Therapeutic agent for cancer having therapeutic resistance to immune checkpoint inhibitors

Abstract

The present invention provides a compound that exhibits an anticancer effect on the basis of CHK1 inhibition. The present disclosure has been accomplished by finding that a compound represented by formula (1) or a pharmaceutically acceptable salt thereof has a strong inhibitory effect on CHK1 and thus shows an excellent anti-tumor effect: # imgabs0 # [in the formula, R1, R2, L, V, W, and Q are as defined in the specification, X, Y, and Z each independently represent CR8 or a nitrogen atom, where X, Y, and Z are not CR8 at the same time, and R8 are as defined in the specification].

Description

Technical Field

[0001] The present disclosure relates to a CHK1 inhibitor, a liposome encapsulating a CHK1 inhibitor, or a combined use of these and an immune checkpoint inhibitor as a therapeutic agent for cancers showing resistance to treatment with an immune checkpoint inhibitor. Background Art

[0002] CHK1 is a serine / threonine protein kinase located downstream of ATR in the checkpoint signal transduction pathway of DNA damage in the cell cycle. In mammalian cells, CHK1 is phosphorylated in an ATR-dependent manner in response to DNA damage caused by ionizing radiation, etc., or DNA replication stress caused by excessive cell proliferation and genomic instability in cancer cells, etc. (Non-patent Documents 1 to 5). CHK1 phosphorylates CDC25A by activating this phosphorylation of CHK1, inhibiting the dephosphorylation of cyclin E / CDK2 caused by CDC25A, and stopping the progression from the S phase. In addition, CHK1 phosphorylates CDC25C, inhibiting the dephosphorylation of cyclin B / CDK1 caused by CDC25C, and stopping the progression from the G2M phase. In any case, the control of CDK activity will induce the arrest of the cell cycle, preventing cell division in the presence of DNA damage, thereby promoting the repair of DNA damage. CHK1 inhibits the checkpoint function that suppresses DNA damage during the cell cycle in cancer cells, thereby causing incomplete DNA repair and uncontrolled DNA synthesis in the presence of DNA damage, ultimately inducing DNA fragmentation, replication catastrophe, and cell death (Patent Documents 1-2).

[0003] Since its launch, immune checkpoint inhibitors have established themselves as the fourth therapy for cancer treatment, following surgery, radiotherapy, and chemotherapy. These immune checkpoint inhibitors are currently approved for use in a wide range of cancer types, including melanoma. As a characteristic of their effectiveness, a long-term survival effect (Durable Clinical Response) has been reported, but this effect has only been found in some patients, such as the 13.3% total efficacy of nivolumab in head and neck squamous cell carcinoma, and improvements in efficacy are being sought (Non-Patent Document 7).

[0004] Various inhibitors of CHK1 have been reported (Patent Documents 1 to 3).

[0005] Prior art literature

[0006] Patent Literature

[0007] [Patent Document 1] International Publication No. 2010 / 077758

[0008] [Patent Document 2] International Publication No. 2012 / 064548

[0009] [Patent Document 3] International Publication No. 2017 / 132928

[0010] Non-patent literature

[0011] [Non-patent document 1] Dai Y and Grant S, Clin Cancer Res, 16(2): 376-383 (2010)

[0012] [Non-patent document 2] Benada J and Macurek L, Biomolecules, 5: 1912-1937 (2015)

[0013] [Non-patent document 3] King C, Mol Cancer Ther, 14(9): 2004-2013 (2015)

[0014] [Non-patent document 4] Dent P, Expert Opinion on Investigational Drugs, 28(12): 1095-1100 (2019)

[0015] [Non-patent document 5] Evangelisti G. et al., Expert Opinion on Investigational Drugs, 29(8):779-792 (2020)

[0016] [Non-patent document 6] David H. et al. J Clin Oncol, 34: 1764-1771 (2016)

[0017] [Non-patent document 7] Raffaele A. et al. Expert Opinion on Biological Therapy, 19:3, 169-171 (2019) Summary of the Invention

[0018] Means used to solve problems

[0019] The present disclosure provides agents for treating cancers that show resistance to treatment with immune checkpoint inhibitors, or preventing the recurrence of cancers that have undergone remission.

[0020] The present inventors conducted in-depth research and found that: by using a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor, the drug was continuously exposed to the cancer tissue, thereby finding a cytocidal effect, hyperantigen presentation, a decrease in M2 macrophages, and a transformation of the tumor into an environment that attracts CD8-positive T cells (inflammatory microenvironment). For cancers that show treatment resistance to immune checkpoint inhibitors, this preparation shows excellent anti-tumor effects. It was also found that by combining the aforementioned inhibitors or liposomes with immune checkpoint inhibitors, a more excellent anti-tumor effect was shown. It was also found that when the aforementioned inhibitors or liposomes and immune checkpoint inhibitors were used in combination, CD8-positive T cells with memory function increased, and the tumor was rejected or tumor growth was inhibited during secondary transplantation, thereby showing a preventive effect on the recurrence of remitted cancers, thereby completing the present disclosure.

[0021] That is, the present disclosure is as follows.

[0022] [Item 1]

[0023] A therapeutic and / or preventive agent for cancer patients showing resistance to treatment with an immune checkpoint inhibitor, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

[0024] [Item 2]

[0025] The therapeutic and / or preventive agent according to item 1, characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are used in combination.

[0026] [Item 3]

[0027] The therapeutic and / or preventive agent according to item 2, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0028] [Item 4]

[0029] The therapeutic and / or preventive agent according to any one of item 2 or 3, characterized in that the immune checkpoint inhibitor is administered after administration of the CHK1 inhibitor.

[0030] [Item 5]

[0031] The therapeutic and / or preventive agent according to any one of items 2 to 4, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered.

[0032] [Item 6]

[0033] The therapeutic and / or preventive agent according to any one of items 2 to 4, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered 3 days later.

[0034] [Item 7]

[0035] The therapeutic and / or preventive agent according to any one of items 2 to 6, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0036] [Item 8]

[0037] The therapeutic and / or preventive agent according to any one of items 2 to 6, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0038] [Item 9]

[0039] The therapeutic and / or preventive agent according to any one of items 2 to 6, wherein the anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0040] [Item 10]

[0041] The therapeutic and / or preventive agent according to any one of items 1 to 9, wherein the number of CD3-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0042] [Item 11]

[0043] The therapeutic and / or preventive agent according to any one of items 1 to 10, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0044] [Item 12]

[0045] The therapeutic and / or preventive agent according to any one of items 1 to 11, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is 0.135 or less.

[0046] [Item 13]

[0047] The therapeutic and / or preventive agent according to any one of items 1 to 12, wherein the M1-M2 ratio of macrophages in the tumor tissue of the cancer patient is 21 or less.

[0048] [Item 14]

[0049] The therapeutic and / or preventive agent according to any one of items 1 to 13, wherein the number of CD206-positive cells in the tumor tissue of the cancer patient is increased compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0050] [Item 15]

[0051] The therapeutic and / or preventive agent according to any one of items 1 to 14, wherein the number of IAd-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0052] [Item 16]

[0053] The therapeutic and / or preventive agent according to any one of items 1 to 15, wherein the number of CD62L-negative CD44-positive cells in the lymph nodes of the cancer patient is reduced compared to lymph nodes of patients responsive to anti-PD-1 antibodies.

[0054] [Item 17]

[0055] The therapeutic and / or preventive agent according to any one of items 1 to 16, wherein PD-L1 expression in the tumor tissue of the cancer patient is lower than that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0056] [Item 18]

[0057] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein VEGFa expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0058] [Item 19]

[0059] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein the expression of granzyme B in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0060] [Item 20]

[0061] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein interferon-γ expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0062] [Item 21]

[0063] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein H2ab1 expression in the tumor tissue of the cancer patient is lower than that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0064] [Item 22]

[0065] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein CD80 expression in the tumor tissue of the cancer patient is lower than that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0066] [Item 23]

[0067] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein Mrc1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0068] [Item 24]

[0069] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein arginase 1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0070] [Item 25]

[0071] The therapeutic and / or preventive agent according to any one of items 1 to 17, wherein DNA replication stress in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0072] [Item 26]

[0073] A therapeutic and / or preventive agent for preventing the recurrence of remitted cancer, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

[0074] [Item 27]

[0075] The therapeutic and / or preventive agent according to item 26, characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are used in combination.

[0076] [Item 28]

[0077] The therapeutic and / or preventive agent according to any one of item 26 or 27, characterized in that the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0078] [Item 29]

[0079] The therapeutic and / or preventive agent according to any one of item 26 or 27, characterized in that the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0080] [Item 30]

[0081] The therapeutic and / or preventive agent according to any one of item 26 or 27, characterized in that the anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0082] [Item 31]

[0083] The therapeutic and / or preventive agent according to any one of items 26 to 30, wherein the cancer is selected from squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic carcinoma, breast cancer, triple-negative breast cancer, gastric cancer, gallbladder / cholangiocarcinoma, liver cancer, hepatocellular carcinoma The invention also provides at least one of cancer selected from the group consisting of: pancreatic cancer, colon cancer, rectal cancer, MSI-high colorectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine corpus cancer, cervical cancer, ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0084] [Item 32]

[0085] The therapeutic and / or preventive agent according to any one of items 26 to 30, wherein the cancer is at least one cancer selected from melanoma, squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, non-muscle invasive bladder cancer, renal cancer, hepatocellular carcinoma, MSI-high colorectal cancer, esophageal cancer, colon cancer, rectal cancer, breast cancer, or uterine corpus cancer.

[0086] [Item 33]

[0087] The therapeutic and / or preventive agent according to any one of items 26 to 30 is characterized in that the aforementioned cancer is at least one cancer selected from head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple-negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or uterine body cancer.

[0088] [Item 34]

[0089] The therapeutic and / or preventive agent according to any one of items 26 to 30, wherein the cancer is a solid tumor with a high tumor mutation burden (TMB-High).

[0090] [Item 35]

[0091] The therapeutic and / or preventive agent according to any one of items 1 to 34, wherein the liposome further contains a phospholipid.

[0092] [Item 36]

[0093] The therapeutic and / or preventive agent according to item 35, wherein the phospholipid is one selected from phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin, or a combination of two or more thereof.

[0094] [Item 37]

[0095] The therapeutic and / or preventive agent according to any one of items 1 to 36, wherein the liposome further contains sterols.

[0096] [Item 38]

[0097] The therapeutic and / or preventive agent according to any one of items 1 to 37, wherein the sterol is cholesterol.

[0098] [Item 39]

[0099] The therapeutic and / or preventive agent according to any one of items 1 to 38, wherein the liposome further comprises a polymer-modified lipid.

[0100] [Item 40]

[0101] The therapeutic and / or preventive agent according to item 39 is characterized in that the polymer portion of the aforementioned polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinyl pyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinyl pyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinyl pyrrolidone.

[0102] [Item 41]

[0103] The therapeutic and / or preventive agent according to Item 39 or 40, wherein the lipid portion of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

[0104] [Item 42]

[0105] The therapeutic and / or preventive agent according to any one of items 1 to 41, wherein

[0106] The liposome encapsulating the CHK1 inhibitor comprises

[0107] (1) 40-70 mol% phospholipids,

[0108] (2) 30 to 50 mol% of cholesterol, and

[0109] (3) 1 to 10 mol% of polymer-modified lipids.

[0110] [Item 43]

[0111] The therapeutic and / or preventive agent according to any one of items 1 to 42, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[0112] [Item 1A]

[0113] Use of a CHK1 inhibitor, or a liposome encapsulating a CHK1 inhibitor, for preparing a therapeutic and / or preventive agent for cancer patients showing resistance to treatment with immune checkpoint inhibitors.

[0114] [Item 2A]

[0115] The use according to item 1A is characterized in that the aforementioned CHK1 inhibitor and immune checkpoint inhibitor are used in combination.

[0116] [Item 3A]

[0117] The use according to item 2A is characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0118] [Item 4A]

[0119] The use according to any one of items 2A or 3A, characterized in that the immune checkpoint inhibitor is administered after the CHK1 inhibitor is administered.

[0120] [Item 5A]

[0121] The use according to any one of items 2A to 4A, wherein the anti-PD-1 antibody is administered after the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0122] [Item 6A]

[0123] The use according to any one of items 2A to 4A, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered 3 days later.

[0124] [Item 7A]

[0125] The use according to any one of items 2A to 6A, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0126] [Item 8A]

[0127] The use according to any one of items 2A to 6A, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0128] [Item 9A]

[0129] The use according to any one of items 2A to 6A, wherein the anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0130] [Item 10A]

[0131] The use according to any one of items 1A to 9A, wherein the number of CD3-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0132] [Item 11A]

[0133] The use according to any one of items 1A to 10A, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0134] [Item 12A]

[0135] The use according to any one of Items 1A to 11A, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is 0.135 or less.

[0136] [Item 13A]

[0137] The use according to any one of items 1A to 12A, wherein the M1-M2 ratio of macrophages in the tumor tissue of the cancer patient is 21 or less.

[0138] [Item 14A]

[0139] The use according to any one of items 1A to 13A, wherein the number of CD206-positive cells in the tumor tissue of the cancer patient is increased compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0140] [Item 15A]

[0141] The use according to any one of items 1A to 14A, wherein the number of IAd-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0142] [Item 16A]

[0143] The use according to any one of items 1A to 15A, wherein the number of CD62L-negative CD44-positive cells in the lymph nodes of the cancer patient is reduced compared to that in the lymph nodes of a patient responsive to an anti-PD-1 antibody.

[0144] [Item 17A]

[0145] The use according to any one of items 1A to 16A, wherein PD-L1 expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0146] [Item 18A]

[0147] The use according to any one of items 1A to 17A, wherein VEGFa expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0148] [Item 19A]

[0149] The use according to any one of items 1A to 17A, wherein the expression of granzyme B in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0150] [Item 20A]

[0151] The use according to any one of items 1A to 17A, wherein interferon-γ expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0152] [Item 21A]

[0153] The use according to any one of items 1A to 17A, wherein H2ab1 expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0154] [Item 22A]

[0155] The use according to any one of items 1A to 17A, wherein CD80 expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0156] [Item 23A]

[0157] The use according to any one of items 1A to 17A, wherein Mrc1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0158] [Item 24A]

[0159] The use according to any one of items 1A to 17A, wherein arginase 1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0160] [Item 25A]

[0161] The use according to any one of items 1A to 17A, wherein DNA replication stress in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0162] [Item 26A]

[0163] Use of a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor for preparing a therapeutic and / or preventive agent for preventing the recurrence of remitted cancer.

[0164] [Item 27A]

[0165] The use according to item 26A is characterized in that the aforementioned CHK1 inhibitor and immune checkpoint inhibitor are used in combination.

[0166] [Item 28A]

[0167] The use according to any one of item 26A or 27A, characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0168] [Item 29A]

[0169] The use according to any one of item 26A or 27A, characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody.

[0170] [Item 30A]

[0171] The use according to any one of item 26A or 27A is characterized in that the aforementioned anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0172] [Item 31A]

[0173] The use according to any one of items 26A to 30A, wherein the cancer is selected from squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma thymic carcinoma, breast cancer, triple-negative breast cancer, gastric cancer, gallbladder cholangiocarcinoma, liver cancer, hepatocellular carcinoma The patient may also be diagnosed with at least one of the following: pancreatic cancer, colon cancer, rectal cancer, MSI-high colorectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine corpus cancer, cervical cancer, ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0174] [Item 32A]

[0175] The use according to any one of items 26A to 30A, wherein the cancer is melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, non-muscle invasive bladder cancer, renal cancer, hepatocellular carcinoma, MSI-high colorectal cancer, esophageal cancer, colon / rectal cancer, breast cancer, or uterine corpus cancer.

[0176] [Item 33A]

[0177] The use according to any one of items 26A to 30A is characterized in that the aforementioned cancer is at least one cancer selected from head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple-negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or uterine body cancer.

[0178] [Item 34A]

[0179] The use according to any one of items 26A to 30A, wherein the cancer is a solid tumor with a high tumor mutation burden (TMB-High).

[0180] [Item 35A]

[0181] The use according to any one of items 1A to 34A, wherein the liposome further comprises a phospholipid.

[0182] [Item 36A]

[0183] The use according to item 35A, wherein the phospholipid is one selected from phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin, or a combination of two or more thereof.

[0184] [Item 37A]

[0185] The use according to any one of items 1A to 36A, wherein the liposome further comprises a sterol.

[0186] [Item 38A]

[0187] The use according to any one of items 1A to 37A, wherein the sterol is cholesterol.

[0188] [Item 39A]

[0189] The use according to any one of Items 1A to 38A, wherein the liposome further comprises a polymer-modified lipid.

[0190] [Item 40A]

[0191] The use according to item 39A is characterized in that the polymer part of the aforementioned polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinyl pyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinyl pyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinyl pyrrolidone.

[0192] [Item 41A]

[0193] The use according to item 39A or 40A, wherein the lipid portion of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

[0194] [Item 42A]

[0195] The use according to any one of items 1A to 41A, wherein

[0196] The liposome encapsulating the CHK1 inhibitor comprises

[0197] (1) 40-70 mol% phospholipids,

[0198] (2) 30 to 50 mol% of cholesterol, and

[0199] (3) 1 to 10 mol% of polymer-modified lipids.

[0200] [Item 43A]

[0201] The use according to any one of items 1A to 42A, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[0202] [Item 1B]

[0203] A therapeutic and / or preventive agent for use in the treatment and / or prevention of cancer patients showing resistance to immune checkpoint inhibitors, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

[0204] [Item 2B]

[0205] The therapeutic and / or preventive agent according to Item 1B, characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are used in combination.

[0206] [Item 3B]

[0207] The therapeutic and / or preventive agent according to Item 2B, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0208] [Item 4B]

[0209] The therapeutic and / or preventive agent according to any one of Items 2B or 3B, wherein the immune checkpoint inhibitor is administered after administration of the CHK1 inhibitor.

[0210] [Item 5B]

[0211] The therapeutic and / or preventive agent according to any one of items 2B to 4B, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered.

[0212] [Item 6B]

[0213] The therapeutic and / or preventive agent according to any one of items 2B to 4B, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered 3 days later.

[0214] [Item 7B]

[0215] The therapeutic and / or preventive agent according to any one of Items 2B to 6B, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0216] [Item 8B]

[0217] The therapeutic and / or preventive agent according to any one of Items 2B to 6B, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0218] [Item 9B]

[0219] The therapeutic and / or preventive agent according to any one of Items 2B to 6B, wherein the anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0220] [Item 10B]

[0221] The therapeutic and / or preventive agent according to any one of Items 1B to 9B, wherein the number of CD3-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0222] [Item 11B]

[0223] The therapeutic and / or preventive agent according to any one of Items 1B to 10B, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0224] [Item 12B]

[0225] The therapeutic and / or preventive agent according to any one of Items 1B to 11B, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is 0.135 or less.

[0226] [Item 13B]

[0227] The therapeutic and / or preventive agent according to any one of Items 1B to 12B, wherein the M1-M2 ratio of macrophages in the tumor tissue of the cancer patient is 21 or less.

[0228] [Item 14B]

[0229] The therapeutic and / or preventive agent according to any one of Items 1B to 13B, wherein the number of CD206-positive cells in the tumor tissue of the cancer patient is increased compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0230] [Item 15B]

[0231] The therapeutic and / or preventive agent according to any one of Items 1B to 14B, wherein the number of IAd-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0232] [Item 16B]

[0233] The therapeutic and / or preventive agent according to any one of items 1B to 15B, wherein the number of CD62L-negative CD44-positive cells in the lymph nodes of the cancer patient is reduced compared to lymph nodes of patients responsive to anti-PD-1 antibodies.

[0234] [Item 17B]

[0235] The therapeutic and / or preventive agent according to any one of Items 1B to 16B, wherein PD-L1 expression in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0236] [Item 18B]

[0237] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein VEGFa expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0238] [Item 19B]

[0239] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein the expression of granzyme B in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0240] [Item 20B]

[0241] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein interferon-γ expression in the tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0242] [Item 21B]

[0243] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein H2ab1 expression in tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0244] [Item 22B]

[0245] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein CD80 expression in the tumor tissue of the cancer patient is lower than that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0246] [Item 23B]

[0247] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein Mrc1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0248] [Item 24B]

[0249] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein arginase 1 expression in the tumor tissue of the cancer patient is increased compared to that in the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0250] [Item 25B]

[0251] The therapeutic and / or preventive agent according to any one of Items 1B to 17B, wherein DNA replication stress in the tumor tissue of the cancer patient is reduced compared to that in the tumor tissue of an anti-PD-1 antibody-responsive patient.

[0252] [Item 26B]

[0253] A therapeutic and / or preventive agent for use in preventing recurrence of remitted cancer, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

[0254] [Item 27B]

[0255] The therapeutic and / or preventive agent according to Item 26B is characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are used in combination.

[0256] [Item 28B]

[0257] The therapeutic agent and / or preventive agent according to any one of item 26B or 27B is characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0258] [Item 29B]

[0259] The therapeutic and / or preventive agent according to any one of item 26B or 27B is characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody.

[0260] [Item 30B]

[0261] The therapeutic and / or preventive agent according to any one of item 26B or 27B is characterized in that the aforementioned anti-PD-1 antibody is bolivianzumab, nivolumab, spartalizumab, or cemiplizumab.

[0262] [Item 31B]

[0263] The therapeutic and / or preventive agent according to any one of items 26B to 30B, wherein the cancer is selected from squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic carcinoma, breast cancer, triple-negative breast cancer, gastric cancer, gallbladder / cholangiocarcinoma, liver cancer , hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colorectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine corpus cancer, cervical cancer, ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0264] [Item 32B]

[0265] The therapeutic and / or preventive agent according to any one of items 26B to 30B, wherein the aforementioned cancer is melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, non-muscle invasive bladder cancer, renal cancer, hepatocellular carcinoma, MSI-high colorectal cancer, esophageal cancer, colon / rectal cancer, breast cancer, or uterine corpus cancer.

[0266] [Item 33B]

[0267] The therapeutic and / or preventive agent according to any one of items 26B to 30B is characterized in that the aforementioned cancer is at least one cancer selected from head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple-negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or uterine body cancer.

[0268] [Item 34B]

[0269] The therapeutic and / or preventive agent according to any one of Items 26B to 30B, wherein the cancer is a solid tumor with a high tumor mutation burden (TMB-High).

[0270] [Item 35B]

[0271] The therapeutic and / or preventive agent according to any one of Items 1B to 34B, wherein the liposome further contains a phospholipid.

[0272] [Item 36B]

[0273] The therapeutic and / or preventive agent according to item 35B, wherein the phospholipid is one selected from phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin, or a combination of two or more thereof.

[0274] [Item 37B]

[0275] The therapeutic and / or preventive agent according to any one of Items 1B to 36B, wherein the liposome further contains a sterol.

[0276] [Item 38B]

[0277] The therapeutic and / or preventive agent according to any one of Items 1B to 37B, wherein the sterol is cholesterol.

[0278] [Item 39B]

[0279] The therapeutic and / or preventive agent according to any one of Items 1B to 38B, wherein the liposome further comprises a polymer-modified lipid.

[0280] [Item 40B]

[0281] The therapeutic and / or preventive agent according to item 39B is characterized in that the polymer portion of the aforementioned polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinyl pyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinyl pyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinyl pyrrolidone.

[0282] [Item 41B]

[0283] The therapeutic and / or preventive agent according to Item 39B or 40B, wherein the lipid portion of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

[0284] [Item 42B]

[0285] The therapeutic and / or preventive agent according to any one of Items 1B to 41B, wherein

[0286] The liposome encapsulating the CHK1 inhibitor comprises

[0287] (1) 40-70 mol% phospholipids,

[0288] (2) 30 to 50 mol% of cholesterol, and

[0289] (3) 1 to 10 mol% of polymer-modified lipids.

[0290] [Item 43B]

[0291] The therapeutic and / or preventive agent according to any one of items 1B to 42B, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[0292] [Item 1C]

[0293] A method for treating and / or preventing a cancer patient who shows resistance to treatment with an immune checkpoint inhibitor, comprising administering a CHK1 inhibitor, or a liposome encapsulating a CHK1 inhibitor, to the patient.

[0294] [Item 2C]

[0295] The method according to item 1C is characterized in that the aforementioned CHK1 inhibitor and immune checkpoint inhibitor are used in combination.

[0296] [Item 3C]

[0297] The method according to item 2C, characterized in that the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0298] [Item 4C]

[0299] The method according to any one of items 2C or 3C, characterized in that the immune checkpoint inhibitor is administered after the CHK1 inhibitor is administered.

[0300] [Item 5C]

[0301] The method according to any one of items 2C to 4C, wherein the anti-PD-1 antibody is administered after the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously.

[0302] [Item 6C]

[0303] The method according to any one of items 2C to 4C, wherein the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, and then the anti-PD-1 antibody is administered 3 days later.

[0304] [Item 7C]

[0305] The method according to any one of items 2C to 6C, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0306] [Item 8C]

[0307] The method according to any one of items 2C to 6C, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0308] [Item 9C]

[0309] The method according to any one of items 2C to 6C, wherein the anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0310] [Item 10C]

[0311] The method according to any one of items 1C to 9C, wherein the number of CD3-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0312] [Item 11C]

[0313] The method according to any one of items 1C to 10C, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0314] [Item 12C]

[0315] The method according to any one of items 1C to 11C, wherein the number of CD8-positive cells in the tumor tissue of the cancer patient is 0.135 or less.

[0316] [Item 13C]

[0317] The method according to any one of items 1C to 12C, wherein the M1-M2 ratio of macrophages in the tumor tissue of the cancer patient is 21 or less.

[0318] [Item 14C]

[0319] The method according to any one of items 1C to 13C, wherein the number of CD206-positive cells in the tumor tissue of the cancer patient is increased compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0320] [Item 15C]

[0321] The method according to any one of items 1C to 14C, wherein the number of IAd-positive cells in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0322] [Item 16C]

[0323] The method according to any one of items 1C to 15C, wherein the number of CD62L-negative CD44-positive cells in the lymph nodes of the cancer patient is reduced compared to lymph nodes of a patient responsive to an anti-PD-1 antibody.

[0324] [Item 17C]

[0325] The method according to any one of items 1C to 16C, wherein PD-L1 expression in tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0326] [Item 18C]

[0327] The method according to any one of items 1C to 17C, wherein VEGFa expression in the tumor tissue of the cancer patient is increased compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0328] [Item 19C]

[0329] The method according to any one of items 1C to 17C, wherein the expression of granzyme B in the tumor tissue of the cancer patient is reduced compared to the tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0330] [Item 20C]

[0331] The method according to any one of items 1C to 17C, wherein interferon-γ expression in the tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0332] [Item 21C]

[0333] The method according to any one of items 1C to 17C, wherein H2ab1 expression in tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0334] [Item 22C]

[0335] The method according to any one of items 1C to 17C, wherein CD80 expression in the tumor tissue of the cancer patient is reduced compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0336] [Item 23C]

[0337] The method according to any one of items 1C to 17C, wherein Mrc1 expression in the tumor tissue of the cancer patient is increased compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0338] [Item 24C]

[0339] The method according to any one of items 1C to 17C, wherein arginase 1 expression in the tumor tissue of the cancer patient is increased compared to tumor tissue of a patient responsive to an anti-PD-1 antibody.

[0340] [Item 25C]

[0341] The method according to any one of items 1C to 17C, wherein DNA replication stress in the tumor tissue of the cancer patient is reduced compared to tumor tissue in a patient responsive to an anti-PD-1 antibody.

[0342] [Item 26C]

[0343] A method for preventing recurrence of cancer that has undergone remission, comprising administering a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor to a patient.

