitors.

[0249] Example 5: Antitumor test (3) - In vivo Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATM Inhibitor AZD1390 (7-fluoro-1-isopropyl-3-methyl-8-[6-[3 -(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline- Combination with 2-on)

[0250] method: Using 5-8 week old female nude mice (Charles River), the process was carried out in a 7-day sequence. After fertilization, they were included in this experiment. 1 × 10⁶ of the female nude mice were placed on their flanks. 7 Individual NCI -N87 tumor cells (1:1 in Matrigel) were subcutaneously transplanted. The tumor was approximately 150 mm. 3 When the tumor size reached a certain level, tumors of similar size were randomly assigned to one of the treatment groups shown in Table 5.

[0251] [Table 5]

[0252] The dosage of the compound for each animal was calculated based on their individual body weight on the day of administration. DS-8 AZD1390 was administered 24 hours after the 201 dose. Unless otherwise stated, the duration of administration was It was 28 days (1 cycle).

[0253] Formulation of DS-8201 at 3 mg / kg and 1 mg / kg On the day of administration, DS-8201 stock (20.1 mg / ml) is administered along with 25 mM histidine. 3 mg / kg and 1 mg / kg were added to the buffer solution, 9% sucrose (pH 5.5). By diluting the given solution to 0.6 mg / ml and 0.2 mg / ml, DS- The 8201 administration solution was prepared. After thoroughly mixing each administration solution using a pipette, The drug was administered by intravenous injection at a dose of 5 ml / kg.

[0254] Formulation of AD1390 at 10 mg / kg To formulate a 10 mg / kg dosage solution, the final concentration of 1 mg / ml AZD1390 is used. The solution was prepared to obtain a dose of 10 mg / kg for PO administration. First, 0.1% Tw Prepare a 5 mg / ml dose solution using 0.5% HPMC containing een 80 (vehicle). This compound was stirred overnight, and then further diluted to a 1 mg / ml dose solution on the day of administration. The solution was then prepared. This administration solution was kept in a light-shielded place and continuously mixed at room temperature for up to 4 days. The final administration matrix for 10 mg / kg AZD1390 was a white suspension.

[0255] measurement Tumor growth inhibition (TGI) from the start of the study to the day of tumor measurement was compared between the control group and the treatment group. Tumor regression was evaluated by comparing the geometric mean change in tumor volume. Calculated as the percentage reduction in tumor volume from the pre-implantation value: Regression%=(1-RTV)×100% (In the formula, RTV = geometric mean relative tumor volume). Final measurement compared to vehicle control. Use a one-sided t-test for (log(relative tumor volume) = log(final volume / initial volume)) over 2 days. Then, we evaluated the statistical significance.

[0256] result: The tumor volume associated with treatment with DS-8201 and / or AZD1390 is shown in Figure 16. The data shows the change in tumor volume over time for the treatment group. The dotted line in Figure 16 represents the administration of This indicates the end of the period. For information on the total dosage and schedule, please refer to Table 5 above. The values ​​shown are mean ± SEM, and initially, n=10 for vehicle-treated mice. For all other treatment groups, n=8.

[0257] In heterologous transplantation of NCI-N87, using DS-8201 or AZD1390 alone Best TGI after treatment or treatment with DS-8201 in combination with AZD1390 The response (maximum TGI / regression) is shown in Table 6.

[0258] [Table 6]

[0259] Monotherapy with DS-8201 at 3 mg / kg showed an 84% success rate on day 33 after treatment. It showed the greatest tumor growth inhibition (TGI). At 1 mg / kg, DS-8201 showed the greatest effect after treatment. On day 37, a maximum TGI of 22% was observed. AZD1390 monotherapy was effective 40 minutes after treatment. On day [number], the maximum TGI reached 37%. This was due to the combination of DS-8201 at 1 mg / kg. Combination treatment resulted in a lower NCI-N87 tumor burden compared to vehicle-treated control mice. It decreased significantly, and at 40 days post-treatment, with a maximum TGI of 82%, DS-8201 1m A significant effect was observed with g / kg + AZD1390. A higher dose of DS-8201 was also observed. Tumor regression was achieved with combination therapy using 3 mg / kg and AZD1390, and treatment was performed. On day 33, the maximum TGI was 143%, demonstrating a better response compared to each monotherapy. All treatment groups showed tolerance, including the vehicle group, monotherapy group, and combination therapy group. No consistent differences in average weight were observed during this period.