[0344] [Item 27C]

[0345] The method according to item 26C is characterized in that the aforementioned CHK1 inhibitor and immune checkpoint inhibitor are used in combination.

[0346] [Item 28C]

[0347] The method according to any one of item 26C or 27C, characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0348] [Item 29C]

[0349] The method according to any one of item 26C or 27C is characterized in that the aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody.

[0350] [Item 30C]

[0351] The method according to any one of item 26C or 27C is characterized in that the aforementioned anti-PD-1 antibody is bolizumab, nivolumab, spartalizumab, or cemiplizumab.

[0352] [Item 31C]

[0353] The method according to any one of items 26C to 30C, wherein the cancer is selected from squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic carcinoma, breast cancer, triple-negative breast cancer, gastric cancer, gallbladder / cholangiocarcinoma, liver cancer, hepatocellular carcinoma The patient may also be diagnosed with at least one of the following: pancreatic cancer, colon cancer, rectal cancer, MSI-high colorectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine corpus cancer, cervical cancer, ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0354] [Item 32C]

[0355] The method according to any one of items 26C to 30C, wherein the aforementioned cancer is melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, non-muscle invasive bladder cancer, renal cancer, hepatocellular carcinoma, MSI-high colorectal cancer, esophageal cancer, colon / rectal cancer, breast cancer, or uterine corpus cancer.

[0356] [Item 33C]

[0357] The method according to any one of items 26C to 30C is characterized in that the aforementioned cancer is at least one cancer selected from head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple-negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or uterine body cancer.

[0358] [Item 34C]

[0359] The method according to any one of items 26C to 30C, wherein the cancer is a solid tumor with a high tumor mutation burden (TMB-High).

[0360] [Item 35C]

[0361] The method according to any one of items 1C to 34C, wherein the liposome further comprises a phospholipid.

[0362] [Item 36C]

[0363] The method according to item 35C, wherein the phospholipid is one selected from phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin, or a combination of two or more thereof.

[0364] [Item 37C]

[0365] The method according to any one of items 1C to 36C, wherein the liposome further comprises a sterol.

[0366] [Item 38C]

[0367] The method according to any one of items 1C to 37C, wherein the sterol is cholesterol.

[0368] [Item 39C]

[0369] The method according to any one of items 1C to 38C, wherein the liposome further comprises a polymer-modified lipid.

[0370] [Item 40C]

[0371] The method according to item 39C is characterized in that the polymer part of the aforementioned polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxy polyethylene glycol, methoxy polypropylene glycol, methoxy polyvinyl alcohol, methoxy polyvinyl pyrrolidone, ethoxy polyethylene glycol, ethoxy polypropylene glycol, ethoxy polyvinyl alcohol, ethoxy polyvinyl pyrrolidone, propoxy polyethylene glycol, propoxy polypropylene glycol, propoxy polyvinyl alcohol, or propoxy polyvinyl pyrrolidone.

[0372] [Item 41C]

[0373] The method according to item 39C or 40C, wherein the lipid portion of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

[0374] [Item 42C]

[0375] The method according to any one of items 1C to 41C, wherein

[0376] The liposome encapsulating the CHK1 inhibitor comprises

[0377] (1) 40-70 mol% phospholipids,

[0378] (2) 30 to 50 mol% of cholesterol, and

[0379] (3) 1 to 10 mol% of polymer-modified lipids.

[0380] [Item 43C]

[0381] The method according to any one of items 1C to 42C, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[0382] [Item 44]

[0383] The therapeutic and / or preventive agent according to any one of items 1 to 43, wherein the CHK1 inhibitor is represented by formula (1):

[0384] [Chemistry 6]

[0385]

[0386] [Where,

[0387] R 1 represents a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl,

[0388] R 2 Represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a sulfonic acid group, a phosphoric acid group, -OR 3 、-SR 3 、-COR 4 、-CO2R 4 、-CONR 5 R 6 、-SO2R 4 、-SO2NR 5 R 6 、-OCOR 4 、-OCO2R 4 、-OCONR 5 R 6 、-NR 5 R 6 、-NR 7 COR 4 、-NR 7 CO2R 4 、-NR 7 CONR 5 R 6 、-NR 7 SO2R 4 、-NR 7 SO2NR 5 R 6 , optionally substituted C 1-6Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl,

[0389] R 3 Represents a hydrogen atom or C 1-6 alkyl,

[0390] R 4 Indicates C 1-6 alkyl,

[0391] R 5 、R 6 and R 7 Each independently represents a hydrogen atom, or C 1-6 Alkyl, wherein R bonded to the same nitrogen atom 5 and R 6 All C 1-6 When the alkyl group is an alkyl group, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded.

[0392] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0393] R 8 When there are multiple groups, each group independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a sulfonic acid group, a phosphoric acid group, a -OR 9 、-SR 9 、-COR 10 、-CO2R 10 、-CONR 11 R 12 、-SO2R 10 、-SO2NR 11 R 12 、-OCOR 10 、-OCO2R 10 、-OCONR 11 R 12 、-NR 11 R 12 、-NR 13 COR 10 、-NR 13 CO2R 10 、-NR 13 CONR 11 R 12 、-NR 13 SO2R10 、-NR 13 SO2NR 11 R 12 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl,

[0394] R 9 Represents a hydrogen atom or C 1-6 alkyl,

[0395] R 10 Indicates C 1-6 alkyl,

[0396] R 11 、R 12 and R 13 Each independently represents a hydrogen atom or C 1-6 Alkyl, wherein R bonded to the same nitrogen atom 11 and R 12 All C 1-6 When the alkyl group is an alkyl group, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded.

[0397] L represents a single bond or an optionally substituted C 1-6 Alkylene,

[0398] V represents a single bond, an optionally substituted C 3-10 cycloalkylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group,

[0399] W represents a single bond or an optionally substituted C 1-6 Alkylene,

[0400] Q represents a hydrogen atom or NHR 14 ,

[0401] R 14 represents a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 cycloalkyl, or an optionally substituted 3- to 10-membered saturated heterocyclic group].

[0402] [Item 45]

[0403] The therapeutic and / or preventive agent according to item 44, wherein R 1 、R 2 、R 8 、R 14, L, V, and W in the optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C 1-6 Alkylene, optionally substituted C 3-10 Cycloalkylene, or optionally substituted 3-10 membered divalent saturated heterocyclic group are each independently selected from

[0404] (1) Halogen atoms,

[0405] (2) hydroxyl groups,

[0406] (3)C 6-10 Aryl,

[0407] (4) 5- to 12-membered heteroaryl groups,

[0408] (5)C 1-6 alkyl,

[0409] (6)C 2-6 Alkenyl,

[0410] (7)C 2-6 Alkynyl,

[0411] (8)C 1-6 Alkoxy,

[0412] (9)C 1-6 Alkylthio,

[0413] (10)C 3-10 Cycloalkyl,

[0414] (11) 3-10 membered saturated heterocyclic group,

[0415] (12) carboxyl,

[0416] (13)-COR 15 、

[0417] (14)-CO2R 15 、

[0418] (15)-CONR 16 R 17 、

[0419] (16)-NR 16 R 17 、

[0420] (17)-NR 18COR 15 、

[0421] (18)-NR 18 CO2R 15 、

[0422] (19)-NR 18 SO2R 15 、

[0423] (20)-NR 18 CONR 16 R 17 、

[0424] (21)-NR 18 SO2NR 16 R 17 、

[0425] (22)-SO2R 15 、

[0426] (23)-SO2NR 16 R 17 、

[0427] (24)-OCOR 15 、

[0428] (25)-OCO2R 15 、

[0429] (26)-OCONR 16 R 17 、

[0430] (27) sulfonic acid,

[0431] (28) Phosphoric acid,

[0432] (29) cyano, and

[0433] (30) Nitro

[0434] are substituted by 1 to 5 identical or different substituents,

[0435] Among them, the aforementioned (3)C 6-10 Aryl, (4) 5- to 12-membered heteroaryl, (5) C 1-6 Alkyl, (6)C 2-6 Alkenyl, (7)C 2-6 Alkynyl, (8)C 1-6 Alkoxy, (9)C 1-6 Alkylthio, (9)C 3-10 The group represented by the cycloalkyl group and (10) the 3- to 10-membered saturated heterocyclic group is optionally selected from

[0436] (a) halogen atoms,

[0437] (b) hydroxyl groups,

[0438] (c)C 6-10 Aryl,

[0439] (d) 5- to 12-membered heteroaryl,

[0440] (e)C 1-6 alkyl,

[0441] (f)C 2-6 Alkenyl,

[0442] (g)C 2-6 Alkynyl,

[0443] (h)C 1-6 Alkoxy,

[0444] (i)C 3-10 Cycloalkyl,

[0445] (j) a 3- to 10-membered saturated heterocyclic group,

[0446] (k) carboxyl,

[0447] (l)-COR 15 、

[0448] (m)-CO2R 15 、

[0449] (n)-CONR 16 R 17 、

[0450] (o)-NR 16 R 17 、

[0451] (p)-NR 18 COR 15 、

[0452] (q)-NR 18 SO2R 15 、

[0453] (r)-SO2R 15 、

[0454] (s)-SO2NR 16 R 17 、

[0455] (t) sulfonic acid,

[0456] (u) phosphoric acid,

[0457] (v) cyano, and

[0458] (w) Nitro

[0459] are substituted by 1 to 5 identical or different substituents,

[0460] R 15 When there are multiple, each is independently C 1-6 alkyl,

[0461] R 16 and R 17 are each independently a hydrogen atom or a C 1-6 Alkyl, R 16 or R 17 When there are multiple 16 or R 17 are optionally the same or different, wherein R bonded to the same nitrogen atom 16 and R 17 All C 1-6 When the alkyl group is an alkyl group, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded.

[0462] R 18 A hydrogen atom or C 1-6 alkyl.

[0463] [Item 46]

[0464] The therapeutic and / or preventive agent according to any one of items 44 to 45, wherein R 1 is a hydrogen atom, or a C optionally substituted by 1 to 3 fluorine atoms 1-6 alkyl.

[0465] [Item 47]

[0466] The therapeutic and / or preventive agent according to any one of items 44 to 46, wherein R 1 It is a methyl group.

[0467] [Item 48]

[0468] The therapeutic and / or preventive agent according to any one of items 44 to 47, wherein R 2 A hydrogen atom, a halogen atom, a cyano group, a -OR 3 、C 1-6 Alkyl, C 3-10 a cycloalkyl group, or a 3- to 10-membered saturated heterocyclic group.

[0469] [Item 49]

[0470] The therapeutic and / or preventive agent according to any one of items 44 to 46, wherein R 2 It is a cyano group.

[0471] [Item 50]

[0472] The therapeutic and / or preventive agent according to any one of items 44 to 49, wherein R 8 When there are multiple, each is independently a hydrogen atom, a halogen atom, a cyano group, -OR 9 、-CO2R 10 、-CONR 11 R 12 、-NR 11 R 12 、-NR 13 COR 10 、C 1-6 Alkyl (the alkyl group is selected from fluorine atom, chlorine atom, bromine atom, hydroxyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered saturated heterocyclic group, -CONR 16 R 17 、-NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), C 3-10 Cycloalkyl (the cycloalkyl is selected from fluorine atom, chlorine atom, bromine atom, hydroxyl, phenyl, 5-6 membered heteroaryl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered saturated heterocyclic group, -CONR 16 R 17 、-NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 3 substituents), 3 to 10 membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, chlorine atoms, bromine atoms, hydroxyl groups, phenyl groups, 5 to 6 membered heteroaryl groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered saturated heterocyclic group, -CONR 16 R 17 、-NR 16 R 17 , and cyano group, optionally substituted with 1 to 3 substituents which are the same or different), phenyl group (the phenyl group is selected from fluorine atom, chlorine atom, bromine atom, hydroxyl group, phenyl group, 5-6 membered heteroaryl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered saturated heterocyclic group, -CONR 16 R 17 、-NR 16 R 17, and cyano group, optionally substituted with the same or different 1 to 3 substituents), or 5 to 6 membered heteroaryl (the heteroaryl is selected from fluorine atoms, chlorine atoms, bromine atoms, hydroxyl groups, phenyl groups, 5 to 6 membered heteroaryl groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered saturated heterocyclic group, -CONR 16 R 17 、-NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0473] [Item 51]

[0474] The therapeutic and / or preventive agent according to any one of items 44 to 50, wherein L is

[0475] Single key, or

[0476] C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0477] [Item 52]

[0478] The therapeutic and / or preventive agent according to any one of items 44 to 51, wherein V is

[0479] single bond,

[0480] C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), or

[0481] 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0482] [Item 53]

[0483] The therapeutic and / or preventive agent according to any one of items 44 to 52, wherein W is a single bond, or

[0484] C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0485] [Item 54]

[0486] The therapeutic and / or preventive agent according to any one of items 44 to 53, wherein R 14 For hydrogen atoms,

[0487] C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano),

[0488] C 3-10 Cycloalkyl (the cycloalkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), or

[0489] 3-10 membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0490] [Item 55]

[0491] The therapeutic and / or preventive agent according to Item 44, wherein Formula (1) is represented by the following Formula (2):

[0492] [Chemistry 7]

[0493]

[0494] [Where,

[0495] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0496] R 8 When there are multiple, each is represented independently

[0497] hydrogen atoms,

[0498] Fluorine atoms,

[0499] Chlorine atoms,

[0500] Bromine atoms,

[0501] C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 2 substituents which are the same or different and optionally substituted in the cyano group), or

[0502] 5-6 membered heteroaryl (the heteroaryl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with the same or different 1 to 2 substituents),

[0503] L represents

[0504] Single key, or

[0505] C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0506] V stands for

[0507] single bond,

[0508] C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), or

[0509] 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0510] W stands for

[0511] Single key, or

[0512] C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0513] Q represents a hydrogen atom, or NHR 14 ,

[0514] R 14 express

[0515] hydrogen atoms,

[0516] C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano),

[0517] C 3-10 Cycloalkyl (the cycloalkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), or

[0518] 3-10 membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0519] R 16 and R 17 Each independently represents a hydrogen atom, or C 1-6 Alkyl, R 16 or R 17 When there are multiple 16 or R 17 are optionally the same or different, wherein R bonded to the same nitrogen atom 16 and R 17 All C 1-6 When the alkyl groups are alkyl groups, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded.

[0520] [Item 56]

[0521] The therapeutic and / or preventive agent according to any one of items 44 to 55, wherein one or two of X, Y, and Z represent a nitrogen atom.

[0522] [Item 57]

[0523] The therapeutic and / or preventive agent according to any one of items 44 to 56, wherein X is a nitrogen atom,

[0524] Y and Z are CR 8 .

[0525] [Item 58]

[0526] The therapeutic and / or preventive agent according to any one of items 44 to 56, wherein Y is a nitrogen atom,

[0527] X and Z are CR 8 .

[0528] [Item 59]

[0529] The therapeutic and / or preventive agent according to any one of items 44 to 56, wherein Z is a nitrogen atom,

[0530] X and Y are CR 8 .

[0531] [Item 60]

[0532] The therapeutic and / or preventive agent according to any one of items 44 to 59, wherein R 8 When there are multiple atoms, each independently represents a hydrogen atom,

[0533] Fluorine atoms,

[0534] Chlorine atoms,

[0535] Bromine atoms, or

[0536] C 1-6 Alkyl (the alkyl group is selected from fluorine atoms, hydroxyl groups, and C 1-3 The alkoxy group may be optionally substituted with 1 to 2 substituents which may be the same or different.

[0537] [Item 61]

[0538] The therapeutic and / or preventive agent according to any one of items 44 to 60, wherein L is a single bond, or

[0539] C 1-6 An alkylene group (the alkylene group may be optionally substituted by 1 to 2 substituents which may be the same or different and selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0540] [Item 62]

[0541] The therapeutic and / or preventive agent according to any one of items 44 to 61, wherein V is

[0542] single bond,

[0543] C 3-7 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 alkyl, and cyano, optionally substituted with the same or different 1 to 2 substituents), or

[0544] 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 The alkyl group and the cyano group may be substituted with 1 to 2 substituents which may be the same or different.

[0545] [Item 63]

[0546] The therapeutic and / or preventive agent according to any one of items 44 to 62, wherein W is a single bond, or

[0547] C 1-6 An alkylene group (the alkylene group may be optionally substituted by 1 to 2 substituents which may be the same or different and selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0548] [Item 64]

[0549] The therapeutic and / or preventive agent according to any one of items 44 to 63, wherein R 14 A hydrogen atom, or

[0550] C 1-6 An alkyl group (the alkyl group may be optionally substituted by 1 to 2 substituents which may be the same or different and selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0551] [Item 65]

[0552] The therapeutic and / or preventive agent according to any one of items 44 to 64, wherein Q is

[0553] hydrogen atoms,

[0554] NH2, or

[0555] NHMe.

[0556] [Item 66]

[0557] The therapeutic and / or preventive agent according to Item 44, wherein Formula (1) is represented by the following Formula (3):

[0558] [Chemistry 8]

[0559]

[0560] [Where,

[0561] R 8a and R 8b Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0562] L represents a single bond, or C optionally substituted by one hydroxyl group 1-6 Alkylene,

[0563] V stands for

[0564] single bond,

[0565] C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or

[0566] 3 to 7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0567] W stands for

[0568] Single key, or

[0569] C optionally substituted with 1 hydroxyl group 1-3 Alkylene,

[0570] Q is a hydrogen atom or NH2].

[0571] [Item 67]

[0572] The therapeutic and / or preventive agent according to item 66, wherein R 8a and R 8b are each independently a hydrogen atom, a fluorine atom or a chlorine atom.

[0573] [Item 68]

[0574] The therapeutic and / or preventive agent according to item 66, wherein R 8a and R 8b are each independently a hydrogen atom or a chlorine atom.

[0575] [Item 69]

[0576] The therapeutic and / or preventive agent according to any one of items 66 to 68, wherein L is C 1-3 Alkylene.

[0577] [Item 70]

[0578] The therapeutic and / or preventive agent according to any one of items 66 to 69, wherein V is a single bond.

[0579] [Item 71]

[0580] The therapeutic and / or preventive agent according to any one of items 66 to 70, wherein V is C 3-7 Cycloalkylene.

[0581] [Item 72]

[0582] The therapeutic and / or preventive agent according to any one of items 66 to 71, wherein W is a single bond.

[0583] [Item 73]

[0584] The therapeutic and / or preventive agent according to any one of items 66 to 71, wherein W is C 1-3 Alkylene.

[0585] [Item 74]

[0586] The therapeutic and / or preventive agent according to any one of items 66 to 73, wherein Q is NH 2 .

[0587] [Item 75]

[0588] The therapeutic and / or preventive agent according to Item 44, wherein Formula (1) is represented by the following Formula (4):

[0589] [Chemistry 9]

[0590]

[0591] [Where,

[0592] R 8b and R 8c Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0593] L represents

[0594] Single key, or

[0595] C 1-6 an alkylene group (the alkylene group is optionally substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group),

[0596] V stands for

[0597] single bond,

[0598] C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or

[0599] 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C groups optionally substituted with 1-3 hydroxyl groups and fluorine atoms) 1-3 1 substituent in the alkyl group is optionally substituted),

[0600] W stands for

[0601] Single key, or

[0602] C optionally substituted with 1 hydroxyl group 1-3 Alkylene,

[0603] Q is a hydrogen atom, NH2, or NHMe].

[0604] [Item 76]

[0605] The therapeutic and / or preventive agent according to item 75, wherein R 8b and R 8c A hydrogen atom.

[0606] [Item 77]

[0607] The therapeutic and / or preventive agent according to any one of item 75 or 76, wherein L is a single bond, or

[0608] C optionally substituted by one hydroxyl group or fluorine atom 1-6 Alkylene.

[0609] [Item 78]

[0610] The therapeutic and / or preventive agent according to any one of items 75 to 77, wherein V is

[0611] single bond,

[0612] C 3-7 Cycloalkylene, or

[0613] 3 to 7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups and C 1-3 1 substituent in the alkyl group is optionally substituted).

[0614] [Item 79]

[0615] The therapeutic and / or preventive agent according to any one of items 75 to 78, wherein W is

[0616] Single key, or

[0617] C 1-3 Alkylene.

[0618] [Item 80]

[0619] The therapeutic and / or preventive agent according to any one of items 75 to 79, wherein Q is a hydrogen atom.

[0620] [Item 81]

[0621] The therapeutic and / or preventive agent according to any one of items 75 to 79, wherein Q is NH 2 .

[0622] [Item 82]

[0623] The therapeutic and / or preventive agent according to any one of items 75 to 79, wherein Q is NHMe.

[0624] [Item 83]

[0625] The therapeutic and / or preventive agent according to Item 44, wherein Formula (1) is represented by the following Formula (5):

[0626] [Chemistry 10]

[0627]

[0628] [Where,

[0629] R 8a and R 8c Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0630] L represents a single bond, or C optionally substituted by one hydroxyl group 1-6 Alkylene,

[0631] V stands for

[0632] single bond,

[0633] C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or

[0634] 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0635] W stands for

[0636] Single key, or

[0637] C optionally substituted with 1 hydroxyl group 1-3 Alkylene,

[0638] Q is a hydrogen atom or NH2].

[0639] [Item 84]

[0640] The therapeutic and / or preventive agent according to item 83, wherein R 8a and R 8c A hydrogen atom.

[0641] [Item 85]

[0642] The therapeutic and / or preventive agent according to any one of item 83 or 84, wherein L is C optionally substituted with one hydroxyl group 1-6 Alkylene.

[0643] [Item 86]

[0644] The therapeutic and / or preventive agent according to any one of items 83 to 85, wherein V is

[0645] single bond,

[0646] C 3-7 Cycloalkylene or

[0647] 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted).

[0648] [Item 87]

[0649] The therapeutic and / or preventive agent according to any one of items 83 to 86, wherein W is a single bond, or

[0650] C 1-3 Alkylene.

[0651] [Item 88]

[0652] The therapeutic and / or preventive agent according to any one of items 83 to 87, wherein Q is a hydrogen atom.

[0653] [Item 89]

[0654] The therapeutic and / or preventive agent according to any one of items 83 to 87, wherein Q is NH 2 .

[0655] [Item 90]

[0656] The therapeutic and / or preventive agent according to Item 44, wherein Formula (1) is represented by the following Formula (6):

[0657] [Chemistry 11]

[0658]

[0659] [Where,

[0660] R 8a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C1-3 alkyl,

[0661] L represents

[0662] Single key, or

[0663] C 1-6 an alkylene group (the alkylene group is optionally substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group),

[0664] V stands for

[0665] single bond,

[0666] C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or

[0667] 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups and C groups optionally substituted by 1-3 fluorine atoms) 1-3 1 substituent in the alkyl group is optionally substituted),

[0668] W stands for

[0669] Single key, or

[0670] C optionally substituted with 1 hydroxyl group 1-3 Alkylene,

[0671] Q is a hydrogen atom, NH2, or NHMe].

[0672] [Item 91]

[0673] The therapeutic and / or preventive agent according to item 90, wherein R 8a A hydrogen atom.

[0674] [Item 92]

[0675] The therapeutic and / or preventive agent according to any one of item 90 or item 91, wherein L is C 1-4 Alkylene.

[0676] [Item 93]

[0677] The therapeutic and / or preventive agent according to any one of items 90 to 92, wherein V is

[0678] Single key, or

[0679] C 3-7 Cycloalkylene.

[0680] [Item 94]

[0681] The therapeutic and / or preventive agent according to any one of items 90 to 93, wherein W is a single bond, or

[0682] C 1-3 Alkylene.

[0683] [Item 95]

[0684] The therapeutic and / or preventive agent according to any one of items 90 to 94, wherein Q is NH 2 .

[0685] [Item 96]

[0686] The therapeutic and / or preventive agent according to Item 44, comprising a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0687] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0688] 5-({5-[2-(3-aminopropoxy)-6-chloro-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0689] 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0690] 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0691] 5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0692] 5-[(5-{2-methoxy-4-[(3-methylazetidin-3-yl)methoxy]pyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0693] 5-[(5-{4-[(3-hydroxyazetidin-3-yl)methoxy]-2-methoxypyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0694] 5-{[5-(4-{[3-(hydroxymethyl)azetidin-3-yl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0695] 5-[(5-{3-[(3R)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0696] 5-[(5-{3-[(3S)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0697] 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0698] 5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0699] 5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0700] 5-[(5-{3-[(2S)-3-amino-2-hydroxypropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0701] N-{5-[2-(3-aminopropyloxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine,

[0702] N-{5-[2-(3-aminopropyloxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-(trifluoromethyl)pyrazin-2-amine,

[0703] 5-({5-[4-(3-aminopropoxy)-6-methoxypyrimidin-5-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0704] 5-({5-[3-(azetidin-3-yl)methoxy-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0705] 5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0706] (S)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0707] (S)-5-[(5-{3-methoxy-[5-(pyrrolidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0708] (R)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0709] 5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-6-methoxypyrimidin-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0710] 5-({5-[3-(3-aminopropoxy)-5-(fluoromethoxy)pyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0711] 5-[(5-{3-methoxy-5-[(3-methylazetidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0712] 5-{[5-(3-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0713] 5-[(5-{3-[(2S)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0714] 5-[(5-{3-[(2R)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0715] 5-[(5-{3-[(2S)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0716] 5-[(5-{3-[(2R)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0717] 5-[(5-{3-methoxy-5-[3-(methylamino)propoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0718] 5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0719] 5-[(5-{3-[(1R)-1-(azetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0720] 5-[(5-{3-[(1R)-1-(3-hydroxyazetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,

[0721] 5-{[5-(3-methoxy-5-{[(1R,3R)-3-(methylamino)cyclopentyl]oxy}pyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0722] 5-{[5-(3-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexan-2-yl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0723] 5-{[5-(2-{[1-(aminomethyl)cyclopropyl]methoxy}-4-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,

[0724] 5-{[5-(4-{[1-(Aminomethyl)cyclopropyl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile.

[0725] [Item 97]

[0726] The therapeutic and / or preventive agent according to Item 44, comprising a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0727] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0728] 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,

[0729] 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

[0730] [Item 98]

[0731] The therapeutic and / or preventive agent according to Item 44, comprising the following compound or a pharmaceutically acceptable salt thereof:

[0732] 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

[0733] [Item 99]

[0734] The therapeutic and / or preventive agent according to Item 44, comprising the following compound or a pharmaceutically acceptable salt thereof:

[0735] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

[0736] [Item 100]

[0737] The therapeutic and / or preventive agent according to Item 44, comprising the following compound or a pharmaceutically acceptable salt thereof:

[0738] 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

[0739] Effects of the Invention

[0740] According to the present disclosure, a therapeutic agent and / or preventive agent for cancer patients who show resistance to treatment with immune checkpoint inhibitors can be provided, containing a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient. Furthermore, when the aforementioned inhibitor or liposome is used in combination with an immune checkpoint inhibitor, a superior anti-tumor effect is shown compared to a single agent. In addition, the aforementioned inhibitor, the aforementioned liposome, or their combination with an immune checkpoint inhibitor also shows an effect of preventing the recurrence of cancer that has been alleviated.

[0741] According to the present disclosure, a CHK1 inhibitor comprising a 5-heteroaryl-1H-pyrazole-3-amine derivative or a pharmaceutically acceptable salt thereof can be provided. The compounds disclosed herein have both excellent CHK1 inhibitory activity and high safety. By being encapsulated in liposomes and slowly released from the liposomes, they can act continuously on cancer, demonstrating a potent anti-tumor effect. The compounds disclosed herein are useful as therapeutic agents for diseases in which CHK1 is involved, and specifically, can be applied to patients with pancreatic cancer, ovarian cancer, osteosarcoma, Ewing sarcoma, chondrosarcoma, or soft tissue sarcoma.

[0742] In the present disclosure, compared with 5-phenyl-1H-pyrazole-3-amine derivatives, namely Prexasertib, although Prexasertib showed a pharmacological effect in a Phase 2 trial on patients with ovarian cancer, it did not achieve the maximum efficacy of 72 hours of continuous exposure as inferred from non-clinical trials. In contrast, the compounds disclosed herein or their salts can further improve it. Moreover, when administered once, compared with Prexasertib, which has side effects due to high maximum blood concentrations, the compounds or salts disclosed herein do not have such side effects. When administered continuously for three days, compared with side effects caused by long-term drug exposure, the compounds or salts disclosed herein did not find such side effects (non-patent literature 3, non-patent literature 6). In addition, the inventors of the present application and others newly discovered that Prexasertib has the risk of hepatotoxicity, and the compounds of the present invention can reduce the risk of hepatotoxicity. In summary, the compounds disclosed herein have both excellent CHK1 inhibitory activity and high safety.

[0743] In particular, compounds represented by formula (3) having a pyridine ring with a nitrogen atom at a specific position have the characteristics of having both high antitumor activity and safety and excellent pharmacokinetics.

[0744] In particular, the compound of Example 1 encompassed by formula (3) exhibits the following characteristics compared to prisertib: it exhibits high CHK1 inhibitory activity, has a potent cell proliferation inhibitory effect, and is highly safe. Furthermore, the compound of Example 1 exhibits favorable pharmacokinetics and can be effectively encapsulated in liposomes. The liposome formulation of the compound of Example 1 exhibits excellent antitumor effects and is highly safe, and can further exert a more specific antitumor effect by combining it with known anticancer agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0745] [ Figure 1 ] shows the powder X-ray diffraction pattern of type I of the compound of Example 39. The horizontal axis represents the diffraction angle 2θ (°), and the vertical axis represents the count (hereinafter, Figures 2 to 6 Same as above).

[0746] [ Figure 2 ] shows the powder X-ray diffraction pattern of Form II of the compound of Example 40.

[0747] [ Figure 3 ] shows the powder X-ray diffraction pattern of Form III of the compound of Example 41.

[0748] [ Figure 4 ] shows the powder X-ray diffraction pattern of Form IV of the compound of Example 42.

[0749] [ Figure 5 ] shows the powder X-ray diffraction pattern of Form V of the compound of Example 43.

[0750] [ Figure 6 ] shows the powder X-ray diffraction pattern of Form VI of the compound of Example 44.

[0751] [ Figure 7 ] Figure 7 This figure shows the tumor PD response of a solution or liposome formulation of Presertib in Experiment A of Test Example 11 using ES-2 tumor-bearing mice. PD response was assessed by Western blotting to detect γH2AX and tubulin expression. Band intensities were quantified using ImageJ software, and γH2AX expression was calculated relative to tubulin expression. The vertical axis represents the relative γH2AX value.

[0752] [ Figure 8 ] Figure 8 This figure shows the tumor PD response in ES-2 tumor-bearing mice using either the solution formulation of Presertib or the liposome formulation of Example 1, Test B, of Test Example 11. PD response was assessed by Western blotting to detect γH2AX and tubulin expression. Band intensities were quantified using ImageJ software, and γH2AX expression was calculated relative to tubulin expression. The vertical axis represents the relative γH2AX value.

[0753] [ Figure 9 ] Figure 9 This figure shows the tumor PD response effect of the liposome formulation of Example 1, Test C, in ES-2 tumor-bearing mice. PD response was assessed by Western blotting to detect γH2AX and tubulin expression. Band intensities were quantified using ImageJ software, and γH2AX expression was calculated relative to tubulin expression. The vertical axis represents the relative γH2AX value.

[0754] [ Figure 10 ] Figure 10: This is a diagram showing an example of an administration schedule for an anti-PD-1 antibody and the liposome formulation of Example 1. The liposome formulation of Example 1 is administered simultaneously with the anti-PD-1 antibody and then administered once a week (A1), twice a week (A2), three weeks (A3), four weeks (A4), or five weeks (A5). After concurrent administration with Example 1, the anti-PD-1 antibody is administered twice a week (B1), three weeks (B2), four weeks (B3), or six weeks (B4) according to the respective schedules. That is, Example 1 and the anti-PD-1 antibody can be administered according to an administration schedule selecting any combination thereof. Preferred are combinations of administration regimens including A1 and B1, A1 and B2, A1 and B3, A1 and B4, A1 and B5, A2 and B1, A2 and B2, A2 and B3, A2 and B4, A2 and B5, A3 and B1, A3 and B2, A3 and B3, A3 and B4, A3 and B5, A4 and B1, A4 and B2, A4 and B3, A4 and B4, A4 and B5, A5 and B1, A5 and B2, A5 and B3, A5 and B4, A5 and B5.

[0755] [ Figure 11 ] Figure 11 This is a graph showing the cell count and clonotype of the TCR repertoire for each clone of CD8-positive T cells in the test of Test Example 28 and the liposome preparation of Example 1.

[0756] [ Figure 12 ] Figure 12 This is a graph showing the CD8 scores of the liposome preparation of Example 1 in the test of Test Example 28.

[0757] [ Figure 13 ] Figure 13 This is a graph showing the M1-M2 ratio of the liposome preparation of Example 1 in the test of Test Example 28.

[0758] [ Figure 14 ] Figure 14 This is a graph showing the expression levels of ssDNA obtained by the test in Test Example 34 and the treatment in Example 1. DETAILED DESCRIPTION

[0759] Below, the present disclosure is described in further detail. It should be understood that throughout this specification, unless otherwise stated, the expression of the singular form also includes the concept of its plural form. Therefore, it should be understood that, unless otherwise stated, the article in the singular form (for example, "a (one)", "an (a kind of)", "the (the)" etc. in the English case) also includes the concept of its plural form. In addition, it should be understood that, unless otherwise stated, the terms used in this specification are used with the meaning commonly used in the field. Therefore, unless otherwise defined, all professional terms and scientific and technical terms used in this specification have the same meaning as those skilled in the art in the field to which the present disclosure belongs. In the event of a conflict, this specification (including definitions) shall prevail.

[0760] The following is an explanation of the terms used in this specification.

[0761] In this specification, the number of substituents in a group defined as "optionally substituted" is not particularly limited as long as substitution is possible. In addition, unless otherwise specified, the description of each group also applies to the case where the group is part of another group or a substituent.

[0762] Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a fluorine atom or a chlorine atom.

[0763] “C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and "C6 alkyl" refers to an alkyl group having 6 carbon atoms. The same applies to other numbers.

[0764] “C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Alkyl, preferably "C 1-4 Alkyl", more preferably "C 1-3 Alkyl. As "C 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. As "C 1-4 Specific examples of "alkyl" include, for example, 1-3 In addition to those listed as specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl and the like can be mentioned. As "C 1-6 Specific examples of "alkyl" include, for example, 1-4 In addition to those exemplified as specific examples of the "alkyl group", there can be mentioned pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

[0765] “C 2-6 "Alkenyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. 2-6 Alkenyl", preferably "C 2-4 Alkenyl". As "C 2-4 Specific examples of "alkenyl" include vinyl, propenyl, methacryl, butenyl, etc. As "C 2-6 Specific examples of "alkenyl" include, for example, 2-4 In addition to those listed as specific examples of "alkenyl", pentenyl, hexenyl and the like can be mentioned.

[0766] “C 2-6 "Alkynyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. 2-6 Alkynyl", preferably "C 2-4 Alkynyl". As "C 2-4 Specific examples of "alkynyl" include propynyl, methylpropynyl, butynyl, etc. As "C 2-6 Specific examples of "alkynyl" include, for example, 2-4 In addition to those listed as specific examples of "alkynyl", methylbutynyl, pentynyl, hexynyl and the like can be mentioned.

[0767] “C 1-6 "Alkoxy" refers to "C 1-6 Alkyloxy", "C 1-6 The "alkyl" part is the same as the aforementioned "C 1-6 Alkyl" is synonymous. As "C 1-6 Alkoxy", preferably "C 1-4 Alkoxy", more preferably "C 1-3 Alkoxy". As "C 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. As "C 1-4 Specific examples of "alkoxy" include, for example, 1-3 In addition to those listed as specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy and the like can be mentioned. As "C 1-6 Specific examples of "alkoxy" include, for example, 1-4 In addition to those listed as specific examples of the "alkoxy group", there can be mentioned pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

[0768] “C1-6 "C" in "alkylthio" 1-6 The "alkyl" part is the same as the aforementioned "C 1-6 Alkyl" has the same meaning. 1-6 "alkylthio" preferably includes "C 1-4 More preferably, "C 1-3 Alkylthio". As "C 1-3 Specific examples of "alkylthio" include methylthio, ethylthio, propylthio, 1-methylethylthio, etc. As "C 1-4 Specific examples of "alkylthio" include, for example, 1-3 In addition to those mentioned as specific examples of "alkylthio", butylthio, 1,1-dimethylethylthio, 1-methylpropylthio, 2-methylpropylthio and the like can be mentioned. As "C 1-6 Specific examples of "alkylthio" include, for example, 1-4 In addition to those listed as specific examples of the "alkylthio group", there can be mentioned a pentylthio group, a 1,1-dimethylpropylthio group, a 1,2-dimethylpropylthio group, a 1-methylbutylthio group, a 2-methylbutylthio group, a 4-methylpentylthio group, a 3-methylpentylthio group, a 2-methylpentylthio group, a 1-methylpentylthio group, a hexylthio group and the like.

[0769] “C 1-6 "Alkylene" refers to a linear or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Alkylene", preferably "C 1-4 Alkylene", more preferably "C 1-3 Alkylene". As "C 1-3 Specific examples of "alkylene" include methylene, ethylene, propylene, etc. As "C 1-4 Specific examples of "alkylene" include, for example, 1-3 In addition to those listed as specific examples of "alkylene", butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, 2-methyltrimethylene and the like can also be mentioned. 1-6 Specific examples of "alkylene" include, for example, 1-4 In addition to those listed as specific examples of the “alkylene group”, there may be mentioned pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene and the like.

[0770] “C 3-10"Cycloalkyl" refers to a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and also includes those having a part of unsaturated bonds and those having a bridged structure. 3-10 Cycloalkyl", preferably "C 3-7 Cycloalkyl". As "C 3-7 Specific examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. As "C 3-10 Specific examples of "cycloalkyl" include, for example, 3-7 In addition to those exemplified as specific examples of the "cycloalkyl group", cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like can also be mentioned.

[0771] In addition, “C 3-10 "Cycloalkyl" also includes the aforementioned C 3-10 A bicyclic group formed by condensing a cycloalkyl group and an aromatic hydrocarbon ring. Specific examples of such condensed compounds include the structures shown below.

[0772] [Chemistry 12]

[0773]

[0774] Specific examples of the bridge structure include the following structures.

[0775] [Chemistry 13]

[0776]

[0777] “C 3-10 "Cycloalkylene" refers to a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and also includes those having a partially unsaturated bond and those having a bridged structure. 3-10 Cycloalkylene", preferably "C 3-7 Cycloalkylene". As "C 3-7 Specific examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene. 3-10 Specific examples of "cycloalkyl" include, for example, 3-7 In addition to those exemplified as specific examples of the "cycloalkyl group", cyclooctylene, cyclononylene, cyclodecylene, adamantylene and the like can be mentioned.

[0778] Specific examples of the bridge structure include the following structures.

[0779] [Chemistry 14]

[0780]

[0781] "3- to 10-membered saturated carbocycle" refers to a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. As the "3- to 10-membered saturated carbocycle", a "4- to 6-membered saturated carbocycle" is preferably mentioned. Specific examples of the "4- to 6-membered saturated carbocycle" include, for example, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. Specific examples of the "3- to 10-membered saturated carbocycle" include, in addition to those mentioned as specific examples of the "4- to 6-membered saturated carbocycle", a cyclopropane ring, a cycloheptane ring, cyclooctane, cyclononane, and cyclodecane.

[0782] A "3- to 10-membered saturated heterocyclic group" refers to a monovalent saturated heterocyclic group composed of 1 to 2 atoms independently selected from nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, including those having partially unsaturated bonds and bridged structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO2-. Preferred examples of a "3- to 10-membered saturated heterocyclic group" include a "4- to 7-membered monocyclic saturated heterocyclic group." Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneimino, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxoxazolidinyl, dioxoxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Examples of the "3- to 10-membered saturated heterocyclic group" include, in addition to those listed as specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group", oxiranyl and aziridinyl.

[0783] Furthermore, the term "3- to 10-membered saturated heterocyclic group" also includes a bicyclic "3- to 10-membered saturated heterocyclic group" in which the aforementioned 3- to 10-membered saturated heterocyclic group forms a condensed ring with a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a condensed ring include dihydroindole, dihydroisoindole, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydronaphthyridinyl.

[0784] A "3- to 8-membered nitrogen-containing saturated heterocycle" refers to a saturated heterocycle consisting of one nitrogen atom and 2 to 7 carbon atoms. As the "3- to 8-membered nitrogen-containing saturated heterocycle", a "4- to 6-membered nitrogen-containing saturated heterocycle" is preferably mentioned. Specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle" include, for example, an azetidine ring, a pyrrolidine ring, and a piperidine ring. Specific examples of the "3- to 8-membered nitrogen-containing saturated heterocycle" include, in addition to those mentioned as specific examples of the aforementioned "4- to 6-membered nitrogen-containing saturated heterocycle", an aziridine ring, an azepane ring, an azoctane ring, and the like.

[0785] A "3- to 10-membered divalent saturated heterocyclic group" refers to a divalent saturated heterocyclic group composed of 1 to 2 atoms independently selected from nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, including those having partially unsaturated bonds and bridged structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO2-. Preferred examples of the "3- to 10-membered saturated heterocyclic group" include a "4- to 7-membered monocyclic saturated heterocyclic group." Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include, for example, oxetanylene, azetidinylene, tetrahydrofuranylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneiminoylene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxazolidinylene, dioxoxazolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, and tetrahydropyranylene. Examples of the "3- to 10-membered saturated heterocyclic group" include, in addition to those exemplified as specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group", oxiranediylene, aziranediylene, and the like.

[0786] Furthermore, the term "3- to 10-membered saturated heterocyclic group" also includes bicyclic "3- to 10-membered saturated heterocyclic groups" formed by condensing the aforementioned 3- to 10-membered saturated heterocyclic groups with a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming the condensed ring include indolinylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidylene, dihydrobenzodioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

[0787] “C 6-10 "Aryl" refers to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. 6-10 Specific examples of the "aryl group" include phenyl, 1-naphthyl, 2-naphthyl, etc. Preferably, phenyl is used.

[0788] In addition, “C 6-10 The "aryl" also includes the aforementioned C 6-10 Aryl and C 4-6 Cycloalkyl or 5- to 6-membered saturated heterocyclic ring forming a condensed bicyclic "C 6-10 Aryl". As a bicyclic "C 6-10 Specific examples of the "aryl group" include the following groups.

[0789] [Chemistry 15]

[0790]

[0791] "Aromatic hydrocarbon ring" refers to the above-mentioned "C 6-10 "aryl" ring portion.

[0792] A "5- to 12-membered heteroaryl group" refers to a monocyclic 5- to 7-membered aromatic heterocyclic ring containing 1 to 4 atoms independently selected from nitrogen, oxygen, and sulfur atoms, or a bicyclic 8- to 12-membered aromatic heterocyclic ring. A "5- to 7-membered monocyclic heteroaryl group" is preferred. A pyridyl, pyrimidyl, quinolyl, or isoquinolyl group is more preferred. Even more preferred is a pyridyl group. Specific examples of "5- to 7-membered monocyclic heteroaryl groups" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, and tetrazolyl. Specific examples of the "5- to 12-membered heteroaryl group" include, in addition to those groups listed as specific examples of the aforementioned "5- to 7-membered monocyclic heteroaryl group", indolyl, indazolyl, benzopyranyl, quinolyl, isoquinolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, and the like.

[0793] The "aromatic heterocycle" refers to the ring portion of the above-mentioned "5- to 12-membered heteroaryl group".

[0794] "Cancer" and "tumor" are used synonymously in this disclosure to refer to malignant tumors and encompass carcinomas, sarcomas, and hematological malignancies. Specific examples of "cancer" or "tumor" include acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell neoplasm, multiple myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma / thymic carcinoma, breast cancer, gastric cancer, gallbladder / cholangiocarcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

[0795] Presetin is a compound having the following structure.

[0796] [Chemistry 16]

[0797]

[0798] In the compounds of the present disclosure represented by formula (1), (2), (3), (4) or (5), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 8a 、R 8b ,R 8c 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 ,R 17 、R 18 Preferred embodiments of X, Y, Z, L, V, W, Q, and Y are as follows, but the technical scope of the present disclosure is not limited to the scope of the compounds listed below.

[0799] As R 1 A preferred embodiment includes C optionally substituted with 1 to 3 fluorine atoms. 1-6 alkyl.

[0800] As R 1A more preferred embodiment includes a methyl group or an ethyl group which may be substituted with 1 to 3 fluorine atoms.

[0801] As R 1 A further preferred embodiment of the present invention includes a methyl group optionally substituted with 1 to 3 fluorine atoms.

[0802] As R 1 A further more preferred embodiment of includes a methyl group.

[0803] As R 2 Preferred embodiments include hydrogen atom, halogen atom, cyano group, -OR 3 , C optionally substituted by 1 to 3 halogen atoms 1-6 Alkyl, C 3-10 a cycloalkyl group, or a 3- to 10-membered saturated heterocyclic group.

[0804] As R 2 A more preferred embodiment includes a hydrogen atom, a halogen atom, a cyano group or a C group optionally substituted by 1 to 3 halogen atoms. 1-6 alkyl.

[0805] As R 2 A further preferred embodiment includes a halogen atom, a cyano group or a C optionally substituted by 1 to 3 halogen atoms. 1-6 alkyl.

[0806] As R 2 A further more preferred embodiment of ] includes a cyano group.

[0807] As R 3 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0808] As R 3 A more preferred embodiment of the present invention is C 1-6 alkyl.

[0809] As R 3 A further preferred embodiment of the present invention is C 1-3 alkyl.

[0810] As R 3 A further more preferred embodiment of includes a methyl group.

[0811] As R 4 The preferred embodiment includes C 1-3 alkyl.

[0812] As R 4 A more preferred embodiment of includes a methyl group.

[0813] As R 5 、R 6 and R7 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0814] As R 5 、R 6 and R 7 A more preferred embodiment of the present invention is C 1-6 alkyl.

[0815] As R 5 、R 6 and R 7 A further preferred embodiment of the present invention is C 1-3 alkyl.

[0816] As R 5 、R 6 and R 7 A further more preferred embodiment of includes a methyl group.

[0817] As R 8 Preferred embodiments include hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 2 substituents), or 5 to 6 membered heteroaryl (the heteroaryl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 2 substituents which are the same or different).

[0818] As R 8 A more preferred embodiment includes a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 2 substituents which are the same or different).

[0819] As R 8 A further preferred embodiment of the present invention includes a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl.

[0820] As R 8 A further more preferred embodiment includes a hydrogen atom or a chlorine atom.

[0821] As R 8a 、R 8b and R8c Preferred embodiments include a hydrogen atom, a fluorine atom, a chlorine atom, and a bromine atom.

[0822] As R 8a 、R 8b and R 8c A more preferred embodiment of the present invention includes a hydrogen atom and a chlorine atom.

[0823] As R 8a 、R 8b and R 8c A further preferred embodiment of includes a hydrogen atom.

[0824] As R 9 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0825] As R 9 A more preferred embodiment of the present invention is C 1-3 alkyl.

[0826] As R 9 A further preferred embodiment of includes a methyl group.

[0827] As R 10 The preferred embodiment includes C 1-3 alkyl.

[0828] As R 10 A further preferred embodiment of includes a methyl group.

[0829] As R 11 、R 12 and R 13 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0830] As R 11 、R 12 and R 13 A more preferred embodiment of the present invention is C 1-3 alkyl.

[0831] As R 11 、R 12 and R 13 A further preferred embodiment of includes a methyl group.

[0832] As R 14 Preferred embodiments include hydrogen atoms, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), C 3-10Cycloalkyl (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0833] As R 14 A more preferred embodiment includes a hydrogen atom, a C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0834] As R 14 A further preferred embodiment of the present invention includes a hydrogen atom, or a C 1-3 An alkyl group (the alkyl group may be substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0835] As R 14 A further more preferred embodiment of includes a hydrogen atom or a methyl group.

[0836] As R 15 The preferred embodiment includes C 1-6 alkyl.

[0837] As R 15 A more preferred embodiment of the present invention is C 1-3 alkyl.

[0838] As R 15 A further preferred embodiment of includes a methyl group.

[0839] As R 16 and R 17 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0840] As R 16 and R 17 A more preferred embodiment of the present invention is C 1-6 alkyl.

[0841] As R 16 and R 17 A further preferred embodiment of the present invention is C1-3 alkyl.

[0842] As R 16 and R 17 A further more preferred embodiment of includes a methyl group.

[0843] As R 18 Preferred embodiments include hydrogen atoms, or C 1-6 alkyl.

[0844] As R 18 A more preferred embodiment of the present invention is C 1-6 alkyl.

[0845] As R 18 A further preferred embodiment of the present invention is C 1-3 alkyl.

[0846] As R 18 A further more preferred embodiment of includes a methyl group.

[0847] Preferred embodiments of X, Y and Z include CR 8 , or nitrogen atom. In the present disclosure, when referring to the compounds or pharmaceutically acceptable salts of the present disclosure, X, Y and Z are not all CR 8 .

[0848] Another preferred embodiment of X, Y, and Z is that one or two of X, Y, and Z represent a nitrogen atom.

[0849] Another preferred embodiment of X, Y and Z is that X is CR 8 , Y and Z are nitrogen atoms.

[0850] As another preferred embodiment of X, Y and Z, Y is CR 8 , X and Z are nitrogen atoms.

[0851] As a further preferred embodiment of X, Y and Z, Z is CR 8 , X and Y are nitrogen atoms.

[0852] Preferred embodiments of L include single bonds, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0853] As a more preferred embodiment of L, a single bond or C 1-6 An alkylene group (the alkylene group may be substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0854] As a further preferred embodiment of L, a single bond or C 1-6 An alkylene group (the alkylene group may be substituted with one substituent selected from a fluorine atom and a hydroxyl group).

[0855] As a more preferred embodiment of L, a single bond or a C optionally substituted with one hydroxyl group can be mentioned. 1-6 Alkylene.

[0856] Preferred embodiments of V include single bonds, C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano optionally substituted with 1 to 3 substituents that are the same or different), or a 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0857] As a more preferred embodiment of V, a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 alkyl, and cyano, optionally substituted with the same or different 1 to 2 substituents), or a 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 The alkyl group and the cyano group may be substituted with 1 to 2 substituents which may be the same or different.

[0858] As a more preferred embodiment of V, a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups and C 1-3 alkyl group optionally substituted with the same or different 1 to 2 substituents), or a 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups and C 1-3 The alkyl group may be optionally substituted with 1 to 2 identical or different substituents).

[0859] As a more preferred embodiment of V, a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3alkyl group, wherein one substituent in the alkyl group is optionally substituted), or a 3- to 7-membered divalent saturated heterocyclic group (the 3- to 7-membered saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted).

[0860] Preferred embodiments of W include single bonds, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different).

[0861] As a more preferred embodiment of W, a single bond or C 1-3 An alkylene group (the alkylene group may be substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group).

[0862] As a further preferred embodiment of W, a single bond or C 1-3 An alkylene group (the alkylene group may be substituted with one substituent selected from a fluorine atom and a hydroxyl group).

[0863] As a more preferred embodiment of W, a single bond or a C optionally substituted with one hydroxyl group can be mentioned. 1-3 Alkylene.

[0864] Preferred embodiments of Q include a hydrogen atom or NHR. 14 .

[0865] As a more preferred embodiment of Q, a hydrogen atom, NH2, or NHMe can be mentioned.

[0866] A further preferred embodiment of Q includes a hydrogen atom or NH 2 .

[0867] As a further more preferred embodiment of Q, a hydrogen atom can be mentioned.

[0868] Another more preferred embodiment of Q is NH 2 .

[0869] One embodiment of the compound represented by formula (1) includes the following (A).

[0870] (A) a compound or a pharmaceutically acceptable salt thereof, wherein

[0871] R 1 is a methyl group or an ethyl group optionally substituted with 1 to 3 fluorine atoms,

[0872] R 2 A hydrogen atom, a halogen atom, a cyano group, a -OR 3 , C optionally substituted by 1 to 3 halogen atoms 1-6Alkyl, C 3-10 Cycloalkyl, or 3-10 membered saturated heterocyclic group,

[0873] R 3 A hydrogen atom or C 1-6 alkyl,

[0874] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0875] R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 2 substituents), or 5 to 6 membered heteroaryl (the heteroaryl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with the same or different 1 to 2 substituents),

[0876] L is a single bond, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0877] V is a single bond, C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano optionally substituted with 1 to 3 substituents that are the same or different), or a 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0878] W is a single bond, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17, and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0879] Q is a hydrogen atom, or NHR 14 ,

[0880] R 14 For hydrogen atoms, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), C 3-10 Cycloalkyl (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0881] R 16 and R 17 A hydrogen atom or C 1-6 alkyl.

[0882] One embodiment of the compound represented by formula (1) includes the following (B).

[0883] (B) a compound or a pharmaceutically acceptable salt thereof, wherein

[0884] R 1 is a methyl group optionally substituted by 1 to 3 fluorine atoms,

[0885] R 2 is a halogen atom, a cyano group, or a C group optionally substituted by 1 to 3 halogen atoms 1-6 alkyl,

[0886] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0887] R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0888] L is a single bond, or C 1-6Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0889] V is a single bond, C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano optionally substituted with 1 to 3 substituents that are the same or different), or a 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0890] W is a single bond, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0891] Q is a hydrogen atom, or NHR 14 ,

[0892] R 14 For hydrogen atoms, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different and optionally substituted with cyano), C 3-10 Cycloalkyl (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano group, optionally substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0893] R 16and R 17 A hydrogen atom or C 1-6 alkyl.

[0894] One embodiment of the compound represented by formula (1) includes the following (C).

[0895] (C) a compound or a pharmaceutically acceptable salt thereof, wherein

[0896] R 1 is methyl, fluoromethyl,

[0897] R 2 is a chlorine atom, a cyano group, or a trifluoromethyl group,

[0898] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0899] R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0900] L is a single bond, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0901] V is a single bond, C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano optionally substituted with 1 to 3 substituents that are the same or different), or a 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0902] W is a single bond, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and cyano are optionally substituted with 1 to 3 substituents which are the same or different),

[0903] Q is a hydrogen atom, or NHR 14 ,

[0904] R 14 A hydrogen atom or C 1-3 an alkyl group (the alkyl group is optionally substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group),

[0905] R 16 and R 17 A hydrogen atom or C 1-6 alkyl.

[0906] One embodiment of the compound represented by formula (1) includes the following (D).

[0907] (D) a compound or a pharmaceutically acceptable salt thereof, wherein

[0908] R 1 is methyl,

[0909] R 2 is cyano,

[0910] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0911] R 8 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl,

[0912] L is a single bond, or C 1-6 an alkylene group (the alkylene group is optionally substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group),

[0913] V is a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 alkyl, and cyano, optionally substituted with the same or different 1 to 2 substituents), or a 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 alkyl, and cyano, which may be substituted with 1 to 2 substituents which are the same or different),

[0914] W is a single bond, or C 1-3 an alkylene group (the alkylene group is optionally substituted with one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group),

[0915] Q is a hydrogen atom, NH2, or NHMe.

[0916] One embodiment of the compound represented by formula (1) or (2) includes the following (E).