[0260] Example 6: Inhibition of ATM signaling Combination of DS-8201 and ATM inhibitor AZD1390

[0261] method Gastric cancer NCI-N87 and breast cancer KPL4 cell lines were subjected to humidification at 37°C and 5% CO2. The cells were cultured in an incubator in RPMI 1640 supplemented with 10% FCS. The cells were placed in 6 wells at the optimal density to allow linear growth during the duration of this assay. Seeds were sown on a plate. Two days after sowing, the cells were treated with the specified compound (AZD1390 alone, or The patient was given DS-8201 (or a combination of DS-8201 and exatecan mesylate) and incubated. It was returned to the tub. 7, 24, or 48 hours after administration, protease inhibitors and HO Dissolution of sphatase inhibitor in 50 mM Tris-HCl pH 7.5, 2% SDS The whole cell extract was obtained by dissolution. The lysate was boiled at 95°C for 5 minutes. 240n The protein concentration was measured using Nanodrop at m, and 50 μg of the lysate was divided into 4-12 The proteins were loaded onto a %Bis Tris gel. The proteins were then transferred using iBlot2. The primary antibody (see Table 7) was added to 3% milk TBS-Tween 0.05%. Incubate overnight at 4°C, then incubate the HRP-conjugated secondary antibody at room temperature for 1 hour. It was incubated over a period of time. The blot was visualized using G-box.

[0262] [Table 7]

[0263] result: The results were obtained from (A) NCI-N87 (gastric cancer) cell lineage and (B) KPL4 (breast cancer) cell lineage. In this case, AZD1390 alone, or DS-8201 (or exatecan mesylate) The antibody blot images obtained using the combinations are shown in Table 17.

[0264] In both Her2-High NCI-N87 and KPL4, pATM-S1981, p As indicated by the increase in Chk2-T68 and pKap1-S824, 30 μg / Exposure to DS-8201 or warhead (exatecan mesylate) in mL can lead to ATM transmission. Activation was induced. In combination with AZD1390 at 100nM, pATM, The activation of pChk2 and pKAP1 is inhibited, leading to DNA damage (pRPA, gH2AX). The condition worsened, and ultimately, cell death (cCasp3) increased.

[0265] Therefore, AZD1390 enables ATM signaling induced by DS-8201. It has been shown to inhibit it.

[0266] Example 7: Antitumor test (4) Antibody-drug conjugate DS-8201 (trastuzumab deruxtecan) and ATM Inhibitor AZD1390 (7-fluoro-1-isopropyl-3-methyl-8-[6-[3 -(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinoline- Combination with 2-on)

[0267] method: High-throughput combination screening is performed, and in this screening, HER Lung cancer cell lines that highly express 2 (Table 8) are used in combination with DS-8201 and AZD1390. The treatment was performed at the hospital.

[0268] [Table 8]

[0269] The results of this screening were obtained using a 7-day cell titer-global cell viability assay. Yes, and this was performed as a 6x6 dose-response matrix for each combination (DS-8201). (Both AZD1390 and AZD1390 were used in semi-logarithmic serial dilutions.) The combined activity was measured by ΔEmax and The evaluation was based on the combination of the HSA synergistic score.

[0270] result: The results are shown in Figures 18A and 18B, and Table 9.

[0271] Figure 18A shows the matrix of measured cell viability signals. The X-axis represents drug A(D The Y-axis represents drug B (AZD1390), and the Y-axis represents drug B (AZD1390). The values ​​in the box are: This represents the ratio of cells treated with drugs A+B compared to DMSO control on day 7. All values ​​are normalized to the cell viability value on day 0. Values ​​from 0 to 100 are: This represents the percentage of growth inhibition; values ​​exceeding 100 indicate cell death.

[0272] Figure 18B shows the HSA excess matrix. The values ​​in the boxes represent HSA (highest single drug). This represents the excess value calculated by the agent model.

[0273] Table 9 below shows the HSA additive score and the Loewe geometric score.

[0274] [Table 9]

[0275] As can be seen from Figures 18A and 18B and Table 9, the AZD1390 is the DS-820 It interacted synergistically with compound 1 and also increased cell death in HER2-positive lung cancer lines.