[0917] (E) a compound or a pharmaceutically acceptable salt thereof, wherein

[0918] X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 ,

[0919] R 8 is a hydrogen atom or a chlorine atom,

[0920] L is a single bond, or C optionally substituted by one hydroxyl group or fluorine atom 1-6 Alkylene,

[0921] V is a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 alkyl group optionally substituted with one substituent), or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0922] W is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0923] Q is a hydrogen atom, NH2, or NHMe.

[0924] One embodiment of the compound represented by formula (3) includes the following (F).

[0925] (F) a compound or a pharmaceutically acceptable salt thereof, wherein

[0926] R 8a and R 8b are each independently a hydrogen atom or a chlorine atom,

[0927] L is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0928] V is a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 alkyl group, wherein one substituent in the alkyl group is optionally substituted), or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0929] W is a single bond or a C optionally substituted by a hydroxyl group 1-3 Alkylene,

[0930] Q is a hydrogen atom or NH2.

[0931] One embodiment of the compound represented by formula (3) includes the following (G).

[0932] (G) a compound or a pharmaceutically acceptable salt thereof, wherein

[0933] R 8a and R 8b are each independently a hydrogen atom or a chlorine atom,

[0934] L is C optionally substituted with one hydroxyl group 1-3 Alkylene,

[0935] V is a single bond,

[0936] W is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0937] Q is NH2.

[0938] One embodiment of the compound represented by formula (3) includes the following (H).

[0939] (H) a compound or a pharmaceutically acceptable salt thereof, wherein

[0940] R 8a and R 8b are each independently a hydrogen atom,

[0941] L is C optionally substituted with one hydroxyl group 1-3 Alkylene,

[0942] V is C 3-7 Cycloalkylene,

[0943] W is C optionally substituted by 1 hydroxyl group 1-3 Alkylene,

[0944] Q is NH2.

[0945] One embodiment of the compound represented by formula (4) includes the following (I).

[0946] (I) a compound or a pharmaceutically acceptable salt thereof, wherein

[0947] R 8b and R 8c is a hydrogen atom,

[0948] L is a single bond, or C optionally substituted by one hydroxyl group or fluorine atom 1-3 Alkylene,

[0949] V is a single bond, C3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 alkyl group optionally substituted with one substituent), or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C groups optionally substituted with 1 to 3 hydroxyl groups or fluorine atoms); 1-3 1 substituent in the alkyl group is optionally substituted),

[0950] W is a single bond or a C optionally substituted by a hydroxyl group 1-3 Alkylene,

[0951] Q is a hydrogen atom, NH2, or NHMe.

[0952] One embodiment of the compound represented by formula (4) includes the following (J).

[0953] (J) a compound or a pharmaceutically acceptable salt thereof, wherein

[0954] R 8b and R 8c are each independently a hydrogen atom,

[0955] L is a C optionally substituted with a hydroxyl group or a fluorine atom 1-3 Alkylene,

[0956] V is a 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0957] W is a single bond,

[0958] Q is a hydrogen atom.

[0959] One embodiment of the compound represented by formula (4) includes the following (K).

[0960] (K) a compound or a pharmaceutically acceptable salt thereof, wherein

[0961] R 8b and R 8c are each independently a hydrogen atom,

[0962] L is a C optionally substituted with a hydroxyl group or a fluorine atom 1-3 Alkylene,

[0963] V is C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0964] W is C optionally substituted by 1 hydroxyl group 1-3 Alkylene,

[0965] Q is NH2.

[0966] One embodiment of the compound represented by formula (4) includes the following (L).

[0967] (L) a compound or a pharmaceutically acceptable salt thereof, wherein

[0968] R 8b and R 8c are each independently a hydrogen atom,

[0969] L is a single bond,

[0970] V is C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0971] W is a single bond,

[0972] Q is NH2 or NHMe.

[0973] One embodiment of the compound represented by formula (4) includes the following (M).

[0974] (M) a compound or a pharmaceutically acceptable salt thereof, wherein

[0975] R 8b and R 8c are each independently a hydrogen atom,

[0976] L is a C optionally substituted with a hydroxyl group or a fluorine atom 1-3 Alkylene,

[0977] V is a single bond,

[0978] W is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0979] Q is NH2 or NHMe.

[0980] One embodiment of the compound represented by formula (5) includes the following (N).

[0981] (N) a compound or a pharmaceutically acceptable salt thereof, wherein

[0982] R 8a and R 8c are each independently a hydrogen atom,

[0983] L is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0984] V is a single bond, C3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 alkyl group optionally substituted with one substituent), or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from a fluorine atom, a cyano group, a hydroxyl group, and a C 1-3 1 substituent in the alkyl group is optionally substituted),

[0985] W is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[0986] Q is a hydrogen atom or NH2.

[0987] One embodiment of the compound represented by formula (5) includes the following (O).

[0988] (O) a compound or a pharmaceutically acceptable salt thereof, wherein

[0989] R 8a and R 8c are each independently a hydrogen atom,

[0990] L is C optionally substituted with one hydroxyl group 1-3 Alkylene,

[0991] V is a 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted),

[0992] W is a single bond,

[0993] Q is a hydrogen atom.

[0994] One embodiment of the compound represented by formula (5) includes the following (P).

[0995] (P) a compound or a pharmaceutically acceptable salt thereof, wherein

[0996] R 8a and R 8c are each independently a hydrogen atom,

[0997] L is C optionally substituted with one hydroxyl group 1-3 Alkylene,

[0998] V is a single bond,

[0999] W is a single bond, or C optionally substituted by one hydroxyl group 1-3 Alkylene,

[1000] Q is NH2.

[1001] One embodiment of the compound represented by formula (5) includes the following (Q).

[1002] (Q) a compound or a pharmaceutically acceptable salt thereof, wherein

[1003] R 8a are each independently a hydrogen atom,

[1004] L is C optionally substituted with one hydroxyl group 1-3 Alkylene,

[1005] V is C 3-7 Cycloalkylene,

[1006] W is C optionally substituted by 1 hydroxyl group 1-3 Alkylene,

[1007] Q is NH2.

[1008] As one embodiment of the compound represented by formula (6), the following (R) can be mentioned.

[1009] (R) a compound or a pharmaceutically acceptable salt thereof, wherein

[1010] R 8a is a hydrogen atom,

[1011] L is C 1-3 Alkylene,

[1012] V is a single bond, or C 3-7 Cycloalkylene,

[1013] W is a single bond, or C 1-3 Alkylene,

[1014] Q is NH2.

[1015] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride can be cited, which is a crystalline form (Type I) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 7.2°±0.2°.

[1016] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride can be cited, which is a crystalline form (Form I) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 8.8°±0.2°.

[1017] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride can be cited, which is a crystalline form (Type I) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 7.2°±0.2° and 8.8°±0.2°.

[1018] As a further embodiment of the present invention, Type I crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride has a powder X-ray diffraction pattern expressed in 2θ and having characteristic peaks at 7.2°±0.2°, 8.8°±0.2°, 9.8°±0.2°, 10.2°±0.2°, 10.7°±0.2°, 16.7°±0.2°, 18.5°±0.2°, 26.2°±0.2°, 27.0°±0.2°, and 26.4°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1019] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate can be cited, which is a crystalline form (Form II) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 6.8°±0.2°.

[1020] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate can be cited, which is a crystalline form (Form II) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 13.0°±0.2°.

[1021] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate can be cited, which is a crystalline form (Form II) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 6.8°±0.2° and 13.0°±0.2°.

[1022] As a further embodiment of the present invention, a Type II crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate can be exemplified, having a powder X-ray diffraction pattern expressed in 2θ and having characteristic peaks at 6.8°±0.2°, 7.5°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 13.0°±0.2°, 16.4°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 22.7°±0.2°, and 24.3°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1023] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile toluenesulfonate can be cited, which is a crystalline form (Form III) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 6.0°±0.2°.

[1024] As a further embodiment of the present invention, a toluenesulfonate salt of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Type III) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 17.0°±0.2°.

[1025] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile toluenesulfonate can be cited, which is a crystalline form (Type III) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 6.0°±0.2° and 17.0°±0.2°.

[1026] As a further embodiment of the present invention, Type III crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile tosylate can be exemplified, having a powder X-ray diffraction pattern expressed in 2θ with characteristic peaks at 6.0°±0.2°, 9.0°±0.2°, 12.1°±0.2°, 14.4°±0.2°, 16.2°±0.2°, 17.0°±0.2°, 22.8°±0.2°, and 26.3°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1027] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Form IV) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 9.3°±0.2°.

[1028] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Form IV) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 10.2°±0.2°.

[1029] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Form IV) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 9.3°±0.2° and 10.2°±0.2°.

[1030] As a further embodiment of the present invention, a Type IV crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be exemplified, having a powder X-ray diffraction pattern expressed in 2θ with characteristic peaks at 9.3°±0.2°, 10.2°±0.2°, 10.7°±0.2°, 13.6°±0.2°, 16.7°±0.2°, 17.1°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 26.1°±0.2°, and 26.4°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1031] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (V form) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 7.9°±0.2°.

[1032] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (V form) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at least at 8.7°±0.2°.

[1033] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (V form) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 7.9°±0.2° and 8.7°±0.2°.

[1034] As a further embodiment of the present invention, a V-type crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be exemplified, having a powder X-ray diffraction pattern expressed in 2θ and having characteristic peaks at 7.9°±0.2°, 8.7°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 15.9°±0.2°, 17.6°±0.2°, 19.9°±0.2°, 21.9°±0.2°, 22.8°±0.2°, and 26.6°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1035] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Form VI) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 5.3°±0.2°.

[1036] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Form VI) having a powder X-ray diffraction pattern represented by 2θ and having a characteristic peak at at least 5.7°±0.2°.

[1037] As a further embodiment of the present invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile can be cited, which is a crystalline form (Type VI) having a powder X-ray diffraction pattern represented by 2θ and having characteristic peaks at at least 5.3°±0.2° and 5.7°±0.2°.

[1038] As a further embodiment of the present invention, a Type VI crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile has a powder X-ray diffraction pattern expressed in 2θ and having characteristic peaks at 5.3°±0.2°, 5.7°±0.2°, 7.0°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 8.4°±0.2°, 9.3°±0.2°, 10.5°±0.2°, 11.5°±0.2°, and 14.1°±0.2°. The crystal can be identified by having four or five peaks selected from these ten peaks.

[1039] When administering the compound of the present disclosure, its usage amount varies according to symptoms, age, administration method, etc. For example, in the case of intravenous injection, for adults, the lower limit is 0.01 mg (preferably 0.1 mg) per day and the upper limit is 1000 mg (preferably 100 mg), divided into 1 or several times, and administered according to symptoms, thus expecting an effect. As its administration schedule, for example, a single administration, 1 day 1 continuous administration for 3 days or 1 day 2 continuous administrations for 1 week can be cited. Furthermore, each administration method of the above record can also be repeated at intervals of about 1 day to about 60 days.

[1040] The compounds of the present disclosure can be administered parenterally or orally, preferably parenterally, more preferably intravenously. In addition, the compounds of the present disclosure are preferably formulated and administered as a pharmaceutically acceptable carrier, such as liposomes.

[1041] The liposomes encapsulating the compounds of the present disclosure contain at least one phospholipid. Examples of the phospholipids include phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin.

[1042] The fatty acid residues in the phospholipids are not particularly limited. Examples include saturated or unsaturated fatty acid residues having 14 to 18 carbon atoms, and specifically, acyl groups derived from fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid. Furthermore, naturally derived phospholipids such as egg yolk lecithin and soybean lecithin, as well as hydrogenated egg yolk lecithin and hydrogenated soybean lecithin (also known as hydrogenated soybean lecithin or hydrogenated soybean phosphatidylcholine) containing hydrogen added to their unsaturated fatty acid residues, can also be used.

[1043] The amount (molar fraction) of phospholipids incorporated with respect to the entire liposome membrane components is not particularly limited, but is preferably 30 to 80%, more preferably 40 to 70%.

[1044] The liposomes encapsulating the compounds of the present disclosure may contain sterols. Examples of sterols include cholesterol, β-sitosterol, stigmasterol, camphorasterol, oleyl sterol, ergosterol, and fucoxanthin. Preferred sterols include cholesterol. The amount (molar fraction) of sterols relative to the total liposome membrane components is not particularly limited, but is preferably 0 to 60%, more preferably 10 to 50%, and even more preferably 30 to 50%.

[1045] The liposomes encapsulating the compounds of the present invention may include polymer-modified lipids in order to improve retention in the body. The amount (molar fraction) of the polymer-modified lipid relative to the overall liposome membrane component is not particularly limited, and preferably 0 to 20%, more preferably 1 to 10%. As the polymer portion of the polymer-modified lipid, preferably a hydrophilic polymer is listed, and more preferably a hydrophilic polymer in which the end of the polymer not bound to the lipid is alkoxylated. As the polymer portion of the polymer-modified lipid, there is no particular limitation, and for example, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinyl pyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinyl pyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, and propoxypolyvinyl pyrrolidone can be cited. Preferred examples of the polymer moiety of the polymer-modified lipid include polyethylene glycol, methoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, propoxypolyethylene glycol, and propoxypolypropylene glycol. More preferred examples of the polymer moiety of the polymer-modified lipid include polyethylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, and propoxypolyethylene glycol. Even more preferred examples of the polymer moiety of the polymer-modified lipid include polyethylene glycol and methoxypolyethylene glycol. Most preferred examples of the polymer moiety of the polymer-modified lipid include methoxypolyethylene glycol. The molecular weight of the polymer moiety of the polymer-modified lipid is not particularly limited, and for example, it can be 100 to 10,000 daltons, preferably 1,000 to 7,000 daltons, more preferably 1,500 to 5,000 daltons, and most preferably 1,500 to 3,000 daltons.

[1046] The lipid portion of the polymer-modified lipid is not particularly limited, but examples thereof include phosphatidylethanolamine and diacylglycerol. Preferred examples of the lipid portion of the polymer-modified lipid include phosphatidylethanolamine having a saturated or unsaturated fatty acid residue with 14 to 18 carbon atoms, and diacylglycerol having a saturated or unsaturated fatty acid residue with 14 to 18 carbon atoms. More preferred examples include phosphatidylethanolamine having a saturated fatty acid residue with 14 to 18 carbon atoms, and diacylglycerol having a saturated fatty acid residue with 14 to 18 carbon atoms. Even more preferred examples include phosphatidylethanolamine having a palmitoyl or stearoyl group, and diacylglycerol having a palmitoyl or stearoyl group. Most preferred examples of the lipid portion of the polymer-modified lipid include distearoylphosphatidylethanolamine.

[1047] The liposomes encapsulating the compounds of the present disclosure may contain pharmaceutically acceptable additives, such as inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

[1048] Examples of the inorganic acid include phosphoric acid, hydrochloric acid, and sulfuric acid.

[1049] Examples of the inorganic acid salt include sodium hydrogen phosphate, sodium chloride, ammonium sulfate, and magnesium sulfate.

[1050] Examples of the organic acid include citric acid, acetic acid, succinic acid, and tartaric acid.

[1051] Examples of the organic acid salt include sodium citrate, sodium acetate, disodium succinate, and sodium tartrate.

[1052] Examples of sugars include glucose, sucrose, mannitol, sorbitol, and trehalose.

[1053] Examples of the buffer include L-arginine, L-histidine, tromethamine (trishydroxymethylaminomethane, Tris), and salts thereof.

[1054] Examples of the antioxidant include sodium sulfite, L-cysteine, sodium thioglycolate, sodium thiosulfate, ascorbic acid, and tocopherol.

[1055] Examples of the polymers include polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, and sodium carboxymethylcellulose.

[1056] The following describes the method for producing the compound of the present disclosure represented by formula (1) by way of example, but the method for producing the compound of the present disclosure is not limited thereto. The compound used in the following production method may form a salt as long as it does not inhibit the reaction.

[1057] The compounds of the present invention can be prepared using known compounds as starting materials by appropriately combining, for example, the following methods A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, and R, or by methods according to these methods or synthetic methods known to those skilled in the art. Compounds of the present invention other than formula (a2) can also be prepared by appropriately combining these methods or synthetic methods known to those skilled in the art.

[1058] Manufacturing Method A

[1059] The compound of the present disclosure represented by formula (a2) can be produced, for example, by the following method.

[1060] [Chemistry 17]

[1061]

[1062] [Where R 1 、R 2 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1. 1 Refers to the protecting group of amino group. 1 Examples thereof include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).

[1063] [Process 1]

[1064] Compound (a2) can be prepared by converting the protective group P of compound (a1) obtained by the following production method into 1 This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[1065] Manufacturing Method B

[1066] The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method.

[1067] [Chemistry 18]

[1068]

[1069] [Where R1 、R 2 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1. 1 refers to the protecting group of amino group, P 2 Refers to the protecting group of phenol. 1 As P, there can be mentioned, for example, the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999), etc. 2 Examples thereof include the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[1070] Compound (b3) is available as a commercial product.

[1071] [Process 1]

[1072] Compound (b2) can be prepared by converting the protective group P of compound (b1) obtained by the following production method into 2 This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[1073] [Process 2]

[1074] Compound (a1) can be produced by the Mitsunobu reaction of compound (b2) and compound (b3) in a suitable solvent in the presence of Mitsunobu's reagent.

[1075] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), isopropyl azodicarboxylate (DIAD), N,N,N',N'-tetraisopropyl azodicarbonamide (TIPA), 1,1'-(azodicarbonyl)dipiperidine (ADDP), N,N,N',N'-tetramethylazodicarbonamide (TMAD), triphenylphosphine, and tributylphosphine. Cyanomethylenetrimethylphosphine (CMMP) and cyanomethylenetributylphosphine (CMBP) can also be used.

[1076] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixed solvents thereof. Preferred solvents include toluene, benzene, THF, 1,4-dioxane, and mixed solvents thereof.

[1077] The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

[1078] The reaction temperature is usually 0°C to 100°C, preferably 0°C to 50°C.

[1079] Manufacturing Method C

[1080] The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method.

[1081] [Chemistry 19]

[1082]

[1083] [Where R 1 、R 2 , X, Y and Z have the same meaning as in item 1. 2 Refers to the protecting group of phenol. 2 Examples thereof include the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[1084] [Process 1]

[1085] Compound (c2) can be produced by reacting compound (c1) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

[1086] Examples of the acid include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, and camphorsulfonic acid. Preferred examples of the acid include acetic acid and p-toluenesulfonic acid.

[1087] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropanol, and butanol; and mixtures thereof. Preferred solvents include 1,4-dioxane, toluene, and ethanol.

[1088] The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

[1089] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[1090] [Process 2]

[1091] Compound (b1) can be produced by reacting compound (c2) with a 5-chloropyrazine derivative in the presence of a suitable base in a suitable solvent. Compound (b1) can also be produced by reacting compound (c2) with a 5-chloropyrazine derivative in the presence of a suitable palladium catalyst, a ligand, and a base in a suitable solvent.

[1092] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), and N-ethylmorpholine; and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide. Preferred bases include triethylamine, diisopropylethylamine, N-ethylmorpholine, potassium carbonate, and cesium carbonate.

[1093] Examples of the palladium catalyst include salts such as palladium chloride and palladium acetate, and zero-valent palladium complexes such as tris(dibenzylideneacetone)dipalladium(0)chloroform adduct.

[1094] Examples of the ligand include phosphine ligands such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantophos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). The ligand is preferably 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantophos).

[1095] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include tetrahydrofuran, 1,4-dioxane, toluene, and dimethyl sulfoxide.

[1096] The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

[1097] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[1098] Manufacturing method D

[1099] The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method.

[1100] [Chemistry 20]

[1101]

[1102] [Where R 1 , X, Y and Z have the same meanings as those in item 1, P 2 Refers to the protecting group of phenol. 2 For example, the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.

[1103] [Process 1]

[1104] Compound (c1) can be produced by reacting compound (d1) with acetonitrile in the presence of a suitable base in a suitable solvent.

[1105] As the base, an inorganic base can be used. Examples of the inorganic base include hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, and alkali metals such as n-butyllithium, methyllithium, and isopropylmagnesium bromide. Preferred bases include sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and n-butyllithium.

[1106] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and mixtures thereof. Preferred solvents include tetrahydrofuran and toluene.

[1107] The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

[1108] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[1109] Manufacturing method E

[1110] The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method.

[1111] [Chemistry 21]

[1112]

[1113] [Where R 1 、R 2 , X, Y and Z have the same meanings as those in item 1, P 2 Refers to the protecting group of phenol. 2 For example, the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.

[1114] [Process 1]

[1115] Compound (e2) can be produced by reacting compound (e1) with carbon disulfide and iodomethane in the presence of a suitable base in a suitable solvent.

[1116] As the base, an inorganic base can be used. Examples of the inorganic base include hydrides such as sodium hydride, alkali metal halides such as potassium fluoride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, and alkali metals such as n-butyllithium, methyllithium, and isopropylmagnesium bromide. Preferred bases include sodium hydride and potassium tert-butoxide.

[1117] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, and N,N-dimethylformamide.

[1118] The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours.

[1119] The reaction temperature is usually -78°C to 200°C, preferably 0°C to 25°C.

[1120] [Process 2]

[1121] Compound (e3) can be produced by reacting compound (e2) with a 5-aminopyrazine derivative in the presence of a suitable base in a suitable solvent.

[1122] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), and N-ethylmorpholine; and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred bases include triethylamine and diisopropylethylamine.

[1123] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, and dimethyl sulfoxide.

[1124] The reaction time is usually 5 minutes to 48 hours, preferably 2 hours to 8 hours.

[1125] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[1126] [Process 3]

[1127] Compound (b1) can be produced by reacting compound (e3) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

[1128] Examples of the acid include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, and camphorsulfonic acid. Preferably, the acid is acetic acid.

[1129] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and mixtures thereof. Preferred solvents include 1,4-dioxane and ethanol.

[1130] The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

[1131] The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[1132] Manufacturing method F

[1133] The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method.

[1134] [Chemistry 22]

[1135]

[1136] [Where R 1 , X, Y and Z have the same meanings as those in item 1, P 2 Refers to the protecting group of phenol. 2 For example, the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.

[1137] [Process 1]

[1138] Compound (f1) can be produced by reacting compound (e1) with dimethylformamide dimethyl acetal in a suitable solvent.

[1139] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include N,N-dimethylformamide.

[1140] The reaction time is usually 5 minutes to 48 hours, preferably 24 hours to 48 hours.

[1141] The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C.

[1142] [Process 2]

[1143] Compound (f2) can be produced by reacting compound (f1) with hydroxylamine hydrochloride in an appropriate solvent.

[1144] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and butanol; and mixtures thereof. Preferred solvents include ethanol and isopropyl alcohol.

[1145] The reaction time is usually 5 minutes to 48 hours, preferably 6 hours to 12 hours.

[1146] The reaction temperature is usually 0°C to 200°C, preferably 40°C to 80°C.

[1147] [Process 3]

[1148] Compound (c1) can be produced by reacting compound (f2) with a base in an appropriate solvent.

[1149] Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred bases include sodium hydroxide and potassium hydroxide.

[1150] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; protic solvents such as water, methanol, ethanol, isopropyl alcohol, and butanol; and mixtures thereof. Preferred solvents include mixed solvents of water and ethanol.

[1151] The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

[1152] The reaction temperature is usually 0°C to 200°C, preferably 20°C to 50°C.

[1153] Manufacturing method G

[1154] The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method.

[1155] [Chemistry 23]

[1156]

[1157] [Where R 1 、R 2 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1158] [Process 1]

[1159] Compound (g2) can be produced from compound (g1) obtained by the following production method by the method described in step 1 of production method C or a method based thereon.

[1160] [Process 2]

[1161] Compound (a1) can be produced from compound (g2) by the method described in step 2 of production method C or a method based thereon.

[1162] Manufacturing method H

[1163] The compound represented by formula (a1) can be produced, for example, by the following method.

[1164] [Chemistry 24]

[1165]

[1166] [Where R 1 、R 2 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1167] [Process 1]

[1168] Compound (h2) can be produced from compound (h1) obtained by the following production method by the method described in step 1 of production method E or a method based thereon.

[1169] [Process 2]

[1170] Compound (h3) can be produced from compound (h2) by the method described in step 2 of Production Method E or a method based thereon.

[1171] [Process 3]

[1172] Compound (a1) can be produced from compound (h3) by the method described in step 3 of Production Method E or a method based thereon.

[1173] Manufacturing Method I

[1174] The compound represented by formula (g1) can be produced, for example, by the following method.

[1175] [Chemistry 25]

[1176]

[1177] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1178] [Process 1]

[1179] Compound (i1) can be produced from compound (h1) obtained by the following production method by the method described in step 1 of production method F or a method based thereon.

[1180] [Process 2]

[1181] Compound (i2) can be produced from compound (i1) by the method described in step 2 of Production Method F or a method based thereon.

[1182] [Process 3]

[1183] Compound (g1) can be produced from Compound (i2) by the method described in Step 3 of Production Method F or a method based thereon.

[1184] Manufacturing method J

[1185] The compound represented by formula (g1) can also be produced, for example, by the following method.

[1186] [Chemistry 26]

[1187]

[1188] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1189] [Process 1]

[1190] Compound (g1) can be produced by the method described in step 1 of Production Method D or a method based thereon, from Compound (j1) obtained by the following Production Method.

[1191] Manufacturing Method K

[1192] The compound of the present disclosure represented by formula (d1) can be produced, for example, by the following method.

[1193] [Chemistry 27]

[1194]

[1195] [Where R 1 , X, Y and Z have the same meanings as those in item 1, P 2 Refers to the protecting group of phenol. 2 For example, the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.

[1196] Compound (k1) is available as a commercial product.

[1197] [Process 1]

[1198] Compound (d1) can be produced from compound (k1) by, for example, the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[1199] Manufacturing method L

[1200] The compound of the present disclosure represented by formula (e1) can be produced, for example, by the following method.

[1201] [Chemistry 28]

[1202]

[1203] [Where R 1 , X, Y and Z have the same meanings as those in item 1, P 2 Refers to the protecting group of phenol. 2 For example, the protecting groups for phenol described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.

[1204] Compound (11) is available as a commercial product.

[1205] [Process 1]

[1206] Compound (e1) can be produced from Compound (l1) by the method described in Step 1 of Production Method K or a method based thereon.

[1207] Manufacturing method M

[1208] The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method.

[1209] [Chemistry 29]

[1210]

[1211] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1212] Compound (k1) and compound (b3) are available as commercial products.

[1213] [Process 1]

[1214] Compound (j1) can be produced from compound (k1) and compound (b3) by the method described in step 2 of production method B or a method based thereon.

[1215] Manufacturing method N

[1216] The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method.

[1217] [Chemistry 30]

[1218]

[1219] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 refers to the protecting group of amino group, LG refers to the leaving group. 1 Examples include amino protecting groups such as those described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons, Inc., 1999). Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.

[1220] Compound (k1) and compound (n1) are available as commercial products.

[1221] [Process 1]

[1222] Compound (j1) can be produced by reacting Compound (k1) and Compound (n1) in the presence or absence of a suitable base in a suitable solvent.

[1223] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM); and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred bases include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydroxide.

[1224] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include 2-propanol, tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide.

[1225] The reaction temperature is usually -80°C to heating under reflux, preferably 25°C to 90°C.

[1226] The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[1227] Manufacturing method O

[1228] The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[1229] [Chemistry 31]

[1230]

[1231] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 Refers to the protecting group of amino group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be cited.]

[1232] Compound (11) and compound (b3) are available as commercial products.

[1233] [Process 1]

[1234] Compound (h1) can be produced from Compound (l1) and Compound (b3) by the method described in Step 2 of Production Method B or a method based thereon.

[1235] Manufacturing method P

[1236] The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[1237] [Chemistry 32]

[1238]

[1239] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 refers to the protecting group of amino group, LG refers to the leaving group. 1 Examples include amino protecting groups such as those described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons, Inc., 1999). Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.

[1240] Compound (l1) and compound (n1) are available as commercial products.

[1241] [Process 1]

[1242] Compound (h1) can be produced from Compound (l1) and Compound (n1) by the method described in Step 2 of Production Method B or a method based thereon.

[1243] Manufacturing method Q

[1244] The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[1245] [Chemistry 33]

[1246]

[1247] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P1 refers to the protecting group of amino group, LG refers to the leaving group. 1 Examples include amino protecting groups such as those described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter G.M. Wuts, published by John Wiley & Sons, Inc., 1999). Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy.

[1248] Compound (q1), compound (q2) and compound (b3) are available as commercial products.

[1249] [Process 1]

[1250] Compound (q3) can be produced from Compound (q1) and Compound (q2) by the method described in Step 1 of Production Method N or a method based thereon.

[1251] [Process 2]

[1252] Compound (q4) can be produced by reacting compound (q3) with acetaldehyde in the presence of a suitable base in a suitable solvent.

[1253] Examples of the base include n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium hexamethylpiperidinium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and isopropylmagnesium chloride-lithium chloride complex.

[1254] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. A preferred solvent is tetrahydrofuran.

[1255] The reaction temperature is usually -80°C to heating under reflux, preferably -80°C to 25°C.

[1256] The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[1257] [Process 3]

[1258] Compound (q5) can be produced by reacting compound (q4) with a suitable oxidizing agent in the presence or absence of a suitable base in a suitable solvent.

[1259] Examples of the oxidizing agent include manganese dioxide, Dess-Martin reagent, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-trifluoroacetic anhydride, sulfur trioxide-pyridine complex, and 2,2,6,6-tetramethylpiperidin-1-oxyl-sodium hypochlorite.

[1260] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM); and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

[1261] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include dichloromethane, tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide.

[1262] The reaction temperature is usually -80°C to heating under reflux, preferably -80°C to 25°C.

[1263] The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[1264] [Process 4]

[1265] Compound (h1) can be produced from compound (q5) and compound (b3) by the method described in step 2 of production method B or a method based thereon.

[1266] Manufacturing method R

[1267] The compound of the present disclosure represented by formula (i2) can be produced, for example, by the following method.

[1268] [Chemistry 34]

[1269]

[1270] [Where R 1 、R 14 , X, Y, Z, L, V and W have the same meanings as those in item 1, P 1 refers to the protecting group of amino group, LG refers to the leaving group. 1 For example, the protecting groups for amino groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) and the like can be cited.

[1271] Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonic acid oxy, and trifluoromethanesulfonic acid oxy.]

[1272] Compound (11) and compound (b3) are available as commercial products.

[1273] [Process 1]

[1274] Compound (r1) can be produced from compound (l1) by the method described in step 1 of production method F or a method based thereon.

[1275] [Process 2]

[1276] Compound (r2) can be produced from compound (r1) by the method described in step 2 of Production Method F or a method based thereon.

[1277] [Process 3]

[1278] Compound (r3) can be produced by reacting compound (r2) with an appropriate halogenating agent or sulfonylating agent in the presence or absence of an appropriate base in an appropriate solvent or without a solvent.

[1279] Examples of the halogenating agent or sulfonylating agent include thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus tribromide, methanesulfonyl chloride, N-phenylbis(trifluoromethanesulfonimide), and trifluoromethanesulfonic anhydride.

[1280] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM); and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.

[1281] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include dichloromethane, tetrahydrofuran, toluene, acetonitrile, and N,N-dimethylformamide.

[1282] The reaction temperature is usually -80°C to heating under reflux, preferably 0°C to heating under reflux.

[1283] The reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 12 hours.

[1284] [Process 4]

[1285] Compound (i2) can be produced by subjecting Compound (r3) and Compound (b3) to a catalytic reaction with a suitable palladium source and a ligand in a suitable solvent in the presence of a suitable base.

[1286] Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM), and inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide. Preferred bases include diisopropylethylamine and cesium carbonate.

[1287] Examples of the palladium source include salts such as palladium chloride and palladium acetate, and zero-valent palladium complexes such as tris(dibenzylideneacetone)dipalladium(0) chloroform adduct.

[1288] Examples of the ligand include phosphine ligands such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantophos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). Preferred ligands include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantophos).

[1289] The solvent is not particularly limited as long as it is unreactive under the reaction conditions of this step. Examples include halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; aprotic solvents such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; and mixtures thereof. Preferred solvents include tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, and N,N-dimethylformamide.

[1290] The reaction temperature is usually 0°C to heating under reflux, preferably 50°C to heating under reflux.

[1291] The reaction time is usually 5 minutes to 72 hours, preferably 2 to 12 hours.

[1292] In the production methods described above, starting materials or intermediates for which the production methods are not described are commercially available, or can be synthesized from commercially available compounds by methods known to those skilled in the art or by methods in accordance therewith.

[1293] In each reaction of the production method described above, unless the use of a protecting group is specifically indicated, a protecting group may be used as needed. For example, if any functional group other than the reaction site is altered under the described reaction conditions, or if the described method is not suitable without a protecting group, the target compound can be obtained by protecting the site other than the reaction site and then deprotecting it after the reaction is completed or after a series of reactions.

[1294] As the protecting group, for example, the protecting group described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G.M. Wuts, published by John Wiley & Sons, Inc. in 1999) can be used. As a specific example of the protecting group of amino, for example, benzyloxycarbonyl, tert-butyloxycarbonyl, acetyl, benzyl, etc. can be enumerated. In addition, as a specific example of the protecting group of hydroxyl, for example, trialkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc. can be enumerated.

[1295] The introduction and removal of the protecting group can be carried out by methods commonly used in organic synthetic chemistry (see, for example, the aforementioned Protective Groups in Organic Synthesis) or methods in accordance therewith.

[1296] In this specification, protecting groups, condensing agents, etc. may be represented by IUPAC-IUB (Commission on Biochemical Nomenclature) abbreviations commonly used in this technical field. It should be noted that the compound names used in this specification do not necessarily follow the IUPAC nomenclature.

[1297] The intermediates or target compounds in the above-described production methods can also be derived into other compounds included in the present disclosure by appropriately modifying their functional groups (e.g., protecting and deprotecting the functional groups as needed, and performing various transformations starting with amino, hydroxyl, carbonyl, halogen, etc.). Functional group transformations can be performed by commonly used general methods (e.g., see Comprehensive Organic Transformations, R.C. Larock, John Wiley & Sons Inc. (1999)).

[1298] The intermediates and target compounds in the above-described production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography methods, etc.). In addition, the intermediates can be used in subsequent reactions without special purification.

[1299] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, hydroiodides, nitrates, and phosphates, or organic acid salts such as citrates, oxalates, phthalates, fumarates, maleates, succinates, malates, acetates, formates, propionates, benzoates, trifluoroacetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, and camphorsulfonates. Base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, "pharmaceutically acceptable salts" include amino acid salts with basic amino acids or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[1300] Suitable salts of starting materials and intermediates and acceptable salts as pharmaceutical raw materials are conventional non-toxic salts. As these salts, for example, except organic acid salts (such as acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formates, toluenesulfonate etc.) and inorganic acid salts (such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate etc.), with amino acid (such as arginine, aspartic acid, glutamic acid etc.) salts, alkali metal salts (such as sodium salt, potassium salt etc.), alkaline earth metal salts (such as calcium salt, magnesium salt etc.) metal salts, ammonium salts, organic base salts (such as trimethylamine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt etc.), etc., those skilled in the art can suitably select.

[1301] In the present disclosure, any one or two or more of the compounds represented by formula (1) to (5) 1 H is transformed into 2 Deuterated forms obtained by reacting H(D) are also included in the compounds represented by formulae (1) to (5).

[1302] The present disclosure includes compounds represented by formulas (1) to (5) or pharmaceutically acceptable salts thereof. Furthermore, the compounds of the present disclosure may exist in the form of hydrates and / or solvates with various solvents (e.g., ethanolates), and such hydrates and / or solvates are also encompassed by the compounds of the present disclosure.

[1303] Furthermore, the compounds of the present disclosure also include all possible isomers such as optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restraint of intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and all forms of crystal forms, and mixtures thereof.

[1304] Particularly optical isomers and atropisomers can be obtained as racemates, or when using optically active starting materials or intermediates, can be obtained as optically active forms. In addition, as required, at the appropriate stage of the aforementioned manufacturing method, the racemate of the corresponding raw material, intermediate or final product can be physically or chemically split into their optical enantiomers by using known separation methods such as the method using an optically active column, fractional crystallization, etc. As their separation methods, for example, a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, and the difference in physical properties is utilized to separate the diastereomers by methods such as fractional crystallization, etc.

[1305] When a pharmaceutically acceptable salt of the compound of the present disclosure is desired, when the compound represented by formula (1) to (5) is obtained as a pharmaceutically acceptable salt, it is sufficient to purify it directly. Alternatively, when it is obtained in a free form, it is sufficient to dissolve or suspend it in a suitable organic solvent, add an acid or a base, and form a salt by a conventional method.

[1306] Liposomes encapsulating the compounds of the present disclosure can be produced, for example, by the following method.

[1307] [Process 1]

[1308] The membrane components such as phospholipids and cholesterol are dissolved in organic solvents such as chloroform, and the organic solvent is removed by distillation in a flask, thereby forming a film of lipid mixture on the inner wall of the flask. As above-mentioned substitution, it is also possible to be dissolved in tert-butyl alcohol etc., then freeze-dried, thereby obtaining lipid mixture as a freeze-dried product. In addition, after the membrane components such as phospholipids and cholesterol are dissolved in an organic solvent, using instant vacuum drying device CRUX (Hosokawa Micron Co., Ltd. system), it is also possible to obtain powdered lipid mixture, which can be obtained by Japan Seika Co., Ltd. under the name of Presome (registered trademark).

[1309] [Process 2]

[1310] An internal aqueous phase solution such as an aqueous ammonium sulfate solution is added to the lipid mixture obtained in step 1 and dispersed to obtain a crude liposome dispersion.

[1311] [Process 3]

[1312] The crude liposome dispersion obtained in step 2 is passed through a filter using an extruder to obtain the desired particle size. Alternatively, the crude liposome dispersion obtained in step 2 is discharged from a nozzle under high pressure using a high-pressure homogenizer to obtain the desired particle size. The particle size of the liposome is not particularly limited, and is, for example, 10 nm to 200 nm, preferably 30 nm to 150 nm, more preferably 40 nm to 140 nm, further preferably 50 to 120 nm, and most preferably 60 to 100 nm. The particle size of the liposome is an average value measured by dynamic light scattering, for example, using a Zetasizer Nano ZS (Malvern Instruments).

[1313] [Process 4]

[1314] The liposome solution obtained in step 3 is subjected to gel filtration, dialysis, tangential flow filtration, ultracentrifugation or the like to replace the external aqueous phase.

[1315] [Process 5]

[1316] The liposome solution obtained in step 4, in which the external aqueous phase has been replaced, is incubated with the compound to be encapsulated, thereby encapsulating the compound in the liposome.

[1317] [Process 6]

[1318] The obtained compound-encapsulated liposomes are subjected to gel filtration, dialysis, tangential flow filtration, or ultracentrifugation to remove unencapsulated compounds. If the desired encapsulation efficiency is obtained in step 5, step 6 can be omitted.

[1319] The compounds of the present disclosure may be used in combination with other drugs to enhance their effects. Specifically, the compounds of the present disclosure may be used in combination with drugs such as hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors. Hereinafter, drugs that can be used in combination with the compounds of the present disclosure are referred to as concomitant drugs.

[1320] The compounds disclosed herein exhibit excellent anticancer effects even when used as a single agent. By further using them in combination with one or more of the aforementioned concomitant drugs (multiple-dose combination), their effects can be further enhanced or the patient's QOL can be improved.

[1321] Examples of the "hormonal therapeutic agent" include fosfostilbestrol, diethylstilbestrol, clobendazone, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprinil, allylestradiol, pregnenolone, nomegestrol, tadenan, mepartricin, raloxifene, ormeloxifene, levomeloxifen, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), pills, meticlostat, testolactone, aminoglutethimide, LH-RH derivatives (LH-RH agonists (e.g., gosereid acetate),

[0014] The present invention also includes but is not limited to: steroids (e.g., steroids, steroids, steroid hormones, steroid hormones, steroid hormone inhibitor ...

[1322] Examples of the "chemotherapeutic agent" include alkylating agents, metabolic antagonists, anticancer antibiotics, plant-derived anticancer agents, molecular targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. Representative examples are listed below.

[1323] Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquinone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitotol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, trotiamide, carmustine, lomustine, streptozotocin, pipobroman, etoglotose, carboplatin, cisplatin, miplatin, nedaplatin, oxaliplatin, hexamethylmelamine, aminostine, spironium dibromide, fotemustine, prednimustine, puromycin, bendamustine (ribomustin), temozolomide, trofosfamide, nistatin, timarazine, adolesin, cysteamine nitrosourea, bisezole, trabectedin, and DDS preparations thereof.

[1324] Examples of the "metabolic antagonist" include mercaptopurine, 6-mercaptopurine nucleoside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine alkylphosphite, ancitabine hydrochloride, 5-FU-based drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, etifur, capecitabine, etc.), aminopterin, nelarabine, methylfolate, thioguanine (tabloid), budosine, folinate, leucovorin, cladribine, etifur, fludarabine, gemcitabine, hydroxyurea, pentostatin, piroxetine, idoxuridine, mitoxantrone, thiazofurine, amoxicillin, bendamustine, and DDS preparations thereof.

[1325] Examples of the "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carcinoglucon, mitotane, daunorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and DDS preparations thereof.

[1326] Examples of the “plant-derived anticancer agent” include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and DDS preparations thereof.

[1327] Examples of the "molecular targeted therapeutic agent" include imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, nilotinib, lapatinib, pazopanib, ruxolitinib, crizotinib, vemurafenib, vandetanib, ponatinib, cabozantinib, tofacitinib, regorafenib, bosutinib, axitinib, dabrafenib, trametinib, nintedanib, adranib, ceritinib, lenvatinib, palbociclib, alectinib, afatinib, and osimertinib. , ribociclib, abemaciclib, brigatinib, neratinib, cupanisib, cobimetinib, ibrutinib, acalabrutinib, connefenib, bimetinib, baricitinib, fostamatinib, lorlatinib, erdafitinib, entrectinib, dacomitinib, sirolimus, everolimus, temsirolimus, olaparib, ricaparib, niraparib, venetola, azacitidine, decitabine, vorinostat, panobinostat, romidepsin, bortezomib, carfilzomib, larotrectinib and ixazomib, etc.

[1328] Examples of the “immunomodulator” include lenalidomide and pomalidomide.

[1329] Examples of the "other chemotherapeutic agents" include sobuzoxane and the like.

[1330] Examples of “immunotherapeutic agents (BRMs)” include bisibanib, versicolor polysaccharide, cisoflavan, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium pumilus, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, and Toll-like receptor agonists (e.g., TLR7 agonists, TLR8 agonists, TLR9 agonists, etc.).

[1331] The cell growth factor in the drug that inhibits the action of the cell growth factor and its receptor may be any substance as long as it promotes cell proliferation. It is usually a peptide with a molecular weight of 20,000 or less, and includes factors that act at low concentrations by binding to receptors. Specific examples include: EGF (epidermal growth factor) or a substance having substantially the same activity therewith (for example, TGFalpha, etc.), insulin or a substance having substantially the same activity therewith (for example, insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same analysis therewith (for example, acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10, etc.), and other cell growth factors (for example, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF-β (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiogenin, etc.).

[1332] The administration period of the compound of the present invention and the concomitant drug is not limited, and they can be administered to the subject at the same time or at intervals. In addition, a mixture of the compound of the present invention and the concomitant drug can be prepared. The dosage of the concomitant drug can be appropriately selected based on the dosage used clinically. In addition, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected based on the subject of administration, administration route, target disease, symptoms, combination, etc. For example, when the subject of administration is a human, it is sufficient to use 0.01 to 100 parts by weight of the concomitant drug relative to 1 part by weight of the compound of the present invention. In addition, in order to suppress its side effects, it can be used in combination with agents (concomitant drugs) such as antiemetics, sleep inducing agents, and anticonvulsants.

[1333] "Showing resistance to treatment with immune checkpoint inhibitors" means a state in which, in solid tumors, tumor growth cannot be suppressed even with the administration of immune checkpoint inhibitors. Showing resistance to anti-PD-1 antibodies means a state in which, even with the administration of the aforementioned anti-PD-1 antibodies, tumor growth cannot be suppressed. Showing resistance to anti-PD-L1 antibodies means a state in which, even with the administration of the aforementioned anti-PD-L1 antibodies, tumor growth cannot be suppressed. In blood cancers, it means a state in which, even with the administration of immune checkpoint inhibitors, the increase in the number of cancer cells in the blood cannot be suppressed. Showing resistance to anti-PD-1 antibodies means a state in which, even with the administration of the aforementioned anti-PD-1 antibodies, the increase in the number of cancer cells in the blood cannot be suppressed. Showing resistance to anti-PD-L1 antibodies means a state in which, even with the administration of the aforementioned anti-PD-L1 antibodies, the increase in the number of cancer cells in the blood cannot be suppressed.

[1334] Anti-PD-1 antibodies are proteins that recognize PD-1 molecules. They have a Y-shaped four-chain structure (two light and two heavy polypeptide chains) and selectively recognize a single PD-1 molecule through their Fab site. Anti-PD-1 antibodies can be produced by preparing hybridomas by fusing antibody-producing B cells with myeloma cells and purifying the antibodies secreted from the culture supernatant.

[1335] The M1-M2 ratio of macrophages refers to the ratio of a cell population defined by M1 macrophage markers (e.g., CD86, STAT1, IL-1beta, iNOS, CXCL9, CXCL10, etc.) to a cell population defined by M2 macrophage markers (e.g., Mrc1, Arg1, CD163, etc.). A higher value indicates a more inflammatory environment within the tumor, meaning that anti-PD-1 / PD-L1 antibodies are more likely to be effective.

[1336] Solid cancers with a high tumor mutation burden (TMB-High) refer to cancers in which the TMB score measured in the FoundationOne CDx Cancer Genomic Profile shows 10 mut / Mb or higher.

[1337] Patients who are responsive to anti-PD-1 antibodies are considered to have tumor growth suppressed by anti-PD-1 antibody administration. This suppression of tumor growth is defined as any of the following: stable disease (SD), partial response (PR), or complete response (CR) according to RECIST criteria. In particular, a sustained suppression of tumor growth for more than 6 months (24 weeks) is considered a durable clinical benefit (DCB).

[1338] After the CHK1 inhibitor and the immune checkpoint inhibitor are administered simultaneously, the anti-PD-1 antibody can be administered 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks later.

[1339] The M1-M2 ratio of macrophages in cancer patients showing resistance to treatment with immune checkpoint inhibitors is preferably 21 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9.9 or less, 9.8 or less, 9.7 or less, 9.6 or less, 9.5 or less, 9.4 or less, 9.3 or less, 9.2 or less, 9.1 or less, 9.0 or less, 8.9 or less, 8.8 or less, 8.7 or less. Below, 8.6 below, 8.5 below, 8.4 below, 8.3 below, 8.2 below, 8.1 below, 8.0 below, 7.9 below, 7.8 below, 7.7 below, 7.6 below, 7.5 below, 7.4 below, 7.3 below, 7.2 below, 7.1 below, 7.0 below, 6.9 below, 6.8 below, 6.7 below, 6.6 below, 6.5 below, 6.4 below, 6.3 below, 6.2 below, 6.1 below, 6.0 below, 5.9 below, 5. 8 or less, 5.7 or less, 5.6 or less, 5.5 or less, 5.4 or less, 5.3 or less, 5.2 or less, 5.1 or less, 5.0 or less, 4.9 or less, 4.8 or less, 4.7 or less, 4.6 or less, 4.5 or less, 4.4 or less, 4.3 or less, 4.2 or less, 4.1 or less, 4.0 or less, 3.9 or less, 3.8 or less, 3.7 or less, 3.6 or less, 3.5 or less, 3.4 or less, 3.3 or less, 3.2 or less, 3.1 or less, 3.0 or less, 2 .9 or less, 2.8 or less, 2.7 or less, 2.6 or less, 2.5 or less, 2.4 or less, 2.3 or less, 2.2 or less, 2.1 or less, 2.0 or less, 1.9 or less, 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, 1.0 or less, 0.9 or less, 0.8 or less, 0.7 or less, 0.6 or less, 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, 0.1 or less.

[1340] The number of CD8-positive cells in tumor tissue of a cancer patient showing resistance to treatment with an immune checkpoint inhibitor is preferably 0.135 or less, 0.130 or less, 0.125 or less, 0.120 or less, 0.115 or less, 0.110 or less, 0.095 or less, 0.090 or less, 0.085 or less, 0.080 or less, 0.075 or less, 0.070 or less, 0.065 or less, 0.060 or less, 0.055 or less, 0.050 or less, 0.045 or less, 0.040 or less, 0.035 or less, 0.030 or less, 0.025 or less, 0.020 or less, 0.015 or less, or 0.010 or less.

[1341] In this specification, "or" is used when "at least one or more" of the items listed in the text can be used. The same applies to "or". In this specification, when the format of "within the range of two values" is described, the range also includes the two values ​​themselves.

[1342] The scientific literature, patents, patent applications and other references cited in this specification are incorporated herein by reference in their entirety to the same extent as if each were specifically described.

[1343] The present disclosure has been described above by way of preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present invention is not limited to the specific embodiments or examples described in this specification, but is defined solely by the claims.

[1344] Example

[1345] The present disclosure will be further specifically described below with reference to reference examples, examples, and test examples, but the present invention is not limited thereto.

[1346] In this specification, the following abbreviations are sometimes used.

[1347] Ts: p-toluenesulfonyl

[1348] THF: Tetrahydrofuran

[1349] TFA: trifluoroacetic acid

[1350] DMF: N,N-dimethylformamide

[1351] DMSO: dimethyl sulfoxide

[1352] MeCN: acetonitrile

[1353] Me:methyl

[1354] Boc: tert-Butoxycarbonyl

[1355] Dess-Martin reagent: Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzidoxyl-3-(1H)-one)

[1356] The NMR (Nuclear Magnetic Resonance) data used for compound identification were acquired using a JNM-ECS400 nuclear magnetic resonance apparatus (400 MHz) manufactured by JEOL Ltd.

[1357] As symbols used in NMR, s refers to singlet, d refers to doublet, dd refers to doublet of doublet, t refers to triplet, td refers to triplet of doublet, q refers to quartet, m refers to multiplet, br refers to broad, brs refers to broad singlet, brm refers to broad multiplet, and J refers to bond constant.

[1358] The LC / MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows. In the observed mass spectrum [MS (m / z)], the value corresponding to the monoisotopic mass (containing only the exact mass of the main isotope) is expressed as [M+H] + , [MH] - or [M+2H] 2+ The retention time is expressed as Rt (minutes).

[1359] Measurement Condition A

[1360] Detection instrument: ACQUITY (registered trademark) SQ detector (Waters)

[1361] HPLC: ACQUITY UPLC (registered trademark) system

[1362] Column: Waters ACQUITY UPLC (registered trademark) BEHC18 (1.7 μm, 2.1 mm × 30 mm)

[1363] Solvent: Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / MeCN

[1364] Gradient conditions: 0.0-1.3min linear gradient B 2%-96%

[1365] Flow rate: 0.8 mL / min

[1366] UV: 220nm and 254nm

[1367] Column temperature: 40°C

[1368] Measurement Condition B

[1369] Detection equipment: APCI 6120 Quadrupole LC / MS (Agilent Technologies)

[1370] HPLC: Agilent Technologies 1260 Infinity (registered trademark) system

[1371] Column: Agilent Technologies (registered trademark) ZORBAX SB-C18 (1.8 μm, 2.1 mm × 50 mm)

[1372] Solvent: Solution A: 0.1% formic acid / H2O, Solution B: MeCN

[1373] Gradient conditions: 0.0-5.0 min linear gradient B 5%-90%

[1374] Flow rate: 0.6 mL / min

[1375] UV: 210nm, 254nm, and 280nm

[1376] Column temperature: 40°C

[1377] Assay Condition C

[1378] Detection equipment: Shimadzu LCMS-2020

[1379] Column: L-column-2ODS (4.6mm×35mm)

[1380] Gradient conditions: MeCN / H2O / HCO2H=10 / 90 / 0.1→100 / 0 / 0.1 (0-2 min), 100 / 0 / 0.1 (2-4 min)

[1381] Flow rate: 2 mL / min

[1382] Column temperature: 40°C

[1383] Reference Example 1:

[1384] tert-Butyl 3-{[(4-acetyl-5-methoxypyridin-3-yl)oxy]methyl}-3-fluoroazetidine-1-carboxylate

[1385] [Chemistry 35]

[1386]

[1387] Preparation of tert-butyl 3-{[(4-acetyl-5-methoxypyridin-3-yl)oxy]methyl}-3-fluoroazetidine-1-carboxylate (Reference Example 1)

[1388] To a solution of 1-(3-hydroxy-5-methoxy-4-pyridyl)ethanone (1.00 g) in THF (50.0 mL) was added tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (1.85 g) and triphenylphosphine (3.15 g) at room temperature and cooled to 0°C. Diisopropyl azodicarboxylate (2.5 mL) was added and stirred at 0°C for 12 hours. Saturated brine was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 1 (720 mg).

[1389] LC-MS; [M+H] + 355.2 / Rt(minutes)0.886(measurement condition A)

[1390] Reference Example 2:

[1391] tert-Butyl 3-{[(3-acetyl-2-methoxypyridin-4-yl)oxy]methyl}-3-(hydroxymethyl)azetidine-1-carboxylate

[1392] [Chemistry 36]

[1393]

[1394] a) Production of tert-butyl 3-(hydroxymethyl)-3-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}azetidine-1-carboxylate

[1395] To a solution of tert-butyl 3,3-bis(hydroxymethyl)azetidine-1-carboxylate (1.50 g) in dichloromethane (20.0 mL) was added pyridine (5.60 mL), trimethylamine hydrochloride (0.13 g) and p-toluenesulfonyl chloride (1.45 g) at 0°C and stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution, quenched, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (2.30 g). The residue was used directly in the subsequent reaction without purification.

[1396] LC-MS; [M+H] + 372.1 / Rt(minutes)0.928(measurement condition A)

[1397] b) Production of tert-butyl 3-{[(3-acetyl-2-methoxypyridin-4-yl)oxy]methyl}-3-(hydroxymethyl)azetidine-1-carboxylate (Reference Example 2)

[1398] To a solution of tert-butyl 3-(hydroxymethyl)-3-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}azetidine-1-carboxylate (2.30 g) in DMF (10.0 mL) was added 1-(4-hydroxy-2-methoxy-3-pyridyl)ethanone (1.00 g) and cesium carbonate (7.80 g), and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution and extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, it was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Reference Example 2 (1.01 g).

[1399] LC-MS; [M+H] + 367.3 / Rt(minutes)0.796(measurement condition A)

[1400] Reference Example 3:

[1401] tert-Butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate

[1402] [Chemistry 37]

[1403]

[1404] a) Production of tert-butyl {3-[(3-acetyl-4-methoxypyridin-2-yl)oxy]propyl}carbamate

[1405] To a solution of 1-(2-hydroxy-4-methoxypyridin-3-yl)ethanone (2.00 g) in DMF (40.0 mL) was added cesium carbonate (7.80 g) and 3-(Boc-amino)propyl bromide (4.27 g) at 0°C, and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.25 g).

[1406] LC-MS; [M+H] + 325.2 / Rt(minutes)0.959(measurement condition A)

[1407] 1H-NMR(CDCl3)δ:8.06(1H,d,J=6.0Hz), 6.55(1H,d,J=6.0

[1408] Hz),4.97(1H,brs),4.40(2H,t,J=6.4Hz),3.86(3H,s),3.27-3.24(2H,m),2.49(3H,s),1.96-1.90(2H,m),1.44(9H,s).