[0276] The above specification is considered sufficient to enable those skilled in the art to carry out this embodiment. The above description and examples detail a particular embodiment, and this invention It describes the best form intended by the enlightened ones. However, the above text is in text form. Even if described in detail, this embodiment can be carried out in many ways, and the claims are It will be understood that this includes any equivalent.

[0277] Free text for sequence listings Sequence ID 1 - Amino chain sequence of the heavy chain of the anti-HER2 antibody Sequence ID No. 2 - Amino chain sequence of the light chain of the anti-HER2 antibody SEQ ID NO: 3 - Amino acid sequence of heavy chain CDRH1 [= Amino acid residues 26-33 of SEQ ID NO: 1] SEQ ID NO: 4 - Amino acid sequence of heavy chain CDRH2 [= Amino acid residues 51-58 of SEQ ID NO: 1] SEQ ID NO: 5 - Amino acid sequence of heavy chain CDRH3 [= Amino acid residues 97-109 of SEQ ID NO: 1] ] SEQ ID NO: 6 - Amino acid sequence of light chain CDRL1 [= Amino acid residues 27-32 of SEQ ID NO: 2] SEQ ID NO: 7 - Amino acid sequence (SAS) containing the amino acid sequence of light chain CDRL2 [=SEQ ID NO: 7] [2 amino acid residues 50-56] SEQ ID NO: 8 - Amino acid sequence of light chain CDRL3 [= Amino acid residues 89-97 of SEQ ID NO: 2] SEQ ID NO: 9 - Amino acid sequence of the heavy chain variable region [= Amino acid residues 1-120 of SEQ ID NO: 1] SEQ ID NO: 10 - Amino acid sequence of the light chain variable region [= Amino acid residues 1-107 of SEQ ID NO: 2] SEQ ID NO: 11 - Amino acid sequence of the heavy chain [= Amino acid residues 1-449 of SEQ ID NO: 1]

Claims

1. A pharmaceutical product containing an anti-HER2 antibody-drug conjugate and an ATM inhibitor for concomitant administration. The anti-HER2 antibody-drug conjugate has the following formula: 【Chemistry 1】 A drug-linker represented by (wherein A represents the attachment site to the antibody) forms a thioether linkage. It is an antibody-drug conjugate that is conjugated to an anti-HER2 antibody via a linkage. , pharmaceuticals.

2. The ATM inhibitor is given by the following formula (I): 【Chemistry 2】 (In the formula, R １ It is methyl; R ２ is hydrogen or methyl; or R １ and R ２ These are the nitrogen atoms to which they bond. Together with it, it forms an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R ３ is hydrogen or fluoro; R ４ is hydrogen or methyl; R ５ (It is hydrogen or fluorine.) The pharmaceutical product according to claim 1, which is a compound represented by or a pharmaceutically acceptable salt thereof.

3. In formula (I), R １ and R ２ are both methyl; or R １ and R ２ are these Along with the nitrogen atom to which it is bonded, the azetidinyl ring, pyrrolidinyl ring, or piperidinyl ring A pharmaceutical product according to claim 2, which is formed.

4. In formula (I), R １ and R ２ These, along with the nitrogen atom to which they are bonded, form an azetidinyl ring. The pharmaceutical product according to claim 2 or 3, which forms a pyrrolidinyl ring or a piperidinyl ring.

5. In formula (I), R ３ The pharmaceutical product according to any one of claims 2 to 4, wherein is hydrogen.

6. In formula (I), R ４ The pharmaceutical product according to any one of claims 2 to 5, wherein is methyl.

7. In formula (I), R ５ The pharmaceutical product according to any one of claims 2 to 6, wherein the compound is fluoro.

8. In formula (I), R １ It is methyl; R ２ is methyl; or R １ and R ２ These, along with the nitrogen atom to which they bond, It forms a zetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring; R ３ is hydrogen or fluoro; R ４ It is methyl; R ５ is hydrogen or fluorine. The pharmaceutical product according to claim 2.

9. The ATM inhibitor is given by the following formula: 【Transformation 3】 Represented as 7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-pipette [Lysyl]propoxy]-3-pyridyl]imidazo[4,5-c]quinoline-2-one (A The pharmaceutical product according to claim 2, which is ZD1390, or a pharmaceutically acceptable salt thereof.