[1409] b) Production of tert-butyl [3-({3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate

[1410] To a solution of {3-[(3-acetyl-4-methoxypyridin-2-yl)oxy]propyl}tert-butylcarbamate (2.25 g) in DMF (10.0 mL) was added N,N-dimethylformamide dimethyl acetal (10.0 mL), and the mixture was stirred at 115°C for 24 hours. After cooling, the solvent in the reaction mixture was distilled off under reduced pressure to obtain the title compound (4.30 g) as a crude product.

[1411] LC-MS; [M+H] + 380.3 / Rt(minutes)0.722(measurement condition A)

[1412] c) Production of tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate

[1413] To a solution of tert-butyl [3-({3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate (4.30 g) in ethanol (30.0 mL) was added hydroxylamine hydrochloride (5.49 g), and the mixture was stirred at 65°C for 2 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution and quenched. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.63 g).

[1414] LC-MS; [M+H] + 350.2 / Rt(minutes)0.722(measurement condition A)

[1415] 1H-NMR(CDCl3)δ:8.32(1H,d,J=1.6Hz), 8.12(1H,d,J=6.0Hz), 6.64(1H,d,J=6.0Hz), 6.59(1H,d,J=1.6H z),4.87(1H,brs),4.45(2H,t,J=6.4Hz),3.92(3H,s),3.28-3.24(2H,m),1.99-1.93(2H,m),1.44(9H,s).

[1416] d) Production of tert-butyl (3-{[3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate

[1417] To a mixed solution of tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate (1.63 g) in ethanol (20.0 mL) and water (5.00 mL) was added potassium hydroxide (0.29 g) and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to saturated brine and quenched. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.50 g).

[1418] LC-MS; [M+H] + 350.2 / Rt(minutes)0.872(measurement condition A)

[1419] 1H-NMR (CDCl3) δ: 8.14 (1H, d, J = 6.0Hz), 6.59 (1H, d, J = 6.0Hz), 4.94 (1H, brs), 4.4 4(2H,t,J=6.0Hz),3.92(3H,s),3.29-3.23(2H,m),1.99-1.93(2H,m),1.43(9H,s).

[1420] e) Production of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (Reference Example 3)

[1421] To a solution of tert-butyl (3-{[3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (1.99 g) in ethanol (20.0 mL) were added acetic acid (3.28 mL) and hydrazine monohydrate (2.78 mL) at 0°C, and the mixture was stirred at 90°C for 24 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution and quenched. The obtained aqueous solution was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Reference Example 3 (1.60 g).

[1422] LC-MS; [M+H] + 364.0 / Rt(minutes)0.684(measurement condition A)

[1423] 1H-NMR(DMSO-D6)δ:11.61-10.91(1H,brs),8.01(1H,d,J=12.0Hz),6.93-6.89(1H,m),6.84(1H,d,J=6.0Hz),5.9 3(1H,brs),4.50(1H,brs),4.32(2H,t,J=6.4Hz),3.89(3H,s),3.09-3.04(2H,m),1.86-1.79(2H,m),1.37(9H,s).

[1424] Reference Example 4:

[1425] tert-Butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-6-chloro-4-methoxypyridin-2-yl]oxy}propyl)carbamate

[1426] [Chemistry 38]

[1427]

[1428] a) Production of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethan-1-ol

[1429] A solution of 2-chloro-4-methoxy-6-[(4-methoxybenzyl)oxy]pyridine (10.0 g) in THF (100 mL) was cooled to -78°C. 2.8 mol / L n-butyllithium (15.3 mL) was added, and the mixture was stirred at -78°C for 3 hours. Acetamide (6.30 mL) was added, and the mixture was stirred at -78°C for 6 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, quenched, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (4.25 g).

[1430] LC-MS; [M+H] + 324.2 / Rt (minutes) 1.118 (measurement conditions A)

[1431] 1H-NMR(CDCl3)δ:7.36(2H,d,J=8.8Hz), 6.89(2H,d,J=8.8

[1432] Hz),6.55(1H,s),5.32(2H,s),5.16-5.11(1H,m),3.85(3H,s),

[1433] 3.80(3H,s),3.30(1H,s),1.41(3H,d,J=6.8Hz).

[1434] 13C-NMR(CDCl3)δ:165.2,159.6,147.6,130.1,128.6,114.1,112.6,101.8,68.7,62.9,56.3,55.4,23.1.

[1435] b) Production of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethan-1-one

[1436] To a solution of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethane-1-ol (3.15 g) in dichloromethane (100 mL) was added Dess-Martin reagent (6.19 g) and stirred at room temperature for 12 hours. The reaction solution was added to a saturated aqueous sodium bicarbonate solution and quenched. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.50 g).

[1437] LC-MS; [M+H] +322.2 / Rt (minutes) 1.081 (measurement condition A)

[1438] c) Production of 1-(6-chloro-2-hydroxy-4-methoxypyridin-3-yl)ethan-1-one

[1439] To a solution of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethan-1-one (2.50 g) in dichloromethane (30.0 mL) was added TFA (6.00 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by amine silica gel column chromatography (chloroform / methanol) to obtain the title compound (2.00 g).

[1440] LC-MS; [M+H] + 202.1 / Rt(minutes)0.773(measurement condition A)

[1441] d) Production of tert-butyl {3-[(3-acetyl-6-chloro-4-methoxypyridin-2-yl)oxy]propyl}carbamate

[1442] To a solution of 1-(6-chloro-2-hydroxy-4-methoxypyridin-3-yl)ethan-1-one (3.00 g) in DMF (50.0 mL) was added cesium carbonate (9.70 g) and 3-(Boc-amino)propyl bromide (5.63 g) at 0°C, and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.01 g).

[1443] LC-MS; [M+H] + 359.3 / Rt(minutes)1.123(measurement condition A)

[1444] e) Production of tert-butyl [3-({6-chloro-3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate

[1445] To a solution of tert-butyl {3-[(3-acetyl-6-chloro-4-methoxypyridin-2-yl)oxy]propyl}carbamate (840 mg) in DMF (10.0 mL) was added N,N-dimethylformamide dimethyl acetal (3.00 mL), and the mixture was stirred at 115°C for 24 hours. After cooling, the solvent in the reaction mixture was evaporated under reduced pressure to obtain the title compound (0.97 g) as a crude product.

[1446] LC-MS; [M+H] +414.4 / Rt(minutes)0.944(measurement condition A)

[1447] f) Production of tert-butyl (3-{[6-chloro-4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate

[1448] To a solution of tert-butyl [3-({6-chloro-3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate (0.97 g) in ethanol (30.0 mL) was added hydroxylamine hydrochloride (1.70 g), and the mixture was stirred at 65°C for 2 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution and quenched. The resulting aqueous solution was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (677 mg).

[1449] LC-MS; [M+H] + 384.3 / Rt (minutes) 1.132 (measurement conditions A)

[1450] g) Production of tert-butyl (3-{[6-chloro-3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate

[1451] To a mixed solution of tert-butyl (3-{[6-chloro-4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate (677 mg) in ethanol (20.0 mL) and water (5.00 mL) was added potassium hydroxide (100 mg) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to saturated brine and quenched. The obtained aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (470 mg).

[1452] LC-MS; [M+H] + 384.3 / Rt (minutes) 1.064 (measurement conditions A)

[1453] h) Production of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-6-chloro-4-methoxypyridin-2-yl]oxy}propyl)carbamate (Reference Example 4)

[1454] To a solution of tert-butyl (3-{[6-chloro-3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (470 mg) in ethanol (20.0 mL) were added acetic acid (0.71 mL) and hydrazine monohydrate (0.77 mL) at 0°C, and the mixture was stirred at 90°C for 24 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution and quenched. The obtained aqueous solution was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain Reference Example 4 (350 mg).

[1455] LC-MS; [M+H] + 398.3 / Rt(minutes)0.911(measurement condition A)

[1456] Reference Example 5:

[1457] 1-(4-Hydroxy-6-methoxypyrimidin-5-yl)ethan-1-one

[1458] [Chemistry 39]

[1459]

[1460] a) Production of 1-(4-hydroxy-6-methoxypyrimidin-5-yl)ethan-1-one

[1461] To a solution of 1-(4,6-dimethoxypyrimidin-5-yl)ethan-1-one (2.00 g) in dichloromethane (30.0 mL) was added a dichloromethane solution of boron tribromide (1.0 mol / L, 54.9 mL) at -60°C, and the mixture was stirred at -50°C or below for 3 hours. Saturated brine was added to the reaction mixture, which was quenched and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform) to obtain the title compound (220 mg).

[1462] LC-MS; [M+H] + 169.1 / Rt(minutes)0.367(measurement condition A)

[1463] 1H-NMR(CDCl3)δ:14.31(1H,brs),8.36(1H,s),4.10(3H,s),2.65(3H,s).

[1464] Reference Example 6:

[1465] tert-Butyl (3-{[4-acetyl-5-(fluoromethoxy)pyridin-3-yl]oxy}propyl)carbamate

[1466] [Chemistry 40]

[1467]

[1468] a) Production of 3-fluoro-5-(fluoromethoxy)pyridine

[1469] To a solution of 5-fluoropyridin-3-ol (1.00 g) in DMF (30.0 mL) was added cesium carbonate (4.32 g) and fluoromethyl 4-methylbenzenesulfonate (2.17 g) at room temperature, and the mixture was heated and stirred at 80°C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (538 mg).

[1470] LC-MS; [M+H] + 146.0 / Rt(minutes)0.574(measurement condition A)

[1471] b) Production of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethan-1-ol

[1472] A solution of N,N-diisopropylethylamine (0.687 mL) in THF (15 mL) was cooled to -78°C, and n-butyllithium (1.58 mol / L, 3.05 mL) was added, followed by stirring at 0°C for 15 minutes. The reaction solution was cooled to -78°C again, 3-fluoro-5-(fluoromethoxy)pyridine (538 mg) was added, and after stirring for 1 hour, acetaldehyde (0.419 mL) was added. The reaction solution was slowly warmed to room temperature, stirred overnight, and then water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (475 mg).

[1473] LC-MS; [M+H] + 190.1 / Rt(minutes)0.494(measurement condition A)

[1474] 1H-NMR(CDCl3)δ:8.30(1H,d,J=1.8Hz),8.26(1H,s),5.85(1H,dd,J=6.7,3.1Hz),5.71(1H ,dd,J=7.2,3.2Hz),5.31-5.22(1H,m),2.60(1H,dd,J=9.8,1.8Hz),1.59(3H,d,J=6.7Hz).

[1475] c) Production of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethan-1-one

[1476] A solution of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethane-1-ol (475 mg) in dichloromethane (10.0 mL) was ice-cooled, and Dess-Martin reagent (1.60 g) was added, followed by stirring at room temperature overnight. Aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (407 mg).

[1477] LC-MS; [M+H] + 188.0 / Rt(minutes)0.618(measurement condition A)

[1478] d) Production of tert-butyl (3-{[4-acetyl-5-(fluoromethoxy)pyridin-3-yl]oxy}propyl)carbamate

[1479] To a solution of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethane-1-one (407 mg) and cesium carbonate (1.42 g) in DMF (10.0 mL) was added tert-butyl (3-hydroxypropyl)carbamate (762 mg), and the mixture was stirred under heating at 80°C for 8 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (67 mg).

[1480] LC-MS; [M+H] + 343.2 / Rt(minutes)0.832(measurement condition A)

[1481] 1H-NMR(CDCl3)δ:8.22(1H,d,J=1.8Hz),8.16(1H,s),5.68(2H,d,J=53.6Hz),4.70(1H,br s), 4.15 (2H, t, J = 6.1Hz), 3.32-3.21 (2H, m), 2.50 (3H, s), 2.00-1.93 (2H, m), 1.41 (9H, s).

[1482] Reference Example 7:

[1483] tert-Butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate

[1484] [Chemistry 41]

[1485]

[1486] a) Production of (2E)-3-(dimethylamino)-1-(2-hydroxy-4-methoxypyridin-3-yl)prop-2-en-1-one

[1487] To a mixture of 1-(2-hydroxy-4-methoxypyridin-3-yl)ethanone (2.50 g) and toluene (6.23 ml) was added tert-butoxybis(dimethylamino)methane (5.21 g), and the mixture was heated and stirred at 55°C for 6 hours. After cooling, toluene (18.6 ml) was added dropwise, and the resulting crystals were collected by filtration and washed with toluene. The crystals were vacuum dried to obtain the title compound (2.87 g). The filtrate was concentrated under reduced pressure, and the crystals precipitated from the ethanol / toluene mixed solvent were washed with an ethanol / toluene mixed solvent and vacuum dried to obtain a second crystal of the title compound (0.20 g).

[1488] LC-MS; [M+H] + 223.1 / Rt(minutes)1.564

[1489] 1H-NMR(DMSO-D6)δ:11.25(1H,br s),7.39(1H,d,J=6.7Hz),7.11(1H,br s),6.21(1H,d,J=7.9Hz),5.00(1H,d,J=11.0Hz),3.73(3H,s),3.00(3H,br s),2.75(3H,brs).

[1490] b) Production of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-ol

[1491] To a mixture of (2E)-3-(dimethylamino)-1-(2-hydroxy-4-methoxypyridin-3-yl)prop-2-en-1-one (2.50 g) and ethanol (37.5 ml) was added hydroxylamine hydrochloride (1.56 g), followed by stirring at room temperature for 16 hours. Water (37.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to 28.5 g. Water (9.0 ml) was then added, and the mixture was stirred at 0°C. The resulting crystals were collected by filtration, washed with cold water, and dried in vacuo to give the title compound (1.53 g).

[1492] LC-MS; [M+H] + 193.1 / Rt(minute)0.928

[1493] 1H-NMR (DMSO-D6) δ: 11.83 (1H, br s), 8.51 (1H, d, J = 1.8Hz), 7.61 (1H, d, J = 7.3Hz), 6.83 (1H, d, J = 1.8Hz), 6.38 (1H, d, J = 7.3Hz), 3.93 (3H, s).

[1494] c) Production of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl trifluoromethanesulfonate

[1495] To a mixture of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-ol (1.23 g) and pyridine (6.1 ml) was added dropwise trifluoromethanesulfonic anhydride (2.16 g) at 0°C. The reaction mixture was warmed and stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C, water (16 ml) was added dropwise, and stirred at 0°C for 1.5 hours. The resulting crystals were collected by filtration, washed with a water / pyridine mixed solvent, then washed with water, and dried in vacuo to give the title compound (1.91 g).

[1496] LC-MS; [M+H] + 325.0 / Rt(minute)4.781

[1497] 1H-NMR(CDCl3)δ:8.37(1H,d,J=1.8Hz), 8.32(1H,d,J=6.1Hz), 7.01(1H,d,J=6.1Hz), 6,67(1H,d,J=1.8Hz), 4.00(3H,s).

[1498] d) Production of tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate

[1499] To a mixture of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl trifluoromethanesulfonate (50 mg), tert-butyl (3-hydroxypropyl)carbamate (54 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (16 mg), and toluene (1.5 ml) was added diisopropylethylamine (72 mg), and the mixture was heated and stirred at 100°C for 4 hours. After the reaction mixture was cooled, the insoluble matter was removed by filtration through celite and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (30 mg).

[1500] LC-MS; [M+H] + 350.2 / Rt(minute)4.647

[1501] Reference Examples 8 to 41:

[1502] The compounds of Reference Examples 8 to 41 shown in the following table were obtained by the same method as described in Reference Examples 1 to 7 using the corresponding raw material compounds.

[1503] [Table 1-1]

[1504]

[1505] [Table 1-2]

[1506]

[1507] [Table 1-3]

[1508]

[1509] [Table 1-4]

[1510]

[1511] [Table 1-5]

[1512]

[1513] [Table 1-6]

[1514]

[1515] [Table 1-7]

[1516]

[1517] [Table 1-8]

[1518]

[1519] Reference Example 42:

[1520] tert-Butyl {3-[(3-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-yl)oxy]propyl}carbamate

[1521] [Chemistry 42]

[1522]

[1523] To a solution of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (600 mg) in DMSO (10.0 mL) was added 4-ethylmorpholine (1.00 mL) and 5-chloropyrazine-2-carbonitrile (461 mg) at room temperature, and the mixture was stirred at 80°C for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.01 g).

[1524] LC-MS; [M+H] + 467.3 / Rt(minutes)0.885(measurement condition A)

[1525] 1H-NMR(DMSO-D6)δ:12.4(1H,s),10.7(1H,s),8.61(1H,s),8.50(1H,brs),8.07(1H,d,J=5.2Hz),7.06(1H,brs) ),6.90(1H,d,J=6.0Hz),4.34(2H,t,J=6.4Hz),3.93(3H,s),3.14-3.08(2H,m),1.87-1.84(2H,m),1.35(9H,s).

[1526] Reference Examples 43-78:

[1527] The compounds of Reference Examples 43 to 78 shown in the following table were obtained by the same method as described in Reference Example 42 using the corresponding starting compounds.

[1528] [Table 2-1]

[1529]

[1530] [Table 2-2]

[1531]

[1532] [Table 2-3]

[1533]

[1534] [Table 2-4]

[1535]

[1536] [Table 2-5]

[1537]

[1538] [Table 2-6]

[1539]

[1540] [Table 2-7]

[1541]

[1542] [Table 2-8]

[1543]

[1544] [Table 2-9]

[1545]

[1546] [Table 2-10]

[1547]

[1548] [Table 2-11]

[1549]

[1550] [Table 2-12]

[1551]

[1552] Reference Example 79:

[1553] tert-Butyl {3-[(3-{3-[(5-chloropyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-yl)oxy]propyl}carbamate

[1554] [Chemistry 43]

[1555]

[1556] To a solution of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (60 mg) in 1,4-dioxane (825 μL) were added 2,5-dichloropyrazine (32.9 μL), tris(dibenzylideneacetone)dipalladium(0) (15.1 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19.1 mg), and cesium carbonate (108 mg) at room temperature, and the mixture was stirred at 150°C for 2 hours under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound.

[1557] LC-MS; [M+H] + 476.3 / Rt(minutes)0.969(measurement condition A)

[1558] Example 1:

[1559] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[1560] [Chemistry 44]

[1561]

[1562] To a solution of tert-butyl {3-[(3-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-yl)oxy]propyl}carbamate (200 mg) obtained in Reference Example 42 in dichloromethane (20.0 mL) was added TFA (2.00 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by amine silica gel column chromatography (ethyl acetate / methanol) to obtain Example 1 (112 mg).

[1563] LC-MS; [M+H] + 367.2 / Rt(minutes)0.671(measurement condition A)

[1564] 1H-NMR(DMSO-D6)δ:8.65(1H,s),8.50(1H,brs),8.06(1H,d,J=6.4Hz),7.04(1H,brs),6.89( 1H,d,J=6.4Hz), 4.41(2H,t,J=6.0Hz), 3.92(3H,s), 2.75(1H,t,J=6.8Hz), 1.85-1.76(2H,m).

[1565] Examples 2 to 38:

[1566] The compounds of Examples 2 to 38 shown in the following table were obtained by the same method as in Example 1 using the corresponding starting compounds.

[1567] [Table 3-1]

[1568]

[1569] [Table 3-2]

[1570]

[1571] [Table 3-3]

[1572]

[1573] [Table 3-4]

[1574]

[1575] [Table 3-5]

[1576]

[1577] [Table 3-6]

[1578]

[1579] [Table 3-7]

[1580]

[1581] [Table 3-8]

[1582]

[1583] [Table 3-9]

[1584]

[1585] [Table 3-10]

[1586]

[1587] [Table 3-11]

[1588]

[1589] [Table 3-12]

[1590]

[1591] [Table 3-13]

[1592]

[1593] [Table 3-14]

[1594]

[1595] The powder X-ray diffraction measurements of Examples 39 to 44 were performed under the following conditions. The obtained diffraction patterns (XRD spectra) are shown in FIG. Figures 1 to 6 Examples 39 to 41 are crystals of various salts of the compound of Example 1, and Examples 42 to 44 are polymorphs of the compound of Example 1.

[1596] When determining the crystal form, according to Figures 1 to 6 It can be judged by the characteristic diffraction peaks of each crystal shown in the diffraction pattern.

[1597] Depend on Figures 1 to 6 The main diffraction peaks and characteristic diffraction peaks determined from the diffraction pattern are listed below. It should be noted that the diffraction peaks at diffraction angles 2θ (°) described in the following examples may be subject to slight measurement errors depending on the measurement equipment or measurement conditions. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1.

[1598] Powder X-ray diffraction determination method:

[1599] Testing machine: Spectris Power X-ray diffraction system Empyrian

[1600] X-ray tube: CuKα (wavelength: 1.54 angstroms)

[1601] Tube voltage: 45kV

[1602] Tube current: 40mA

[1603] Measuring range: 4 to 40 degrees (2θ)

[1604] Stride: 0.013 degrees

[1605] Cumulative time: 100 seconds / step

[1606] Example 39:

[1607] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride

[1608] Methanol (0.6 mL) was added to the compound of Example 1 (30.0 mg), followed by a 5-10% (W / V) hydrochloric acid-methanol solution (60 μL), and the mixture was stirred at 60°C for 2 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form I).

[1609] [Type I] powder X-ray diffraction pattern is shown in Figure 1 .

[1610] Main diffraction peaks: 2θ(°)=7.2、8.8、9.8、10.2、10.7、16.7、18.5、26.2、27.0

[1611] Characteristic diffraction peaks: 2θ(°)=7.2, 8.8, 9.8, 10.2, 10.7

[1612] Example 40:

[1613] 5-({5-[2-(3-aminopropyloxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate

[1614] To the compound of Example 1 (30.0 mg) was added a 13.4 mg / mL phosphoric acid-methanol solution (1200 μL), and the mixture was stirred at 60°C for 4 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form II).

[1615] [Type II] Powder X-ray diffraction pattern is shown in Figure 2 .

[1616] Main diffraction peaks: 2θ(°)=6.8, 7.5, 11.7, 11.9, 13.0, 16.4, 19.3, 20.4, 22.7, 24.3

[1617] Characteristic diffraction peaks: 2θ(°)=6.8, 7.5, 11.7, 11.9, 13.0

[1618] Example 41:

[1619] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile tosylate

[1620] Methanol (0.6 mL) was added to the compound of Example 1 (30.0 mg), followed by a 26.0 mg / mL toluenesulfonic acid-methanol solution (0.6 mL), and the mixture was stirred at 60°C for 2 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form III).

[1621] [Type III] powder X-ray diffraction pattern is shown in Figure 3 .

[1622] Main diffraction peaks: 2θ(°)=6.0、9.0、12.1、14.4、16.2、17.0、22.8、26.3 Characteristic diffraction peaks: 2θ(°)=6.0、9.0、12.1、14.4、16.2、17.0

[1623] Example 42:

[1624] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[1625] [Type IV] Powder X-ray diffraction pattern is shown in Figure 4 .

[1626] The title compound was obtained as a crystal (Form IV) according to Example 1.

[1627] Main diffraction peaks: 2θ(°)=9.3、10.2、10.7、13.6、16.7、17.1、17.8、18.6、26.1、26.4

[1628] Characteristic diffraction peaks: 2θ(°)=9.3、10.2、10.7、16.7、26.1、26.4

[1629] Example 43:

[1630] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[1631] [V-type] powder X-ray diffraction pattern is shown in Figure 5 .

[1632] A solution of the compound from Example 1 (5 mg) in tetrahydrofuran / water (10 / 1, 0.5 mL) was added and heated at 105°C for 1 hour. After cooling, the mixture was sealed and allowed to stand for 4 days. The mixture was then opened and allowed to stand for 3 days, and the solvent was distilled off. A solid precipitated, the title compound, was obtained as crystals (V-form).

[1633] Main diffraction peaks: 2θ(°)=7.9, 8.7, 12.2, 13.1, 15.9, 17.6, 19.9, 21.9, 22.8, 26.6

[1634] Characteristic diffraction peaks: 2θ(°)=7.9, 8.7, 12.2, 13.1, 15.9, 26.6

[1635] Example 44:

[1636] 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[1637] [Type VI] Powder X-ray diffraction pattern is shown in Figure 6 .

[1638] A solution of the compound from Example 1 (5 mg) in acetone / water (10 / 1, 0.5 mL) was added and heated at 105°C for 1 hour. After cooling, the mixture was sealed and allowed to stand for 4 days. The mixture was then opened and allowed to stand for 3 days, and the solvent was distilled off. The title compound was obtained as a precipitated solid (Form VI) crystal.

[1639] Main diffraction peaks: 2θ(°)=5.3、5.7、7.0、7.3、7.8、8.4、9.3、10.5、11.5、14.1

[1640] Characteristic diffraction peaks: 2θ(°)=5.3, 5.7, 7.0, 7.3, 8.4, 9.3

[1641] Test example

[1642] Test Example 1: CHK1 inhibitory activity test

[1643] The IMAP TR-FRET Screening Express Kit (R8160) was obtained from Molecular Devices. CHK1 kinase (02-117, CarnaBio), FAM-labeled CHK1tide (R7185, Molecular Devices), and ATP were diluted in assay buffer to final concentrations of 4 μg / mL, 2 μM, and 20 μM, respectively. FAM-PKAtide (R7255, Molecular Devices) and FAM-Phospho-PKAtide (R7304, Molecular Devices) were diluted and mixed to create a calibration standard set ranging from 0 to 100% phosphorylation levels. 5 μL of compound dissolved in 0.4% DMSO was added to a 384-well plate. A compound study group with 5 μL each of CHK1, CHK1tide, and ATP was prepared, and a standard group with 20 μL each of the standards was prepared. The kinase reaction was performed at 30°C for 3 hours. Then, 60 μL of binding reagent (80% buffer A, 20% buffer B, 1:600 ​​binding reagent, 1:400 Tb-Donor) was added and the binding reaction was carried out at room temperature for 2 hours. Using SpectraMax Paradigm (Molecular Devices), the fluorescence intensity at 520 nm and 490 nm was obtained when excited at 340 nm. The phosphorylation level of CHK1tide was calculated using the standard, and the phosphorylation level of the DMSO-treated group was set to 100%. The kinase activity was calculated using the calculation formula shown below, and the IC value of the concentration of the evaluation compound equivalent to 50% kinase activity was calculated. 50 value.

[1644] Kinase inhibition (%) = 100-A / B×100

[1645] A: Evaluate the signal in the presence of the compound

[1646] B: Signal of negative control (DMSO-treated group)

[1647] The test shown in Test Example 1 was carried out on the compounds obtained in the Examples and Prestige purchased from MedChemExpress (the same place of purchase was used in the following Test Examples). 50 The values ​​(nM) are shown in the following table.

[1648] [Table 4-1]

[1649]

[1650] [Table 4-2]

[1651] 33 0.69 <5 34 1.82 <5 35 0.62 <5 36 0.73 <5 37 0.32 18 38 0.70 <5

[1652] As shown in the table above, the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19, 20, 21, 22, 24, 26, 28, 30, and 37 showed a stronger inhibitory effect on CHK1 activity than prisertib. Among them, the compounds of Examples 1 and 8 had a particularly potent and specific effect of inhibiting CHK1 activity.

[1653] Experimental Example 2: Cell proliferation inhibition experiment

[1654] ES-2 cells were obtained from the American Culture Collection Center (ATCC) and cultured at 37°C in the presence of 5% CO2 using McCoy's 5a medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[1655] 500 cells were seeded per well in a 384-well plate, and the compound to be evaluated was added to a final DMSO concentration of 0.1%, and cultured for 2 days. After the culture was completed, the cell viability was calculated using CellTiter-Glo (registered trademark) 3D reagent (Promega, G968B). Based on the survival curve, the IC value of the concentration of the compound to inhibit cell proliferation by 50% was calculated. 50 Note that ES-2 cells are known to show cisplatin resistance.

[1656] The compounds obtained in the Examples and Presertib were subjected to the test described in Test Example 2. The concentration of each test substance that inhibited cell proliferation by 50% (IC 50 The following table lists the results of cell proliferation inhibition tests for representative compounds of the present disclosure according to the ranking of I, II, III, IV, and V (1000 nM < I, 1000 nM > II > 300 nM, 300 nM > III > 100 nM, 100 nM > IV > 30 nM, and 30 nM > V).

[1657] [Table 5]

[1658]

[1659] As shown in the table above, the compounds of Examples 1, 3, 4, 5, 6, 11, 15, 17, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 37 and 38 showed a good cell proliferation inhibitory effect comparable to that of prisertib.

[1660] Test Example 3: hERG current inhibition test

[1661] Test substances were added to cultured CHO cells stably expressing the hERG (human Ether-a-go-go related gene) gene at concentrations ranging from 0.27 to 100 μM. The hERG current under potential stimulation was measured using Qube 384 (Sophion Bioscience), and the concentration of each test substance that inhibited the hERG current by 50% (IC) was calculated. 50 value; μM).

[1662] The compounds obtained in the examples and prisertib were subjected to the test shown in Test Example 3. In addition, the hERG IC values ​​obtained in Test Example 3 were used to determine the compounds of the examples. 50 Divide by the IC50 of CHK1 inhibition obtained in Experiment 1 50 The obtained value was calculated as hERG / CHK1. The results are shown in the following table.

[1663] [Table 6-1]

[1664]

[1665] [Table 6-2]

[1666] 32 56.4 74211 33 14.5 21014 34 >100 >54945 35 8.7 14032 36 22.0 30137 37 <2.7 <8438 38 <2.7 <4500

[1667] As shown in the table above, the compounds of Examples 1, 3, 4, 7 to 10, 14, 24, 32 and 34 showed an IC of CHK1 inhibition. 50与 hERG IC 50 The deviation amplitude was more than 50,000 times. Among them, the compounds of Examples 1, 3, 7, 8, 14 and 24 showed an IC of CHK1 inhibition. 50 IC with hERG 50 The deviation amplitude is more than 100,000 times.

[1668] These six compounds showed a deviation of more than 18 times compared to prisertib, and possessed specific effects with high safety.

[1669] Experimental Example 4: Evaluation of CYP3A4 MBI and Enzyme Inactivation Clearance

[1670] Cytochrome P450 (CYP) is the most important enzyme group involved in drug metabolism, and many pharmacokinetic interactions are based on the inhibition of these CYP activities. CYPs exist in a variety of molecular species, with CYP3A4 in particular being the most involved in drug metabolism among CYP oxidation reactions and accounting for the majority of CYPs present in the liver.

[1671] There are two main types of CYP inhibition: reversible inhibition and irreversible inhibition (mechanism-based inhibition: MBI). In particular, MBI-based CYP inhibition is known to cause not only drug interactions but also serious side effects (hepatotoxicity, etc.) (Curr Opin Drug Discov Devel. 2010 January, 13(1), 66-77, Therapeutics and Clinical Risk Management, 2005, 1(1), 3-13).

[1672] The MBI and enzyme inactivation clearance of CYP3A4 were evaluated using the compound of this example and prisertib.

[1673] The inhibitory effect and inhibition pattern of the test compound on CYP3A4 were evaluated using human liver microsomes as the enzyme source and midazolam or testosterone as the substrate. After 30 minutes of metabolic reaction at 37°C, the substrate-derived metabolites in the test compound-added group (4 concentrations) and the substrate-derived metabolites in the non-added group were measured by LC-MS / MS, and the inhibition rate was calculated from the ratio. In addition, the IC value was calculated from the concentration graph. 50 When a test compound is known to have an MBI effect, the IC50 is reduced by adding the substrate after pre-incubation in the presence of NADPH (cofactor) (Xenobiotica, 2009, 39(2), 99-112). 50 When the value changed by 2 times or more, it was determined that there was an MBI effect.

[1674] When the MBI effect is determined, k is calculated by nonlinear least squares method. inact (maximum enzyme inactivation rate constant) and K I (The concentration of the inhibitor that causes 50% of the maximum enzyme inactivation rate) In addition, the enzyme inactivation clearance rate (CL) was calculated according to the method described in Drug Metabolism and Disposition, 2011, 39(7), 1247-1254. int＝ k inact / K I (ml / min / mmol) × CYP content (pmol / mg protein)).

[1675] The IC values ​​obtained by pre-incubation were used as an indicator of the MBI effect of each example compound and prisertib on CYP3A4. 50 The fold change of the values ​​and the enzyme inactivation clearance rates are shown in the table below.

[1676] [Table 7-1]

[1677]

[1678] [Table 7-2]

[1679] 31 Not detected 32 3.4 3.831 33 2.3 0.8887 34 Not detected 0.002 35 2.9 0.192 36 3.9 0.4430 37 Not detected - 38 Not detected -

[1680] The inventors of the present application have newly discovered that prasertib inhibits CYP3A4 by MBI, and therefore carries the risk of causing serious side effects such as hepatotoxicity.

[1681] As shown in the table above, while Prestige demonstrated MBI-based CYP3A4 inhibition, the compounds of Examples 1, 2, 4, 6-8, 14, 29-31, 34, 37, and 38 did not. These results demonstrate that the compounds of Examples 1, 2, 4, 6-8, 14, 29-31, 34, 37, and 38 possess specific effects with high safety profiles, reducing not only drug interactions but also the risk of serious side effects such as hepatotoxicity. Among these, the compound represented by formula (3) exhibited particularly high safety and specific effects.

[1682] Test Example 5. Human bone marrow cell colony formation test (blood toxicity evaluation test)

[1683] Human bone marrow CD34-positive hematopoietic stem cells were obtained from LONZA Co., Ltd. The frozen cells were thawed using a medium obtained by mixing MethocultExpress medium and RPMI1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin in a ratio of 9:1, and 5,000 cells were seeded per well in a 6-well plate and cultured overnight at 37°C and 5% CO2. The evaluation compound was added at a final concentration of 0.1% DMSO and 100 nM, and cultured for 48 hours. The cells were recovered and washed with PBS. 1 / 6 of the cells were seeded in a 12-well plate and cultured at 37°C and 5% CO2 for about 2 weeks. After the culture was completed, the number of colonies formed was calculated using thiazolyl blue tetrazolium bromide (MTT).

[1684] The representative compounds obtained in the Examples and puraseti were subjected to the test shown in Test Example 5. The results are shown in the table below.

[1685] [Table 8]

[1686]

[1687] As shown in the table above, while 100 nM of Prestige showed an inhibitory effect on human bone marrow cell colony formation, 100 nM of Example 1 did not. This result indicates that the compound of Example 1 has a specific effect on hematotoxicity and is highly safe.

[1688] Test Example 6. Liposome encapsulation test

[1689] Liposome encapsulation experiments were performed on representative example compounds and pristine.

[1690] 6.48 g of hydrogenated soybean phosphatidylcholine (COATSOME NC-21E, manufactured by NOF Corporation), 2.32 g of cholesterol (manufactured by Sigma), and 2.06 g of distearoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 (SUNBRIGHT DSPE-020CN, manufactured by NOF Corporation) were dissolved in 560 mL of tert-butanol heated to 65° C. The solution was frozen in a dry ice / acetone bath, and then the tert-butanol was removed by distillation under reduced pressure to obtain a lipid mixture.

[1691] 200mL of 250mM ammonium sulfate solution was added to the above lipid mixture, heated to 65°C, and dispersed with a homogenizer (ULTRA-TURRAX, IKA company) to obtain a crude liposome dispersion. Further, the crude liposome dispersion was dispersed under a pressure of 100MPa with a high-pressure homogenizer (Nano-Mizer NM2, Yoshida Machinery Industry Co., Ltd.) to obtain liposomes with an average particle size (Z-average) of about 80nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20KMWCO, ThermoScientific company), the extraliposome aqueous phase was replaced with a 10mM L-histidine buffer / 10% sucrose solution (pH 6.5) to obtain an empty liposome solution. The solution was filtered through a 0.22 μm membrane filter and a 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) was added to adjust the total lipid concentration to 75 mM (75 μmol / mL) or 50 mM (50 μmol / mL).

[1692] Weigh 2-3 mg of the test compound and add it to 1 mL of empty liposome solution with a total lipid concentration of 50 mM. Adjust the pH to 5.5-7 by adding 1 mol / L hydrochloric acid or 1 mol / L sodium hydroxide solution. Warm the solution in a 65°C water bath for 10-30 minutes, then cool on ice. Remove any insoluble matter by centrifugation at 15,000 × g for 5 minutes.

[1693] The liposome encapsulation rate was calculated as follows.

[1694] 100 μL of the liposome solution was passed through an ultrafiltration filter (Amicon Ultra, 100K, 0.5 mL, manufactured by Merck) and centrifuged at 15,000×g for 10 minutes at 4° C. The compound concentration in the filtrate after ultrafiltration was measured by HPLC and defined as the unencapsulated compound concentration.

[1695] The liposome solution was diluted with a trifluoroacetic acid / water / methanol mixture (0.1 / 25 / 75) and allowed to stand at 5°C for at least 10 minutes. Insoluble matter was removed by centrifugation at 15,000×g for 5 minutes, and the compound concentration in the supernatant was measured by HPLC and used as the compound concentration in the liposome solution.

[1696] The encapsulation rate and encapsulation efficiency were calculated using the following formula.

[1697] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration in liposome fluid

[1698] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration at the time of introduction

[1699] The measurement conditions of HPLC are as follows.

[1700] HPLC conditions

[1701] Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm

[1702] Column temperature: 40°C

[1703] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1704] B: Acetonitrile

[1705] A / B(min):95 / 5(0)→0 / 100(3.5)→0 / 100(4)→95 / 5(4.01)→95 / 5(5)

[1706] Flow rate: 0.8 mL / min

[1707] Detection: UV-visible detector at a wavelength of 254 nm

[1708] Injection volume: 3μL or 5μL

[1709] [Table 9]

[1710]

[1711] It can be confirmed that Presetin, Examples 1, 3, 4, 5, and 6 can achieve a high encapsulation efficiency of 80% or more. It should be noted that in the liposome encapsulation operation of Example 4, when 1 mol / L hydrochloric acid was added to adjust the pH, a significant increase in liquid viscosity was observed. This increase in viscosity may become a problem when liposomes are produced in large quantities. On the other hand, in Examples 1, 3, 5, and 6, no increase in viscosity was found during the liposome encapsulation operation. Therefore, the compounds represented by formula (3) and (4) show particularly good liposome encapsulation operability.

[1712] Test Example 6A. Liposome encapsulation test of Example 1

[1713] For the compound of Example 1, a liposome encapsulation test was performed.

[1714] 11.08 g of Presome ACD-1 (a pre-mixed mixture containing hydrogenated soybean phosphatidylcholine, cholesterol, and distearoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 in a mass ratio of 3:1:1, manufactured by Nippon Seika Co., Ltd.) was weighed, 200 mL of a 250 mM ammonium sulfate solution was added, and the mixture was heated to 65°C and dispersed using a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. The crude liposome dispersion was further dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Machinery Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 80 nm. The extraliposome aqueous phase was replaced with a 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific). The liposomes were then filtered through a 0.22 μm filter to obtain an empty liposome solution having a total lipid concentration of 75 mM (75 μmol / mL).

[1715] The compound of Example 1 was weighed, and approximately 0.4 mL of a 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5), approximately 0.1 mL of 0.1 mol / L hydrochloric acid, and 1 mL of the above empty liposome solution were added. 1 mol / L hydrochloric acid was added to adjust the pH to 6-6.5. The mixture was heated in a 65°C water bath for 30 minutes, then ice-cooled. The mixture was then filtered through a 0.22 μm filter membrane.

[1716] The liposome encapsulation efficiency was calculated as follows.

[1717] Unencapsulated compound concentration: The compound concentration was measured by HPLC in a solution obtained by adding 100 μL of a 4% phosphoric acid aqueous solution to 100 μL of the liposome solution. The HPLC measurement conditions are as follows.

[1718] HPLC conditions

[1719] Column: MonoSelect nPEC (GL Sciences Inc.)

[1720] Column temperature: 30°C

[1721] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1722] B: Acetonitrile

[1723] A / B(min):

[1724] 95 / 5(0)→95 / 5(1)→70 / 30(6)→70 / 30(7)→95 / 5(7.01)→95 / 5(10)

[1725] Flow rate: 1 mL / min

[1726] Detection: UV-visible detector at a wavelength of 254 nm

[1727] Injection volume: 2 μL

[1728] Compound concentration in liposome fluid: Dilute the liposome fluid with a mixture of trifluoroacetic acid / water / methanol (0.1 / 25 / 75) and let it stand at 5°C for at least 10 minutes. Centrifuge at 15,000 × g for 5 minutes to remove insoluble matter, and measure the compound concentration in the supernatant by HPLC. HPLC measurement conditions are as follows.

[1729] HPLC conditions

[1730] Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm

[1731] Column temperature: 40°C

[1732] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1733] B: Acetonitrile

[1734] A / B(min):95 / 5(0)→0 / 100(3.5)→0 / 100(4)→95 / 5(4.01)→95 / 5(5)

[1735] Flow rate: 0.8 mL / min

[1736] Detection: UV-visible detector at a wavelength of 254 nm

[1737] Injection volume: 5 μL

[1738] The encapsulation rate and encapsulation efficiency were calculated using the following formula.

[1739] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration in liposome fluid

[1740] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration at the time of introduction

[1741] [Table 10]

[1742]

[1743] It was confirmed that Example 1 can achieve a high liposome encapsulation efficiency of 90% or more.

[1744] Test Example 6B. Liposome encapsulation test of Example 1

[1745] For the compound of Example 1, a liposome encapsulation test was performed.

[1746] 11.08 g of Presome ACD-1 (a pre-mixed mixture containing hydrogenated soybean phosphatidylcholine, cholesterol, and distearoylphosphatidylethanolamine-methoxypolyethylene glycol 2000 in a mass ratio of 3:1:1, manufactured by Nippon Seika Co., Ltd.) was weighed, 200 mL of a 250 mM ammonium sulfate solution was added, and the mixture was heated to 65°C and dispersed using a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. The crude liposome dispersion was further dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Machinery Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. The extraliposome aqueous phase was replaced with a 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5) using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific) and filtered through a 0.22 μm filter to obtain an empty liposome solution having a total lipid concentration of 53.1 mg / mL.

[1747] 120 mg of the compound from Example 1 was weighed, and 18.3 mL of a 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), 0.3 mL of 1 mol / L hydrochloric acid, and 41.7 mL of the empty liposome solution were added. The pH was adjusted to 6.5 with 1 mol / L hydrochloric acid or 1 mol / L sodium hydroxide. The solution was heated in a 50°C water bath for 30 minutes, then ice-cooled and filtered through a 0.22 μm filter. The concentration of the compound in the liposome solution from Example 1 was 2.00 mg / mL, the encapsulation efficiency was 98.0%, and the average particle size (Z-average) was 84 nm.

[1748] The liposome encapsulation efficiency was calculated as follows.

[1749] Concentration of unencapsulated compound: 100 μL of liposome solution, 100 μL of 4% aqueous phosphoric acid solution, and 300 μL of physiological saline were mixed, centrifuged at 100,000 × g for 60 minutes to remove insoluble matter, and the compound concentration in the supernatant was measured by HPLC.

[1750] Compound concentration in liposome solution: Liposome solution was diluted with a mixture of trifluoroacetic acid / water / methanol (0.1 / 25 / 75) and allowed to stand at 5°C for at least 10 minutes. Insoluble matter was removed by centrifugation at 15,000 × g for 5 minutes, and the compound concentration in the supernatant was determined by HPLC.

[1751] The measurement conditions of HPLC are as follows.

[1752] HPLC conditions

[1753] Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm

[1754] Column temperature: 40°C

[1755] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1756] B: Acetonitrile

[1757] A / B(min):95 / 5(0)→0 / 100(3.5)→0 / 100(4)→95 / 5(4.01)→95 / 5(5)

[1758] Flow rate: 0.8 mL / min

[1759] Detection: UV-visible detector at a wavelength of 254 nm

[1760] Injection volume: 5 μL

[1761] The encapsulation efficiency was calculated using the following formula.

[1762] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration in liposome fluid

[1763] Liposomes encapsulating the compound of Example 1 were stored at 5°C, and changes in compound concentration, encapsulation efficiency, and average particle size were observed. As shown in Table 11, no significant changes in compound concentration, encapsulation efficiency, or average particle size were observed in the liposomes encapsulating Example 1, indicating excellent storage stability.

[1764] [Table 11]

[1765]

[1766] Test Example 7. Pharmacokinetic Test

[1767] The solution preparation of Presertib, Examples 1, 3, and 6, and the liposome preparation of Presertib were intravenously administered to mice, and the concentration of the test substance in the blood was measured.

[1768] For the solution preparation, the solution was dissolved in a 10 mM glycine / 5% mannitol solution (pH 2) or a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutyl ether-β-cyclodextrin, and then filtered through a 0.22 μm filter membrane.

[1769] The liposome preparation used the following substances: liposomes encapsulating the test compound were prepared by the same method as in Test Example 6, and the extraliposome aqueous phase was replaced with a 10mM L-histidine buffer / 10% sucrose solution (pH 6.5) using a gel filtration column PD-10 (manufactured by GE Healthcare), and then filtered with a 0.22μm membrane filter. 10mM L-histidine buffer / 10% sucrose solution (pH 6.5) was added to adjust the concentration to obtain a liposome preparation.

[1770] <Administration test>

[1771] The solution or liposome formulation was transiently administered intravenously to 7-week-old female BALB / c mice. Blood was collected from the jugular vein without anesthesia for 72 hours after administration. A 4-fold volume of methanol was added to the blood immediately after collection, and the resulting material was centrifuged. The test compound concentration in the resulting supernatant was quantified by LC-MS / MS.

[1772] The measurement conditions of LC-MS / MS are as follows.

[1773] HPLC: Prominence system (Shimadzu Corporation)

[1774] MS / MS:4000QTRAP (SCIEX)

[1775] Column: Cadenza CD-C18, 3μm, 50×2mm (Imtakt Co., Ltd.) Column temperature: 40°C

[1776] Mobile phase: A: water containing 0.1% formic acid

[1777] B: Acetonitrile containing 0.1% formic acid

[1778] A / B(min):90 / 10(0)→10 / 90(2.5)→10 / 90(3.5)→90 / 10(3.6)→90 / 10(5.0)

[1779] Flow rate: 0.4 mL / min

[1780] Detection: ESI (positive mode)

[1781] Injection volume: 0.1~5μL

[1782] The test results are shown in the table below. In the table, "mean" refers to the average and "SD" refers to the standard deviation. The plasma concentrations of the test compound from 0 hours after administration to 72 hours after administration are shown in Tables 12, 13, 14, 15, and 16.

[1783] [Table 12]

[1784]

[1785] [Table 13]

[1786]

[1787] [Table 14]

[1788]

[1789] [Table 15]

[1790]

[1791] [Table 16]

[1792]

[1793] The AUCs of Examples 1, 3, 6, and the liposome preparations of Presertib were calculated by the trapezoidal method from 0 hours after administration to the time (t) when the plasma concentration of the test compound could be quantified. Table 17 shows the AUCs.

[1794] [Table 17]

[1795]

[1796] According to the above results, when the encapsulated liposomes of Example 1 and Example 3 were administered intravenously, high blood retention was confirmed. This result shows that a sustained exposure of 72 hours, which is crucial for maximizing the efficacy reported in non-clinical trials of prasentia, was achieved. Therefore, Example 1 and Example 3 have excellent pharmacokinetic profiles and are extremely useful as anticancer agents. It is important that the nitrogen atom on the pyridine ring, which is a characteristic of the compound represented by formula (3), is present in a specific position.

[1797] Test Example 8. Drug efficacy evaluation test using ES-2 cell-transplanted cancer-bearing mice

[1798] Using prasertib, a liposome preparation encapsulating prasertib, and a liposome preparation encapsulating Example 1, the antitumor effect was evaluated.

[1799] The solution preparation of Presertib was prepared by dissolving Presertib in a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutyl ether-β-cyclodextrin and filtering the solution through a 0.22 μm filter membrane.

[1800] The liposome preparation was prepared using the same method as in Test Example 6. The test compound was weighed, and an empty liposome solution with a total lipid concentration of 50 mM was added to make the compound concentration reach 2 mg / mL, and 1 mol / L hydrochloric acid was added to adjust the pH to 6-7. Alternatively, 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) and hydrochloric acid were added to the test compound to dissolve or disperse the compound, and an empty liposome solution with a total lipid concentration of 75 mM was added to make the compound concentration reach 2 mg / mL, and the pH was adjusted to 6-7. The liquid was heated in a 65°C water bath for 10-30 minutes and then ice-cooled. After standing in a refrigerator at 5°C for more than one night, it was filtered with a 0.22 μm filter membrane. The liposome encapsulation efficiency calculated using the method described in Test Example 6 was 99% or more.

[1801] ES-2 cells (ATCC) were intradermally transplanted into the ventral periphery of 4-7 week-old BALB / c-nu / nu mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River, Japan) at a density of 1×10 6 Cells / mouse. After confirming the implantation of ES-2 cells 5 to 14 days after transplantation, the solution preparation was intravenously administered once a week at a dose of 30 mg / kg or the liposome preparation was administered at a dose of 3 mg / kg, 7.5 mg / kg, or 20 mg / kg, or subcutaneously twice a day for 3 consecutive days (a total of 6 times a week). The tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect caused by the administration of the compound. The tumor volume was calculated by the following formula using the short diameter and long diameter of the tumor measured using an electronic vernier caliper (Mitutoyo).

[1802] Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × long diameter [mm]

[1803] A control group administered with only the solvent was compared with a group administered with the compound of the present disclosure, and the anti-tumor effect was evaluated by calculating T / C using the following formula. Furthermore, the individual rates of complete tumor regression (CR) at the end of administration, resulting from administration of the solution or liposome formulation, were reported. The control group used an empty liposome solution prepared using the same method as in Test Example 6.

[1804] T / C (%) = (tumor volume of the compound of the present disclosure administration group at the end of administration - tumor volume of the compound of the present disclosure administration group at the start of administration) / (tumor volume of the control administration group at the end of administration - tumor volume of the control administration group at the start of administration) × 100

[1805] Table 18 shows each administration dose of the test compound, T / C (%) and CR individual rate in ES-2 cell-transplanted tumor-bearing mice during the administration period.

[1806] [Table 18]

[1807]

[1808] In efficacy evaluation tests using cancer-bearing mice, the liposome-formulated Example 1 demonstrated similarly superior antitumor efficacy to the liposome-formulated prasentin at all doses. In evaluation tests using a 20 mg / kg dose, these liposome formulations achieved tumor regression, which was not achieved with the solution-formulated prasentin. These test results demonstrate that Example 1 is a promising compound exhibiting superior antitumor efficacy and possesses exceptional efficacy.

[1809] Test Example 9. Measurement of Neutrophil Count in ES-2 Cell-Transplanted Cancer-Bearing Mice

[1810] ES-2 cells (ATCC) were intradermally transplanted into the ventral periphery of 4-7 week-old BALB / c-nu / nu mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River, Japan) at a density of 1×10 6 cells / mouse. After confirming ES-2 cell engraftment 5-14 days after transplantation, a single intravenous administration of the liposome formulation encapsulating pristine and the liposome formulation encapsulating Example 1 was performed. Blood was collected 72 hours after administration, and the neutrophil count was measured. For comparison in this experiment, an empty liposome solution prepared using the same method as in Experimental Example 6 was used.

[1811] A control group administered with an empty liposome solution was compared with groups administered with liposome-formulated Example 1 and liposome-formulated Presertib, respectively. The neutrophil survival rate was calculated using the following formula to evaluate the safety of each preparation.

[1812] Neutrophil survival rate (%) = (neutrophil count in the administration group 72 hours after administration) / (neutrophil count in the control administration group 72 hours after administration) × 100

[1813] Table 19 shows the survival rate of neutrophils in tumor-bearing mice transplanted with ES-2 cells.

[1814] [Table 19]

[1815]

[1816] Liposomal formulation Example 1 showed the same anti-tumor effect at the same dosage as liposomal formulation of prasutamide. At 3 mg / kg, the minimum effective dose of liposomal formulation of prasutamide, the neutrophil survival rate was 15%, and anti-tumor effect and blood toxicity were observed at the same time. On the other hand, at 3 mg / kg, the minimum effective dose of liposomal formulation Example 1, the neutrophil survival rate was 61%, and the side effects of blood toxicity were reduced. In addition, as shown in Test Example 8, the liposomal formulation Example 1 also showed a higher neutrophil survival rate at the dosage of 20 mg / kg, at which tumor regression was observed, than when 7.5 mg / kg of liposomal formulation of prasutamide was administered. In summary, Example 1 is an excellent compound with both higher safety and efficacy than prasutamide, and has a special effect. In addition, the liposomal formulation of Example 1 is also an excellent compound with both high safety and efficacy, and has a special effect.

[1817] Test Example 10. Human bone marrow cell myeloid differentiation induction test (hematotoxicity evaluation test)

[1818] Human bone marrow CD34-positive hematopoietic stem cells were obtained from LONZA Co., Ltd. The frozen cells were thawed using 1% fetal bovine serum-containing IMDM culture medium, suspended using Complete hemaTox (registered trademark) myeloid culture medium, and 1,000 cells were seeded per well in a 96-well plate. The evaluation compound was added to a final concentration of DMSO of 0.1% and 3 nM, and cultured at 37°C in the presence of 5% CO2 for 7 days. After the culture was completed, half of the cell suspension in each well was recovered, and the luminescence value was measured using CellTiter-Glo (registered trademark) 3D Reagent (Promega, G968B). The cell survival rate was calculated using the following formula.

[1819] Cell survival rate (%) = (luminescence measurement value of the evaluation compound after 7 days) / (luminescence measurement value of the control group after 7 days) × 100

[1820] The representative compounds obtained in the Examples and prasetib were subjected to the test shown in Test Example 10. The results are shown in the table below.

[1821] [Table 20]

[1822]

[1823] As shown in the table above, while 3 nM of prasertib showed an inhibitory effect on myeloid cells induced by differentiation of human bone marrow cells, 3 nM of Example 1 clearly showed no inhibitory effect on myeloid cells induced by differentiation of human bone marrow cells. Based on this result, Example 1 is a compound with a high safety profile against hematotoxicity compared to prasertib, and exhibits a unique and specific effect.

[1824] Test Example 11. Tumor PD test using ES-2 cell-transplanted cancer-bearing mice

[1825] Using prasertib, a liposome formulation encapsulating prasertib, and a liposome formulation encapsulating Example 1, the pharmacodynamic (Pharmaco Dynamics: PD) response in tumors was evaluated.

[1826] The solution preparation of Presertib was prepared by dissolving Presertib in a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutyl ether-β-cyclodextrin and filtering the solution through a 0.22 μm filter membrane.

[1827] The liposome preparation was prepared using the same method as in Test Example 6. The test compound was weighed, and an empty liposome solution with a total lipid concentration of 50 mM was added to make the compound concentration reach 2 mg / mL, and 1 mol / L hydrochloric acid was added to adjust the pH to 6-7. Alternatively, 10 mM L-histidine buffer / 10% sucrose solution (pH 6.5) and hydrochloric acid were added to the test compound to dissolve or disperse the compound, and an empty liposome solution with a total lipid concentration of 75 mM was added to make the compound concentration reach 2 mg / mL, and the pH was adjusted to 6-7. The liquid was heated in a 65°C water bath for 10-30 minutes and then ice-cooled. After standing in a refrigerator at 5°C for more than one night, it was filtered with a 0.22 μm filter membrane. The liposome encapsulation efficiency calculated using the method described in Test Example 6 was 99% or more.