10. The aforementioned anti-HER2 antibody consists of CDRH1, which comprises the amino acid sequence represented by Sequence ID No. 3, CDRH2 consisting of the amino acid sequence represented by number 4, and the amino acid represented by sequence number 5 A heavy chain containing CDRH3 consisting of a sequence and a CD consisting of the amino acid sequence represented by Sequence ID No. 6 RL1, CDRL2 consisting of amino acid sequences of amino acid residues 1-3 of SEQ ID NO: 7, and This antibody contains a light chain containing CDRL3, which consists of the amino acid sequence represented by Sequence ID No.

8. , a pharmaceutical product according to any one of claims 1 to 9.

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

9. It includes a heavy chain and a light chain containing a variable region consisting of the amino acid sequence represented by Sequence ID No.

10. A pharmaceutical product according to any one of claims 1 to 9, which is an antibody.

12. The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1, and SEQ ID NO: An antibody comprising a light chain consisting of the amino acid sequence represented by 2, any one of claims 1 to 9 The pharmaceuticals listed in the section.

13. The anti-HER2 antibody comprises a heavy chain consisting of the amino acid sequence represented by Sequence ID No. 11, and a sequence number An antibody comprising a light chain consisting of the amino acid sequence represented by No. 2, any one of claims 1 to 9. The pharmaceuticals listed in item 1.

14. The aforementioned anti-HER2 antibody-drug conjugate is given by the following formula: 【Chemistry 4】 (In the formula, “antibody” is conjugated to the drug-linker via a thioether bond) The anti-HER2 antibody is shown, and n is one of the antibody-drug conjugates. This indicates the average number of conjugated drug-linker units per antibody molecule. A pharmaceutical product according to any one of claims 1 to 13, where n is in the range of 7 to 8. Item.

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

16. The aforementioned product comprises the anti-HER2 antibody-drug conjugate and the ATM inhibitor for simultaneous administration. A pharmaceutical product according to any one of claims 1 to 15, comprising a harmful agent.

17. The aforementioned product is a combination of the anti-HER2 antibody-drug conjugate and a product for continuous or simultaneous administration. A compound formulation comprising the aforementioned ATM inhibitor, according to any one of claims 1 to 15. Item.

18. The aforementioned product is 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. Road cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal cancer Stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer Cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, At least one selected from the group consisting of glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. A pharmaceutical product according to claim 18, which is one.

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

21. The breast cancer is as described in claim 20, with a HER2 status score of IHC 3+. Medicine.

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

23. The breast cancer is as described in claim 20, wherein the HER2 status score is IHC 2+. Medicine.

24. The breast cancer is as described in claim 20, with a HER2 status score of IHC 1+. Medicine.

25. The breast cancer is one in which the HER2 status score is IHC > 0 and < 1+, Pharmaceuticals as described in item 20.

26. The pharmaceutical product according to claim 20, wherein the breast cancer is a type 3-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 renal cancer.

35. A pharmaceutical product as defined in any one of claims 1 to 17, for use in the treatment of cancer.

36. 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. Road cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal cancer Stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer Cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, At least one selected from the group consisting of glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. A pharmaceutical product for use according to claim 35.

37. The aforementioned cancer is breast cancer, the pharmaceutical product for use according to claim 35.

38. The breast cancer described in claim 37 has an IHC status score of 3+. Medicines for practical use.

39. The pharmaceutical product for use according to claim 37, wherein the breast cancer is HER2-low expressing breast cancer.

40. The breast cancer described in claim 37 is characterized by having an HER2 status score of IHC 2+. Medicines for practical use.

41. The breast cancer described in claim 37 is characterized by having an HER2 status score of IHC 1+. Medicines for practical use.

42. The breast cancer is one in which the HER2 status score is IHC > 0 and < 1+, A pharmaceutical product for use as described in item 37.

43. The pharmaceutical product for use according to claim 37, wherein the breast cancer is a trine-negative breast cancer.