[1828] Ovarian cancer ES-2 cells (ATCC) were transplanted intradermally around the ventral part of 4-7 week-old BALB / c-nu / nu mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River, Japan) at a density of 1×10 6Cells / mouse. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, each experiment was administered under the following conditions:

[1829] Test A: A single intravenous dose of 30 mg / kg of a solution formulation or 7.5 mg / kg, 3 mg / kg, 1 mg / kg, or 0.3 mg / kg of a liposome formulation was administered. Test B: A single intravenous dose of 30 mg / kg of a solution formulation or 7.5 mg / kg, 3 mg / kg, 1 mg / kg, or 0.3 mg / kg of a liposome formulation was administered. Test C: A single intravenous dose of 20 mg / kg, 7.5 mg / kg, 3 mg / kg, 1 mg / kg, or 0.3 mg / kg of a liposome formulation was administered. Tumors were recovered 1, 3, or 6 days after administration, and the PD response of the tumors based on compound administration was evaluated.

[1830] The PD response in tumors was evaluated by Western blotting. The intensity of each band detected by anti-γH2AX antibody (05-636, Merck) and anti-tubulin antibody (3873, Cell Signaling Technology) was calculated using ImageJ software.

[1831] The control group administered with the solvent alone was compared with the compound-administered group, and the relative value of each band intensity was calculated using the following formula to evaluate the PD response in the tumor.

[1832] Intensity of γH2AX={(band intensity of γH2AX in the tumor of the compound-administered group of the present invention) / (band intensity of tubulin in the tumor of the compound-administered group of the present invention)} / {(band intensity of γH2AX in the tumor of the control-administered group / band intensity of tubulin in the tumor of the control-administered group)}×100

[1833] Figure 7-9 The intensity of γH2AX in ES-2 cancer-bearing mice transplanted with cells is shown at each administration dose of the test compound and during the administration period.

[1834] According to the above results, as shown in Test Example 11 Test A, when liposome-formulated prasutamide was administered, a strong PD response effect at a dose of 7.5 mg / kg was confirmed 3 days after administration, achieving a PD response effect that could not be achieved with solution-formulated prasutamide. As shown in Test Example 11 Test B, when liposome-formulated Example 1 was administered, a strong PD response effect at a dose of 7.5 mg / kg was confirmed 1 day after administration, achieving a PD response effect that could not be achieved with solution-formulated prasutamide. As shown in Test Example 11 Test C, when liposome-formulated Example 1 was administered, a strong PD response effect at doses of 7.5 mg / kg and 20 mg / kg was confirmed 3 days after administration and 6 days after administration. These liposome formulations, as shown in Test Example 7, achieved the 72-hour sustained exposure that was reported in non-clinical trials of prasutamide, which is crucial for maximizing drug efficacy. Therefore, Example 1 has excellent pharmacokinetic and pharmacodynamic profiles and is extremely useful as an anticancer agent.

[1835] Test Example 12. Drug efficacy evaluation test using ES-2 cell-transplanted peritoneal inoculation in cancer-bearing mice

[1836] Using prasertib, a liposome preparation encapsulating prasertib, and a liposome preparation encapsulating Example 1, the antitumor effect was evaluated.

[1837] The solution preparation of Presertib was prepared by dissolving Presertib in a 10 mM glycine / 5% mannitol solution (pH 2) containing 20% ​​sulfobutyl ether-β-cyclodextrin and filtering the solution through a 0.22 μm filter membrane.

[1838] The liposome formulation encapsulating pristine was prepared as follows.

[1839] Presome ACD-1 (made by Nippon Seika Co., Ltd.) 11.08 g and 200 mL of 250 mM ammonium sulfate solution were mixed and dispersed using a homogenizer (ULTRA-TURRAX, made by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed under a pressure of 100 MPa using a high-pressure homogenizer (Nano-Mizer NM2, made by Yoshida Machinery Industry Co., Ltd.) to obtain liposomes with an average particle size (Z-average) of 80 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20KMWCO, made by Thermo Scientific), the extraliposomal aqueous phase was replaced with a 10 mM L-histidine buffer solution / 10% sucrose solution (pH 6.5) and filtered with a 0.22 μm filter membrane to obtain an empty liposome solution with a total lipid concentration of 75 mM. 60 mg of prusetib, 10 mL of a 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), and 20 mL of the above empty liposome solution were added to adjust the pH to 6.5. The solution was heated in a 50°C water bath for 30 minutes, then ice-cooled and filtered through a 0.22 μm filter. The prusetib concentration in the liposome solution was 1.97 mg / mL, and the encapsulation efficiency was 98%.

[1840] The compound concentration and entrapment efficiency in the liposome fluid were calculated as follows.

[1841] Concentration of unencapsulated compound: 100 μL of liposome solution, 100 μL of 4% aqueous phosphoric acid solution, and 300 μL of physiological saline were mixed, centrifuged at 100,000 × g for 60 minutes to remove insoluble matter, and the compound concentration in the supernatant was measured by HPLC.

[1842] Compound concentration in liposome fluid: The liposome fluid was diluted with a mixture of trifluoroacetic acid / water / methanol (0.1 / 25 / 75), centrifuged at 4°C and 15,000×g for 10 minutes to remove insoluble matter, and the compound concentration in the supernatant was measured by HPLC.

[1843] The measurement conditions of HPLC are as follows.

[1844] HPLC conditions

[1845] Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm

[1846] Column temperature: 40°C

[1847] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1848] B: Acetonitrile

[1849] A / B(min):

[1850] 90 / 10(0)→70 / 30(3)→0 / 100(3.5)→0 / 100(4)→90 / 10(4.01)→90 / 10(5)

[1851] Flow rate: 0.8 mL / min

[1852] Detection: UV-visible detector at a wavelength of 254 nm

[1853] Injection volume: 5 μL

[1854] The encapsulation efficiency was calculated using the following formula.

[1855] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration in liposome fluid

[1856] The liposome preparation encapsulating Example 1 was prepared as follows.

[1857] Presome ACD-1 (made by Nippon Seika Co., Ltd.) 11.08 g and 200 mL of 250 mM ammonium sulfate solution were mixed and dispersed using a homogenizer (ULTRA-TURRAX, made by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed under a pressure of 100 MPa using a high-pressure homogenizer (Nano-Mizer NM2, made by Yoshida Machinery Industry Co., Ltd.) to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20KMWCO, made by Thermo Scientific), the extraliposomal aqueous phase was replaced with a 10 mM L-histidine buffer solution / 9.4% sucrose solution (pH 6.5) and filtered with a 0.22 μm filter membrane to obtain an empty liposome solution with a total lipid concentration of 53.1 mg / mL. 80 mg of the compound from Example 1, 12.2 mL of a 10 mM L-histidine buffer / 9.4% sucrose solution (pH 6.5), and 27.8 mL of the empty liposome solution were added to adjust the pH to 6.5. The solution was heated in a 50°C water bath for 30 minutes, then ice-cooled and filtered through a 0.22 μm filter. The concentration of the compound from Example 1 in the liposome solution was 1.99 mg / mL, and the encapsulation efficiency was 97%.

[1858] The liposome encapsulation efficiency was calculated as follows.

[1859] Unencapsulated compound concentration: The compound concentration was measured by HPLC in a solution obtained by adding 100 μL of a 4% phosphoric acid aqueous solution to 100 μL of the liposome solution. The HPLC measurement conditions are as follows.

[1860] HPLC conditions

[1861] Column: MonoSelect nPEC (GL Sciences Inc.)

[1862] Column temperature: 30°C

[1863] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1864] B: Acetonitrile

[1865] A / B(min):

[1866] 95 / 5(0)→95 / 5(1)→70 / 30(6)→70 / 30(7)→95 / 5(7.01)→95 / 5(10)

[1867] Flow rate: 1 mL / min

[1868] Detection: UV-visible detector at a wavelength of 254 nm

[1869] Injection volume: 2 μL

[1870] Compound concentration in liposome fluid: The liposome fluid was diluted with a mixture of trifluoroacetic acid / water / methanol (0.1 / 25 / 75), centrifuged at 4°C, 15,000 × g for 10 minutes to remove insoluble matter, and the compound concentration in the supernatant was measured by HPLC. The HPLC measurement conditions are as follows.

[1871] HPLC conditions

[1872] Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm

[1873] Column temperature: 40°C

[1874] Mobile phase: A: water containing 0.1% trifluoroacetic acid

[1875] B: Acetonitrile

[1876] A / B(min):95 / 5(0)→0 / 100(3.5)→0 / 100(4)→95 / 5(4.01)→95 / 5(5)

[1877] Flow rate: 0.8 mL / min

[1878] Detection: UV-visible detector at a wavelength of 254 nm

[1879] Injection volume: 5 μL

[1880] The encapsulation efficiency was calculated using the following formula.

[1881] Encapsulation efficiency (%) = (compound concentration in liposome fluid - unencapsulated compound concentration) × 100 / compound concentration in liposome fluid

[1882] Luciferase-expressing ovarian cancer ES-2 cells (ATCC) were transplanted into the abdominal cavity of 5-week-old BALB / c-nu / nu mice (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River, Japan) at a concentration of 1×10 6 Cells / mouse. After confirming t...

Claims

1. A therapeutic and / or preventive agent for cancer patients showing resistance to treatment with an immune checkpoint inhibitor, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

2. The therapeutic and / or preventive agent according to claim 1, characterized in that Combined with the aforementioned CHK1 inhibitors and immune checkpoint inhibitors.

3. The therapeutic and / or preventive agent according to claim 2, characterized in that The aforementioned CHK1 inhibitor and the aforementioned immune checkpoint inhibitor are administered simultaneously.

4. The therapeutic and / or preventive agent according to any one of claims 2 or 3, characterized in that After administration of the aforementioned CHK1 inhibitor, the aforementioned immune checkpoint inhibitor is administered.

5. The therapeutic and / or preventive agent according to any one of claims 2 to 4, characterized in that The aforementioned CHK1 inhibitor and the aforementioned immune checkpoint inhibitor are administered simultaneously, and then the aforementioned anti-PD-1 antibody is administered.

6. The therapeutic and / or preventive agent according to any one of claims 2 to 4, characterized in that The aforementioned CHK1 inhibitor and the aforementioned immune checkpoint inhibitor are administered simultaneously, and then the aforementioned anti-PD-1 antibody is administered 3 days later.

7. The therapeutic and / or preventive agent according to any one of claims 2 to 6, wherein The aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

8. The therapeutic and / or preventive agent according to any one of claims 2 to 6, wherein The aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody.

9. The therapeutic and / or preventive agent according to any one of claims 2 to 6, characterized in that The aforementioned anti-PD-1 antibodies are bolivianzumab, nivolumab, spartalizumab, and cemiplizumab.

10. The therapeutic and / or preventive agent according to any one of claims 1 to 9, characterized in that The number of CD3-positive cells in the tumor tissues of the aforementioned cancer patients was lower than that in the tumor tissues of the patients responsive to the anti-PD-1 antibody.

11. The therapeutic and / or preventive agent according to any one of claims 1 to 10, characterized in that The number of CD8-positive cells in the tumor tissues of the aforementioned cancer patients was lower than that in the tumor tissues of the patients responsive to the anti-PD-1 antibody.

12. The therapeutic and / or preventive agent according to any one of claims 1 to 11, characterized in that The number of CD8 positive cells in the tumor tissue of the aforementioned cancer patient was less than 0.

135.

13. The therapeutic and / or preventive agent according to any one of claims 1 to 12, characterized in that The M1-M2 ratio of macrophages in the tumor tissue of the aforementioned cancer patient is 21 or less.

14. The therapeutic and / or preventive agent according to any one of claims 1 to 13, characterized in that The number of CD206-positive cells in the tumor tissues of the aforementioned cancer patients was increased compared with that in the tumor tissues of the patients responsive to the anti-PD-1 antibody.

15. The therapeutic and / or preventive agent according to any one of claims 1 to 14, characterized in that The number of IAd-positive cells in the tumor tissues of the aforementioned cancer patients was reduced compared with that in the tumor tissues of patients responsive to anti-PD-1 antibodies.

16. The therapeutic and / or preventive agent according to any one of claims 1 to 15, characterized in that The number of CD62L-negative CD44-positive cells in the lymph nodes of the aforementioned cancer patients was reduced compared with that in the lymph nodes of the patients responsive to the anti-PD-1 antibody.

17. The therapeutic and / or preventive agent according to any one of claims 1 to 16, characterized in that The expression of PD-L1 in tumor tissues of the aforementioned cancer patients is lower than that in tumor tissues of patients responsive to anti-PD-1 antibodies.

18. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The expression of VEGFa in tumor tissues of the aforementioned cancer patients was increased compared with that in tumor tissues of patients responsive to anti-PD-1 antibodies.

19. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that Granzyme B expression in tumor tissues of the aforementioned cancer patients was lower than that in tumor tissues of patients responsive to anti-PD-1 antibodies.

20. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The expression of interferon-γ in tumor tissues of the aforementioned cancer patients was lower than that in tumor tissues of patients responsive to anti-PD-1 antibodies.

21. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The expression of H2ab1 in tumor tissues of the aforementioned cancer patients was lower than that in tumor tissues of patients responsive to anti-PD-1 antibodies.

22. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The expression of CD80 in tumor tissues of the aforementioned cancer patients was lower than that in tumor tissues of patients responsive to anti-PD-1 antibodies.

23. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that Mrc1 expression in tumor tissues of the aforementioned cancer patients was increased compared with that in tumor tissues of patients responsive to anti-PD-1 antibodies.

24. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The expression of arginase 1 in tumor tissues of the aforementioned cancer patients was increased compared with that in tumor tissues of patients responsive to anti-PD-1 antibodies.

25. The therapeutic and / or preventive agent according to any one of claims 1 to 17, characterized in that The DNA replication stress in the tumor tissues of the aforementioned cancer patients was reduced compared with the tumor tissues in the patients who were responsive to the anti-PD-1 antibody.

26. A therapeutic and / or preventive agent for preventing the recurrence of a remitted cancer, comprising a CHK1 inhibitor or a liposome encapsulating a CHK1 inhibitor as an active ingredient.

27. The therapeutic and / or preventive agent according to claim 26, characterized in that Combined with the aforementioned CHK1 inhibitors and immune checkpoint inhibitors.

28. The therapeutic and / or preventive agent according to any one of claims 26 or 27, characterized in that The aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

29. The therapeutic and / or preventive agent according to any one of claims 26 or 27, characterized in that The aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody.

30. The therapeutic and / or preventive agent according to any one of claims 26 or 27, characterized in that The aforementioned anti-PD-1 antibodies are bolivianzumab, nivolumab, spartalizumab, and cemiplizumab.

31. The therapeutic and / or preventive agent according to any one of claims 26 to 30, wherein The aforementioned cancer is selected from squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer, squamous cell carcinoma of the head and neck, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma · thymic carcinoma, breast cancer, triple negative breast cancer, gastric cancer, gallbladder · bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, At least one of MSI-high colorectal cancer, anal cancer, gastrointestinal stromal tumor, choriocarcinoma, uterine corpus cancer, cervical cancer, ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

32. The therapeutic and / or preventive agent according to any one of claims 26 to 30, wherein The aforementioned cancer is melanoma, squamous cell carcinoma, non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, urothelial carcinoma, non-muscle invasive bladder cancer, renal cancer, hepatocellular carcinoma, MSI-high colorectal cancer, esophageal cancer, colon cancer, rectal cancer, breast cancer, uterine corpus cancer or ovarian cancer.

33. The therapeutic and / or preventive agent according to any one of claims 26 to 30, characterized in that The aforementioned cancer is at least one cancer selected from head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple-negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or uterine endometrial cancer.

34. The therapeutic and / or preventive agent according to any one of claims 26 to 30, wherein The aforementioned cancers are solid tumors with high tumor mutation burden (Tumor Mutation Burden-High; TMB-High).

35. The therapeutic and / or preventive agent according to any one of claims 1 to 34, wherein The aforementioned liposome further contains phospholipids.

36. The therapeutic and / or preventive agent according to claim 35, wherein The phospholipid is one selected from phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin, or a combination of two or more thereof.

37. The therapeutic and / or preventive agent according to any one of claims 1 to 36, wherein The aforementioned liposome further contains sterols.

38. The therapeutic and / or preventive agent according to any one of claims 1 to 37, wherein The aforementioned sterol is cholesterol.

39. The therapeutic and / or preventive agent according to any one of claims 1 to 38, wherein The aforementioned liposome further comprises a polymer-modified lipid.

40. The therapeutic and / or preventive agent according to claim 39, characterized in that The polymer portion of the aforementioned polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methoxy polyethylene glycol, methoxy polypropylene glycol, methoxy polyvinyl alcohol, methoxy polyvinyl pyrrolidone, ethoxy polyethylene glycol, ethoxy polypropylene glycol, ethoxy polyvinyl alcohol, ethoxy polyvinyl pyrrolidone, propoxy polyethylene glycol, propoxy polypropylene glycol, propoxy polyvinyl alcohol, or propoxy polyvinyl pyrrolidone.

41. The therapeutic and / or preventive agent according to claim 39 or 40, wherein The lipid portion of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.

42. The therapeutic and / or preventive agent according to any one of claims 1 to 41, wherein The liposome encapsulating the CHK1 inhibitor comprises (1) 40 to 70 mol% of phospholipids, (2) 30 to 50 mol% cholesterol, and (3) 1 to 10 mol% of polymer-modified lipids.

43. The therapeutic and / or preventive agent according to any one of claims 1 to 42, wherein The aforementioned liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

44. The therapeutic and / or preventive agent according to any one of claims 1 to 43, wherein The aforementioned CHK1 inhibitor is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof: [Chemistry 1] In the formula, R 1 represents a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl, R 2 Represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a sulfonic acid group, a phosphoric acid group, -OR 3 、-SR 3 、-COR 4 、-CO2R 4 、-CONR 5 R 6 、-SO2R 4 、-SO2NR 5 R 6 、-OCOR 4 、-OCO2R 4 、-OCONR 5 R 6 、-NR 5 R 6 、-NR 7 COR 4 、-NR 7 CO2R 4 、-NR 7 CONR 5 R 6 、-NR 7 S02R 4 、-NR 7 SO2NR 5 R 6 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl, R 3 Represents a hydrogen atom or C 1-6 alkyl, R 4 Represents C 1-6 alkyl, R 5 , R 6 and R 7 Each independently represents a hydrogen atom, or C 1-6 Alkyl, wherein the R 5 and R 6 Both C 1-6 When they are alkyl, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded. X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 , R 8 When there are plural groups, each independently represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a carboxyl group, a sulfonic acid group, a phosphoric acid group, -OR 9 、-SR 9 、-COR 10 、-CO2R 10 、-CONR 11 R 12 、-SO2R 10 、-SO2NR 11 R 12 、-OCOR 10 、-OCO2R 10 、-OCONR 11 R 12 、-NR 11 R 12 、-NR 13 COR 10 、-NR 13 CO2R 10 、-NR 13 CONR 11 R 12 、-NR 13 S02R 10 、-NR 13 SO2NR 11 R 12 , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 cycloalkyl, optionally substituted 3-10 membered saturated heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl, R 9 Represents a hydrogen atom or C 1-6 alkyl, R 10 Represents C 1-6 alkyl, R 11 , R 12 and R 13 Each independently represents a hydrogen atom or a C 1-6 Alkyl, wherein the R 11 and R 12 Both C 1-6 When they are alkyl, they may optionally form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded. L represents a single bond or an optionally substituted C 1-6 Alkylene, V represents a single bond, an optionally substituted C 3-10 a cycloalkylene group or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, W represents a single bond or an optionally substituted C 1-6 Alkylene, Q represents hydrogen atom or NHR 14 , R 14 represents a hydrogen atom, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 cycloalkyl or an optionally substituted 3- to 10-membered saturated heterocyclic group.

45. The therapeutic and / or preventive agent according to claim 44, wherein Formula (1) is represented by the following formula (2): [Chemistry 2] In the formula, X, Y and Z each independently represent CR 8 or nitrogen atoms, wherein X, Y and Z are not CR at the same time 8 , R 8 When there are multiple, each is represented independently Hydrogen atoms, Fluorine atom, Chlorine atom, Bromine atom, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 2 substituents which are the same or different in cyano are optionally substituted), or 5-6 membered heteroaryl (the heteroaryl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 2 identical or different substituents in the cyano group are optionally substituted), L stands for Single key, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 identical or different substituents in the cyano group are optionally substituted), V stands for single bond, C 3-10 Cycloalkylene (the cycloalkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different in the cyano group are optionally substituted), or A 3-10 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from a fluorine atom, a hydroxyl group, a C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 identical or different substituents in the cyano group are optionally substituted), W stands for Single key, or C 1-6 Alkylene (the alkylene is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 identical or different substituents in the cyano group are optionally substituted), Q represents a hydrogen atom, or NHR 14 , R 14 express Hydrogen atoms, C 1-6 Alkyl (the alkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different in the cyano group are optionally substituted), C 3-10 Cycloalkyl (the cycloalkyl is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 substituents which are the same or different in the cyano group are optionally substituted), or 3-10 membered saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups, C 1-3 Alkyl, C 1-3 Alkoxy, -NR 16 R 17 , and 1 to 3 identical or different substituents in the cyano group are optionally substituted), R 16 and R 17 Each independently represents a hydrogen atom, or C 1-6 Alkyl, R 16 or R 17 When there are multiple 16 or R 17 are optionally the same or different, wherein R bonded to the same nitrogen atom 16 and R 17 Both C 1-6 When they are alkyl groups, they may form a 3- to 8-membered nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded.

46. ​​The therapeutic and / or preventive agent according to claim 44, wherein Formula (1) is represented by the following formula (3): [Chemistry 3] In the formula, R 8a and R 8b Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl, L represents a single bond, or a C optionally substituted by a hydroxyl group 1-6 Alkylene, V represents a single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted), W represents a single bond, or C optionally substituted with 1 hydroxyl group 1-3 Alkylene, Q is a hydrogen atom or NH2.

47. The therapeutic and / or preventive agent according to claim 46, wherein R 8a and R 8b Each is independently a hydrogen atom, a fluorine atom or a chlorine atom.

48. The therapeutic and / or preventive agent according to claim 46, wherein R 8a and R 8b Each is independently a hydrogen atom or a chlorine atom.

49. The therapeutic and / or preventive agent according to any one of claims 46 to 48, wherein L is C 1-3 Alkylene.

50. The therapeutic and / or preventive agent according to any one of claims 46 to 49, wherein V is a single bond.

51. The therapeutic and / or preventive agent according to any one of claims 46 to 50, wherein V = C 3-7 Cycloalkylene.

52. The therapeutic and / or preventive agent according to any one of claims 46 to 51, wherein W is a single bond.

53. The therapeutic and / or preventive agent according to any one of claims 46 to 51, wherein W is C 1-3 Alkylene.

54. The therapeutic and / or preventive agent according to any one of claims 46 to 53, wherein Q is NH2.

55. The therapeutic and / or preventive agent according to claim 44, wherein Formula (1) is represented by the following formula (4): [Chemistry 4] In the formula, R 8b and R 8c Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl, L stands for Single key, or C 1-6 an alkylene group (the alkylene group may be substituted by one substituent selected from a fluorine atom, a hydroxyl group, and a cyano group), V stands for single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or A 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, cyano groups, hydroxyl groups, and C 1-3 1 substituent in the alkyl group is optionally substituted), W stands for Single key, or C optionally substituted with 1 hydroxyl group 1-3 Alkylene, Q is a hydrogen atom, NH2, or NHMe.

56. The therapeutic and / or preventive agent according to claim 55, wherein R 8b and R 8c A hydrogen atom.

57. The therapeutic and / or preventive agent according to any one of claims 55 or 56, wherein L is Single key, or C optionally substituted by 1 hydroxyl group or fluorine atom 1-6 Alkylene.

58. The therapeutic and / or preventive agent according to any one of claims 55 to 57, wherein V single bond, C 3-7 Cycloalkylene, or A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from fluorine atoms, hydroxyl groups and C 1-3 1 substituent in the alkyl group is optionally substituted).

59. The therapeutic and / or preventive agent according to any one of claims 55 to 58, wherein W is a single bond, or C 1-3 Alkylene.

60. The therapeutic and / or preventive agent according to any one of claims 55 to 59, wherein Q is a hydrogen atom.

61. The therapeutic and / or preventive agent according to any one of claims 55 to 59, wherein Q is NH2.

62. The therapeutic and / or preventive agent according to any one of claims 55 to 59, wherein Q is NHMe.

63. The therapeutic and / or preventive agent according to claim 44, wherein Formula (1) is represented by the following formula (5): [Chemistry 5] In the formula, R 8a and R 8c Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or C 1-3 alkyl, L represents a single bond, or a C optionally substituted by a hydroxyl group 1-6 Alkylene, V stands for single bond, C 3-7 Cycloalkylene (the cycloalkylene is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted), or A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from a fluorine atom, a cyano group, a hydroxyl group, and a C 1-3 1 substituent in the alkyl group is optionally substituted), W stands for Single key, or C optionally substituted with 1 hydroxyl group 1-3 Alkylene, Q is a hydrogen atom or NH2.

64. The therapeutic and / or preventive agent according to claim 63, wherein R 8a and R 8c A hydrogen atom.

65. The therapeutic and / or preventive agent according to any one of claims 63 or 64, wherein L is C optionally substituted by 1 hydroxyl group 1-6 Alkylene.

66. The therapeutic and / or preventive agent according to any one of claims 63 to 65, wherein V is a single bond, C 3-7 Cycloalkylene or a 3-7 membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from hydroxyl, and C 1-3 1 substituent in the alkyl group is optionally substituted).

67. The therapeutic and / or preventive agent according to any one of claims 63 to 66, wherein W is a single bond, or C 1-3 Alkylene.

68. The therapeutic and / or preventive agent according to any one of claims 63 to 67, wherein Q is a hydrogen atom.

69. The therapeutic and / or preventive agent according to any one of claims 63 to 67, wherein Q is NH2.

70. The therapeutic and / or preventive agent according to claim 44, comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[2-(3-aminopropoxy)-6-chloro-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{2-methoxy-4-[(3-methylazetidin-3-yl)methoxy]pyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{4-[(3-hydroxyazetidin-3-yl)methoxy]-2-methoxypyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(4-{[3-(hydroxymethyl)azetidin-3-yl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(3R)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(3S)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(2S)-3-amino-2-hydroxypropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine, N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-(trifluoromethyl)pyrazin-2-amine, 5-({5-[4-(3-aminopropoxy)-6-methoxypyrimidin-5-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(azetidin-3-yl)methoxy-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, (S)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, (S)-5-[(5-{3-methoxy-[5-(pyrrolidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, (R)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-6-methoxypyrimidin-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-5-(fluoromethoxy)pyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-[(5-{3-methoxy-5-[(3-methylazetidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(2S)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(2R)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(2S)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(2R)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-methoxy-5-[3-(methylamino)propoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-[(5-{3-[(1R)-1-(azetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-[(5-{3-[(1R)-1-(3-hydroxyazetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile, 5-{[5-(3-methoxy-5-{[(1R,3R)-3-(methylamino)cyclopentyl]oxy}pyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(3-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexane-2-yl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(2-{[1-(aminomethyl)cyclopropyl]methoxy}-4-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile, 5-{[5-(4-{[1-(Aminomethyl)cyclopropyl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile.

71. The therapeutic and / or preventive agent according to claim 44, comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile, 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

72. The therapeutic and / or preventive agent according to claim 44, comprising a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof: 5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

73. The therapeutic and / or preventive agent according to claim 44, comprising the following compound or a pharmaceutically acceptable salt thereof: 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

74. The therapeutic and / or preventive agent according to claim 44, comprising the following compound or a pharmaceutically acceptable salt thereof: 5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.

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