44. The pharmaceutical product for use according to claim 35, wherein the cancer is gastric cancer.

45. The pharmaceutical product for use according to claim 35, wherein the cancer is colorectal cancer.

46. The drug for use according to claim 35, wherein the cancer is lung cancer.

47. The pharmaceutical product for use according to claim 46, wherein the lung cancer is non-small cell lung cancer.

48. The pharmaceutical product for use according to claim 35, wherein the cancer is pancreatic cancer.

49. The pharmaceutical product for use according to claim 35, wherein the cancer is ovarian cancer.

50. The pharmaceutical product for use according to claim 35, wherein the cancer is prostate cancer.

51. The drug for use according to claim 35, wherein the cancer is renal cancer.

52. A combination of an anti-HER2 antibody-drug conjugate and an ATM inhibitor for cancer treatment. The anti-HER2 antibody-drug conjugate or the A in the manufacture of a drug for administration The use of a TM inhibitor, wherein the anti-HER2 antibody-drug conjugate and the ATM inhibitor Use of the agent as defined in any one of claims 1 to 15.

53. 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. Road cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal cancer Stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer Cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, At least one selected from the group consisting of glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. The use described in claim 52, which is one.

54. The use according to claim 52, wherein the cancer is breast cancer.

55. The breast cancer described in claim 54 has an HER2 status score of IHC 3+. For.

56. The use according to claim 54, wherein the breast cancer is a HER2-low-expressing breast cancer.

57. The breast cancer described in claim 54 is characterized by having an HER2 status score of IHC 2+. For.

58. The breast cancer described in claim 54 has an HER2 status score of IHC 1+. For.

59. The breast cancer is one in which the HER2 status score is IHC > 0 and < 1+, Use as described in item 54.

60. The use according to claim 54, wherein the breast cancer is a type 3-negative breast cancer.

61. The use according to claim 52, wherein the cancer is gastric cancer.

62. The use according to claim 52, wherein the cancer is colorectal cancer.

63. The use according to claim 52, wherein the cancer is lung cancer.

64. The use according to claim 63, wherein the lung cancer is non-small cell lung cancer.

65. The use according to claim 52, wherein the cancer is pancreatic cancer.

66. The use according to claim 52, wherein the cancer is ovarian cancer.

67. The use according to claim 52, wherein the cancer is prostate cancer.

68. The use according to claim 52, wherein the cancer is renal cancer.

69. The aforementioned drugs are administered simultaneously with the anti-HER2 antibody-drug conjugate and the ATM inhibitor. The use according to any one of claims 52 to 68, wherein the composition contains a harmful agent.

70. The aforementioned drug is a combination of the anti-HER2 antibody-drug conjugate and a drug for continuous or simultaneous administration. The use according to any one of claims 52 to 68, which is a compound formulation comprising the ATM inhibitor. For.

71. A method for treating cancer, wherein the required target is defined in any one of claims 1 to 15. The combination of an anti-HER2 antibody-drug conjugate and an ATM inhibitor is administered. A method that includes [this].

72. 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. urinary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal cancer Stromal tumors, gastrointestinal stromal tumors, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer Cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, At least one selected from the group consisting of glioma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma. The method according to claim 71, which is one.

73. The method according to claim 71, wherein the cancer is breast cancer.

74. The breast cancer described above is the one described in claim 73, wherein the HER2 status score is IHC 3+. Law.

75. The method according to claim 73, wherein the breast cancer is a HER2-low-expressing breast cancer.

76. The breast cancer is as described in claim 73, wherein the HER2 status score is IHC 2+. Law.

77. The breast cancer is as described in claim 73, wherein the HER2 status score is IHC 1+. Law.

78. The breast cancer is one in which the HER2 status score is IHC > 0 and < 1+, The method described in paragraph 73.

79. The method according to claim 73, wherein the breast cancer is a type 3 negative breast cancer.

80. The method according to claim 71, wherein the cancer is gastric cancer.

81. The method according to claim 71, wherein the cancer is colorectal cancer.

82. The method according to claim 71, wherein the cancer is lung cancer.

83. The method according to claim 82, wherein the lung cancer is non-small cell lung cancer.

84. The method according to claim 71, wherein the cancer is pancreatic cancer.

85. The method according to claim 71, wherein the cancer is ovarian cancer.

86. The method according to claim 71, wherein the cancer is prostate cancer.

87. The method according to claim 71, wherein the cancer is renal cancer.

88. The above method involves sequentially administering the anti-HER2 antibody-drug conjugate and the ATM inhibitor. The method according to any one of claims 71 to 87, comprising administering to [a person].

89. The above method involves simultaneously using the anti-HER2 antibody-drug conjugate and the ATM inhibitor. The method according to any one of claims 71 to 87, comprising administering.

Images